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Authors: Eman Abdulfatah, M.D., Laura Adhikari, M.D., Hafza Asma Adnan, M.B.B.S., Rouba Ali-Fehmi, M.D., Fatemeh Ghazanfari Amlashi, M.D., Doaa Atwi, M.D., Ayse Ayhan, M.D., Ph.D., Sudeshna Bandyopadhyay, M.D., Jennifer A. Bennett, M.D., Jessica L. Bentz, M.D., Swati Bhardwaj, M.B.B.S., M.D., Aurelia Busca, M.D., Ph.D., Natalia Buza, M.D., Indranil Chakrabarti, M.D., Victoria Collins, M.D., Shahrzad Ehdaivand, M.D., Erna Forgó, M.D., Rochelle Garcia, M.D., Mohiedean Ghofrani, M.D., C. Blake Gilks, M.D., Arun Gopinath, M.D., Nalini Gupta, M.D., Lisa Han, M.D., Krisztina Hanley, M.D., Saroona Haroon, M.B.B.S., Lewis A. Hassell, M.D., Jutta Huvila, M.D., Ph.D., Shahid Islam, M.D., Ph.D., Tamara Kalir, M.D., Ph.D., Mahmoud A. Khalifa, M.D., Ph.D., Felix K.F. Kommoss, M.D., Elisabetta Kuhn, M.D., Ricardo R. Lastra, M.D., Adam Lechner, B.M., Cheng-Han Lee, M.D., Ph.D., Krisztina Lengyel, M.D., Teri A. Longacre, M.D., Lucy Ma, M.D., Rajit Malliah, M.D., Kruti P. Maniar, M.D., Azin Mashayekhi, M.D., M.B.A., Ekaterina Menshikova, M.D., Aysha Mubeen, M.D., Neshat Nilforoushan, M.D., Carlos Parra-Herran, M.D., Nat Pernick, M.D., Jian-Hua Qiao, M.D., Jack Reid, M.D., M. Carolina Reyes, M.D., Nicole D. Riddle, M.D., Catherine J. Roe, M.D., Ozlen Saglam, M.D., Carolina Sforza, M.D., Aarti Sharma, M.D., Dong Ping Shi, M.D., Jamie Shutter, M.D., Rayan Sibira, M.D., Kamaljeet Singh, M.D., Stephanie L. Skala, M.D., Sharon Song, M.D., M.S., Basile Tessier-Cloutier, M.D., Gulisa Turashvili, M.D., Ph.D., Brandon Umphress, M.D., Russell Vang, M.D., Leena Varughese, M.D., Laura J. Vidis, D.O., Shannon Mingo Welter, M.D., Y. Albert Yeh, M.D., Ph.D., Shabnam Zarei, M.D.

Editorial Board Members: Jennifer A. Bennett, M.D., David B. Chapel, M.D., Kyle Devins, M.D., C. Blake Gilks, M.D., Ricardo R. Lastra, M.D., Lucy Ma, M.D., Carlos Parra-Herran, M.D., Stephanie L. Skala, M.D., Gulisa Turashvili, M.D., Ph.D.

Deputy Editors-in-Chief: Jennifer A. Bennett, M.D., Gulisa Turashvili, M.D., Ph.D.

Editor-in-Chief: Debra L. Zynger, M.D.

Copyright: 2002-2024, PathologyOutlines.com, Inc.

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Related chapters: Fallopian tubes, Pleura & peritoneum

Editorial Board oversight: Gulisa Turashvili, M.D., Ph.D. (last reviewed December 2023)

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Superpage Topics

46XX DSD Anatomy & histology Appendiceal neoplasms Autoimmune oophoritis (pending) Benign, borderline and malignant Brenner tumors Breast carcinoma Calcification Carcinoid tumor Carcinoid tumor metastatic to ovary Carcinosarcoma Cervical carcinoma metastatic to ovary Choriocarcinoma Clear cell borderline tumor Clear cell carcinoma Clear cell cystadenoma and adenofibroma Colorectal adenocarcinoma Corpus luteum cyst Cortical inclusion cyst Disorders of sex development-general Dysgerminoma Ectopic decidual reaction Embryonal carcinoma Endometrial stromal sarcoma Endometrioid borderline tumor Endometrioid carcinoma Endometrioid cystadenoma and adenofibroma Endometriosis Endosalpingiosis Epidermoid cyst Epithelial tumors-overview / molecular Features to report Fibroma Fibromatosis and massive edema Fibrosarcoma Follicle cyst Gonadoblastoma Granulomatous inflammation Granulosa cell tumor-adult Granulosa cell tumor-juvenile Gynandroblastoma High grade serous carcinoma Hyperreactio luteinalis Large solitary luteinized follicular cyst of pregnancy and puerperium Leiomyoma Leiomyosarcoma Leydig cell hyperplasia (pending) Leydig cell tumor Low grade serous carcinoma Luteinized thecoma associated with sclerosing peritonitis Müllerian adenosarcoma Mesonephric-like adenocarcinoma (uterus / ovary) Metastases to ovary Microcystic stromal tumor Mixed carcinoma (pending) Mixed germ cell - sex cord stromal tumor, unclassified (pending) Mixed germ cell tumor Monodermal cystic teratoma Mucinous borderline tumor Mucinous carcinoma Mucinous cystadenoma and adenofibroma Mural nodules in mucinous cystic neoplasms Neuroectodermal type tumors (pending) Olaparib Ovarian myxoma (pending) Ovotesticular DSD Polycystic ovary disease Pregnancy luteoma Rete cystadenoma, adenoma and adenocarcinoma Sclerosing stromal tumor Seromucinous borderline tumor Seromucinous cystadenoma and adenofibroma Serous borderline tumor Serous cystadenoma, adenofibroma and surface papilloma Serous cystadenoma, adenofibroma and surface papilloma Sertoli cell tumor Sertoli-Leydig cell tumor Sex chromosome DSD Sex cord stromal tumor NOS (pending) Sex cord tumor with annular tubules Signet ring stromal tumor Small cell carcinoma of ovary, hypercalcemic type Solid pseudopapillary tumor Somatic neoplasms arising from teratomas (pending) Staging Steroid cell tumor Stromal hyperplasia and hyperthecosis Struma ovarii Strumal carcinoid Teratoma-immature Teratoma-mature Thecoma Torsion Tubo-ovarian abscess Undifferentiated / dedifferentiated carcinoma (endometrium / ovary) Upper gastrointestinal tract WHO classification Wilms tumor (nephroblastoma) Xanthogranulomatous oophoritis Yolk sac tumor

46XX DSD

Table of Contents

Female pseudohermaphroditism | Female pseudohermaphroditism associated with congenital adrenal hyperplasia | Female pseudohermaphroditism-nonadrenal

Female pseudohermaphroditism

Definition / general

Disorder of sex development (DSD) with female genotype (46,XX), female internal phenotype (2 ovaries) but variable degrees of virilization

Terminology

In 2006 the International Consensus Conference on Intersex recommended using the designation "46,XX DSD" instead of the potentially pejorative and confusing term "female pseudohermaphroditism"

Etiology

Most virilized 46,XX infants have congenital adrenal hyperplasia (CAH)
Non-CAH etiologies include gestational hyperandrogenism

Clinical features

In CAH, depending on the site of the steroid biosynthesis defect, there may be under or overproduction of mineralcorticoid, resulting in imbalances in serum electrolytes and blood pressure

Laboratory

Serum steroid measurements can confirm or rule out congenital adrenal hyperplasia in most 46,XX DSD cases

Additional references

Pediatrics 2006;118:e488

Female pseudohermaphroditism associated with congenital adrenal hyperplasia

Definition / general

Most common form of female pseudohermaphroditism in which a female genotype (46,XX) and female internal phenotype (two ovaries) is associated with variable degrees of virilization due to a defect in the steroid biosynthetic pathway

Terminology

In 2006, the International Consensus Conference on Intersex recommended using the designation "46,XX DSD" to replace the potentially pejorative and confusing term female "pseudohermaphroditism" (Pediatrics 2006;118:e488)

Epidemiology

CAH is the most common cause of 46,XX DSD

Etiology

CAH is usually due to 21 alpha hydroxylase or 11 beta hydroxylase deficiency
There are also other rare mutations (Arg Bras Endocrinol Metabol 2005;49:126)
Partial 17 alpha hydroxylase / 17,20 lyase deficiency (Gynecol Endocrinol 2008;24:362)

Diagrams / tables

Images hosted on other servers:

Steroid pathways

Clinical features

Depending on the site of the steroid biosynthesis defect, there may be under or overproduction of mineralcorticoid, resulting in imbalances in serum electrolytes and blood pressure
21 alpha hydroxylase deficiency often leads to hyponatremia, hyperkalemia and hypotension; these patients are at risk for life threatening adrenal crises

Laboratory

Serum steroid measurements can confirm or rule out CAH in the vast majority of 46,XX DSD cases
11 beta hydroxylase deficiency and 3 beta hydroxysteroid dehydrogenase deficiency have characteristic serum steroid patterns

Female pseudohermaphroditism-nonadrenal

Definition / general

Rarer form of female pseudohermaphroditism in which a female genotype (46,XX) and female internal phenotype (two ovaries) is associated with variable degrees of virilization due to etiologies other than congenital adrenal hyperplasia, including gestational hyperandrogenism (maternal exposure to progestins or androgens)
46,XX Barr bodies are chromatin positive
Ovary with female ducts and variable virilized external genitalia

Terminology

In 2006, the International Consensus Conference on Intersex recommended using the designation "46,XX DSD" to replace the potentially pejorative and confusing term female "pseudohermaphroditism" (Pediatrics 2006;118:e488)

Epidemiology

Gestational hyperandrogenism is a rarer cause of 46,XX DSD

Etiology

May be due to exposure to maternal androgen (maternal luteoma, theca lutein cysts, placental aromatase enzyme deficiency) or synthetic progestational agents

Clinical features

Diagnosis may be suggested by history of exposure to exogenous progestin or androgen or maternal virilization

Laboratory

17 ketosteroids and estrogen levels are normal

Case reports

With luteoma of pregnancy (Hum Reprod 2002;17:821)

Additional references

eMedicine: Disorders of Sex Development [Accessed 15 January 2024]

Anatomy & histology

Table of Contents

Definition / general

Paired female reproductive glands located on each side of the uterus, adjacent to the lateral pelvic wall, posterior to the broad ligament and anterior to the rectum
Originate from the genital ridge formed by the thickening of the coelomic epithelium with oogonia later migrating from the yolk sac endoderm (Am J Surg Pathol 1987;11:277)

Essential features

Paired ovoid organs located on each side of the uterus
Responsible for the development of the dominant follicle and the production of hormones
Multiple histologic components can be seen in the normal ovaries and can mimic pathologic findings

Embryology

Ovary is composed of 4 main components, each with different embryologic origins, all of which eventually come together in the developed ovary: surface epithelium, stroma, germ cells and sex cords
Embryonic coelomic cavity is initially lined by primitive mesothelium (modified coelomic epithelium), which arises from the underlying mesoderm
At ~5 weeks gestation, the gonadal ridge develops as a coelomic thickening and mesenchymal growth high in the abdominal cavity near where the kidneys develop
- Coelomic epithelium forms the ovarian surface epithelium
- Subcoelomic mesoderm forms the ovarian stroma
- Primordial germ cells migrate from the yolk sac endoderm to the developing ovary
- Invaginations of coelomic epithelium in the superficial ovarian cortex form the sex cords (pregranulosa cells)
During weeks 12 - 20, the vascular network develops from the hilus towards the cortex and pregranulosa cells encircle germ cells to form primordial follicles, which in turn are encircled by stroma derived theca cells
Germ cells differentiate into oogonia, which differentiate into primary oocytes and arrest in this stage until puberty
Each ovary descends into the pelvis along the gubernaculum (attached inferiorly to the inguinal region); the gubernaculum becomes part of the uterine wall at entry of the fallopian tube and persists in adults as ovarian and round ligaments
Invaginations of the coelomic epithelium at the site of the gonadal ridge also give rise to two types of genital ducts: the mesonephric (Wolffian) ducts and the paramesonephric (Müllerian) ducts
Müllerian ducts eventually give rise to the fallopian tubes and fuse to form the uterus
Wolffian (mesonephric) duct remnants may be seen in the vicinity of the Müllerian system later in life
Gonadal development is influenced by both male and female promoting signals (Mol Endocrinol 2008;22:1)
References: Wikipedia: Gonadal Ridge [Accessed 26 December 2023], Embryology: Human Embryology [Accessed 26 December 2023]

Physiology

Function first described by Reinier de Graaf (Arch Pathol Lab Med 2000;124:1115)
Ovaries play an essential role in the fertility and cycling of reproductive activity in women, mainly by controlling the development of the dominant follicle and producing hormones (estrogen and progesterone) (Endotext: Morphology and Physiology of the Ovary [Accessed 9 September 2021])
- Folliculogenesis starts by recruiting primordial follicles into growing follicles that eventually proceed either to ovulation or death
- Folliculogenesis is divided into preantral (growth and differentiation of follicles) and antral phase (increase in the follicle size)
- Folliculogenesis will result in the production of a single dominant follicle (Graafian follicle), which will eventually ovulate
- ~400,000 primordial follicles containing primary oocytes are present at birth in ovarian stroma (100,000 at gestational age of 15 weeks; 680,000 at 8 months) (Fertil Steril 2007;88:675)
- Follicular decay appears to advance with increasing age; prominent cystic follicles are present at birth and at puberty (Hum Reprod 2008;23:699)
- Germ cells travel from yolk sac endoderm to ovary where they develop into oogonia and oocytes, arresting at prophase of mitosis
Ovulation: induces cyclic rupture and regenerative repair of the ovarian surface epithelium
Following ovulation, the dominant follicle becomes the corpus luteum responsible for the production of progesterone during the luteal phase of each menstrual cycle or becomes the corpus luteum of pregnancy to sustain gestation
Hormones produced by the dominant follicle are essential for the preparation of the uterus for implantation of the embryo (Endotext: Morphology and Physiology of the Ovary [Accessed 9 September 2021])
Hilus cells produce steroids (predominantly androstenedione); resemble Leydig cells of testis; may produce masculinizing tumors (hilus cell tumors)

Diagrams / tables

AFIP images

Ovary - lymphatics

Images hosted on other servers:

Anatomic relationships of ovary

Ovary - vascular relations

Section of the ovary

Ovarian stroma

Folliculogenesis

Clinical features

Characteristic streak gonads in patients with Turner syndrome, also known as congenital ovarian hypoplasia, due to monosomy X (45,XO); these are not functional and will subsequently manifest with symptoms of ovarian failure (J Minim Invasive Gynecol 2015;22:S15)
Primary ovarian insufficiency: a condition diagnosed in women less than 40 years of age and characterized by depletion or dysfunction of the ovarian follicles with subsequent impaired ovarian function (N Engl J Med 2009;360:606)

Laboratory

Tests that evaluate the ovarian function usually done in the context of primary or secondary amenorrhea or infertility problems (Am Fam Physician 2013;87:781)
These tests include but are not limited to
- Measurement of follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels
- Estrogen production: serum 17 beta estradiol level
- Serum progesterone level

Gross description

Attachment:
- Along its anterior (hilar) margin to posterior aspect of broad ligament by mesovarium (double fold of peritoneum)
- At its medial pole to ipsilateral uterine cornu by utero-ovarian ligament
- At superior aspect of lateral pole to lateral pelvic side wall by infundibulopelvic (suspensory) ligament
Laterality in a hysterectomy and bilateral salpingo-oophorectomy specimen established based on the
- Utero-ovarian ligament, which connects each ovary to the ipsilateral uterine cornu and is situated posterolateral and inferior to the attachment of the fallopian tubes
- Posterior peritoneal reflection, which extends over a longer segment of the uterus compared to the anterior surface, which has a longer roughened area
Appearance of the ovary depends widely on the age / menopausal state:
- Prepubertal ovaries:
  - Newborn ovaries are elongated and approximately 1.3 cm in greatest dimension
  - Ovaries enlarge during infancy and childhood and reach adult size and shape by the time of puberty
  - Neonatal ovaries often have cysts, which resolve spontaneously (J Pediatr Endocrinol Metab 2007;20:397)
- Premenopausal ovaries:
  - 3 - 5 cm long and weigh 5 - 8 g; size and weight depend on the amount of follicular derivatives (cysts and corpora albicantia / lutea)
  - Pink-white exterior is initially smooth but gradually becomes more convoluted
  - Cystic follicles and corpora lutea may be visible from outside
  - Cut section may exhibit 3 zones: cortex, medulla and hilus, with follicular derivatives usually in the cortex and medulla
- Postmenopausal ovaries:
  - Firm consistency with solid, pale cut surface
  - Occasional cysts measuring several millimeters in diameter (inclusion cysts) may be discernible within the cortex
  - Small white scars (corpora albicantia) are typically present within the medulla
  - Thick walled blood vessels may be appreciable within the medulla and the hilus
Blood supply and drainage:
- Arterial supply: approximately 10 arterial branches from anastomotic arcade of ovarian artery (branch of aorta) and ovarian branch of uterine artery penetrate hilus into medulla and cortex
- Venous drainage: left ovarian vein drains to left renal vein, right ovarian vein drains to inferior vena cava
- Lymphatic drainage: originates predominantly from theca layer of follicles, exiting through the hilus, to the mesovarium, along the infundibulopelvic ligament, into upper paraaortic lymph nodes; may bypass to internal iliac, external iliac, common iliac, sacral, obturator, pelvic, retroperitoneal or inguinal nodes

Gross images

Contributed by Doaa Atwi, M.D.

Ovarian attachment

Images hosted on other servers:

Corpus luteum

Frozen section description

Enlarged corpus luteum cyst can trigger an intraoperative consultation; the cyst lining is yellow and has a convoluted appearance
Luteoma of pregnancy can be discovered incidentally during cesarean section or preoperatively on imaging study mimicking an ovarian mass (J Magn Reson Imaging 2009;29:713)

Frozen section images

Contributed by Doaa Atwi, M.D.

Corpus luteum cyst

Corpus luteum lining

Microscopic (histologic) description

Ovarian parenchyma can largely be divided into 3 compartments:
- Albuginea: a protective hypocellular compartment, composed of a fibrotic layer measuring approximately 0.3 mm and occupying the most superficial part of the ovary (Obstet Gynecol 1971;37:832, Ann Diagn Pathol 2020;46:151475)
- Cortex: a 0.3 mm hypercellular layer composed of spindle cells arranged parallel to the surface and housing the majority of the follicles in a premenopausal woman (Ann Diagn Pathol 2020;46:151475)
- Medulla: a hypocellular area beneath the cellular cortex and housing abundant blood vessels; nodular or diffuse proliferation of spindle cells can commonly be seen in the medulla (Ann Diagn Pathol 2020;46:151475)
Stroma:
- Comprises bulk of ovarian tissue
- Resembles fibroblasts in whorls / storiform pattern surrounded by dense reticulin network
- Contains luteinized stromal cells, decidual cells, smooth muscle, fat, neuroendocrine cells and endometrial stroma-like cells
Ovarian parenchyma can alternatively be defined as the ovarian follicles, given that the follicles are the constituents that perform the function of the ovary with all the other constituents being labeled as ovarian stroma (Reproduction 2020;160:R25)
- Number of primordial follicles and oocytes in premenopausal women can be markedly different between the 2 ovaries (Ann Diagn Pathol 2020;46:151475)
- Within the same ovary, the primordial follicles and oocytes exhibit an uneven distribution in the cortex with clustering in few areas (Ann Diagn Pathol 2020;46:151475)
- In addition to their more common location in the cortex, the primordial follicles can be seen in the medulla within areas of nodular proliferations, especially in women with abundant follicular cysts (Ann Diagn Pathol 2020;46:151475)
- Follicle is designated cystic when it measures 2 mm or more but less than 9 mm; these are very common and can be lateralized to 1 ovary in some individuals (Endocrinol Metab Clin North Am 1998;27:877)
Stages of follicular development:
- Primordial follicle:
  - Diplotene oocyte surrounded by a layer of flattened granulosa cells (Hum Mol Genet 2010;19:397)
  - Neo-oogenesis may occur in adults (Endocrine 2005;26:301)
- Maturing follicle:
  - Oocyte with surrounding granulosa cell layer
  - Lacks reticulum
  - Contains Call-Exner bodies (rosette-like formations with central filamentous / eosinophilic material consisting of excess basal lamina) and theca cells (within follicle are luteinized and produce sex hormones, external to follicle are very cellular)
- Corpus luteum:
  - 2 cm, round to serpiginous, yellow, lobulated structure with cystic center
  - Has luteinized granulosa and theca cells
  - In pregnancy, is larger, bright yellow with prominent central cavity, hyaline droplets and calcification
- Corpus albicans: remnant of corpus luteum, hyalinized, paucicellular fibrotic scar with serpiginous contours
Other normal components:
- Surface epithelium:
  - Ovarian surface epithelium (OSE) is a modified mesothelium, also called coelomic or germinal epithelium (Reprod Biol Endocrinol 2006;4:42)
  - Single layer of flat to cuboidal mesothelial type cells, which appear to actively participate in the ovulatory rupture and repair process (J Histochem Cytochem 2020;68:113)
  - Closely related to Müllerian duct lining epithelium
- Mesothelial inclusion cyst:
  - Superficial cysts that are lined by mesothelial cells and represent invagination of the surface mesothelial epithelium
  - Usually seen in ovaries with clefts (Ann Diagn Pathol 2020;46:151475)
- Endosalpingiosis:
  - Group of glands and cysts with a tubal epithelial lining
  - Usually seen in ovaries without clefts and commonly associated with calcification
  - Rim of fibrotic tissue can surround them (Ann Diagn Pathol 2020;46:151475)
  - In contrast to inclusion cysts, their presence can be associated with the recurrence of low grade serous neoplasms (Int J Gynecol Pathol 1998;17:1)
- Hilus (hilar) cells:
  - Located in ovarian medulla, rarely within ovarian stroma; located away from the hilum, round to polygonal, epithelial appearing, presumed vestigial remnant of gonad from its ambisexual phase
  - Closely associated with large hilar veins and lymphatics and may protrude within their lumina; also associated with nerves
  - May contain Reinke crystalloids, lipid, lipochrome pigment
  - Resemble steroid cells by electron microscopy with microtubular smooth endoplasmic reticulum, mitochondria with tubular cristae
  - Hilar cells are seen in the fetal ovary but not in infancy and childhood; they reappear at puberty
  - Hilar cell hyperplasia: associated with hCG administration, pregnancy and choriocarcinoma
- Rete ovarii:
  - Counterpart of rete testis
  - Seen as clefts, tubules, cysts, papillae lined by cuboidal or columnar epithelium
  - Located usually in the hilum of the ovary, surrounded by spindle cell stroma
- Walthard cell nests:
  - Usually microscopic cystic / solid structures with urothelial type epithelium and variable mucin seen in mesovarium, mesosalpinx and ovarian hilus
- Ovarian stem cells:
  - Ovary can house stem cells for variable cell types with both somatic and germline stem cells being mentioned
  - Somatic stem cells include granulosa cells, surface epithelial cells, thecal cells and stromal cells (Reproduction 2019;157:545)
- Cortical granuloma:
  - Common incidental finding in the ovaries of late reproductive and postmenopausal women, composed of an aggregate of epithelioid histiocytes surrounded by a rim of lymphocytes
  - They are of uncertain origin but could represent previous areas of endometriosis, luteinized stromal cells or ectopic decidua (Int J Gynecol Pathol 2016;35:544)
Can show significant difference in the composition between the right and left side (Int J Gynecol Pathol 1998;17:1)

Microscopic (histologic) images

Contributed by Doaa Atwi, M.D.

Mature follicle

Corpus luteum

Cortical granuloma

Ovarian surface epithelium

Luteinized stromal cells

CD68

AFIP images

Undifferentiated gonad

Ovulation age of 48 days

Ovulation age of 5 months

Virtual slides

Images hosted on other servers:

Ovary in a newborn female

Ovary in premenopausal woman

Positive stains

Cortical epithelium: keratin, EMA, CA-125, WT1, BerEP4, desmoplakin
Stroma: vimentin, calretinin, actin / desmin, ER beta, PR, Inhibin
Granulosa / theca cells: WT1, calretinin, Inhibin, MART1, CD56
Hilus cells: MART1, Inhibin, vimentin
Rete ovarii: CAM5.2, EMA, vimentin, PR, CD56

Negative stains

CD10
Ovarian surface epithelium is negative for CA125, unlike other coelomic derivatives

Videos

Corpus luteum

Corpus albicans

Board review style question #1

The image above represents a section of a well circumscribed, yellow, cystic nodule seen on gross examination of the ovary. The cells are positive for inhibin and calretinin. Which statement is correct?

Its presence is permanent and does not depend on the phase of the menstrual cycle or the age of the patient
Surgical removal of the ovary is indicated to prevent metastasis
The image represents a physiologic constituent of the ovary
The image represents a sex cord stromal tumor

Board review style answer #1

C. The image represents a mature corpus luteum, which is a physiologic structure present in the luteal phase of menstruation. The constituent cells are polygonal with abundant, pale, eosinophilic cytoplasm representing the luteinized granulosa cells. The round nucleus contains 1 or 2 large nucleoli. These cells usually stain similar to steroid hormone producing cells and are typically positive for inhibin and calretinin.

Comment Here

Reference: Ovary - Anatomy & histology

Board review style question #2

Which of the following microscopic findings in an ovary are indicators of a pathologic condition?

Benign tubular structures located within the ovarian cortex; constituent cells are positive for mesothelial markers
Benign polygonal cells with clear cytoplasm, round nucleus and positive staining for inhibin and calretinin
Epithelial cell proliferation composed of papillary structures lined by cuboidal cells and exhibiting hierarchical branching and tufting of the lining cells
Urothelial-like nests of cells known as Walthard nests

Board review style answer #2

C. The description is that of a serous neoplasm. Complex architecture including hierarchical branching and tufting of lining epithelial cells should not be seen in normal ovary or in the context of endosalpingiosis.

Comment Here

Reference: Ovary - Anatomy & histology

Appendiceal neoplasms

Table of Contents

Definition / general

Mucinous neoplastic proliferations of the cecal appendix commonly manifest with signs of extra-appendiceal spread, particularly in the form of pseudomyxoma peritonei
Involvement of other organs such as the ovary may be the first manifestation of the disease
Current evidence supports that, in the context of pseudomyxoma peritonei, an ovarian mucinous tumor should be regarded as appendiceal in origin, with the exception of a mucinous tumor arising in a mature teratoma (Am J Surg Pathol 1991;15:415, Int J Gynecol Pathol 1997;16:1)

Terminology

Pseudomyxoma peritonei is a clinicopathologic syndrome characterized by mucinous ascites
Intra-abdominal mucin is abundant and can be admixed with neoplastic mucinous epithelium (Am Soc Clin Oncol Educ Book 2013;221)
Although commonly used to refer to all metastatic carcinomas involving the ovary, the term Krukenberg tumor strictly refers to adenocarcinomas with signet-ring cell differentiation, of which most (76%) arise from the stomach (J Clin Pathol 2012;65:585)

Epidemiology

Primary appendiceal tumors are found in < 2% of surgically removed appendices (Arch Pathol Lab Med 2011;135:1261)
28 - 37% of appendiceal tumors not associated with pseudomyxoma peritoneii present with ovarian metastases (Gynecol Oncol 2014;133:155)
Among patients with ovarian mucinous tumors showing borderline features, only about 2% have a documented primary appendiceal malignancy
Despite this low incidence, there is significant overlap of clinical, radiologic and pathologic features between primary and metastatic ovarian adenocarcinoma; in the work-up of a mucinous or endometrioid-like ovarian neoplasm, a secondary malignancy should always be considered pathologically or clinically
Pseudomyxoma peritonei is 2 - 3 times more common in women than in men

Pathophysiology

Spread to the ovaries can be hematogenous, lymphatic, transperitoneal or by direct extension (Rev Gastroenterol Mex 1994;59:290)
The pathogenesis of pseudomyxoma peritonei is still unknown; current theories postulate that the mucin is produced by very low quantities (sometimes undetectable) of neoplastic intestinal-type epithelium, which colonizes the peritoneal cavity presumably after appendiceal tumor rupture

Clinical features

Patients with metastatic appendiceal adenocarcinoma involving the ovary have a poor prognosis
Patients with a low grade appendiceal mucinous neoplasm (LAMN) and pseudomyxoma peritonei has a protracted clinical course with multiple recurrences, progressive fibrous adhesions and complications such as fatal obstructive disease

Laboratory

Elevated CA-125 levels (> 100 U/mL) are common, which has been suggested as a useful feature to distinguish metastatic from primary ovarian mucinous carcinomas (Gynecol Obstet Invest 2011;72:196)
Elevated CEA levels (> 5 ng/mL) and CA19-9 levels (> 37 U/mL) are seen in a minority of cases

Radiology description

Bilaterality is seen in up to 83.3% of cases
On imaging, pseudomyxoma peritonei is suspected if there is irregularly localized or loculated fluid with scalloped appearance within the peritoneal cavity
The ovarian mass can be cystic, solid or a mixture

Gross description

Ovarian mass is frequently complex (solid and cystic) or purely solid
Purely cystic unilocular lesions are rare
Solid tumors have a multinodular appearance and extend to the ovarian / tumor surface
Cut surface reveals mucinous contents in cystic areas and a soft, glistening appearance of solid areas, sometimes with easily expressed mucinous material from it

Microscopic (histologic) description

Low grade appendiceal mucinous neoplasms (LAMN) have bland cytomorphology and mimic benign and borderline ovarian mucinous tumors
LAMN involving the ovary display certain distinctive microscopic features (Int J Gynecol Pathol 2014;33:1):
- Bilaterality
- Tall mucinous cells with indistinct apical borders and lack of cellular stratification
- Elongated glands with shallow epithelial invaginations (scalloping)
- Subepithelial clefts
These characteristics, however, can also be seen in up to 38.8% of ovarian mucinous borderline tumors
Appendiceal adenocarcinomas can have a mucinous or a conventional (mucin-depleted) glandular appearance
- Mucinous carcinomas have intestinal (goblet cell) differentiation
- Mucin extravasation and signet-ring cell morphology can be seen
- The term Krukenberg tumor should be reserved to adenocarcinomas involving the ovary with a signet ring cell component > 10% of the tumor volume, regardless of its site of origin (Adv Anat Pathol 2006;13:205)
- Conventional tumor cytomorphology with mucin depletion mimics the architecture and cytoplasmic appearance of primary endometrioid tumors; however, nuclear pleomorphism and hyperchromasia tend to be prominent, and exceed that expected for a primary ovarian tumor
- Central glandular necrosis is also more typical of intestinal tumors, although is not entirely specific
Several clinical and pathologic features have been described as indicative of secondary (metastatic) origin (Am J Surg Pathol 2003;27:281, J Clin Pathol 2012;65:591), including:
- Bilaterality
- Size less than 10 cm
- Surface involvement
- Infiltrative pattern of invasion
- Presence of signet ring cells
- Extensive lymphovascular space invasion
- Mucin extravasation
If any of the above features is present, the possibility of a metastasis should be considered and prompt ancillary testing and clinical investigation

Microscopic (histologic) images

Contributed by Carlos Parra-Herran, M.D.

Appendiceal adenocarcinoma

Low grade appendiceal mucinous neoplasm

Positive stains

Immunohistochemistry is a reliable tool in the distinction between primary ovarian tumors and metastases from appendiceal origin
SATB2 is a sensitive and specific marker of colorectal epithelium
- Also positive in appendiceal epithelium
- This marker has shown 93.8% sensitivity and 97.5% specificity in determining appendiceal origin (Histopathol 2016;68:977)
CK20, CDX2 and MUC2 are also optimal markers of appendiceal origin; although they are frequently expressed in primary ovarian tumors, such expression is usually patchy / focal
Diffuse and strong expression for CK20, CDX2 and MUC2 has 90%, 87.5% and 95% specificity for appendiceal origin

Negative stains

PAX8: 0% (vs 30 - 65% of primary ovarian mucinous tumors and 80% of primary ovarian endometrioid tumors)
ER: 0% (vs 30% of primary ovarian tumors)

Differential diagnosis

Low grade mucinous neoplasm or mucinous carcinoma with pseudomyxoma peritonei arising in a mature cystic teratoma (Am J Surg Pathol 2007;31:854)
Metastases from cervix: p16 positive (strong, diffuse)
Metastases from colon and rectum: mass located in the large intestine, normal appendix (colorectal and appendiceal tumors have a similar IHC profile)
Metastases from upper GI tract: CK7 positive, CK20 / CDX2 / SATB2 variable (mostly negative)
Primary ovarian neoplasm (benign, borderline or malignant): absence of suspicious features described above (bilaterality, surface involvement, signet-ring cell morphology, etc), SATB2 negative, CK20 / CDX2 / MUC2 negative or patchy, PAX8 positive

Autoimmune oophoritis (pending)

[Pending]

Benign, borderline and malignant Brenner tumors

Table of Contents

Definition / general

Tumor composed of transitional / urothelial-like epithelium, typically embedded in fibromatous stroma
Benign, borderline and malignant variants are recognized, based on the growth pattern and cytological features of the epithelial cells

Essential features

Benign Brenner tumor:
- Adenofibromatous architecture with nests of bland transitional epithelium present within fibromatous stroma
Borderline Brenner tumor:
- Papillary architecture with papillae covered by multilayered transitional epithelium
- There is variable but usually low grade cytological atypia
Malignant Brenner tumor:
- Stromal invasion by carcinoma with transitional cell features, associated with a benign or borderline Brenner tumor

ICD coding

ICD-O:
- 9000/0 - Brenner tumor, NOS
- 9000/1 - Brenner tumor, borderline malignancy
- 9000/3 - Brenner tumor, malignant
ICD-11:
- 2F32.Y & XH5DX3 - Brenner tumor, NOS
- 2C73.Y & XH2CH8 - Brenner tumor, borderline malignancy
- 2C73.Y & XH6NJ7 - Brenner tumor, malignant

Epidemiology

Brenner tumors are most common in the fifth and sixth decades but can occur across a wide age range

Sites

Ovary
Rare extraovarian Brenner tumors are reported

Pathophysiology

Cell of origin of Brenner tumors is controversial; they may arise from Walthard rests

Etiology

Unknown

Clinical features

Benign Brenner tumors are usually asymptomatic
Borderline and malignant Brenner tumors are larger and usually present with findings secondary to an adnexal mass

Diagnosis

Most benign Brenner tumors are an incidental finding in an ovary removed for other reasons
Borderline and malignant Brenner tumors are usually diagnosed at the time of removal of an adnexal mass

Radiology description

Nonspecific findings of a solid or solid and cystic ovarian mass

Prognostic factors

All reported cases of benign and borderline Brenner tumor have had a benign course, although local recurrence has rarely been reported for the latter (Acta Pathol Microbiol Scand Suppl 1972;233:56)

Case reports

Benign Brenner tumor:
- 58 year old woman with a coexisting benign Brenner tumor and mucinous cystadenoma (Iran J Pathol 2020;15:334)
- 60 year old postmenopausal woman with ovarian mucinous cystic tumor associated with sarcomatous mural nodule and benign Brenner tumor (Medicine (Baltimore) 2019;98:e14066)
- 68 year old woman with a benign Brenner tumor arising in an ectopic ovary (Int J Gynecol Pathol 2020 Sep 17 [Epub ahead of print])
Borderline Brenner tumor:
- 68 year old woman with borderline Brenner tumor (J Ovarian Res 2014;7:101)
Malignant Brenner tumor:
- 62 year old woman with malignant Brenner tumor manifesting as bowel obstruction (BMJ Case Rep 2020;13:e235394)
- 77 year old woman with malignant Brenner tumor (Gynecol Oncol Rep 2017;22:26)

Treatment

Oophorectomy
No adjuvant treatment for benign or borderline Brenner tumors
Adjuvant chemotherapy for advanced stage malignant Brenner tumors

Gross description

Benign Brenner tumor:
- Small (usually < 2 cm), circumscribed, fibrous tumor with a uniform cut surface
- Calcifications may be present
Borderline and malignant Brenner tumor:
- Smooth surface, larger (usually > 10 cm) with fleshy, polypoid masses projecting into cystic cavity(s)

Gross images

Contributed by Jutta Huvila, M.D., Ph.D. and C. Blake Gilks, M.D. and AFIP images

Solid, uniform cut surface

Fleshy appearance

Sharply demarcated

Fibroma-like appearance

Solid fibroma-like component and 2 cysts

Images hosted on other servers:

Infarcted tumor

Frozen section description

Benign:
- Adenofibromatous architecture, smooth contoured nests of bland epithelial cells within benign fibromatous stroma
Borderline or malignant:
- Resembling low grade papillary urothelial tumor of the bladder, with papillary fronds covered by transitional-like epithelium

Frozen section images

Contributed by Jutta Huvila, M.D., Ph.D. and C. Blake Gilks, M.D.

Benign Brenner tumor

Microscopic (histologic) description

Benign:
- Smooth contoured nests of bland transitional epithelium within fibromatous stroma
- Transitional cells have uniform oval nuclei and may have a longitudinal nuclear groove
- There may be mucinous epithelium at the center of the nests, with microcyst formation
- Ciliated or nondescript glandular epithelium may be present; a coexistent mucinous cystadenoma is present in 10% of cases
- Calcification is common
Borderline:
- Papillary architecture with papillae covered by multilayered transitional epithelium
- There is variable cytological atypia; usually low grade but on occasion moderate or marked cytological atypia may be present
- Benign Brenner tumor component is often present
Malignant:
- Stromal invasion by carcinoma with transitional cell features, with irregular nests of cells and single cells in an infiltrative pattern
- Squamous or mucinous differentiation may be present
- Benign or borderline Brenner tumor component is present
Reference: Int J Gynecol Pathol 2012;31:499

Microscopic (histologic) images

Contributed by Jutta Huvila, M.D., Ph.D. and C. Blake Gilks, M.D.

Benign transitional nests

Nuclear grooves

Papillary architecture

Nuclear atypia

Stromal invasion

Malignant nuclear features

AFIP images

Fibromatous stromal component

Resembling coffee beans

Several lumens

Mucinous epithelium

Ciliated epithelium

Positive stains

p63, GATA3 (Am J Surg Pathol 2009;33:556, Am J Surg Pathol 2009;33:347, Histopathology 2007;51:477, Am J Surg Pathol 2003;27:1434)

Negative stains

ER, PR, WT1 (weak / focal positivity may be seen)
Wild type p53 staining in benign and borderline Brenner tumors; malignant Brenner tumors may show mutant pattern staining

Sample pathology report

Right ovary, oophorectomy:
- Borderline Brenner tumor (see comment)
- Comment: This borderline Brenner tumor is associated with a component of benign Brenner tumor. Negative for invasive carcinoma.

Differential diagnosis

For Benign Brenner tumor
- Endometrioid adenofibroma:
  - Glandular: lacks multilayered epithelial nests with transitional differentiation
- Adult granulosa cell tumor:
  - More characteristic patterns of adult granulosa cell tumor present, such as microfollicular, trabecular or solid growth
  - Inhibin immunoreactivity and negative for epithelial markers
- Carcinoid tumor:
  - Insular or trabecular architecture
  - Lacks prominent fibromatous stroma
  - Expression of neuroendocrine markers
For borderline / malignant Brenner tumors
- High grade serous carcinoma, transitional architectural pattern:
  - Areas of conventional high grade serous carcinoma
  - High grade nuclear features
  - Absence of a benign Brenner component
  - WT1 and ER positivity (Int J Gynecol Pathol 2012;31:49)
- Squamous cell carcinoma:
  - Keratinization
  - High grade cytological features
  - Teratoma component
- Endometrioid borderline tumor or carcinoma:
  - More prominent glandular component with endometrioid (not mucinous) glands
  - ER positive
- Metastatic squamous cell carcinoma:
  - History of primary squamous cell carcinoma elsewhere in the body
  - Bilateral and multinodular growth
  - Lacks prominent papillary architecture
- Metastatic urothelial carcinoma:
  - History of urothelial carcinoma
  - Bilateral and multinodular growth
  - Lacks benign Brenner component

Additional references

Int J Gynecol Cancer 2012;22:1332, WHO Classification of Tumours Editorial Board: Female Genital Tumours, 5th Edition, 2020

Board review style question #1

Which of the following is true about benign Brenner tumors of the ovary?

Composed of both epithelium and fibromatous stroma
Papillary architecture
Typically > 10 cm
Usually present with abdominal pain

Board review style answer #1

A. Composed of both epithelium and fibromatous stroma

Comment Here

Reference: Brenner tumor

Board review style question #2

Brenner tumors of the ovary typically have which of the following immunophenotypes?

GATA3 and ER positive
GATA3 and p63 positive
GATA3 and WT1 positive
GATA3 positive and mutant pattern p53 expression

Board review style answer #2

B. GATA3 and p63 positive

Comment Here

Reference: Brenner tumor

Breast carcinoma

Table of Contents

Definition / general

Usually incidental finding associated with (a) staging, (b) oophorectomy for patient with BRCA mutation or strong family history of breast cancer, or (c) therapeutic oophorectomy (induced hormone suppression for hormone receptor+ breast carcinoma)
Ovarian involvement is seen in ~30% of therapeutic oophorectomies for advanced breast cancer, and at autopsy in ~10% of breast cancer cases (Am J Surg Pathol 2006;30:277)
Involvement by lobular carcinoma (36%, including signet-ring cell type) is more frequent than ductal carcinoma (2.6%) (Br J Cancer 1984;50:23, Adv Anat Pathol 2007;14:149)
Metastatic disease frequently arises up to 5 years post diagnosis, median 11.5 months, and is related to breast cancer stage (Br J Cancer 1984;50:23)

Pathophysiology

High rates of hormone receptor+ breast cancer and premenopausal status suggest that hormone regulation is important in metastases to ovary

Clinical features

Ovarian involvement is usually asymptomatic
May have GI symptoms of abdominal pain, distension or pressure, abnormal uterine bleeding or mass (Gynecol Oncol 2003;90:397, Gynecol Oncol 2005;98:235)

Radiology description

USG: mostly bilateral ovarian involvement by solid tumors 10 cm in size or less

Case reports

58 year old woman (J Cytol 2009;26:144)
Two case reports and review of three additional cases (Cancer 1981;48:210)
Sixteen cases reported as part of a cohort of patients with breast cancer and ovarian disease (Obstet Gynecol 1994;84:449)

Treatment

Diagnosis of metastatic carcinoma to the ovary is usually done on salpingo-oophorectomy specimens:
Subsequent treatment is commonly not necessary
More extensive surgery (contralateral salpingo-oophorectomy, hysterectomy, lymph node dissection) may be considered if obvious or suspected residual tumor and no other sites of metastatic involvement on imaging
Minimal (e.g., palliative debulking) can also be considered
Surgery is defined as "optimal" when largest residual tumor mass is <2 cm (J Korean Med Sci 2009;24:114)

Gross description

80% are bilateral
Multiple solid tumor nodules with soft consistency
Involvement of ovarian surface and superficial cortex is common

Microscopic (histologic) description

Morphology mirrors the architecture and cytomorphology of the breast primary (including histologic grade)
Lobular carcinoma: small cords and clusters of tumor cells in ovarian cortex, single cells in between normal cortical stroma; histiocytoid or signet ring cell morphology can be seen
Ductal carcinoma: tubules / glands or solid nests of tumor cells in a variable fibrous stroma

Microscopic (histologic) images

Images hosted on other servers:

Diffuse infilitration
by lobular type
epithelial cells

Ductal

Cytology description

Cell clusters have high nuclear-cytoplasmic ratio, moderate cytoplasm, vesicular nuclei, conspicuous nucleoli

Cytology images

Images hosted on other servers:

Malignant cells
in cluster, Giemsa

Positive stains

GATA3 is consistently positive in mammary carcinomas (Am J Clin Pathol 2012;138:57)
- It is consistently positive in ER positive tumors but is also positive in 69% of ER negative tumors (Am J Clin Pathol 2014;14:648)
ER, PR and HER2 are not always expressed; expression usually mirrors that of the primary mammary tumor
Variable (~50%) GCDFP and mammaglobin staining (Hum Pathol 1991;22:368, Mod Pathol 2007;20:208, Am J Clin Pathol 2007;127:103)

Negative stains

PAX8: usually positive in most ovarian carcinomas subtypes (Am J Surg Pathol 2008;32:1566)
WT1: positive in only 2% of breast metastases versus 63% of ovarian tumors, but also negative in ovarian clear cell, mucinous and endometroid subtypes
CA125: weak / negative in breast carcinomas, 90% of ovarian carcinomas are CA125+ (Am J Surg Pathol 2005;29:1482)

Differential diagnosis

Primary ovarian adenocarcinoma: PAX8+, CA125+
Metastatic carcinoma from other sites (GI tract): history of known primary and IHC for primary site (CK20, CDX2, TTF1, Napsin A)

Calcification

Table of Contents

Definition / general

Ovarian calcifications are commonly found in the context of a neoplasm (mature teratoma, mucinous cystadenoma, serous neoplasia, etc.) or as incidental findings in grossly normal ovaries

Essential features

Ovarian calcifications can be idiopathic or associated with benign or malignant conditions (endometriosis, teratoma, mucinous lesions, serous neoplasms, etc.)
Calcifications are divided into psammomatous (psammoma bodies) and nonpsammomatous
Calcifications associated with a neoplasm do not need to be reported but identifying psammomatous calcifications in an otherwise normal ovarian specimen should prompt additional sampling to rule out the possibility of an underlying serous neoplasm

Terminology

Calcifications, microcalcifications, osseous metaplasia

Sites

Ovary

Pathophysiology

Pathologic calcifications are metastatic (associated with hypercalcemia) or dystrophic (associated with normal calcemia); ovarian calcifications are considered dystrophic, due to calcium deposition in areas of cellular degeneration or necrosis
Presence of stromal calcifications suggests a paracrine effect in the stromal cells in response to hormonal stimuli (Mod Pathol 2003;16:219)
Gallstones spilled into the peritoneal cavity during laparoscopic cholecystectomy can lead to secondary cholelithiasis of the ovary (J Reprod Med 2007;52:968)

Etiology

No known causes

Clinical features

Calcifications are usually asymptomatic

Diagnosis

Identified by ultrasound or at the time of histologic examination

Laboratory

No specific laboratory findings

Radiology description

Curvilinear or punctate echogenic foci, usually between 1 - 3 mm (Radiology 1996;198:415)

Radiology images

Images hosted on other servers:

Calcifications associated with a mature teratoma

Prognostic factors

In a study of 28 patients, the presence of large ovarian calcifications (> 5 mm) identified by imaging in otherwise normal ovaries remained stable and was not associated with ovarian neoplasms (Ultrasound Obstet Gynecol 2007;29:438)

Case reports

34 year old woman with ossification in the ovary associated with an old hemorrhagic cyst (Int J Clin Exp Pathol 2020;13:2356)
46 year old woman with ovarian ossification associated with endometriosis (Clin Exp Obstet Gynecol 2007;34:113)
65 year old woman with bilateral ovarian endometriotic cysts showing extensive ossification (Gynecological Surgery 2007;4:191)

Treatment

Resection if symptomatic, rupture or suspicion for neoplastic process

Gross description

Microcalcifications usually not apparent grossly
Areas of bone formation are nodular and calcified

Microscopic (histologic) description

Most ovarian calcifications consist of calcium phosphate, which stains dark purple on H&E sections
Psammomatous calcifications: round with concentric laminations (onion-like appearance)
Nonpsammomatous: irregular shape, dense, nonlaminated
Bone formation shows well developed bone trabeculae
Background ovary can be otherwise normal or show other associated pathology, such as endometriosis, teratoma, mucinous lesions, serous lesions; calcifications can be stromal or associated with the epithelial component (Mod Pathol 2003;16:219, J Nippon Med Sch 2005;72:29)
Psammomatous calcifications in the absence of a serous neoplasm should prompt additional sampling to rule out a neoplastic process; their presence should be mentioned in the report if a serous tumor cannot be identified

Microscopic (histologic) images

Contributed by Aurelia Busca, M.D., Ph.D.

Calcifications

Calcifications associated with low grade serous carcinoma of the ovary

Osseous metaplasia of the ovary

Sample pathology report

Ovary, right, oophorectomy:
- Benign ovary with surface adhesions and focal stromal psamommatous calcifications (see comment)
- Comment: The ovary has been extensively sampled, without evidence of a neoplastic process.

Differential diagnosis

Teratoma:
- Osseous metaplasia versus teratoma: teratoma will have other components apart from bone

Board review style question #1

Which of the following is true about the finding shown in the ovary in the above image?

Has an increased risk of malignancy
Is a benign incidental finding
Is a precursor lesion of serous neoplasia
Requires correlation with imaging findings

Board review style answer #1

B. Is a benign incidental finding

Comment Here

Reference: Ovary calcification

Board review style question #2

Which of the following is true about calcifications of the ovary?

Are often symptomatic
Can be associated with a neoplastic process
Often arise in the context of hypercalcemia
Their presence on imaging studies prompts a resection

Board review style answer #2

B. Can be associated with a neoplastic process

Comment Here

Reference: Ovary calcification

Carcinoid tumor

Table of Contents

Definition / general

Primary ovarian carcinoid tumors are well differentiated neuroendocrine tumors resembling those arising in the gastrointestinal tract
In some cases, teratomatous components are identified (component of mature cystic teratoma)
4 types: insular, trabecular, strumal and mucinous

Essential features

Unilateral
May be associated with carcinoid syndrome
Rare

Terminology

Classified as monodermal teratomas

ICD coding

ICD-O: 9091/1 - strumal carcinoid
ICD-10
- C56 - malignant neoplasm of ovary
- C56.9 - malignant neoplasm of unspecified ovary
- C7A.09 - malignant carcinoid tumors of other sites
- D3A.09 - benign carcinoid tumors of other sites
ICD-11: 2F76 & XH2XW3 - neoplasms of uncertain behavior of female genital organs & strumal carcinoid

Epidemiology

Primary ovarian carcinoid is rare and accounts for
- < 0.1% of all ovarian neoplasms (Medicine (Baltimore) 2020;99:e21109)
- < 2% of all carcinoid tumors (Cancer 2003;97:934)
Patient age at time of presentation ranges from 17 to 83 years with a median of 55 (Gynecol Oncol 1996;61:259)
- Mucinous: observed in a younger group of patients compared to other ovarian carcinoids
Insular type is the most common (~50%); mucinous is the least common

Sites

Ovary (Curr Opin Obstet Gynecol 1997;9:44)
- Primary ovarian carcinoids are unilateral
- Metastatic nearly always bilateral
Most arise in mature cystic teratoma or in association with mucinous tumor
Pure form is less frequent; may be associated with struma ovarii

Pathophysiology

Pathogenesis remains unclear

Etiology

Arises from neuroendocrine cells within gastrointestinal type epithelium of mature cystic teratoma or rarely other tumors
- A case of carcinoid arising from the teratomatous bronchial mucosa in an ovarian mature cystic teratoma has been reported (Int J Gynecol Pathol 2018;37:123)

Clinical features

Asymptomatic, incidental finding
Abdominal mass
Ascites
Carcinoid syndrome
- ~33% of patients are > 50 years old
- Presence of carcinoid syndrome correlates with size of the tumor; typically seen in tumors > 7 cm, rarely seen in tumors < 4 cm
- Most common in insular type
- Does not require the presence of liver metastasis since venous drainage bypasses portal venous circulation (Tex Heart Inst J 2019;46:21)
- Carcinoid heart disease may be the initial manifestation
  - Occurs in < 10% of cases of primary ovarian carcinoid
  - Generally involves right chambers and valves
Endocrine effects thought to occur due to stromal luteinization (Diagnostics (Basel) 2022;12:2706)
- Virilization
- Hirsutism
- Endometrial hyperplasia
- Cushing syndrome
Constipation due to inhibitory effect on gastrointestinal motility of peptide YY secreted in strumal carcinoid (Obstet Gynecol Sci 2017;60:602)
Hyperthyroidism in strumal carcinoid

Diagnosis

Preoperative diagnosis of primary ovarian carcinoid is challenging; typically, the mass is properly classified postoperatively
May be detected as a mass on physical examination
Imaging: ovarian mass lacks typical imaging characteristics
Somatostatin receptor scintigraphy: useful in detection of neuroendocrine tumors that show intensive octreotide intake (Am J Case Rep 2022;23:e937403)
Cytologic features: polygonal uniform cells, round monotonous nuclei, salt and pepper chromatin, ample to eosinophilic cytoplasm, often containing red to brown argentaffin granules; low mitotic activity
Mucinous carcinoids cytologically show cells exhibiting neuroendocrine and mucinous differentiation; signet ring cells may be seen in the stroma
WHO essential and desirable diagnostic criteria
- Essential
  - Insular architecture (if insular carcinoid)
  - Trabecular or corded architecture (if trabecular carcinoid)
  - Thyroid follicles intimately admixed or juxtaposed with carcinoid (if strumal carcinoid)
  - Acini or glands with goblet cells free floating in mucin (if mucinous carcinoid)
  - Salt and pepper chromatin pattern of the nuclei, with or without cytoplasmic granules
- Desirable: positivity for neuroendocrine markers

Laboratory

Tumor markers may be elevated (Acta Obstet Gynecol Scand 2023;102:935)
- Elevation of CA125 and CA19-9 may mimic ovarian carcinoma
- Neuron specific enolase (NSE)
- Carcinoembryonic antigen (CEA)
Tumor markers used in carcinoid syndrome to monitor disease activity, response to therapy and early detection of metastasis (Endocrinol Metab Clin North Am 2017;46:669)
- 5-hydroxyindole acetic acid (5-HIAA)
- Chromogranin A

Radiology description

Ultrasound
- Hypoechoic solid or cystic with solid component adnexal mass (Medicine (Baltimore) 2020;99:e21109)
Computed tomography (CT)
- Unilateral, lobulated adnexal mass with scattered necrotic areas indistinguishable from other solid ovarian neoplasms
- Solid enhancing nodule in the wall of a mature cystic teratoma or a mucinous neoplasm
Magnetic resonance imaging (MRI)
- On T2 weighted MR images, hypointense solid adnexal mass or low intensity focus within a multilocular cystic mass

Radiology images

Contributed by Chenxi Wu, M.D., Ph.D.

T1 precontast MRI

T2 MRI

Noncontrast CT, coronal plane

Prognostic factors

5 year survival rate of ovarian carcinoid is 84% and 94% in patients with and without mature cystic teratoma, respectively
Insular carcinoid
- Favorable prognosis
- Slow growing
- Only occasionally has metastasis
Trabecular carcinoid
- Favorable prognosis
- Not associated with metastasis
Strumal carcinoid
- Favorable prognosis
- 15 year recurrence rate is 4.4% (BMC Cancer 2022;22:1090)
Mucinous
- Behaves more aggressively than other types of primary ovarian carcinoid
- Tends to spread mainly via lymphatics and can metastasize
- No metastases, better prognosis
Low Ki67 proliferative index; mean index of 2.5% with a maximum of 5% (Acta Obstet Gynecol Scand 2023;102:935)
Carcinoid heart syndrome has been reported to be associated with overall poor outcome

Case reports

18 year old woman with mucinous adenocarcinoma and carcinoid tumor arising within an ovarian mature cystic teratoma (Oman Med J 2023;38:e538)
40 year old woman with insular carcinoid with hyperandrogenism and carcinoid heart syndrome (Am J Case Rep 2022;23:e937403)
40 year old woman with trabecular carcinoid tumor arising from a mature cystic teratoma (Ci Ji Yi Xue Za Zhi 2019;3:192)
51 year old postmenopausal woman with primary ovarian carcinoid exhibiting mixed growth pattern (Medicine (Baltimore) 2023;102:e34391)
56 year old woman with ovarian strumal carcinoid (Fukushima J Med Sci 2023;69:51)

Treatment

Treatment strategies vary (Acta Obstet Gynecol Scand 2023;102:935)
Surgical
- Conservative
  - Cystectomy
  - Unilateral salpingo-oophorectomy, especially in reproductive age women
- Radical surgery
  - Bilateral salpingo-oophorectomy
  - Hysterectomy and bilateral salpingo-oophorectomy
  - In mucinous carcinoid, regional lymph node dissection may be required
- Cytoreductive surgery
Adjuvant treatment restricted to patients with residual or metastatic diseases
Somatostatin analogs: may be used in metastatic or recurrent primary ovarian carcinoids; treatment of symptoms of excess hormone secretion and for tumor growth control

Clinical images

Images hosted on other servers:

Ovarian mass intraoperatively

Gross description

Usually present as firm, solid and homogeneous gray to yellow masses in association with mature teratoma or mucinous tumor (Curr Opin Obstet Gynecol 1997;9:44)
If pure (Curr Opin Obstet Gynecol 1997;9:44)
- Strumal carcinoid: solid yellow-brown nodule with fleshy areas
- Mucinous carcinoid: gray-yellow, firm, usually solid but may contain cystic areas even when seen in a pure form; most tumors > 8 cm

Gross images

AFIP images

Insular tumor

Microscopic (histologic) description

4 types (J Int Med Res 2021;49:3000605211034666)
- Insular carcinoid
  - Most common type of ovarian carcinoid
  - Growth pattern usually shows large islands, variable sized nests, small acini or glands within the fibrous stroma
    - Simple tubular glands, cribriform nests may also be seen
    - Retraction artifact around tumor cells is common
  - Composed of uniform polygonal epithelial cells with abundant cytoplasm and round, centrally located nuclei; cytoplasm contains red-brown granules, located basally
  - Secretions in lumina, psammoma bodies
  - Stroma is dense and hyalinized
  - Low mitotic activity
- Trabecular carcinoid
  - Associated with mature cystic teratoma, rare in pure form
  - 1 or 2 cell layers arranged in long, wavy, branching cords, parallel ribbons or trabeculae
  - Occasionally, acinar pattern may be seen admixed with trabecular pattern
  - Tumor cells are uniform, round to oval, with amphophilic, slightly granular cytoplasm at the base and prominent, centrally located, ovoid or elongated nuclei with finely stippled chromatin; red-brown granules may be seen at the cell base
  - Stroma is represented by dense fibrous connective tissue, which may be hyalinized or luteinized
  - Low mitotic activity, only occasional mitoses
- Strumal carcinoid
  - Associated with mature cystic teratoma > pure (40%) >> associated with mucinous tumor
  - Composed of thyroid tissue intimately admixed or juxtaposed with a neuroendocrine neoplasm (struma ovarii and carcinoid)
  - Either of the components may be predominant
    - Trabecular pattern >> both trabecular and insular patterns > insular only
    - Thyroid component resembles normal thyroid tissue; rarely, papillary or follicular carcinoma may be present
  - Stroma may show luteinization
- Mucinous carcinoid
  - These morphologically resemble low grade goblet cell adenocarcinoma of the appendix (previously termed goblet cell carcinoid)
  - Pure form >> in association with mature cystic teratoma
  - Composed of numerous small glands or acini with very small lumina floating in pools of mucin (pseudomyoxoma ovarii); some of the glands or acini may be cystically dilated containing mucin
  - Lined by uniform cuboid or columnar and goblet cells and containing small round or oval nuclei and cytoplasmic neuroendocrine granules
  - In some areas, the tumor cells tend to invade the surrounding connective tissue, often assuming signet ring appearance
  - Tumor may form large solid aggregates, show a less uniform appearance and have more atypical features with large hyperchromatic nuclei and brisk mitotic activity
Can also be mixed and present as a combination of 2 or more types of carcinoids

Microscopic (histologic) images

Contributed by Krisztina Hanley, M.D., Rulong Shen, M.D. and AFIP

Trabecular pattern

Nuclear features

Mixed patterns

Strumal carcinoid

Thyroid component

Cytologic features of carcinoid

Chromogranin in strumal ovarian carcinoid

Synaptophysin in strumal ovarian carcinoid

Insular carcinoid

TTF1

AE1 / AE3

CDX2

Synaptophysin

Chromogranin

Inhibin

Mucinous carcinoid

Trabecular tumor

Virtual slides

Images hosted on other servers:

Carcinoid and mature cystic teratoma

Positive stains

Insular: chromogranin, synaptophysin, CD56
Trabecular: synaptophysin, CD56, serotonin
Strumal: chromogranin, synaptophysin, NSE, galectin3 in carcinoid component; TTF1 in thyroid component (Medicine (Baltimore) 2019;98:e18009)
Mucinous: pankeratin, synaptophysin, chromogranin, CDX2, CK20
Reference: Cancers (Basel) 2022;14:1835

Negative stains

TTF1, PAX8, thyroglobulin only stain the struma component

Electron microscopy description

Numerous neurosecretory granules

Videos

Germ cell neoplasms of the ovary - ovarian carcinoid tumor
by Dr. Wafaey Badawy

Sample pathology report

Right ovary, oophorectomy:
- Ovarian carcinoid tumor, arising from struma ovarii (see comment)
- Comment: Sections show extensive involvement of the ovary by a well differentiated neuroendocrine tumor, showing acinar, trabecular, tubular, corded and some rare areas of solid growth patterns, confined to the ovary without surface involvement. Background shows benign thyroid tissue. Immunohistochemical stains including chromogranin and synaptophysin support neuroendocrine differentiation. Given the presence of benign thyroid tissue, this neoplasm is classified as a strumal carcinoid. The use of proliferative markers such as Ki67 has not been established in the grading of these tumors and in this case, it is < 1%

Left ovarian cyst, resection:
- Ovarian carcinoid tumor (4.5 mm), trabecular type, arising in a mature cystic teratoma (dermoid cyst) (see comment)
- Comment: Extensive sampling of this mature teratoma shows a 4.5 mm trabecular carcinoid tumor. Immunohistochemical stains confirm neuroendocrine differentiation as the tumor cells are positive for synaptophysin, chromogranin, CD56, MCK (AE1 / AE3) and Ki67 is ~2%. This small focus of carcinoid tumor shows CDX2 positivity indicating midgut origin, similar to the gastrointestinal counterpart.

Differential diagnosis

Carcinoid metastasis:
- Bilateral, no associated teratoma or struma ovarii
- Often multinodular growth
- Microscopically indistinguishable from primary
- Most commonly from midgut primary
Brenner tumor:
- May be confused with insular carcinoid
- Transitional epithelial cells, grooved nuclei, lack of cytoplasmic granules
Krukenberg tumor:
- Bilateral, marked cellular and nuclear pleomorphism
- Mitotically active, abundant mucin
- Signet ring cells are common
- Lymphovascular invasion is common
Sertoli cell tumor (SCT) with trabecular architecture:
- SCT is positive for inhibin and calretinin, negative for synaptophysin
- Trabecular carcinoid is positive for synaptophysin, negative for inhibin and calretinin

Additional references

J Cancer Res Clin Oncol 1984;107:125, Front Endocrinol (Lausanne) 2022;13:871210, Abdom Radiol (NY) 2017;42:1472, Magn Reson Med Sci 2011;10:205

Board review style question #1

Which of the following is true for primary ovarian carcinoid?

Most cases of primary ovarian carcinoid are associated with mature cystic teratoma
Mucinous ovarian carcinoid behaves less aggressively than other types
Primary ovarian carcinoids are poorly differentiated neuroendocrine tumors
To cause carcinoid syndrome, the presence of liver metastasis is required

Board review style answer #1

A. Most cases of primary ovarian carcinoid are associated with mature cystic teratoma. Despite mucinous ovarian carcinoids more frequently occurring in pure form, 3 of 4 types, including the most common insular type, mostly arise in mature cystic teratoma. Answer B is incorrect because mucinous ovarian carcinoid is more aggressive than other types of primary ovarian carcinoid. Answer C is incorrect because per definition, primary ovarian carcinoid tumors are well differentiated neuroendocrine tumors. Answer D is incorrect because ovarian veins drain directly into systemic circulation: the right ovarian vein drains directly into the inferior vena cava, while the left ovarian vein joins the left renal vein. Therefore, hormones produced by a carcinoid tumor do not undergo hepatic metabolism.

Comment Here

Reference: Carcinoid tumor

Board review style question #2

Which of the following indicates poor prognosis of patients with primary ovarian carcinoid?

Carcinoid heart syndrome
Insular type
Low Ki67 proliferative index
Trabecular type
Tumor confined to the ovary

Board review style answer #2

A. Carcinoid heart syndrome can be a presenting symptom even in the absence of liver metastases. The 3 year survival has been reported to be 31%. Answer B is incorrect because insular type is slow growing and only occasionally metastasizes. The prognosis is favorable. Answer C is incorrect because a high Ki67 proliferative index, not low, is associated with worse outcomes. Answer D is incorrect because trabecular type is not associated with metastasis and has favorable prognosis. Answer E is incorrect because the absence of tumor spread is a good prognostic factor.

Comment Here

Reference: Carcinoid tumor

Carcinoid tumor metastatic to ovary

Table of Contents

Definition / general

Carcinoid tumors involving the ovary can be primary (see Ovary tumor > germ cell tumors > Carcinoid tumors) or metastatic
Primary ovarian carcinoid tumors are frequently seen in the context of a teratoma
- Robboy et al. reported 35/48 (73%) insular carcinoids were associated with a mature teratoma component
- Also, 2/48 tumors (4%) had a mucinous cystadenoma component (Cancer 1975;36:404)
Metastatic carcinoid tumors originate from the GI tract
- Most common primary site is distal ileum: 20/30 (67%) as reported by Robboy et al. (Cancer 1974;33:798), and 15/17 (88%) as reported by Strosberg et al. (Gynecol Oncol 2007;106:65)
- Less frequent locations are cecum, appendix, jejunum and pancreas
- Synchronous metastases are frequent at time of diagnosis (88 - 100% of cases) (Cancer 1974;33:798, Gynecol Oncol 2007;106:65)
  - Involved sites include pelvis (uterine and tubal serosa), abdominal cavity (peritoneum, intestinal serosa, liver) and retroperitoneum (periaortic lymph nodes)

Epidemiology

Average age 57 to 62 years, range 21 to 82 years (Cancer 1974;33:798, Gynecol Oncol 2007;106:65, Hum Pathol 2013;44:2536, Int J Gynecol Pathol 2008;28:41)
Most patients (>90%) are Caucasian; a minority are Black and Hispanic (Cancer 1974;33:798, Gynecol Oncol 2007;106:65)

Clinical features

Symptoms of carcinoid syndrome are seen in 30 - 53% of cases, and include intermittent diarrhea, flushing, ankle edema, involuntary weight loss and cardiac murmurs
Other symptoms are due to mass effect, including abdominal/pelvic pain and bowel obstruction
Rarely, tumors are diagnosed incidentally during routine gynecologic examination

Laboratory

Elevated urinary levels of 5-hydroxyindole acetic acid and serum serotonin are consistently found, as observed by Strosberg et al. (average peak of 24h 5-HIAA urine levels was 60 mg, reference range 0 - 6 mg) (Gynecol Oncol 2007;106:65)

Radiology description

Pelvic ultrasound confirms the presence of an ovarian mass (and usually detects bilaterality)
Most patients have abnormal radiotracer uptake on indium-111-pentetreotid scintigraphy

Prognostic factors

In 1974, the first and largest case series of carcinoid tumors metastatic to the ovary, Robboy et al. reported an overall poor prognosis, with a survival rate of 66% after the first year and 33% at 4 years post-diagnosis (Cancer 1974;33:798)
A 2007 case series by Strosberg et al. reported an excellent response to long-term Ocreotide treatment and cytoreductive surgery, with only 2 deaths out of 17 patients and a projected 5 year survival rate of 94% (Gynecol Oncol 2007;106:65)

Case reports

Goblet cell carcinoid of vermiform appendix metastatic to ovary, mimicking primary ovarian mucinous cystadenocarcinoma (Acta Pathol Jpn 1991;41:455)

Gross description

Tumor size ranges from 4 to 32 cm with an average of 10.2 cm (Int J Gynecol Pathol 2008;28:41)
Most tumors are purely solid (80% in case series by Rabban et al.) (Int J Gynecol Pathol 2008;28:41); a minority may display a cystic component
Multinodular growth is frequently observed (60% in case series by Rabban et al.) (Int J Gynecol Pathol 2008;28:41)
Bilateral ovarian involvement is seen in most cases (60 - 95%) (Cancer 1974;33:798)

Gross images

Contributed by Hayam Aiad, M.D.

Cut section

Microscopic (histologic) description

Insular pattern is the most frequently observed; mucinous and trabecular patterns have also been reported (Cancer 1975;36:157, Int J Gynecol Pathol 2008;28:41)
Insular architecture is characterized by sharply demarcated nests of tumor cells of varying sizes and shapes in a variable fibromatous stroma
Acinar configurations and calcifications can also be observed
Neoplastic cells are typically small and uniform in size, with a central round nucleus containing coarsely and evenly clumped chromatin ("salt and pepper" pattern)
Cytoplasm is moderate to abundant and eosinophilic, occasionally granular
Mitotic activity is absent to low (up to 2 mitoses / 10 HPFs)
Tumor cell necrosis is absent

Microscopic (histologic) images

Contributed by Hayam Aiad, M.D.

Higher power

Low power

Carcinoid in meckels

High power showing uniform monotonus nuclei

Positive stains

Chromogranin, synaptophysin, CD56, NSE, pan-cytokeratin (commonly with a perinuclear staining pattern)
CDX2: positive in 90 - 100% of carcinoids metastatic to ovary; positivity is frequent in tumors arising in small intestine (95%), appendix (92%) and duodenum (80%), but rare in tumors of colorectum (12%) and stomoach (0%) (Hum Pathol 2013;44:2536)

Negative stains

CA125 , PAX8
TTF1, CK7 and CK20 (Int J Gynecol Pathol 2008;28:41)

Differential diagnosis

Primary ovarian carcinoid tumor: distinction relies on conventional clinicopathologic features, as outlined by Rabban et al. (Int J Gynecol Pathol 2008;28:41):
- Laterality: Frequent in metastatic carcinoid; but all confirmed primary ovarian carcinoids reported have been unilateral
- Multinodular growth: Frequent in metastases, but not seen in primary ovarian carcinoids
- Size: Primary ovarian carcinoids average 3.4 cm in size (excluding any teratomatous element) versus 10.2 cm for metastatic carcinoids (range: 4-32 cm); 75% of primary ovarian carcinoids were 3 cm or less, compared to 0% of metastatic carcinoids to ovary
- Presence of teratomatous elements: supports primary ovarian origin
- Metastates in other sites: as mentioned above, very common in metastatic carcinoid to the ovary
  - Nonetheless, primary ovarian carcinoid tumors can rarely present with metastases (J Obstet Gynaecol Res 2010;36:567, Case Rep Obstet Gynecol 2012;2012:961087, Gynecol Oncol 1994;54:222)
- Immunohistochemistry has controversial value in this differential
  - Rabban et al. reported 37.5% expression of CDX2 in primary ovarian carcinoids; importantly, most (4/6) insular primary carcinoids expressed this marker and recommended against the use of immunohistochemistry (Int J Gynecol Pathol 2008;28:41)
  - In contrast, Desouki et al. found that all 30 primary ovarian carcinoids tested were negative for CDX2, and therefore suggested this marker as sensitive and specific for small intestinal or appendiceal origin (Hum Pathol 2013;44:2536)
Brenner tumor: nests composed of epithelioid, urothelial type cells with oval, pale, grooved nuclei
Granulosa cell tumor: Call-Exner bodies, inhibin and calretinin expression

Carcinosarcoma

Table of Contents

Definition / general

Aggressive tumor with malignant epithelial and sarcomatous components
Most common in postmenopausal, low parity women
Very poor prognosis; stage is best predictor and most patients present at advanced stage

Terminology

Previously called malignant mixed mesodermal tumor, MMMT

Epidemiology

Mostly postmenopausal females, peaks in sixth decade

Sites

Uterus, cervix, fallopian tube (rare)

Pathophysiology

Appear to have epithelial origin (Am J Surg Pathol 1990;14:317, Am J Surg Pathol 1995;19:666)

Clinical features

Abdominal mass, pain, vaginal bleeding
Risk factors include advanced age, excess estrogen exposure, nulliparity, prior pelvic irradiation, tamoxifen use (Lancet 2000;356:881)

Laboratory

No useful biochemical marker (Curr Opin Obstet Gynecol 2006;18:20)

Radiology description

Pelvic ultrasound and CT: heterogeneous pelvic mass containing solid parts with/without ascites

Case reports

52 year old woman (Taiwan J Obstet Gynecol 2010;49:87)
70 year old woman (Journal of Medical Cases 2010;1:55)
Growing into an inguinal hernia sac (Surg Today 2003;33:797)

Treatment

Surgical cytoreduction with adjuvant chemotherapy (Gynecol Oncol 2000;79:196)

Gross description

Soft and fleshy mass, often with bleeding and necrosis

Gross images

Contributed by Mona Kandil, M.D., Ph.D. and AFIP

Ovary

Uterus

Omental deposit

Fallopian tube

Microscopic (histologic) description

Malignant epithelial and sarcomatous elements
Sarcomatous element can be homologous (nonspecific malignant stroma) or heterologous (malignant elements of a different tissue type, particularly cartilage)
Often contains cytoplasmic hyaline droplets containing alpha-1-antitrypsin (Hum Pathol 1982;13:930)
Rarely trophoblastic tissue (Hum Pathol 1988;19:1235)

Microscopic (histologic) images

Contributed by Mona Kandil, M.D., Ph.D.

Malignant stroma

High grade malignant glands

Necrotic foci

High grade epithelial tumor cells and necrosis

High grade tumor cells with mitotic figures

Images hosted on other servers:

Rhabdomyosarcoma component

Positive stains

Tumor cell droplets: PAS+ diastase resistant
Epithelial component: CEA, EMA
Mesenchymal componen: vimentin
SALL4, Glypican3 (Pathology Research International, vol. 2012, Article ID 569609)

Negative stains

AFP, CDX2, desmin

Differential diagnosis

Cervical carcinoma metastatic to ovary

Table of Contents

Definition / general

Cervical cancers only rarely metastasize to ovaries
- Proportion of cases presenting with ovarian metastases at the time of surgery ranges from 0.66 to 1.5% (Int J Gynecol Oncol 1997;57:173, Gynecol Oncol 2006;101:234)
Adenocarcinomas are more likely to metastasize to the ovaries than squamous cell carcinomas
- In different series, 5.3 – 8.2% of cervical adenocarcinomas vs 0.4 - 1.3% of squamous cell carcinomas metastasized to ovary (Gynecol Oncol 2001;82:312, Gynecol Oncol 2006;101:234, Gynecol Oncol 2001;82:504)
Independent risk factors for ovarian spread include histologic type (adenocarcinoma > squamous cell carcinoma) and uterine corpus involvement
Other risk factors include vaginal involvement, lymphovascular space invasion and lymph node metastases (J Gynecol Oncol 2008;19:181, Gynecol Oncol 2001;82:312)
Among HPV negative endocervical adenocarcinomas, risk is low for clear cell carcinomas (Onco Targets Ther 2014;7:111), but high (up to 35%) for gastric type adenocarcinoma (Am J Surg Pathol 2015;39:1449)

Risk also increases with tumor stage, ranging from 0% in stage IA squamous cell carcinomas to 9.8% in stage IIB adenocarcinomas (Gynecol Oncol 1987;28:255, Gynecol Oncol 2006;101:234)

Epidemiology

Mean age of presentation is 57.4 years for squamous cell carcinoma and 50.2 years for adenocarcinoma (Gynecol Oncol 1991;41:46)

Pathophysiology

Carcinomatous spread from the cervix to the ovaries is hematogenous or lymphatic (Cancer 2000;88:2578)
Cervical and ovarian tumors are grossly discontinuous with no direct invasion from cervix to ovary reported to date, which also supports the hematogenous spread theory (Diagn Pathol 2014;9:109, Int J Gynecol Pathol 2015;34:551)
Based on the strong association between uterine corpus involvement and ovarian metastasis, transtubal implantation has also been postulated as a mechanism (Int J Gynaecol Obstet 1997;57:173)

Clinical features

Mean age of presentation is 45 - 50 years (Gynecol Oncol 2001;82:312, Gynecol Oncol 2006;101:234, Gynecol Oncol 2001;82:504)
Signs and symptoms are usually related to the cervical lesion (vaginal bleeding, pelvic pain, abnormal cytology)
Rarely, the presence of an ovarian mass is the only finding at presentation and a cervical primary is initially unsuspected

Radiology description

USG: enlarged ovaries

Prognostic factors

Very poor outcome with 5 year overall survival close to 0% (Int J Gynecol Oncol 1997;57:173)
Outcome not related to tumor stage or histological type (Gynecol Oncol 2006;101:234)

Treatment

In patients with cervical cancer, ovarian preservation and transposition is recommended in:
- Women 44 years old or younger with squamous cell carcinoma stage IB-II
- Clinically normal ovaries and no history of breast cancer or family history of ovarian cancer (Gynecol Oncol 2001;82:312)
Oophorectomy is recommended in patients that do not fulfill these criteria, in particular those with adenocarcinoma or locally advanced tumors (Int J Gynaecol Obstet 2007;99:64)

Gross description

Most ovaries appear grossly normal
When abnormal, ovaries have a nodular surface and cystic areas (Int J Gynecol Pathol 2015;34:551, Int J Gynecol Oncol 1997;57:173)
Bilateral involvement and size < 10 cm, features regarded as helpful in the distinction between primary ovarian and gastrointestinal carcinomas, are seen in only 55% of metastatic adenocarcinomas from the cervix (Am J Surg Pathol 2008;32:128, Int J Gynecol Pathol 2015;34:551-63)

Gross images

Images hosted on other servers:

Uterus, growth
in cervix
extending up to
endocervical canal

Bisected uterus, cut surface ovary

Microscopic (histologic) description

Squamous cell carcinoma:
- Nodular growth of malignant squamous epithelium (keratinizing or non-keratinizing) with confluent and destructive growth (Int J Gynecol Pathol 2015;34:551)
Adenocarcinoma:
- Malignant glandular proliferation with confluent glandular, cribriform and papillary architecture
- Stromal invasion may be expansile or infiltrative (J Clin Pathol 2012;65:591)
- Usual (endocervical) type:
  - Glandular epithelium with mucinous or endometrioid differentiation
  - Neoplastic cells have pleomorphic, hyperchromatic, round to elongated nuclei with stratification and conspicuous apical mitoses
- Gastric type:
  - Neoplastic cells have columnar shape and granular eosinophilic apical cytoplasm
  - Nuclei are round in shape and display significant atypia and pleomorphism
- Importantly, malignant areas usually coexist with regions showing a benign and borderline appearance (architectural and cytologic)

Microscopic (histologic) images

Contributed by Carlos Parra-Herran, M.D.

Endocervical carcinoma primary

Images hosted on other servers:

Foci of metastatic squamous cells, H&E

CIN

Metastases

p63, CK5/6, CK7, CK20

Cytology images

Image hosted on other servers:

High grade SIL

Negative stains

Adenocarcinoma: CK20, ER, PR, vimentin, SATB2 (Am J Surg Pathol 2015 Nov 5 [Epub ahead of print])

Molecular / cytogenetics description

Detection of HPV ribonucleic acid by PCR or in situ hybridization is a reliable method to differentiate metastatic HPV related cervical carcinoma (squamous cell and usual type adenocarcinoma) from primary ovarian tumors and other secondary lesions (Int J Gynecol Pathol 2004;23:7)

Differential diagnosis

Primary mucinous and endometrioid carcinoma of ovary:
- There is significant morphologic and immunophenotypic overlap
- Correlation with clinical history and presentation (laterality, size) is important
- Primary ovarian adenocarcinoma usually has bland cytology; cervical tumors display hyperchromasia, nuclear overlapping and apical mitoses, at least focally
- "Block" positivity for p16 favors a primary HPV+ endocervical adenocarcinoma (Am J Surg Pathol 2007;31:653)
Metastatic adenocarcinoma from gastrointestinal tract origin:
- Signet ring cell differentiation (uncommon in endocervical primaries), CK20+ and CDX2+ [strong and diffuse staining favors appendiceal and colorectal origin (Histopathology 2015 Nov 6 [Epub ahead of print], Int J Gynecol Pathol 2015 Nov 3 [Epub ahead of print])], SATB2+ (Int J Gynecol Pathol 2015 Nov 3 [Epub ahead of print], Am J Surg Pathol 2015 Nov 5 [Epub ahead of print]), p16- (although gastric type endocervical adenocarcinoma is also p16-)
Primary squamous cell carcinoma:
- Exceedingly rare and seen in a background of mature teratoma
- Absence of teratomatous elements and "block" positivity for p16 favor a cervical primary
Metastatic squamous cell carcinoma from skin: p16-

Choriocarcinoma

Table of Contents

Definition / general

Rare primary ovarian tumor; < 1% of primitive ovarian germ cell tumors
May develop from ovarian pregnancy (gestational choriocarcinoma), as a germ cell tumor (pure or mixed, non-gestational choriocarcinoma) or as a surface epithelial tumor with choriocarcinomatous differentiation

Epidemiology

Primary ovarian choriocarcinomas are more common in children and adolescents
After puberty, origin from an ovarian ectopic pregnancy cannot be excluded

Clinical features

Presentation similar to ectopic or tubal pregnancy
Abdominal enlargement
Pain, sometimes hemoperitoneum
Isosexual precocity, menstrual abnormalities, androgenic changes

Laboratory

Markedly elevated serum β hCG
Monitoring serum levels of β hCG is helpful in predicting recurrence and response to therapy

Radiology description

On imaging, appears as vascular solid tumor with cystic, hemorrhagic, necrotic areas

Prognostic factors

In contrast to gestational choriocarcinomas, non-gestational choriocarcinomas are difficult to treat, generally unresponsive to chemotherapy
Metastases to lungs, liver, bone and viscera are common at diagnosis

Case reports

19 year old woman with pure choriocarcinoma of ovary diagnosed by FNA (Indian J Pathol Microbiol 2009;52:417)
48 year old woman with pure choriocarcinoma of ovary (J Gynecol Oncol 2011;22:135)

Treatment

Surgery, chemotherapy

Gross description

Hemorrhagic, soft, tan with necrosis

Gross images

Images hosted on other servers:

Hemorrhagic mass

Ovarian mass

TAHBSO specimen

Microscopic (histologic) description

Composed of cytotrophoblast, intermediate trophopblast and multinucleated syncytiotrophoblast around periphery of blood channels
Cytotrophoblasts have clearly defined cytoplasmic borders, are mononucleated with vesicular nuclei and distinct nucleolus
Syncytiotrophoblasts contain basophilic to amphophilic cytoplasm with mutiple nuclei

Microscopic (histologic) images

AFIP images

Plexiform pattern

Images hosted on other servers:

H&E stain

Atypical syncytio
cytotrophoblast

β hcG+

Positive stains

Cytokeratin, CD10, human placental lactogen, EMA
Syncytiotrophoblasts are hCG+

Negative stains

CD31, CD34 (Mod Pathol 2011;24:646)

Molecular / cytogenetics description

Gestational choriocarcinomas have component of paternal chromosomes, often aneuploid, but hyperploidy and other variations have been described (Atlas of Genetics and Cytogenetics in Oncology and Haematology)

Differential diagnosis

Adrenocortical carcinoma: see UC Davis-Department of Pathology and Laboratory Medicine
Malignant pheochromocytoma
Metastatic choriocarcinoma
Mixed germ cell tumor with choriocarcinoma component

Additional references

Prat: Pathology of the Ovary, 1st Edition, 2004

Clear cell borderline tumor

Table of Contents

Definition / general

Adenofibromatous tumor with clear cells demonstrating low grade cytologic atypia and some degree of glandular crowding but without stromal invasion

Essential features

Abundant adenofibromatous stroma with small glands / cysts with low grade nuclear atypia but without stromal invasion
No solid, papillary or cribriform growth
Pure clear cell borderline tumors are rare; more frequently associated with clear cell carcinoma
- If pure clear cell adenofibroma or borderline tumor is present, additional sampling is recommended to exclude clear cell carcinoma

Terminology

No longer recommended historical terms:
- Atypical proliferative clear cell tumor
- Clear cell tumor of low malignant potential

ICD coding

ICD-10: D39.10 - neoplasm of uncertain behavior of unspecified ovary

Epidemiology

Pure clear cell borderline tumors are very rare
- < 1% of all ovarian borderline tumors
~21% of ovarian clear cell carcinomas contain a clear cell adenofibromatous component (Am J Surg Pathol 2007;31:999)
Most patients are postmenopausal (age range of 36 - 82 years old) (Ann Surg Oncol 2022;29:1165)

Sites

Ovary, almost all unilateral

Pathophysiology

May be a component of the adenofibromatous pathway of the pathogenesis of ovarian clear cell carcinoma (see Diagrams / tables) (J Cancer 2011;2:94)
Also see Molecular / cytogenetics description

Etiology

Associated with endometriosis (~15%) (J Cancer 2011;2:94)

Diagrams / tables

Images hosted on other servers:

Clear cell carcinoma
development may
occur via 2 pathways

Clinical features

Incidental imaging finding
Abdominal / pelvic pain

Diagnosis

Surgical excision
Definite diagnosis requires extensive sampling

Prognostic factors

Good prognosis
- No clinical evidence of aggressive behavior (Cancer 1984;53:1156, J Cancer 2011;2:94)
Rare recurrences have been reported (Int J Gynaecol Obstet 1996;54:37)

Case reports

50 year old woman with 6.5 cm cystic mass in right ovary (Int J Surg Pathol 2018;26:578)
53 year old postmenopausal woman with a 12 cm solid ovarian mass (Oman Med J 2012;27:e031)
53 year old woman with benign, borderline and clear cell carcinoma of the ovary arising in endometriosis (J Pathol Transl Med 2016;50:155)
58 year old woman with 8 cm solid ovarian mass (Case Rep Pathol 2017;2017:3860107)

Treatment

Surgical resection
Tumors are typically stage I (Int J Gynecol Cancer 2012;22:993)

Gross description

Predominantly solid, white-tan mass
May have small or large cysts, imparting a honeycomb cut surface

Frozen section description

Small glands or cysts in background of fibromatous stroma
- Lining epithelium comprising 1 - 2 layers of cuboidal, flat or hobnail cells
Absence of the admixture of growth patterns characteristic of clear cell carcinoma (tubulocystic, papillary and solid)

Microscopic (histologic) description

Abundant fibromatous stroma
Small glands or cysts lined by 1 - 2 layers of cuboidal, flat or hobnail cells with clear cytoplasm and low grade nuclear atypia (Cancer 1985;56:2922)
- Atypia: nuclear enlargement, hyperchromasia, small nucleoli
- Presence of atypia may be subjective
No stromal invasion; lacks architectural complexity
- No confluent, solid, papillary and cribriform architecture
May show intraluminal eosinophilic secretions
May show simple cystic outpouchings
Typically a component of clear cell carcinoma
- Initial sections that demonstrate exclusive clear cell borderline tumor or pure adenofibromatous component warrant additional sampling to exclude clear cell carcinoma

Microscopic (histologic) images

Contributed by Lucy Ma, M.D.

Small glands / cysts

Low grade cytologic atypia

Adenofibromatous component

Positive stains

PAX8
Napsin A and HNF1β (Mod Pathol 2015;28:111)
CK7

Negative stains

ER, PR
WT1

Molecular / cytogenetics description

Loss of ARID1A is seen in both clear cell carcinoma and its adjacent adenofibromatous component (Mod Pathol 2012;25:615)
Loss of heterozygosity (LOH) of 5q, 10q and 22q is seen in benign, borderline and malignant clear cell tumors (J Pathol 2008;216:103)
- However, LOH of 1p and 13q is only seen in clear cell carcinoma, suggesting association with malignant transformation

Sample pathology report

Right ovary and fallopian tube, salpingo-oophorectomy:
- Clear cell borderline tumor, 6 cm

Differential diagnosis

Clear cell adenofibroma:
- Extremely rare
- No cytologic atypia (Cancer 1984;53:1156)
- No glandular crowding
Clear cell carcinoma:
- Variety of architectural patterns
  - Tubulocystic, papillary, solid
- More often cystic with mural nodule
- Presence of hyalinized stroma
Endometrioid adenofibroma:
- Endometrioid type glands lined by cuboidal to columnar cells
- May show squamous differentiation
- ER, PR positive
- Napsin A, HNF1β negative
Clear cell struma ovarii:
- May be associated with a component of mature cystic teratoma
- Areas of classic thyroid tissue typically present, including macrofollicles filled with colloid
- TTF1, thyroglobulin positive
- Napsin A, HNF1β negative
Yolk sac tumor, polyvesicular vitelline pattern:
- Younger patients; elevated serum AFP levels
- May have prominent cystic component (Am J Surg Pathol 2013;37:393)
- May be associated with other yolk sac tumor patterns
- SALL4, AFP, glypican 3 positive
- Napsin A, PAX8, CK7, EMA negative

Additional references

Crum: Diagnostic Gynecologic and Obstetric Pathology, 3rd Edition, 2017, Clement: Atlas of Gynecologic Surgical Pathology, 4th Edition, 2019

Board review style question #1

A 52 year old patient undergoes a left salpingo-oophorectomy for a 6 cm ovarian mass. The mass is well sampled and a representative section is shown. Immunohistochemical stains demonstrate that the tumor is positive for PAX8, CK7 and Napsin A, while it is negative for ER, PR, TTF1 and AFP. What is the best diagnosis?

Clear cell borderline tumor
Endometrioid adenofibroma
Struma ovarii
Yolk sac tumor

Board review style answer #1

A. Clear cell borderline tumor. The image shows an adenofibromatous neoplasm with an immunoprofile consistent with clear cell borderline tumor. Endometrioid adenofibromas are typically ER and PR positive. Yolk sac tumors are typically AFP positive and mostly negative for PAX8 and CK7. While struma ovarii is positive for PAX8 and CK7, it is also positive for TTF1 and negative for Napsin A.

Comment Here

Reference: Clear cell borderline tumor

Clear cell carcinoma

Table of Contents

Definition / general

Malignant epithelial tumor composed of clear, eosinophilic or hobnail cells with tubulocystic, papillary and solid growth patterns

Essential features

Admixture of tubulocystic, papillary and solid growth patterns comprised of cells with uniform nuclear atypia without brisk mitotic figures
Usually positive for CK7, PAX8, napsin A and HNF1β and negative for ER, PR and WT1, with aberrant p53 expression in up to 24% of cases
May be associated with endometriosis or Lynch syndrome
Stage is the most important prognostic factor

ICD coding

ICD-O: 8310/3 - clear cell adenocarcinoma, NOS
ICD-10: C56 - malignant neoplasm of ovary
ICD-11: 2C73.00 - clear cell adenocarcinoma of ovary

Epidemiology

Accounts for 10 - 12% of ovarian carcinomas in North America (Int J Gynecol Pathol 2010;29:203, J Natl Cancer Inst 2019;111:60)
Racial distribution in United States: 4.8% white, 3.1% black, 11.1% Asian (Gynecol Oncol 2011;121:407)
Higher incidence in Asia (up to 27% in Japan) (J Obstet Gynaecol Res 2014;40:338, Gynecol Oncol 2019;153:589)
Mean age is 55 - 56 years (Gynecol Oncol 2008;109:370, J Pathol Clin Res 2018;4:250)
Increased risk associated with:
- Endometriosis, including endometriotic cysts (50 - 74%) (Lancet Oncol 2012;13:385, Int J Gynecol Cancer 2012;22:1310)
- Less frequently, Lynch syndrome (Eur J Cancer 2016;55:65, Am J Surg Pathol 2008;32:1029, Am J Surg Pathol 2014;38:1173, Clin Cancer Res 2019;25:3962, Int J Clin Exp Pathol 2008;1:502)
  - Mismatch repair (MMR) deficiency in 6 - 43.75% of cases
  - Younger patients
  - 10% develop endometriosis associated carcinomas, including clear cell carcinoma
- Family history of ovarian cancer in a first degree relative (PLoS One 2018;13:e0205000)
Decreased risk associated with:
- Late menarche (> 15 years), early menopause (< 40 years), tubal ligation, parity, hysterectomy, smoking, oral contraceptives (J Clin Oncol 2016;34:2888)
- Expression of the genetic susceptibility locus (HNF1β) via epigenetic mechanisms (Nat Commun 2013;4:1628)

Sites

Ovary
Any extraovarian site with endometriosis

Pathophysiology

Genetic alterations due to various mutations (see Molecular / cytogenetics description)

Etiology

Endometriosis (J Pathol 2018;245:265, Int J Gynecol Cancer 2012;22:1310)
Mutation signatures: age related (40%) and APOBEC mediated (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (26%), a family of evolutionarily conserved cytidine deaminases) (Nat Genet 2017;49:856)

Clinical features

Symptoms related to endometriosis or pelvic mass (Gynecol Oncol 2010;116:374)
Most common ovarian epithelial neoplasm associated with paraneoplastic syndromes, such as hypercalcemia, thromboembolism, subacute cerebellar degeneration or bilateral diffuse uveal melanocytic proliferation (Onkologie 2009;32:517, Gynecol Oncol 2007;104:406, Semin Diagn Pathol 2019;36:246)
May be incidental (asymptomatic)

Diagnosis

Microscopic examination

Laboratory

May be associated with mildly elevated CA-125 (usually ≤ 200 U/mL) (Medicine (Baltimore) 2018;97:e10881)

Radiology description

Large unilocular, mainly cystic, smooth marginated mass with 1 or more solid nodular protrusions into the cavity on all imaging modalities
High attenuated cystic portion on computed tomography (J Comput Assist Tomogr 2006;30:875)
Variable T1 signal, depending on hemorrhagic components on magnetic resonance imaging
Blood flow in solid nodules on Doppler ultrasound examination
In postmenopausal women, ground glass appearance in a cyst ultrasonographically should be evaluated carefully to rule out a component of clear cell carcinoma (Ultrasonography 2015;34:173)

Radiology images

Images hosted on other servers:

Ovarian mass on ultrasound

Prognostic factors

Negative prognostic factors:
- Advanced stage (most important) (Histopathology 2015;66:808, Medicine (Baltimore) 2018;97:e10881)
  - Most cases are FIGO stage I (BMC Cancer 2018;18:347, J Natl Cancer Inst 2019;111:60)
  - Worse prognosis in stage IC disease compared with stage IA
  - Overall 5 year cause specific survival of 66%, including 85% for stage I, 71% for stage II, 35% for stage III and 16% for stage IV (CA Cancer J Clin 2018;68:284)
  - Better prognosis than high grade serous carcinoma when confined to the pelvis but worse prognosis if advanced stage except for some MMR deficient tumors (Am J Surg Pathol 2011;35:36)
- Positive lymph nodes (Histopathology 2015;66:808)
- Lymphovascular invasion
- Immunohistochemically, loss of ARID1A, aberrant p53 and block-like p16 staining, expression of IMP3, nuclear expression of beta catenin, fibroblast growth factor receptor 2, chromobox homolog 7 (CBX7), Emi1, CXCR4, HOXA10, glypican 3 and Rsf-1 (HBXAP) (Surg Pathol Clin 2019;12:529)
- Genetic alterations, including amplification of MET or MDM2 (in TP53 wild type cases), CCNE1 copy number gain, somatic copy number variations such as chr20q13.2 harboring the ZNF217 gene (Surg Pathol Clin 2019;12:529)
Positive prognostic factors:
- PIK3CA mutations (Hum Pathol 2012;43:2197)

Case reports

28 year old woman with Cowden syndrome diagnosed with PTEN negative ovarian clear cell carcinoma (J Natl Compr Canc Netw 2019;17:7)
50 year old woman with cerebellar metastasis of ovarian clear cell carcinoma (Int J Gynecol Pathol 2020;39:68)
55 year old woman with primary diaphragmatic clear cell carcinoma associated with endometriosis (Gynecol Oncol Rep 2021;36:100733)
61 year old woman with bilateral breast metastases of ovarian clear cell carcinoma (Case Rep Oncol Med 2019;2019:8013913)
62 year old woman with ovarian clear cell carcinoma associated with low grade endometrial stromal sarcoma (Gynecol Obstet Invest 2020;85:371)

Treatment

Hysterectomy, bilateral salpingo-oophorectomy, omentectomy and staging biopsies
Adjuvant chemoradiation in some patients (Ann Oncol 2016;27:i50)
- Often platinum resistant (Am J Surg Pathol 2011;35:36)

Gross description

Usually unilateral
Mean size 13 cm (range 0.8 - 35 cm) (Histopathology 2015;66:808)
Variable appearance on cut surface:
- Mainly cystic, with fleshy nodules protruding into the cyst lumen
- Solid and cystic (spongy appearance due to small cysts)
- Solid (may be arising from clear cell adenofibroma or borderline clear cell tumor)
- Cyst may contain chocolate brown fluid
- Pale yellow to brown appearance
- Necrosis or hemorrhage
Ovarian surface involvement in 11% of cases (Histopathology 2015;66:808)

Gross images

Contributed by Ayse Ayhan, M.D. and AFIP images

External surface

Cut surface

External surface

Cut surface

Polypoid areas in a cyst

Frozen section description

Admixure of characteristic tubulocystic, papillary and solid growth patterns
Uniformly atypical cells with clear to eosinophilic cytoplasm, no brisk mitoses

Frozen section images

Contributed by Gulisa Turashvili, M.D., Ph.D.

Epithelial neoplasm

Uniform cytologic atypia

Microscopic (histologic) description

3 classic growth patterns, frequently admixed but 1 pattern (usually papillary or tubulocystic) may predominate (Am J Surg Pathol 2011;35:36, Adv Anat Pathol 2012;19:296, Am J Surg Pathol 2016;40:656, Histopathology 2015;66:808):
- Papillary:
  - Most frequent (70%)
  - Usually small, round, simple, nonbranching papillae with fibrous / hyalinized, edematous / myxoid or empty (open tumor rings) stromal cores
  - Lined by 1 - 2 layers of cuboidal, flattened or hobnail cells
  - Micropapillary tufts may be seen
  - Rarely irregular, broad papillae with or without hierarchical branching and micropapillae (Am J Surg Pathol 2008;32:269)
- Tubulocystic:
  - Frequent (65%)
  - Variably sized tubules and cysts, with or without intraluminal dense eosinophilic secretions and outpouchings
  - Lined by a single layer of hobnail, cuboidal or flattened cells
  - Often associated with an adenofibromatous background
- Solid:
  - Least common (62%)
  - Diffuse sheets or nested clusters of polyhedral cells separated by delicate septa exhibiting clear to eosinophilic cytoplasm
General features:
- Low cuboidal, polyhedral, hobnail or flattened cells with uniform nuclear atypia, prominent nucleoli and variable mitotic activity (usually low at < 6 per 10 high power fields)
- Hobnail cells have hyperchromatic nuclei protruding into lumina of tubulocystic structures or lining papillae
- Focal nuclear pleomorphism may be present in 40%
- Eosinophilic hyaline globules (Am J Surg Pathol 2011;35:36, Adv Anat Pathol 2012;19:296)
- Nuclear pseudoinclusions
- Peritumoural or diffuse lymphoplasmacytic infiltrate may be present
- May be associated with clear cell adenofibroma, clear cell borderline tumor, endometriosis or endometrioid adenocarcinoma
- Not graded (high grade by definition)
- Oxyphilic variant of clear cell carcinoma is composed of tumor cells with variable amounts of clear to granular eosinophilic cytoplasm (oxyphil cells), especially in nested, solid or trabecular growths (Am J Surg Pathol 1987;11:661)
Rare features:
- Multinucleated cells
- Psammoma bodies
- Diastase resistant intracytoplasmic material imparting a signet ring appearance (so called targetoid cells)
- Intraglandular cellular sloughing mimicking high grade serous carcinoma
- Uncommon growth patterns include glandular, nested, trabecular and reticular-like (myxoid stroma)

Microscopic (histologic) images

Contributed by Gulisa Turashvili, M.D., Ph.D., Sonali Lanjewar, M.D., M.B.B.S., Semir Vranić, M.D., Ph.D. and AFIP images

Variable architecture

Papillary architecture

Tubulocystic architecture

Tubulocystic and papillary architecture

Solid architecture

Targetoid cells

Left: cystic pattern; right: hobnail cells

Adenofibroma component

Hyaline bodies

HNF1β

Napsin A

Cytology description

Round to oval nuclei with fine chromatin
Abundant, pale, finely granular to vacuolated cytoplasm and indistinct cytoplasmic membranes
Hyaline extracellular material forming so called raspberry bodies or globule-like structures (Cytopathology 2016;27:427)
Psammoma bodies in ascitic fluid (Acta Cytol 2000;44:1005)

Positive stains

CK7
EMA
PAX8
HNF1β: sensitive but not specific (Mod Pathol 2006;19:83, Pathology 2015;47:105)
Napsin A: specific with intermediate sensitivity (Mod Pathol 2015;28:111, Pathology 2015;47:105)
AMACR: specific but not sensitive (Pathology 2015;47:105, Appl Immunohistochem Mol Morphol 2020;28:593)
p53: aberrant in 7 - 24% of cases (Am J Surg Pathol 2019;43:1591, Am J Surg Pathol 2011;35:36)
PAS positive diastase sensitive material (glycogen) in clear cells, diastase resistant intracytoplasmic material in targetoid cells

Negative stains

ARID1A: loss of expression in 15 - 75% (Mod Pathol 2012;25:282, Int J Gynecol Cancer 2012;22:1310)
MMR: loss of expression in 6 - 43.75% (not adjusted for age) (Am J Surg Pathol 2016;40:656, Int J Clin Exp Pathol 2008;1:502)
WT1 (Int J Gynecol Pathol 2019;38:353)
ER
PR
AFP: rarely positive
Glypican 3: rarely positive
OCT4: rarely positive
SALL4
CD10 (Int J Gynecol Pathol 2003;22:272)
p16: block-like in 20% of cases

Molecular / cytogenetics description

Loss of function mutations in ARID1A, a tumor suppressor gene from the SWI / SNF chromatin remodelling complex (50%) (N Engl J Med 2010;363:1532, Science 2010;330:228)
PIK3CA mutations (40%), often associated with ARID1A mutations (Cancer Res 2004;64:7678, Am J Pathol 2009;174:1597, Mod Pathol 2012;25:615, Int J Gynecol Cancer 2016;26:648)
TERT promoter mutations (16%) (J Pathol 2014;232:473)
KRAS mutations (10%) (Nat Genet 2017;49:856)
TP53 mutations (< 10%) (Am J Surg Pathol 2019;43:1591)
DNA mismatch repair deficiency (up to 6%), most commonly germline mutations in MSH2 (Int J Gynecol Pathol 2012;31:524, Histopathology 2016;69:288, Am J Surg Pathol 2019;43:1591, Clin Cancer Res 2019;25:3962, Am J Surg Pathol 2016;40:656)
PTEN mutations (5%) (Cancer Res 2000;60:7052)
Rarely MET, ARID1B, PIK3R1, SMARCA4 and SMARCD3 mutations

Sample pathology report

Uterus with cervix, fallopian tubes and ovaries, total hysterectomy and bilateral salpingo-oophorectomy:
- Right ovary: clear cell carcinoma, positive for ovarian surface involvement (see synoptic report)
- Left ovary and fallopian tubes: benign
- Endometrium: inactive
- Myometrium: leiomyomata
- Uterine serosa and cervix: benign

Differential diagnosis

Clear cell adenofibroma:
- Extremely rare
- Scattered tubulocystic structures lined by bland flat to low cuboidal cells, with clear to eosinophilic cytoplasm in a fibromatous background
- Associated with clear cell carcinoma in up to 33% of cases; therefore, extensive sampling is important to rule out clear cell carcinoma (J Cancer 2011;2:94)
Borderline clear cell tumor:
- Very rare
- Growth pattern similar to clear cell adenofibroma but with cytologic atypia
- Lacks stromal invasion by back to back glands, papillary or solid architecture or solid growth within cysts
Serous borderline tumor or low grade serous carcinoma:
- Clear cell carcinoma with broad papillae; may mimic serous borderline tumor or low grade serous carcinoma
- Hierarchical branching, cellular stratification and cellular budding usually present
- Positive for WT1 and ER
- Negative for HNF1β and napsin A
High grade serous carcinoma with clear cell features:
- Usually diagnosed at advanced stage
- May be associated with serous tubal intraepithelial carcinoma
- Typical papillary growth pattern
- Lack of small rounded papillae and tubulocystic structures
- Greater cytologic atypia with brisk mitoses
- Usually shows aberrant p53 expression, diffuse WT1, patchy to diffuse ER and PR; lacks HNF1β and napsin A
- Panel of WT1, napsin A, HNF1β and ER recommended for distinction of clear cell carcinoma from high grade serous carcinoma (Am J Surg Pathol 2009;33:14, Int J Gynecol Pathol 2016;35:430)
Endometrioid carcinoma with clear cell features:
- Endometrioid morphology with or without squamous or mucinous differentiation and cribriform architecture
- Positive for ER and PR
- Negative for HNF1β and napsin A
- Panel of napsin A and PR recommended for distinction of clear cell carcinoma from endometrioid carcinoma (Am J Surg Pathol 2015;39:1061)
Metastatic clear cell renal carcinoma:
- Prior history or concurrent renal mass
- Nested alveolar pattern with interalveolar stromal vascularity
- Composed of tumor cells with mostly clear cytoplasm
- Lack of tubulocystic architecture, small rounded papillae and hobnail cells
- Diffuse expression of RCC, carbonic anhydrase IX and CD10 and no reactivity for CK7, ER, PR, napsin A and AMACR (Am J Surg Pathol 2008;32:377)
Dysgerminoma:
- Nests of primitive cells separated by fibrous septa containing abundant lymphocytes
- Positive for SALL4 and OCT4
- Negative for CK7
Yolk sac tumor:
- Young patients
- Elevated serum α fetoprotein
- Variable growth patterns with brisk mitoses
- Schiller-Duval bodies may be seen
- Diffusely positive for SALL4, AFP and glypican 3
- Negative or focally positive for CK7 and EMA

Additional references

J Pathol Clin Res 2018;4:154, Mod Pathol 2014;27:983, Oncotarget 2016;7:54758, Int J Clin Oncol 2015;20:967, Int J Gynaecol Obstet 2015;130:27, Mol Clin Oncol 2016;5:395, PLoS One 2018;13:e0192881

Board review style question #1

ARID1A mutation
BRAF mutation
MSH2 mutation
PMS2 mutation
PTEN mutation

Board review style answer #1

C. MSH2 mutation

Comment Here

Reference: Clear cell carcinoma

Board review style question #2

ER, PR, WT1 and p53
ER, PR, WT1 and SALL4
PAX8, p16, napsin A and HNF1β
WT1, ER, napsin A and HNF1β
WT1, napsin A, p16 and SALL4

Board review style answer #2

D. WT1, ER, napsin A and HNF1β

Comment Here

Reference: Clear cell carcinoma

Clear cell cystadenoma and adenofibroma

Table of Contents

Gross images | Microscopic (histologic) images

Gross images

AFIP images

Borderline malignancy

Microscopic (histologic) images

AFIP images

Borderline malignancy

Colorectal adenocarcinoma

Table of Contents

Definition / general

Secondary ovarian involvement by colorectal cancer (CRC) is, by definition, evidence of advanced tumor stage (pM1)
There is significant overlap of clinical, radiologic and pathologic features between primary and metastatic ovarian adenocarcinoma
In the workup of mucinous or endometrioid-like ovarian neoplasms, a secondary malignancy should always be excluded, either pathologically or clinically

Essential features

Mimic of primary ovarian endometrioid or mucinous adenocarcinoma
Most common metastatic tumor to ovary; usually arising from rectosigmoid colon (Int J Colorectal Dis 2020;35:1035)
Usual gross morphologic features of ovarian metastasis (bilateral, < 10 cm, surface involvement) may not be seen
Variably sized glands, nuclear atypia that is more pronounced than in ovarian primary, dirty necrosis, multinodular / infiltrative growth
SATB2+, CK20+, CDX2+, CK7-, PAX8-

Terminology

Metastases to the ovary (OM) are also known as secondary tumors of ovary (STO)
Although commonly used to refer to all metastatic carcinoma involving the ovary, Krukenberg tumor (KT) strictly refers to adenocarcinoma with signet ring cell differentiation, most of which (76%) arise from the stomach (Am J Surg Pathol 2006;30:277)

ICD coding

ICD-O: 8144/6 - metastatic adenocarcinoma, intestinal type
ICD-10:
- C79.6 - secondary malignant neoplasm of ovary
- C79.60 - secondary malignant neoplasm of unspecified ovary

Epidemiology

Rate of OM among all ovarian malignancies varies from 15 - 30% (Int J Gynecol Cancer 2006;16:132, Virchows Arch 2015;467:79, Anal Quant Cytopathol Histpathol 2013;35:241)
Between 10 - 33% of OM are from CRC, which is the most common primary tumor type (World J Gastrointest Surg 2010;2:109, Virchows Arch 2015;467:79, Anal Quant Cytopathol Histpathol 2013;35:241)
- Median age is 51 - 60 years; 24% are 40 years or younger (World J Gastrointest Surg 2010;2:109, Virchows Arch 2015;467:79, Anal Quant Cytopathol Histpathol 2013;35:241)
3.4 - 4.2% of women with CRC present with or will develop OM (Int J Colorectal Dis 2020;35:1035, Int J Colorectal Dis 2021;36:2567)
- Slightly more frequent in premenopausal / perimenopausal (≤ 55 years) women (Int J Colorectal Dis 2021;36:2567)

Pathophysiology

Spread to the ovaries can be hematogenous, lymphatic, transperitoneal or by direct extension (Clin Exp Metastasis 2017;34:295)
- Hematogenous spread may be more important for colorectal primary than other sites of origin (Obstet Gynecol Int 2011;2011:612817)

Diagrams / tables

See Figure 5 for algorithm to determine origin using currently available markers: Int J Gynecol Pathol 2016;35:191

Table 1. Most common immunohistochemical expression
patterns seen in primary ovarian mucinous neoplasms and
secondary epithelial tumors from gastrointestinal origin

	Lower GI	Upper GI	Ovarian
CK7	Negative	Positive	Positive
SATB2	Positive	Negative	Negative
PAX8	Negative	Negative	Positive*
CK20	Positive	Pos / neg	Pos / neg
CDX2	Positive	Pos / neg	Pos / neg
MUC2	Positive	Pos / neg	Pos / neg
ER	Negative	Negative	Pos / neg
Beta catenin	Pos / neg	Negative	Negative
MUC1	Pos / neg	Positive	Positive

GI = gastrointestinal; pos = positive; neg = negative
In this table, positive markers are those with expression in > 75% and negative markers those with expression in < 25% of tumors in the indicated category
Expression ranging from 25 to 75% is coded as pos / neg
*PAX8 expression was 75% in all primary ovarian neoplasms but lower in the subgroup of primary ovarian carcinomas (65%)
Table contents adapted from Int J Gynecol Pathol 2016;35:191

Clinical features

Most patients manifest changes in bowel habits, rectal bleeding and bloating; constitutional symptoms are less frequent
Symptoms related to a pelvic mass include abdominal pain, discomfort or bowel obstruction
- Abnormal vaginal bleeding or even virilization may result from metastasis induced luteinization of the ovarian stroma (Am J Surg Pathol 2006;30:277)
Mean size of the metastatic lesion usually exceeds the size of the primary tumor
- Right sided CRC with OM is more likely to present with peritoneal carcinomatosis than those with left sided primary (Curr Oncol 2021;28:2914)
Most cases are stage pT3 (full thickness wall involvement) or pT4 (perforation of visceral peritoneum or direct invasion of adjacent structures); nodal involvement occurs in 87% (Int J Clin Oncol 2020;25:1822)
Left sided CRC is more common among OM (Curr Oncol 2021;28:2914)
- Rectosigmoid is most common site (Int J Colorectal Dis 2020;35:1035, Virchows Arch 2015;467:79)

Diagnosis

Imaging is not reliable in distinguishing STO from primary malignancy; definitive diagnosis requires pathologic evaluation

Laboratory

Elevated CA125 levels (> 100 U/mL) are more characteristic of primary ovarian malignancy but may be seen in OM (J Gastrointest Oncol 2021;12:226)
- In the setting of known CRC, elevated CA125 may suggest OM
CA125:CEA ratio < 25 is common and accurately excludes ovarian primary; CA19-9 may be elevated but is more specific for pancreaticobiliary origin (Indian J Surg Oncol 2021;12:152)

Radiology description

On imaging, the ovarian mass often has cystic and solid components (Int J Clin Oncol 2020;25:1663)
- Palisading layered structures (mille-feuille sign) were specific for colorectal origin in one study (Eur J Radiol 2020;124:108823)
Necrosis is common (Transl Cancer Res 2021;10:3248)
Smooth mass margin (contour) on CT is seen in most lesions (92%), compared to primary ovarian tumors (45%) (Abdom Radiol (NY) 2019;44:1493, J Comput Assist Tomogr 2005;29:69)

Prognostic factors

Median survival of 25.5 months when ovary is sole site of metastasis (Int J Colorectal Dis 2020;35:1035)
Poor prognostic factors (Int J Colorectal Dis 2020;35:1035, Int J Clin Oncol 2020;25:1822):
- Additional sites of metastasis
- Residual disease after cytoreductive surgery
- Poorly differentiated or undifferentiated tumor or signet ring cell differentiation
- Age ≥ 70

Case reports

29 year old woman with cystic ovarian lesion found 1 month after low anterior resection for pT4bN1b CRC (J Gastrointest Oncol 2021;12:3141)
44 year old woman with menorrhagia and a mixed cystic and solid adnexal mass (Radiol Case Rep 2021;16:2799)
74 year old woman with pelvic mass, elevated CA125 and CA19-9 (Medicine (Baltimore) 2019;98:e17782)

Treatment

Given the high frequency of ovarian involvement by CRC and the high proportion of cases that are unsuspected before oophorectomy, preoperative investigation in a patient with an ovarian mass should include consideration for colonoscopy (Int J Gynecol Pathol 2008;27:182)
Prophylactic oophorectomy is not universally recommended in the setting of known CRC but has been considered in certain contexts (e.g., postmenopausal, synchronous cystic ovarian lesions, ovarian tethering to site of primary tumor, pelvic ascites accumulation) (Updates Surg 2021;73:391)
Cytoreductive surgery with adjuvant chemotherapy (particularly hyperthermic intraperitoneal chemotherapy [HIPEC]) shows improved survival over primary resection or palliative treatment alone (Int J Colorectal Dis 2020;35:1035, J Gastrointest Oncol 2021;12:226)

Gross description

Bilateral in 45 - 59% of cases; left sided colorectal primary is most likely to present with unilateral OM (Curr Oncol 2021;28:2914, Int J Clin Oncol 2020;25:1663, Eur J Radiol 2020;124:108823)
Mass is frequently complex (solid and cystic) or purely solid with multinodular growth (Int J Clin Oncol 2020;25:1822, J Gastrointest Oncol 2021;12:226)
Purely cystic unilocular lesions are rare
Surface involvement varies (Curr Oncol 2021;28:2914):
- Right sided primary (58%)
- Left sided primary (25%)
Although OM are generally smaller (< 10 cm) than ovarian primaries, OM from CRC can be large ranging from 5 - 20 cm (Int J Clin Oncol 2020;25:1822)
A simple size and laterality algorithm accurately distinguishes OM from primary ovarian malignancy in several metastatic tumor types; however, metastatic CRC appears to routinely violate this model (Am J Surg Pathol 2008;32:128)

Gross images

Images hosted on other servers:

Cystic and solid architecture

Frozen section description

OM can frequently be mistaken for primary ovarian malignancy on frozen section, particularly in the setting of an occult primary (Int J Gynecol Pathol 2005;24:356)
Useful features to suggest OM include:
- Bilateral
- Small (< 10 cm)
- Surface involvement
- Multinodular growth pattern with desmoplasia
- Intervening benign ovarian stroma
Features suggestive of CRC origin (Am J Surg Pathol 2006;30:177):
- Variably sized glands often with cystic dilation
- Garland pattern
- Intraluminal dirty necrosis
Diagnostic accuracy of frozen section for CRC with OM specifically, is not well known

Frozen section images

Contributed by Adam Lechner

Glandular features

Stromal desmoplasia

Microscopic (histologic) description

Metastatic colorectal adenocarcinoma to the ovary usually has a mucinous or a conventional glandular appearance
- Mucinous carcinomas have intestinal (goblet cell) differentiation
- Mucin extravasation and signet ring cell morphology can be seen
- Krukenberg tumor is a term that should be reserved for adenocarcinoma involving the ovary with a signet ring cell component > 10% of the tumor volume, regardless of its site of origin (Adv Anat Pathol 2006;13:205)
- Conventional tumor cytomorphology with mucin depletion mimics the architecture and cytoplasmic appearance of a primary ovarian endometrioid tumor
- Nuclear pleomorphism and hyperchromasia tend to be prominent and exceed what is expected for a primary ovarian tumor
- Central glandular necrosis (dirty necrosis) is also more typical of colorectal tumors, although it is not entirely specific
- Desmoplastic stromal response
- Mucinous metastases frequently mimic the appearance of an ovarian mucinous neoplasm and may have areas mimicking a borderline or even benign primary mucinous tumor
Several clinical and pathologic features have been described as indicative of secondary (metastatic) origin, including (Am J Surg Pathol 2003;27:281, Diagn Pathol 2021;16:20):
- Bilaterality
- Size < 10 cm
- Surface involvement
- Infiltrative pattern of growth with intervening benign ovarian stroma
- Presence of signet ring cells
- Extensive lymphovascular space invasion
- Mucin extravasation
If any of the above features is present, the possibility of a metastasis should be considered and prompt ancillary testing and clinical investigation should be performed

Microscopic (histologic) images

Contributed by Carlos Parra-Herran, M.D. and Adam Lechner

Neoplastic columnar epithelium

Dirty necrosis

Dilated glands

Sharply defined, angulated glands

CK7

SATB2

CDX2

CK20

See Colon - adenocarcinoma

Positive stains

Immunohistochemistry is useful to distinguish primary ovarian tumors and GI metastases but must be interpreted with caution, since there is significant overlap in expression (Int J Gynecol Pathol 2016;35:191)
CK20, CDX2 and MUC2 are sensitive markers of colorectal origin
- They lack specificity since they are frequently positive in primary ovarian tumors
SATB2 is a more specific marker of colorectal origin (Int J Gynecol Pathol 2016;35:191, BMC Res Notes 2019;12:770)
- Combination of CK7 and SATB2 using 3 tiered interpretation (absent / focal / diffuse) yields diagnostic accuracy of > 95% (Mod Pathol 2019;32:1834)
Rates of expression in colorectal tumors are (Am J Surg Pathol 2016;40:419, Am J Surg Pathol 2018;42:160, Int J Gynecol Pathol 2016;35:191, Ann Diagn Pathol 2015;19:249):
- SATB2: 75 - 79% (versus 5% of primary ovarian mucinous tumors and 0% of primary ovarian endometrioid tumors)
- CK20: 68 - 85% (versus 45% of primary ovarian tumors)
- CDX2: 64 - 100% (versus 50% of primary ovarian tumors)
- MUC2: 97% (versus 40% of primary ovarian tumors)
- Beta catenin: 51% (versus 5% of primary ovarian tumors)
- CK7: 21% (versus 95% of primary ovarian tumors)

Negative stains

PAX8: 0% (versus 30 - 65% of primary ovarian mucinous tumors and 80% of primary ovarian endometrioid tumors)
ER: 0% (versus 30% of primary ovarian tumors)
See Diagrams / tables

Molecular / cytogenetics description

EGFR and HER2 overexpression is more common in OM than other metastatic sites of CRC (BMC Clin Pathol 2019;19:3)
PIK3CA mutations are significantly less common in CRC with OM (Cancer Biol Ther 2015;16:1726)
Lower RRM1 protein expression is also seen and may indicate sensitivity to gemcitabine (Cancer Biol Ther 2015;16:1726)
Reference: Cancer 2017;123:1134

Sample pathology report

Ovary, oopherectomy:
- Metastatic adenocarcinoma, moderately differentiated (see comment)
- Comment: Immunostaining demonstrates SATB2+, CDX2+, CK20+, CK7- and PAX8- in lesional cells. The cytomorphology and immunohistochemical profile is most consistent with metastatic adenocarcinoma of colorectal primary.

Differential diagnosis

Metastases from upper GI tract:
- CK7 positive
- CK20 / CDX2 / SATB2 variable (mostly negative)
Metastases from cervix:
- p16 positive (strong, diffuse)
Primary ovarian neoplasm (benign, borderline or malignant):
- Most often mucinous or endometrioid types; less likely high grade serous and clear cell types
- No suspicious features described above (bilaterality, surface involvement, signet ring cell morphology, etc.)
- PAX8+, CK7+, CK20-, CDX2-, SATB2-
- For endometrioid tumors: squamous differentiation, adenofibromatous background, involvement by endometriosis, ER+
- For mucinous tumors: association with teratoma or Brenner tumor, CK7+, PAX8+ (50 - 65% of cases)
- For serous tumors: complex papillary architecture, severe pleomorphism, ER+, WT1+

Board review style question #1

A 51 year old woman presents with a 6 month history of menorrhagia and abdominal discomfort. Pelvic imaging identifies bilateral complex cystic adnexal masses of 7 and 9 centimeters. Whole body PET / CT identifies an additional hypermetabolic lesion in the cecum and in the liver. A representative section taken from a bilateral salpingo-oopherectomy specimen is shown above. Which of the following immunohistochemical results provides the strongest support for the diagnosis?

CDX2+
CK7+
MUC2+
SATB2+

Board review style answer #1

D. SATB2+. Bilateral, small (< 10 cm) ovarian masses are concerning for a metastatic process. The presence of a lesion in the cecum with an additional metastatic focus in the liver raises the possibility of colorectal origin. Histology shows punched out, angulated glands with intraluminal dirty necrosis consistent with metastatic colorectal adenocarcinoma. The immunoprofile of this tumor is CK7- / CK20+, CDX2+, SATB2+, MUC2+, PAX8-. Although MUC2, CDX2 and SATB2 are both positive in CRC, primary ovarian malignancies (particularly mucinous neoplasms) are often positive for CDX2 and MUC2 as well (usually with patchy distribution).

Comment Here

Reference: Colorectal adenocarcinoma

Board review style question #2

A 60 year old woman is diagnosed with colorectal adenocarcinoma with isolated metastases to the left ovary. She undergoes cytoreductive surgery, including low anterior resection and oophorectomy. Which of the following statements is correct?

Adjuvant chemotherapy is contraindicated
The presence of signet ring cell differentiation would indicate better overall survival
This patient's colorectal cancer likely originated in the cecum
This patient has a relatively better prognosis compared to those with additional metastases beyond the ovary

Board review style answer #2

D. This patient has a relatively better prognosis compared to those with additional metastases beyond the ovary. Isolated ovarian metastasis in colorectal adenocarcinoma shows improved survival over additional metastases to extraovarian sites. Unilateral ovarian metastasis in CRC most commonly originates from a left sided primary. HIPEC adjuvant therapy at the time of cytoreductive surgery improves survival. Signet ring cell differentiation is a uniformly negative prognostic factor.

Comment Here

Reference: Colorectal adenocarcinoma

Corpus luteum cyst

Table of Contents

Definition / general

Ovarian cyst > 3 cm in diameter, lined by luteinized granulosa and theca cells

Essential features

Cyst over 3 cm in size
Cyst lining composed of inner layer of luteinized granulosa cells and outer layer of theca cells

ICD coding

ICD-11: GA18.1 - Corpus luteum cyst

Epidemiology

Functional cysts in women of reproductive age, including pregnancy
Rare in postmenopausal women

Sites

Ovary

Pathophysiology

Corpus luteum is a physiological postovulatory structure formed after the dominant follicle releases the ovum
Its main purpose is to secrete estrogen and progesterone and it normally regresses at the end of the cycle
Cystic dilation happens when corpus luteum fails to regress and becomes enlarged with fluid / blood
Reference: StatPearls: Anatomy, Abdomen and Pelvis, Ovary Corpus Luteum [Accessed 20 May 2021]

Clinical features

Patients can be asymptomatic or present with menstrual irregularities, amenorrhea, abdominal pain, palpable abdominal mass if large size
If cyst ruptures, patient may present with acute abdomen and hemoperitoneum
Reference: Turk J Obstet Gynecol 2020;17:300

Diagnosis

On pelvic ultrasound, appears as simple ovarian cyst, often hemorrhagic; incidental finding or diagnosed during symptomatic workup

Laboratory

No specific laboratory findings

Radiology description

On ultrasound: unilocular cyst with prominent peripheral blood flow and thick crenulated vascular walls
On CT: unilocular structure with crenulated walls and brisk enhancement (Abdom Radiol (NY) 2016;41:2270)

Radiology images

Images hosted on other servers:

CT: ruptured corpus luteum cyst and hemoperitoneum

Prognostic factors

Most cysts resolve spontaneously
Hemorrhagic cysts over 5 cm or simple cysts between 5 and 7 cm in women of reproductive age require follow up to ensure resolution (Ultrasound Q 2010;26:121)
In postmenopausal women, consider surgical evaluation of hemorrhagic cysts, as the etiology is more likely neoplastic than functional (Radiology 2010;256:943)
Vast majority of pregnancy associated simple cysts < 5 cm resolve by weeks 16 - 20 and require no intervention (Clin Obstet Gynecol 2006;49:492)

Case reports

15 year old girl with ruptured hemorrhagic corpus luteum cyst of undescended ovary, a rare cause of acute abdomen in an adolescent (J Pediatr Adolesc Gynecol 2016;29:e21)
15 year old girl with ruptured corpus luteum cyst of pregnancy with massive hemoperitoneum (J Pediatr Adolesc Gynecol 2007;20:97)
16 year old girl with hemoperitoneum from corpus luteum cyst rupture (Case Rep Emerg Med 2014;2014:252657)
18 year old woman with congenital hypofibrinogenemia with hemoperitoneum caused by ovulation (Obstet Gynecol Sci 2015;58:427)

Treatment

Resection if symptomatic, rupture or suspicion for neoplastic process (Radiology 2010;256:943)
For asymptomatic unilocular cysts with normal CA125, optimal management includes surveillance with ultrasound (Clin Obstet Gynecol 2006;49:506, Clin Exp Obstet Gynecol 2014;41:609)

Clinical images

Images hosted on other servers:

Intraoperative: hemorrhage of corpus luteum cyst

Gross description

Single unilocular cyst with smooth surface
Cyst wall and lining appears yellow and convoluted
Serous or hemorrhagic contents
Reference: Kurman: Blaustein's Pathology of the Female Genital Tract, 7th Edition, 2019

Gross images

Images hosted on other servers:

Corpus luteum cyst

Frozen section description

Convoluted cyst wall lined by cells with abundant eosinophilic cytoplasm and bland nuclear features
Cytoplasm may appear vacuolated on frozen tissue

Microscopic (histologic) description

Cyst lining is convoluted, composed of an inner layer of luteinized granulosa cells and outer layer of theca cells
Granulosa cells are polygonal in shape, with abundant eosinophilic cytoplasm and central round nuclei
Mitotic figures may be seen in the granulosa cells
Outer theca cells are smaller in size
Prominent inner layer of fibrous tissue
Reference: Kurman: Blaustein's Pathology of the Female Genital Tract, 7th Edition, 2019

Microscopic (histologic) images

Contributed by Aurelia Busca, M.D., Ph.D.

Convoluted cyst lining

Bilayered cyst lining

Granulosa and theca cells

Reticulin stain

Cytology description

Rarely performed
Luteinized granulosa cells and hemosiderin laden macrophages in the background of blood and fibrin (Diagn Cytopathol 1990;6:77)

Positive stains

Usually not necessary for diagnosis
Calretinin (Histopathology 2001;38:403)
Inhibin (J Clin Endocrinol Metab 1991;73:470)
Progesterone receptor (Reproduction 2004;128:423)
Reticulin preserved within the theca interna layer

Negative stains

Cytokeratin
Reticulin diminished / absent in the granulosa layer

Sample pathology report

Ovary, right, cystectomy:
- Corpus luteum cyst
- Background ovary with cystic follicles and epithelial inclusion cysts
- Negative for malignancy

Differential diagnosis

Cystic granulosa cell tumor:
- Usually larger
- The 2 cell types in the cyst wall have a more disorderly pattern
- Neoplastic cells can infiltrate the cyst wall
- With or without Call-Exner bodies
Endometriotic cyst:
- Endometrial glands and stroma, hemosiderin laden macrophages
Epithelial inclusion cyst:
- Lined by either ciliated (tubal type) or flat (ovarian surface / peritoneal type) epithelium
Follicular cyst:
- > 3 cm: lined by an inner layer of granulosa cells and an outer layer of theca cells
- Luteinization is either absent or only focal
- Lacks the convoluted appearance on low power magnification
Cystic corpus luteum:
- Size < 3 cm

Board review style question #1

Which of the following is true about the 4 cm ovarian cyst shown in the image above?

Affects predominantly postmenopausal women
It is a benign finding, expected to undergo regression
It is a precursor lesion for granulosa cell tumor
It is lined by a single layer of granulosa cells

Board review style answer #1

B. It is a benign finding, expected to undergo regression

Comment Here

Reference: Corpus luteum cyst

Board review style question #2

Which of the following is characteristic of a corpus luteum cyst of the ovary?

Bilayered lining of granulosa and theca cells
Presence of endometrial type stroma
Single layer of ciliated cells with eosinophilic cytoplasm
Single layer of granulosa cells

Board review style answer #2

A. Bilayered lining of granulosa and theca cells

Comment Here

Reference: Corpus luteum cyst

Cortical inclusion cyst

Table of Contents

Definition / general

Cystically dilated glands within the ovarian cortex that result from the invagination of the surface lining or implantation of tubal epithelium

Essential features

2 types based on morphology and pathophysiology:
- Peritoneal inclusion cyst: lined by flat epithelium that is invaginated from ovarian surface epithelium; these express a peritoneal phenotype (calretinin, WT1 and D2-40 positive, PAX8 and BerEP4 negative)
- Müllerian inclusion cyst: lined by ciliated tubal epithelium as a result of the implantation of tubal epithelium in the ovarian parenchyma, presumably at the time of ovulation when the ovarian surface epithelium is disrupted; these cysts express a tubal Müllerian phenotype (PAX8, BerEP4 and WT1 positive, calretinin and D2-40 negative)
Size is less than 1 cm; if more than 1 cm, by convention the lesion is designated as cystadenoma or cystadenofibroma

Terminology

Cortical inclusion cyst
Some terminology overlap with endosalpingiosis

Epidemiology

Can occur at any age but more common postmenopausal

Sites

Ovary

Pathophysiology

Via invagination of the ovarian surface epithelium (peritoneal type cyst) or implantation of tubal epithelium at ovulation, when the ovarian surface epithelium is disrupted (Müllerian type cyst) (Histopathology 2018;72:766, Int J Gynecol Pathol 2015;34:3, Mod Pathol 2011;24:1488)

Clinical features

Incidental findings, usually asymptomatic

Diagnosis

Histologic examination, usually incidental findings in oophorectomy specimens

Prognostic factors

Benign entities
Presence of inclusion cyst in postmenopausal women does not increase the risk of ovarian or other hormone driven cancers (breast and endometrial cancers) (BJOG 2012;119:207)
Traditionally thought to represent a precursor lesion of ovarian carcinoma; however most ovarian serous carcinomas are now considered to be tubal in origin with serous tubal intraepithelial carcinoma (STIC) as the precursor lesion
For a subset of ovarian serous carcinomas (in which STIC or tubal involvement is not identified), a potential origin in epithelial inclusion cyst of Müllerian (tubal) phenotype has been postulated (Gynecol Oncol 2013;130:246, Mod Pathol 2011;24:1488, Int J Gynecol Pathol 2015;34:3)
Use of oral contraceptives for more than 5 years was shown to reduce the number of Müllerian type inclusion cysts (PAX8 positive); this suggests a possible mechanism for reducing the risk of epithelial neoplasms and supports the hypothesis that these cysts constitute a precursor lesion of ovarian serous carcinoma (Diagn Pathol 2016;11:30)

Treatment

Not required, as these are often incidental findings

Gross description

Most are not apparent grossly unless very superficial in the cortex
When visible, they appear as small cysts bulging at the ovarian surface

Microscopic (histologic) description

Small cysts (< 1 cm), singly or in clusters within the ovarian cortex
Peritoneal inclusion cyst: lined by simple flat epithelium devoid of cilia or mucinous cytoplasm
Müllerian inclusion cyst: lined by simple cuboidal to columnar epithelium with ciliated cells, sometimes admixed with nonciliated (secretory, peg) cells
Can have psammomatous calcifications in adjacent stroma
Reference: Int J Gynecol Pathol 2015;34:3

Microscopic (histologic) images

Contributed by Aurelia Busca, M.D., Ph.D.

Cystically dilated glands

Positive stains

Müllerian type cyst: PAX8, BerEP4 and WT1 (Histopathology 2018;72:766, Hum Pathol 2015;46:948, Int J Gynecol Pathol 2000;19:158)
Peritoneal type cyst: calretinin, WT1 and D2-40 (Int J Gynecol Pathol 2015;34:3)

Negative stains

Müllerian type cyst: calretinin and D2-40 (Histopathology 2018;72:766, Hum Pathol 2015;46:948, Int J Gynecol Pathol 2000;19:158)
Peritoneal type cyst: PAX8 and BerEP4 (Int J Gynecol Pathol 2015;34:3)

Sample pathology report

Left and right ovary, bilateral oophorectomy:
- Benign ovaries with cortical inclusion cysts
Note: many pathologists do not report the finding of inclusion cysts since they are common and benign

Differential diagnosis

Endometriosis:
- Presence of endometrial stroma or hemosiderin laden macrophages
Serous cystadenoma:
- Size: > 1 cm

Board review style question #1

Which of the following is true about the finding illustrated in this photo of the ovary?

Direct precursor of high grade serous carcinoma
PAX8 is always positive
Tubal differentiation distinguishes it from endometriosis
Usually is an incidental finding

Board review style answer #1

D. Usually is an incidental finding. Epithelial inclusion cysts are incidental findings and can be PAX8 positive (Müllerian type) or negative (peritoneal type). Presence of endometrial stroma distinguishes them from endometriosis, as both can have focal tubal differentiation. Although some relationship with risk of serous neoplasia, they are considered benign findings (not a serous tubal intraepithelial carcinoma [STIC] lesion).

Comment Here

Reference: Epithelial inclusion cyst

Board review style question #2

What is the typical immunoprofile of Müllerian type epithelial inclusion cyst of the ovary?

BerEP4 and D2-40 positive
BerEP4 and PAX8 positive
Calretinin and PAX8 positive
Calretinin and WT1 positive

Board review style answer #2

B. BerEP4 and PAX8 positive

Comment Here

Reference: Epithelial inclusion cyst

Disorders of sex development-general

Table of Contents

Definition / general

Disorder of sex development (DSD) in which one or both gonad(s) is / are undeveloped (streak gonad)
Disorders of sex development are either female pseudohermaphroditism (46XX with 2 ovaries), male pseudohermaphroditism (46XY with two testes), true hermaphroditism (ovotestis present) or gonadal dysgenesis (either pure with normal 46XX or 46XY chromosomes and bilateral streak gonads or mixed with streak gonad)

Terminology

Pure gonadal dysgenesis (PGD): both gonads are streak gonads (i.e. dysfunctional gonads without germ cells)
Mixed gonadal dysgenesis (MGD): patient has a testis on one side and a streak gonad on the other

Etiology

Chromosomal abnormality: may be 46XX, 46XY or 45XO

Clinical features

Patients with pure gonadal dysgenesis have underdeveloped Müllerian organs (sexual infantilism), sometimes with clitoromegaly, while patients with mixed gonadal dysgenesis have ambiguous or female genitalia
46XX and 46XY patients present with primary amenorrhea and delayed secondary sexual development; 45XO present with typical Turner syndrome features

Prognostic factors

Patients with pure gonadal dysgenesis are raised as female since there is no sexual ambiguity at birth; however, gender assignment in patients with mixed gonadal dysgenesis is variable and depends on the degree of virilization
Approximately 20% of patients with gonadal dysgenesis develop a gonadal neoplasm within the first two decades of life, usually gonadoblastoma; almost all cases of gonadoblastoma have been reported in patients with pure or mixed gonadal dysgenesis or male pseudohermaphroditism
Other neoplasms include seminomatous germ cell tumors such as seminoma and dysgerminoma, nonseminomatous germ cell tumors such as embryonal carcinoma and choriocarcinoma, as well as nongerm cell tumors such as Wilms tumor

Treatment

Given the higher risk of malignancy in dysgenetic gonads, early surgical removal is indicated

Molecular / cytogenetics description

Pure gonadal dysgenesis: 46XX, 46XY or 45XO
Mixed gonadal dysgenesis: 45XY / 45XO (mosaic)

Pure (complete) gonadal dysgenesis

Definition / general

Presence of undeveloped (streak) gonads in a phenotypic female who may have an either 46,XX female or 46,XY male genotype

Terminology

Term gonadal dysgenesis originally referred to Turner syndrome but it is now applied to other conditions as well
Under the new nomenclature, pure (complete) gonadal dysgenesis is considered a type of either 46,XY DSD (disorder of sex development) or 46,XX DSD

Etiology

For a variety of reasons, known and unknown, primordial germ cells do not form or interact with the gonadal ridge or undergo accelerated atresia, leading to extremely hypoplastic (underdeveloped) and dysfunctioning gonads that are mainly composed of fibrous tissue, hence the name streak gonads
Gonadal dysfunction leads to deficiency of both Müllerian inhibiting factor and testosterone

Clinical features

During embryonal development, the human reproductive system has an inherent tendency to give rise to female reproductive organs; therefore, in the absence of hormonal influences from the undeveloped and dysfunctional gonads, patients with complete gonadal dysgenesis are phenotypically female, regardless of genotype
First clinical manifestation is usually absence of expected female secondary sex characteristic development at puberty

Microscopic (histologic) description

Streak gonads are mainly composed of fibrous tissue
Absence of testosterone results in regression of Wolffian ducts; i.e. normal male internal reproductive tracts do not develop
Absence of Müllerian inhibiting factor allows Müllerian ducts to differentiate into oviducts and the uterus

Pure (complete) gonadal dysgenesis 46XX

Definition / general

Form of gonadal dysgenesis (underdeveloped and dysfunctioning ovaries) associated with female 46,XX genotype and female internal and external phenotype
Phenotypic female 46,XX but no functional ovaries are present to induce puberty (may have streak ovaries)

Terminology

Term gonadal dysgenesis originally referred to Turner syndrome but it is now applied to other conditions as well
Under the new nomenclature, this form of gonadal dysgenesis is considered a type of 46,XX DSD (disorder of sex development)
Perrault syndrome: 46,XX gonadal dysgenesis with sensorineural hearing loss

Etiology

May be familial (Am J Med Sci 1980;280:157)
Occasionally due to mutation in FSH receptor (Cell 1995;82:959)
For reasons that are not clear, primordial germ cells do not form or interact with the gonadal ridge or undergo accelerated atresia

Clinical features

First clinical manifestation is usually absence of expected female secondary sex characteristic development at puberty

Laboratory

Low serum estrogen and progesterone (since no functional ovaries), high serum FSH and LH

Treatment

Estrogen and progesterone therapy

Microscopic (histologic) description

Progressive loss of primordial germ cells in the developing gonads of the embryo leads to extremely hypoplastic ovaries mainly composed of fibrous tissue, hence the name streak gonads

Additional references

OMIM: Ovarian Dysgenesis 1 [Accessed 15 January 2024], Wikipedia: XX Gonadal Dysgenesis [Accessed 15 January 2024]

Pure (complete) gonadal dysgenesis 46XY

Definition / general

Form of gonadal dysgenesis (underdeveloped and dysfunctioning testes) associated with male 46,XY genotype and female internal and external phenotype
Phenotypic female, hypoplastic (streak) gonads without germ cells

Terminology

Term gonadal dysgenesis originally referred to Turner syndrome but it is now applied to other conditions as well
Under the new nomenclature, this form of gonadal dysgenesis is considered a type of 46,XY DSD (disorder of sex development)
Also called Swyer syndrome

Etiology

Mutation in SRY, the sex determining region of the Y chromosome, is reported in 10 - 15%
Defects in the genetic pathways that lead to development of testes from indifferent gonads result in hypoplastic (streak) testes and lack of testosterone or anti-Müllerian hormone (AMH) production

Clinical features

In the absence of testosterone, external genitalia fail to virilize and the Wolffian ducts fail to develop, leading to normal female genitalia and absent internal male organs
Presents with primary amenorrhea (delayed puberty) since no functional gonads are present to induce puberty
May develop pubic hair through androgens produced from adrenal gland

Laboratory

Low serum estrogen and progesterone, high serum FSH and LH

Prognostic factors

High risk of gonadoblastoma or germ cell tumor from gonads (Zhonghua Fu Chan Ke Za Zhi 2008;43:442)
Dysgerminoma may develop by age 10 (BJOG 2008;115:737)

Case reports

Successful pregnancy using donor oocytes and oocyte transfer (Fertil Steril 2008;90:2015.e1)

Treatment

Early excision of gonads (J Gynecol Obstet Biol Reprod (Paris) 2009;38:220)
Estrogen and progesterone therapy

Microscopic (histologic) description

Hypoplastic (streak) gonads without primordial germ cells
In the absence of AMH, Müllerian ducts develop into normal internal female organs (uterus, fallopian tubes, cervix, vagina)

Additional references

OMIM: 46,XY Sex Reversal 1 [Accessed 15 January 2024], GeneReviews: Nonsyndromic Disorders of Testicular Development [Accessed 15 January 2024]

Testicular feminization

Definition / general

Male genotype (46,XY) but impaired or absent masculinization of male genitalia or development of male secondary sexual characteristics at puberty due to partial or complete inability of cells to respond to androgens (androgen insensitivity)
Most common type of male pseudohermaphroditism
Patients present with amenorrhea or sterility
Vagina but no uterus
Also, bilateral cryptorchid testes with nodular masses of immature tubules resembling Sertoli-Leydig tumor

Terminology

Also called androgen insensitivity syndrome (AIS)
Divided into three categories:
- Complete androgen insensitivity syndrome (CAIS): normal female external genitalia
- Mild androgen insensitivity syndrome (MAIS): normal male external genitalia
- Partial androgen insensitivity syndrome (PAIS): partially but not fully masculinized external genitalia

Etiology

Most commonly, a mutation in the androgen receptor (AR) gene
Other etiologies include: chromosomal abnormalities, dysfunctional androgen biosynthesis, developmental syndromes, teratogens

Clinical features

Depending on the severity of androgen insensitivity, patients may present with male, female or ambiguous phenotype
Given the presence of a Y chromosome (more specifically, SRY gene), gonads are testes regardless of phenotype
Physical exam may reveal a vagina but no ovaries or uterus

Prognostic factors

9% develop tumors in cryptorchid testis, which should be removed after puberty

Case reports

36 year old with abdominal seminoma (J Obstet Gynaecol Res 2004;30:109)

Treatment

Currently limited to symptomatic management, including sex assignment, genitoplasty, gonadectomy, hormone replacement, counseling

Gross images

AFIP images

Multiple hamartomas

Microscopic (histologic) description

Bilateral cryptorchid testes with nodular masses of immature tubules resembling Sertoli-Leydig tumor

Microscopic (histologic) images

AFIP images

Ovarian type
stroma with a
storiform pattern

Tubules containing
immature
Sertoli cells

Testis is composed
almost entirely of
stroma resembling
ovarian stroma

Hamartomas are
composed of Sertoli
and Leydig cells

Additional references

Wikipedia: Androgen Insensitivity Syndrome [Accessed 15 January 2024], eMedicine: Androgen Insensitivity Syndrome [Accessed 15 January 2024]

Dysgerminoma

Table of Contents

Definition / general

Malignant primitive germ cell tumor with no specific type of differentiation

Essential features

Most common malignant ovarian germ cell tumor; female counterpart to testicular seminoma
Most common in children and young women
Excellent prognosis with chemotherapy
Composed of sheets or nests of uniform cells with clear or eosinophilic cytoplasm and distinct cell membranes; nuclei are rounded, often with angulated edges; tumor often separated by fibrous septae containing cytotoxic T cells and epithelioid histiocytes that can extend into tumor
Positive for SALL4, OCT3/4, D2-40, CD117, PLAP

ICD coding

ICD-10: C56 - malignant neoplasm of ovary
ICD-11: 2C73.1 - dysgerminoma of ovary

Epidemiology

Constitutes 1 - 2% of all malignant ovarian tumors (Am J Surg Pathol 2021;45:1009)
Most common malignant germ cell tumor of ovary (50%)
Most common in children and young women

Sites

Ovary
Rarely, extraovarian sites, including abdomen, fallopian tube and uterus (J Pediatr Adolesc Gynecol 2021 May 11 [Epub ahead of print], Curr Probl Cancer 2021;45:100667, Indian J Pathol Microbiol 2018;61:590)

Pathophysiology

Unknown

Etiology

Arises from primordial germ cells of the ovary

Clinical features

Most common in children and young women
May present in pure form or as a component of a malignant mixed germ cell tumor
Present with abdominal pain or distention
Bilateral ovarian involvement in 10 - 15% of patients; involvement of contralateral ovary may be microscopic (Cancer Treat Rev 2008;34:427)
Extraovarian spread in 33% of cases
One of the most common neoplasms in pregnancy (Cancer Treat Rev 2008;34:427)
Rare association with gonadal dysgenesis and chromosome Y abnormalities; may arise from gonadoblastoma
Rare estrogenic manifestations

Diagnosis

Diagnosis informed by patient's age, radiology and laboratory values (e.g. elevated lactate dehydrogenase [LDH] levels) but ultimately made based on histologic examination of surgical specimen

Laboratory

Serum LDH often elevated (95%)
3 - 5% show low level hCG production related to the presence of multinucleated syncytiotrophoblastic giant cells that are not associated with cytotrophoblasts (Cancer Treat Rev 2008;34:427)
Serum placental alkaline phosphatase (PLAP) may be elevated (Cancer Treat Rev 2008;34:427)
Hypercalcemia may develop as a paraneoplastic syndrome, due to tumor production of 1,25-dihydroxyvitamin D3 (active form of vitamin D) (Cureus 2019;11:e6097)

Radiology description

On ultrasound, tends to appear as a highly vascularized, large, solid, lobulated adnexal mass with irregular internal echogenicity (Ultrasound Obstet Gynecol 2011;37:596)
Enhancing septa and areas of cystic change that may represent necrosis or hemorrhage may be seen; calcifications may manifest as a speckled pattern (Radiographics 2014;34:777)

Prognostic factors

Most tumors are stage I at diagnosis
Recurrence rate is low
KIT mutations associated with advanced stage at presentation (Cancer 2011;117:2096)
With treatment, excellent prognosis and overall survival > 90%
Dysgerminoma patients have the most favorable outcomes compared with those with other malignant germ cell tumors; young age, low grade and surgery are significant predictors for improved survival (Oncol Res Treat 2021;44:145)

Case reports

16 year old girl with Swyer syndrome underwent prophylactic bilateral gonadectomy and salpingectomies and was found to have dysgerminoma solely within the fallopian tube (J Pediatr Adolesc Gynecol 2021 May 11 [Epub ahead of print])
19 year old woman with 29 cm dysgerminoma and pseudo-Meigs syndrome (Medicine (Baltimore) 2021;100:e26319)
22 year old woman with uncommon vaginal metastasis by dysgerminoma (Medicina (Kaunas) 2021;57:534)
26 year old pregnant woman with extraovarian (abdominal) dysgerminoma (Curr Probl Cancer 2021;45:100667)
27 year old woman with Swyer syndrome and stage IIA dysgerminoma in streak gonad (Gynecol Endocrinol 2018;34:464)

Treatment

Radiosensitive but responds very well to cisplatin based chemotherapy, with overall survival > 90% (Cancer Treat Rev 2008;34:427)
Fertility sparing surgery in patients with pure ovarian dysgerminoma with additional staging surgery, including retroperitoneal lymph node dissection to determine stage IA patients exempt from adjuvant chemotherapy (J Adolesc Young Adult Oncol 2021;10:303)

Gross description

Usually > 10 cm
Solid and lobulated with fleshy tan-white cut surface (Am J Surg Pathol 2021;45:1009)
Hemorrhage and necrosis with cystic degeneration may be present
Presence of calcifications may suggest an associated component of gonadoblastoma but not specific

Gross images

AFIP images

Solid, fleshy, lobulated

Cystic degeneration

Images hosted on other servers:

Pale brown parenchyma and central scarring

Frozen section description

May favor diagnosis of high grade malignant germ cell tumor or malignant epithelioid neoplasm on frozen section; however, final diagnosis should be deferred to permanent sections
Clear cytoplasm or distinct cell membranes may not be appreciated on frozen section due to artifact
May mimic large cell lymphoma, both of which share similar gross appearance, large neoplastic nuclei and infiltrating background lymphocytes (Int J Gynecol Pathol 2020;39:79, Int J Surg Pathol 2019;27:387)
- Features favoring dysgerminoma include presence of fibrous septae and squared off nuclei
- Thickening of the fallopian tube is more suggestive of lymphoma (Int J Gynecol Pathol 2008;27:353)
May mimic small cell carcinoma, hypercalcemic type, both of which typically occur in young women and show overlapping features, including paraneoplastic hypercalcemia (Semin Diagn Pathol 2019;36:246)
- Features favoring dysgerminoma include elevated LDH levels, moderately abundant cytoplasm
- In small cell carcinoma, hypercalcemic type, tumor cells usually have scant cytoplasm unless admixed component of large cell variant present

Frozen section images

Contributed by Sharon Song, M.D., M.S.

Necrosis and calcifications

Nests of tumor cells

Sheets and follicle-like spaces

Nests of tumor cells

Sheets of tumor cells

Microscopic (histologic) description

Histomorphology identical to that of testicular seminoma
In a well preserved specimen, characteristic appearance of nests of large, uniform polygonal cells with clear or eosinophilic cytoplasm and distinct cell membranes (alveolar pattern)
May also show sheets, cords, macronodules, insular growth, microcysts, tubules, pseudoglandular spaces or trabeculae (Arch Pathol Lab Med 2014;138:351, Am J Surg Pathol 2021;45:1009)
Rarely may show pseudopapillary or macrofollicular growth pattern (Iran J Pathol 2018;13:94)
Tumor separated by fibrous septae containing cytotoxic T cells and epithelioid histiocytes, often with spillover into tumor; plasma cells, eosinophils, Langhans type giant cells, syncytiotrophoblasts, noncaseating granulomas or lymphoid follicles with germinal centers may be present (Am J Surg Pathol 2021;45:1009)
Stroma usually loose and delicate but in some cases may be hyalinized, myxoid or luteinized
Numerous mitotic figures
Rare cases show syncytiotrophoblastic cells, singly or in clusters, without cytotrophoblastic cells; sample tumor thoroughly to exclude choriocarcinoma
Extensive hemorrhage and necrosis may be present with dystrophic calcification; if large areas of dystrophic calcification seen in the absence of necrosis, may be a gonadoblastoma
- As gonadoblastomas give rise to dysgerminomas, thorough sampling indicated to rule out its presence

Microscopic (histologic) images

Contributed by Sharon Song, M.D.

Medium sized cells

Eosinophilic cytoplasm

Cells growing as cords

Varied growth pattern

Nested growth

Inflammation in fibrous septae

Poor preservation

Epithelioid cytomorphology

OCT3/4

SALL4

CD117

AFIP images

Lymphocytes

Cords

Solid tubular pattern

Syncytiotrophoblasts

Cytology description

Uniform population of medium to large sized cells (Diagn Cytopathol 2020;48:356)
Centrally located, round to oval nuclei, often with angulated, squared off borders
Vesicular, finely granular or coarse chromatin
Prominent single or multiple nucleoli
With poor fixation, cells may show loss of cohesion, nuclei can appear hyperchromatic and cytoplasm may appear scant and eosinophilic, mimicking cells of embryonal carcinoma

Positive stains

OCT3/4 (nuclear), CD117 (KIT; membranous), D2-40 (membranous and cytoplasmic) (Histopathology 2013;62:71)
NANOG (nuclear) and SALL4 (nuclear) stem cell markers
PLAP (membranous and cytoplasmic)
May focally express keratins with cytoplasmic dot or rim-like staining: CAM 5.2 (positive in up to 10% of tumor cells in < 50% of dysgerminomas); AE1 / AE3 and CK7 (positive in up to 10% of tumor cells in < 25% of dysgerminomas)
hCG, inhibin, glypican 3 and CK7 can highlight syncytiotrophoblastic giant cells; can search for these cells in patients with moderate serum hCG elevation (Histopathology 2013;62:71)

Negative stains

EMA, CEA, hCG, CD30, glypican 3, AFP, SOX2

Molecular / cytogenetics description

Isochromosome 12p in 81% (Pathol Res Pract 2012;208:628, Mod Pathol 2006;19:611)
KIT mutations in exon 17 codon 816 or KIT amplification detected in approximately 33% of cases and associated with advanced stage at presentation (Cancer 2011;117:2096)
- As this KIT mutation involves exon 17, not exon 11 as in gastrointestinal stromal tumors, these cases are not responsive to KIT receptor inhibitors

Sample pathology report

Left ovary, left oophorectomy:
- Dysgerminoma (11 cm) (see synoptic report)
- No ovarian surface involvement identified

Differential diagnosis

Important to rule out other types of mixed germ cell tumor
- Embryonal carcinoma:
  - Mimicker, especially in poorly fixed specimens
  - Nuclei are more pleomorphic, with amphophilic cytoplasm and frequent apoptotic cells
  - Lack fibrous septae containing lymphocytes
  - CD30+, SOX2+, NANOG+, OCT3/4+, CD117-, D2-40-
- Yolk sac tumor:
  - Classically variable morphologic patterns (commonly reticular / microcystic)
  - Lacks fibrous septae containing lymphocytes
  - Glypican 3+, AFP+, OCT3/4-, CD117-, D2-40-

Clear cell carcinoma:
- Tubulocystic or papillary architecture
- Usually older patients
- EMA+, Napsin A+, racemase+, HNF-1B+, PAX8+, SALL4-, OCT3/4-, CD117-, D2-40-

Lymphoma:
- Lacks fibrous septae
- May be associated with thickened fallopian tube
- Positive lymphoid markers and IgH clonality

Small cell carcinoma, hypercalcemic type:
- Tumor cells are usually small with scant cytoplasm; may see larger eosinophilic cells with rhabdoid inclusions in the large cell variant
- Pseudofollicular spaces
- EMA+, loss of SMARCA4, SALL4-

Board review style question #1

Choriocarcinoma
Dysgerminoma
Embryonal carcinoma
Mature cystic teratoma
Mixed germ cell tumor

Board review style answer #1

B. Dysgerminoma is the most common malignant ovarian germ cell tumor.

Comment Here

Reference: Dysgerminoma

Board review style question #2

AFP, SALL4, OCT3/4, hCG
D2-40, CD117, OCT3/4, SALL4
OCT3/4, EMA, hCG, SALL4
PLAP, AFP, hCG, AE1 / AE3

Board review style answer #2

B. D2-40, CD117, OCT3/4, SALL4. SALL4 is positive in germ cell tumors. OCT3/4 positivity narrows the differential of germ cell tumors to dysgerminomas and embryonal carcinomas. Dysgerminomas are positive for CD117 and D2-40.

Comment Here

Reference: Dysgerminoma

Ectopic decidual reaction

Table of Contents

Definition / general

Presence of ectopic decidualized uterine stromal cells in the ovary

Essential features

Presence of ectopic decidualized uterine stromal cells in the ovary
Usually an incidental finding associated with pregnancy
Typically transient, will regress 4 - 6 weeks postpartum

Terminology

Ectopic decidua or ovarian deciduosis

Epidemiology

Associated with pregnancy
In a study of 307 consecutive caesarean sections, macroscopic deciduosis was found in 31 (10.1%) cases (Eur J Obstet Gynecol Reprod Biol 2016;197:54)
Can also develop as a result of exogenous progesterone effect

Sites

Ectopic decidua have been described in the cervix, ovary and fallopian tube; also peritoneal surface, appendix, bladder, small and large intestine, mesentery, lymph nodes

Pathophysiology

High levels of estrogen and progesterone during pregnancy induce mesenchymal fibroblast differentiation into decidual cells (Eur J Obstet Gynecol Reprod Biol 2016;197:54, Pathol Res Pract 1993;189:352, Korean J Obstet Gynecol 2011;54:373)

Diagnosis

Often an incidental finding in surgical specimens or a discrete nodule / mass discovered during caesarean section

Radiology description

When the ovarian deciduosis is mass forming, it may be difficult to differentiate from a neoplastic process (Case Rep Obstet Gynecol 2015;2015:217367)

Case reports

31 year old woman with decidualized ovarian mass mimicking malignancy (Case Rep Obstet Gynecol 2015;2015:217367)
32 year old woman with ovarian deciduosis in pregnancy (Korean J Obstet Gynecol 2011;54:373)
33 year old woman with ovarian and peritoneal deciduosis in pregnancy (Diagn Histopathol 2011;17:313)

Treatment

Benign entity, no further treatment necessary; usually regresses 4 - 6 weeks postpartum
If mass forming and showing worrisome features for malignancy on imaging, the lesion is excised to establish the correct diagnosis
Reference: Case Rep Obstet Gynecol 2015;2015:217367

Clinical images

Images hosted on other servers:

Macroscopic appearance

Microscopic (histologic) description

Large polygonal cells with abundant eosinophilic cytoplasm, bland nuclei and visible nucleoli
No glands present (to differentiate it from decidualized endometriosis)
Reference: Case Rep Obstet Gynecol 2015;2015:217367

Microscopic (histologic) images

Contributed by Aurelia Busca, M.D., Ph.D.

Deciduosis of ovarian stroma

Areas of deciduosis

Ovarian surface adhesions with deciduosis

Ovarian deciduosis in a patient on progestin therapy

Positive stains

Negative stains

Cytokeratin
Mesothelial markers (WT1, calretinin)

Sample pathology report

Ovary, oophorectomy:
- Benign ovary with focal deciduosis

Differential diagnosis

Endometriosis:
- Can also undergo decidualization during pregnancy
- Main difference is that ectopic decidua have no glands (Gynecol Obstet Invest 2008;66:241)
Epithelial ovarian neoplasm when mass forming:
- Histologic features are bland and mitotic activity is low in deciduosis
- Absence of glands in deciduosis
- Epithelial proliferation with variable atypia and architectural complexity in epithelial neoplasms
Peritoneal mesothelioma or peritoneal carcinomatosis when there is additional involvement of peritoneal surface:
- Histologic features are bland in deciduosis; also, context of pregnancy is helpful
- Increased atypia, proliferation and architectural complexity in carcinomatosis and mesothelioma
Metastatic squamous cell carcinoma with keratinization:
- More atypical
- Presence of necrosis
- Mitotically active
- Cytokeratin+

Additional references

Gynecol Obstet Fertil 2012;40:235, BMJ Case Rep 2014;2014:bcr2013202480, Gynecol Oncol Rep 2021;37:100827

Board review style question #1

Which of the following is true about the ovarian change illustrated in the figure shown above?

It is a malignant process
It is only seen in the ovary
It requires lymph node sampling and full staging for management
More sampling is required to demonstrate the presence of glands
Typically associated with pregnancy

Board review style answer #1

E. Typically associated with pregnancy. The image shows ovarian deciduosis, which is associated with pregnancy, is typically transient and resolves postpartum. Answer A is incorrect because ovarian deciduosis is a benign process typically associated with pregnancy. Answer D is incorrect because it consists of stromal tissue, without glands. Answer C is incorrect because it typically regresses after pregnancy and does not require treatment. Answer B is incorrect because deciduosis can be seen at other sites (cervix, peritoneal cavity, etc.).

Comment Here

Reference: Ectopic decidual reaction

Board review style question #2

Which of the following is true about ovarian deciduosis?

It can be mistaken for endometriosis
It is CD10 negative by immunohistochemistry
Presence of nuclear atypia indicates malignant potential
Responds to chemotherapy
Treatment includes resection with or without chemotherapy

Board review style answer #2

A. It can be mistaken for endometriosis with stromal decidualization but unlike endometriosis, it does not contain glands. Answer B is incorrect because both have CD10 positive stroma. Answers C, D and E are incorrect because ovarian deciduosis is a benign incidental process and does not require treatment.

Comment Here

Reference: Ectopic decidual reaction

Embryonal carcinoma

Table of Contents

Definition / general

Primitive appearing ovarian tumor that is histologically similar to embryonal carcinoma of the testis
Often a component in a malignant mixed germ cell tumor of the ovary; the pure form is exceedingly rare

Essential features

Median age is 14 - 15 years; patients often present with precocious puberty, vaginal bleeding, infertility, amenorrhea and mild hirsutism (Semin Diagn Pathol 2023;40:22)
Both serum alpha fetoprotein (AFP) and beta human chorionic gonadotropin (βhCG) can be elevated (which can result in a positive pregnancy test) (Semin Diagn Pathol 2023;40:22)
Positive IHC expression with OCT 3/4, CD30, SOX2, SALL4 and βhCG (if syncytiotrophoblast is present); negative for glypican and CD117
Worst prognosis among germ cell tumors, even at low stage (Cancer 1976;38:2420)
Large, primitive pleomorphic cells with abundant cytoplasm arranged in sheets and nests

ICD coding

ICD-O: 9070/3 - embryonal carcinoma, NOS
ICD-11: 2C73.Y & XH8MB9 - other specified malignant neoplasms of the ovary & embryonal carcinoma, NOS

Epidemiology

Primarily in adolescents and young women with average age of 14 - 15 years (Cancer 1976;38:2420, Semin Diagn Pathol 2023;40:22)
First described in 1976 by Kurman and Norris as a distinct type of malignant germ cell neoplasm to distinguish from endodermal sinus tumor of ovary (Cancer 1976;38:2420)
Estimated to account for < 1% of malignant ovarian germ cell tumors (Cancer 1976;38:2420)

Sites

Ovary
Metastasis is possible to liver, lungs, retroperitoneal lymph nodes, peritoneal surfaces in up to half of all cases (Cancer 1976;38:2420)

Pathophysiology

Chromosome 12 abnormalities in 5 of 6 cases analyzed by FISH (iscochromosome 12p or 12p amplification) (Hum Pathol 2010;41:716)

Etiology

Unknown

Clinical features

Hormonal manifestation, including precocious puberty, vaginal bleeding, infertility, amenorrhea and mild hirsutism, in approximately half of patients (Cancer 1976;38:2420, Semin Diagn Pathol 2023;40:22)
May show serum elevation of AFP or βhCG with positive pregnancy test
Palpable unilateral abdominal or pelvic mass in 80% of patients (Cancer 1976;38:2420)
May present with abdominal pain, fever, menstrual irregularities or weight loss (Cancer 1976;38:2420)
Clinical evidence of an endocrinopathy is seen in approximately half of patients (Cancer 1976;38:2420)

Diagnosis

Large, unilateral abdominal or adnexal mass on imaging (Ultrasound Obstet Gynecol 2021;57:987, Cancer 1976;38:2420)
Pregnancy test may be positive (increased βhCG) (Cancer 1976;38:2420, Semin Diagn Pathol 2023;40:22)
AFP may be increased (Cancer 1976;38:2420, Semin Diagn Pathol 2023;40:22)
Definitive diagnosis made by histologic examination of surgical specimen (Semin Diagn Pathol 2023;40:22)

Laboratory

Serum βhCG elevation resulting in positive pregnancy test (Semin Diagn Pathol 2023;40:22)
Serum AFP may be elevated

Radiology description

Unilateral, solid mass with cystic areas, irregular margins, rich vascularization (Radiographics 2014;34:777, Ultrasound Obstet Gynecol 2021;57:987)
No reported preference for right or left ovary (Cancer 1976;38:2420)
1 embryonal carcinoma of the ovary measured at 216 mm (Ultrasound Obstet Gynecol 2021;57:987)

Radiology images

Images hosted on other servers:

Ultrasound

CT abdominal mass & ascites

Prognostic factors

Worst prognosis among germ cell tumors
5 year survival rate for stage I cases: 50% (Semin Diagn Pathol 2023;40:22, Cancer 1976;38:2420)

Case reports

11 year old girl with large abdominal mass and ascites (Med Arch 2018;72:371)
13 year old girl with abdominal pain and 25 cm mass (Iran J Pathol 2016;11:66)
19 year old woman with abdominal pain and massive ascites (J Pediatr Adolesc Gynecol 2011;24:e1)
53 year old woman with irregular menses, pelvic pain and positive pregnancy test (Gynecol Oncol 1996;63:133)

Treatment

Surgery with adjuvant chemotherapy
- Bleomycin, etoposide and cisplatin (BEP) most common chemotherapy regimen (Ann Oncol 2018;29:iv1)

Gross description

Large, with median size of 17 cm (Cancer 1976;38:2420)
Cut surface is gray-white or yellow (Cancer 1976;38:2420)
With or without cysts containing hemorrhage or necrosis (Cancer 1976;38:2420)

Gross images

Images hosted on other servers:

External and cut surface of ovarian tumor

Frozen section description

High grade malignant neoplasm with necrosis

Frozen section images

Contributed by Jessica L. Bentz, M.D.

Pleomorphism, cytologic atypia

Pleomorphic cells, cytologic atypia, necrosis

Pleomorphism, cytologic atypia, apoptosis

Microscopic (histologic) description

Similar to embryonal carcinoma of the testis (Cancer 1976;38:2420)
Often mixed with other malignant germ cell tumor components (Semin Diagn Pathol 2023;40:22, Cancer 1976;38:2420)
Sheets and nests of large, primitive pleomorphic cells with abundant cytoplasm (Semin Diagn Pathol 2023;40:22, Cancer 1976;38:2420)
Round nuclei with coarse membranes, at least 1 prominent nucleolus and brisk mitotic activity (Semin Diagn Pathol 2023;40:22)
Occasional papillae and gland morphology (Semin Diagn Pathol 2023;40:22)
Syncytiotrophoblast-like tumor cells are seen (hCG+) around sheets of tumor cells or within stroma (Semin Diagn Pathol 2023;40:22, Cancer 1976;38:2420)
Hyaline globules, similar to yolk sac tumor, may also be present (Semin Diagn Pathol 2023;40:22)
Glandular pattern may mimic endometrial carcinoma or glandular morphology of a yolk sac tumor (Semin Diagn Pathol 2023;40:22)

Microscopic (histologic) images

Contributed by Jessica L. Bentz, M.D. and AFIP

Primitive atypical cells

Mitoses and apoptotic debris

Papillary pattern

CD30

OCT 3/4

CK AE1 / AE3

Virtual slides

Images hosted on other servers:

OCT4 positive in embryonal carcinoma component

CD30 positive in embryonal carcinoma component

Immunofluorescence description

Chromosome 12p overrepresentation
Isochromosome 12p

Positive stains

SALL4, OCT 3/4 and SOX2 nuclear positivity (Am J Surg Pathol 2009;33:894, Histopathology 2013;62:71)
CD30 membranous positivity (Hum Pathol 2010;41:716)
- OCT 3/4 more sensitive than CD30 but can also be expressed in dysgerminoma (Histopathology 2013;62:71)
AE1 / AE3 (Histopathology 2013;62:71)
βhCG positive in syncytiotrophoblastic cells (Semin Diagn Pathol 2023;40:22)
AFP may be expressed in both tumor cells and hyaline globules (Semin Diagn Pathol 2023;40:22)
CD30 expression might decrease after chemotherapy (Hum Pathol 2006;37:662)

Negative stains

Molecular / cytogenetics description

Chromosome 12p FISH can be helpful in establishing a diagnosis in conjunction with IHC (Hum Pathol 2010;41:716)

Sample pathology report

Left ovary and fallopian tube, left salpingo-oophorectomy:
- Malignant mixed germ cell tumor (see comment)
- Comment: The ovarian tumor is compatible with a malignant mixed germ cell tumor composed of embryonal carcinoma (__%) (e.g., yolk sac tumor __%; immature teratoma __%; with or without choriocarcinoma __%). Sheets of pleomorphic, primitive cells with brisk mitotic activity, tumor cell necrosis and positive expression of OCT 3/4 and CD30 are consistent with a component of embryonal carcinoma. Syncytiotrophoblastic cells are present (hCG+), which can raise concern for a component of choriocarcinoma; however, the presence of isolated syncytiotrophoblastic cells has been reported in embryonal carcinoma and there is no evidence of choriocarcinoma in examined sections of this extensively sampled ovarian tumor.

Differential diagnosis

Yolk sac tumor:
- Microcystic / reticular, polyvesicular vitelline and festoon-like patterns
- Less nuclear pleomorphism
- Positive expression with AFP and glypican 3
- Negative for OCT 3/4 or SOX2
Dysgerminoma:
- Lack of glandular and papillary architecture
- Nuclei smaller / more monotonous and less pleomorphic
- Presence of lymphocytic or granulomatous stromal infiltrate
- CD30 negative
- CD117 and D2-40 positive
- No diffuse keratin expression
Choriocarcinoma:
- Mixture of multinucleated syncytiotrophoblast and mononucleated cytotrophoblast
- More extensive hemorrhage with dilated sinusoids
- hCG, inhibin and GATA3 positive
- Negative for CD30 and OCT 3/4
Poorly or undifferentiated carcinoma:
- Late reproductive age and postmenopausal patients
- Usually has a glandular component
- Typically SALL4, AFP and hCG negative
Juvenile granulosa cell tumor:
- Follicle-like spaces with luteinized tumor cells
- Lack of syncytiotrophoblast
- Positive for inhibin, calretinin and negative for AFP
Poorly differentiated Sertoli-Leydig cell tumor (SLCT):
- Portion of the tumor will contain a better differentiated component of SLCT
- Positive for inhibin and calretinin

Board review style question #1

What is the most specific immunohistochemical stain for an embryonal carcinoma of the ovary?

AFP
βhCG
CD30
CD117
OCT 3/4

Board review style answer #1

C. CD30. CD30 is the most specific marker for embryonal carcinoma of the ovary. Answer A is incorrect because AFP is a marker for yolk sac tumor. Answer D is incorrect because CD117 highlights dysgerminoma. Answer B is incorrect because βhCG is a marker for syncytiotrophoblast and choriocarcinoma. Answer E is incorrect because while OCT 3/4 can stain embryonal carcinoma of the ovary, it also stains dysgerminoma, whereas dysgerminoma should be negative for CD30.

Comment Here

Reference: Embryonal carcinoma

Board review style question #2

The glandular pattern of embryonal carcinoma, particularly if present with hyaline globules, can mimic which of the following tumors?

Choriocarcinoma
Dysgerminoma
Leydig cell tumor
Sertoli-Leydig cell tumor
Yolk sac tumor

Board review style answer #2

E. Yolk sac tumor. The glandular pattern of embryonal carcinoma can mimic a yolk sac tumor, particularly in the presence of hyaline globules. Glandular architecture can also mimic a poorly differentiated carcinoma. Answer A is incorrect because choriocarcinoma will have a mixture of syncytiotrophoblast and cytotrophoblast without a prominent glandular architecture. Answer B is incorrect because dysgerminoma will not show a glandular architecture and will have fibrous septa with lymphocytic or granulomatous infiltrate. Answer D is incorrect because Sertoli-Leydig cell tumors will not show a prominent glandular architecture and stain with inhibin / calretinin. Answer C is incorrect because Leydig cell tumors are rare and arise in the hilum and have Reinke crystals.

Comment Here

Reference: Embryonal carcinoma

Endometrial stromal sarcoma

Table of Contents

Definition / general

Composed of cells resembling endometrial stromal cells in the proliferative stage
Rare in extra-uterine sites

Sites

Most common site is uterus
Extrauterine sites rare - includes ovary, fallopian tube, pelvic cavity, abdominal cavity, and retroperitoneum (Int J Gynecol Pathol 1993;12:282)

Clinical features

Lower abdominal pain
20 to 76 years, mean average, 54 years (Cancer 1984;53:1143)

Radiology description

Ultrasound / USG: solid cystic mass
CT scan with IV contrast: peripheral enhancement

Prognostic factors

Behavior resembles high stage primary uterine ESS (Int J Gynecol Pathol 1993;12:282)

Case reports

18 month old infant with endometriosis associated serous borderline tumor and endometrial stromal sarcoma of the ovary (Int J Gynecol Pathol 2012;31:98)
50 year old woman with endometrial stromal sarcoma presenting as an ovarian cyst (SEAJCRR 2013;2:139)
56 year old woman with undifferentiated endometrial sarcoma of ovary (Patholog Res Int 2010;2010:608519)

Treatment

Salphingo-opherectomy

Gross description

Solid cystic mass (SEAJCRR 2013;2:139)

Microscopic (histologic) description

High or low grade
Low grade: infiltrative and diffuse proliferation of uniform round or oval cells, abundant small vessels
Undifferentiated: pleomorphic round / oval to spindled cells, high mitotic rate, necrosis

Microscopic (histologic) images

AFIP images

Endometrioid stromal sarcoma

With sex cord-like differentiation

Reticulin stain

Metastatic to omentum

Images hosted on other servers:

High grade tumor

Monotonous cells

Endometrium-like glands

CD10+

Positive stains

Vimentin and patchy strong staining for CD10

Negative stains

AE1/AE3, CD20, CD31, c-kit, desmin, LCA, S100

Differential diagnosis

Malignant mixed Müllerian tumor: smooth / skeletal muscle / carcinoma cells
Metastatic spread from uterine ESS: primary mass in uterus
Sex cord stromal tumor

Endometrioid borderline tumor

Table of Contents

Definition / general | Microscopic (histologic) description | Microscopic (histologic) images | Differential diagnosis

Definition / general

Rare (< 200 cases reported)
Mean age 55 years, range 28-86 years
97% present with stage I disease
36% associated with endometriosis
Typically no recurrent disease or metastasis on follow-up, even if intraepithelial carcinoma or microinvasion (Am J Surg Pathol 2003;27:1253, Am J Surg Pathol 2000;24:1465)

Microscopic (histologic) description

Composed of aggregates, glands or cysts of endometrioid-type epithelium that is atypical or cytologically malignant
May have architectural atypia including non-branching villous papillae, cribriform glands but lacks destructive stromal invasion, glandular confluence or stromal disappearance
Often has adenofibromatous pattern (47%) or squamous differentiation (47%)
May have foci of intraepithelial carcinoma (7%, high grade / grade 3 nuclei are large, pleomorphic with coarse chromatin or hypochromasia, large irregular nucleoli; also many mitotic figures; associated with villoglandular architecture or microinvasion)
Microinvasion if areas of invasion are 10 mm² or less (7%)

Microscopic (histologic) images

AFIP images

With intraepithelial carcinoma, grade 1

Atypical
endometrioid
glands separated
by stroma

Differential diagnosis

Atypical endometriosis: will have endometrial stroma

Endometrioid carcinoma

Table of Contents

Definition / general

Ovarian carcinoma resembling endometrioid adenocarcinoma of the endometrium

Essential features

Most common ovarian endometrioid tumor
Usually low grade and diagnosed at early stages
May be associated with endometriosis and adenofibroma

Terminology

Seromucinous carcinoma is included as a subtype of endometrioid ovarian carcinoma in the 2020 WHO blue book for female genital tumors

ICD coding

ICD-11: 2C73.01 - endometrioid adenocarcinoma of ovary

Epidemiology

10% of primary ovarian carcinomas (J Natl Cancer Inst 2019;111:60)
Mean patient age is 55 years
Associated with endometriosis / endometriotic cyst (15%), endometrioid adenofibroma, synchronous endometrial endometrioid adenocarcinoma or endometrial hyperplasia (15 - 30%) (Eur J Gynaecol Oncol 2015;36:21)
Risk factors: endometriosis, hormone replacement therapy, first degree family history of breast carcinoma (Lancet Oncol 2012;13:385, J Clin Oncol 2016;34:2888)
May occur in the setting of Lynch syndrome (Gynecol Oncol 2018;150:92, Am J Surg Pathol 2014;38:1173)

Sites

Ovaries

Pathophysiology

Most common molecular alterations: WNT / beta catenin signaling pathway (CTNNB1 - 53%), PI3K pathway (PIK3CA - 40% and PTEN - 17%) (Mod Pathol 2014;27:128)

Etiology

Unknown

Clinical features

Most common symptoms are abdominal distention and pain
Background endometriosis is not associated with survival (J Gynecol Oncol 2018;29:e18)

Laboratory

Elevated CA-125 (Asian Pac J Cancer Prev 2013;14:4545)

Radiology description

Most common appearance is a cystic lesion (Acta Radiol 2016;57:758)

Prognostic factors

Stage is the most important prognostic factor
Survival rates: > 95% for stage IA and IB and 51% for stage III and IV (J Natl Cancer Inst 2019;111:60)
Most tumors are confined to the ovary at diagnosis
CTNNB1 (beta catenin) mutation and low tumor grade are associated with a favorable outcome (Histopathology 2019;74:452, Am J Surg Pathol 2021;45:68)
Synchronous endometrioid carcinomas of the endometrium and ovaries are often clonally related but typically have indolent clinical behavior (J Natl Cancer Inst 2016;108:djv428, J Natl Cancer Inst 2016;108:djv427, Mod Pathol 2021;34:994)

Case reports

39 year old woman with Cowden syndrome incidentally detected from a metachronous ovarian endometrioid carcinoma (BMC Cancer 2019;19:1014)
41 year old woman with mixed adenocarcinoma and yolk sac tumor (Int J Clin Exp Pathol 2019;12:3549)
45 year old woman with endometrial endometrioid and synchronous bilateral endometrioid ovarian cancer (Anticancer Res 2017;37:969)
52 year old woman with ovarian mass on computed tomography imaging and a raised CA-125 (Case of the Month #500)
65 year old postmenopausal woman with ovarian endometrioid carcinoma presenting as an abdominal wall abscess (J Midlife Health 2018;9:222)

Treatment

Surgery for early stage cancers
Adjuvant chemotherapy is associated with survival benefit for patients with inadequately staged and grade 2 stage I cancers (Gynecol Oncol 2020;156:315)
Patients with advanced stage disease (FIGO III and IV) might benefit from platinum based chemotherapy (Future Oncol 2018;14:123)

Gross description

Usually unilateral; only 5% bilateral
Cystic with solid component and areas of hemorrhage
With or without polypoid nodule in endometriotic cyst
Mean tumor size: 11 cm (range: 3 - 22 cm)
Reference: Arch Gynecol Obstet 2008;278:209

Gross images

AFIP images

Ovary and uterus with tumor

Tumor arising in endometriotic cyst

Contributed by Ayse Ayhan, M.D.

Bilateral endometrioid cancer, left: 730g, 14.5x12.6cm

Smooth ovarian capsule

Multiple papillary excrescences

Papillary / nodular solid component

Partially opened cyst wall

Cyst wall outer surface

Solid / papillary areas

Serial sections

Cross section

Outer aspect

Partially opened cyst wall

Fixation

Ovarian mass lesion

Frozen section description

Depending on histologic grade, a combination of glandular and solid areas may be seen
Squamous differentiation may be present
Differential diagnosis depends on histologic grade but includes metastatic carcinoma, well differentiated Sertoli-Leydig cell tumor and serous carcinoma (Arch Pathol Lab Med 2019;143:47)

Frozen section images

Contributed by Ozlen Saglam, M.D.

Endometrioid carcinoma with papillary architecture

Low grade nuclear features

Microscopic (histologic) description

Most common morphologic pattern is confluent (back to back) glands
Stromal invasion is usually by expansion; rarely, destructive stromal invasion can be observed
Squamous metaplasia (morules or keratin pearls), cytoplasmic mucin, intracytoplasmic vacuoles, oncocytic changes, clear cell changes and cilia and sex cord-like elements (sertoliform) can be observed; none of these morphologic features affect the histologic grade (Am J Surg Pathol 2007;31:1203)
Histologic grading: same as for endometrial endometrioid adenocarcinoma
- FIGO grade 1: less than 5% solid component
- FIGO grade 2: 6 - 50% solid component
- FIGO grade 3: more than 50% solid component
Endometriosis or adenofibroma may be present in the background
Vascular invasion is rare
Might be associated with serous, undifferentiated carcinoma and yolk sac tumor (mixed carcinoma) (Am J Surg Pathol 1994;18:687, Am J Surg Pathol 1996;20:1056)
Morphologic features in favor of synchronous endometrial and ovarian tumors:
- Both tumors are low grade
- No myometrial invasion or less than 50% myometrial inivasion
- There is no involvement in any other anatomical sites
- No lymphovascular involvement in either tumor
- Background atypical endometrial hyperplasia in the endometrium
- Unilateral ovarian involvement and unifocal parenchymal distribution of tumor
- Lack of ovarian capsular, multifocal or hilar involvement
- Presence of endometriosis or adenofibroma in the ovary (Int J Gynecol Pathol 2019;38:S75)

Microscopic (histologic) images

Contributed by Ozlen Saglam, M.D.

Endometrioid adenocarcinoma, FIGO grade 1

Endometrioid adenocarcinoma, FIGO grade 2

Endometrioid adenocarcinoma, FIGO grade 3

Squamous differentiation

Peritoneal keratin granuloma

Ciliated cells

Secretory change

Oncocytic cells

Spindle variant

Trabecular pattern
resembling sex
cord stromal tumor

Endometrioid cancer and background adenofibroma

Endometrioid carcinoma and background adenofibroma

Endometriosis

Contributed by Sakinah A Thiryayi, M.D. and Gulisa Turashvili, M.D., Ph.D. (Case #500)

Glandular architecture

Back to back glands

Low grade cytology

Cellular intervening stroma

Plump stromal cells

Inhibin

p53

Virtual slides

Images hosted on other servers:

FIGO grade 1, background endometriosis

Cytology description

Large cohesive cell clusters
Mild nuclear membrane irregularities
May see squamous differentiation
Detection in pelvic washing: sensitivity 58%, specificity 89% Cancer 2004;102:150

Positive stains

Keratin cocktails, EMA, CK7, PAX8 (15% negative), ER and PR (Semin Diagn Pathol 2005;22:3, Int J Gynecol Pathol 2016;35:430)
p53: wild / normal type expression (most tumors) (Int J Gynecol Pathol 2016;35:430, Am J Surg Pathol 2018;42:534)
- High grade endometrioid cancers might demonstrate mutational pattern (nuclear staining in > 80% of cells, complete absence of staining, diffuse cytoplasmic staining)
Mismatch repair protein deficiency has been reported in up to 23% of tumors (Gynecol Oncol 2020;156:669, Am J Surg Pathol 2019;43:235)

Negative stains

WT1 (10 - 14% can express) (Int J Gynecol Pathol 2019;38:353)
Napsin A
CDX2
SATB2 (15% positive in squamous morules)
Inhibin

Molecular / cytogenetics description

Ovarian endometrioid cancers and associated endometriosis share mutations in majority of cases (85 - 90%) (J Pathol 2018;245:265)
CTNNB1 (53%), PIK3CA (40%), KRAS (33%), ARID1A (30%) and PTEN (17%) are common mutations (Cancer Cell 2007;11:321, Mod Pathol 2014;27:128)
The Cancer Genome Atlas (TCGA) molecular classifiers for endometrial carcinoma has categorized ovarian endometrioid carcinoma into prognostically significant groups (Mod Pathol 2017;30:1748)

Sample pathology report

Left ovary and fallopian tube, salpingo-oophorectomy:
- Endometrioid adenocarcinoma, FIGO grade 1 (see synoptic report)
- Tumor size: 8.5 cm
- Ovarian surface: not involved by carcinoma
- Fallopian tube: not involved by carcinoma
- Additional findings: background endometriotic cyst

Differential diagnosis

Adult granulosa cell tumor:
- Presence of other patterns throughout the tumor
- Squamous differentiation in endometroid carcinoma
- Nuclear grooves in adult granulosa cell tumor
- Adult granulosa cell tumor: inhibin+ and EMA-
Sertoli cell tumor / Sertoli-Leydig cell tumor:
- Presence of other architectural patterns
- Leydig cells
- Heterologous elements of Sertoli-Leydig cell tumor (if present)
- Presence of squamous differentiation in endometrioid carcinoma
- Sertoli-Leydig cell tumor: inhibin A+ and EMA-
High grade serous carcinoma:
- Architecture: solid, papillary, labyrinthine, glandular
- Nuclei are large
- Nuclear size variability > 3 fold
- High mitotic activity (> 12 mitoses per 10 high power fields)
Metastatic colonic carcinoma:
- Multinodular growth
- Presence of glands with dirty necrosis
- Metastatic colonic carcinoma: CDX2+, CK20+
Metastatic endometrial endometrioid adenocarcinoma:
- Metastatic endometrial endometrioid adenocarcinoma is usually high grade (FIGO grade 3)
- Bilateral involvement
- Multinodular growth
- No endometriosis / adenofibroma background
Clear cell carcinoma:
- Papillary, tubular and solid architectural patterns
- Uniformly atypical nuclei hobnail cells
- Napsin A+, HNF1β+

Board review style question #1

A 48 year old woman with endometrial carcinoma underwent laparoscopic staging procedure and a right ovarian adenocarcinoma was identified. Endometrial and ovarian lesions have identical morphology (see image). The ovarian lesion is confined to the right ovary and endometrial cancer has superficial myometrial invasion. Which immunostain can be useful to rule out metastatic endometrial adenocarcinoma?

Immunostains are not contributory in differential diagnosis
Napsin A
PAX8
Vimentin
WT1

Board review style answer #1

A. Immunostains are not contributory in a differential diagnosis

Comment Here

Reference: Endometrioid carcinoma

Board review style question #2

Which of the following is associated with favorable disease outcome in patients with ovarian endometrioid carcinoma?

Strong PAX8 expression
WT1 expression
Vimentin expression
Cytoplasmic napsin A expression
Low grade tumor and nuclear beta catenin expression

Board review style answer #2

E. Low grade tumor and nuclear beta catenin expression

Comment Here

Reference: Endometrioid carcinoma

Board review style question #3

What clinical manifestations have most commonly been associated with functioning stroma in ovarian tumors?

Adrenergic manifestations
Androgenic manifestations
Estrogenic manifestations
Progestogenic manifestations

Board review style answer #3

C. Estrogenic manifestations

Comment Here

Reference: Endometrioid carcinoma

Endometrioid cystadenoma and adenofibroma

Table of Contents

Definition / general

Benign tumors with endometrioid type glands, sometimes associated with endometriosis

Essential features

Benign biphasic tumor with endometrioid type glands and fibromatous stroma
Sometimes associated with endometriosis
Squamous or mucinous metaplasia or dystrophic stromal calcifications can be seen

ICD coding

ICD-O:
- 8380/0 - endometrioid cystadenoma, NOS
- 8381/0 - endometrioid adenofibroma, NOS
ICD-11:
- 2F32.Y & XH1CX5 - other specified benign neoplasm of ovary & endometrioid adenofibroma, NOS

Epidemiology

Uncommon tumors, most often seen in postmenopausal women (Int J Gynecol Pathol 2000;19:276)

Sites

Ovary

Pathophysiology

In some cases, endometrioid cystadenomas may represent endometriotic cysts without obvious endometrial type stroma

Etiology

Unknown

Clinical features

Can be an incidental finding
Symptoms may include abnormal vaginal bleeding, abdominal pain or pelvic mass (J Obstet Gynaecol 2011;31:352)

Diagnosis

Detected on pelvic imaging (ultrasound, CT, MRI)
Cystectomy / oophorectomy

Radiology description

Low T2 weighted signal intensity of solid components (Radiographics 2021;41:289)

Prognostic factors

These tumors are benign

Case reports

46 year old woman with pelvic pain, postmenopausal bleeding and 6.3 cm complex solid and cystic right adnexal mass (J Obstet Gynaecol 2011;31:352)
60 year old woman with vaginal bleeding and 14 cm pelvic mass (Diagn Cytopathol 2004;31:38)
64 year old woman with solid pelvic tumor (J Obstet Gynaecol Res 1998;24:161)

Treatment

Not applicable; these tumors are benign

Gross description

Cystadenoma: usually unilocular cyst
Adenofibroma: firm, white nodule with honeycomb appearance to cut surface, sometimes in the wall of an endometriotic cyst (J Obstet Gynaecol 2011;31:352)

Gross images

AFIP images

With endometriosis

Microscopic (histologic) description

Cystadenoma:
- Cyst lined by benign endometrioid epithelium without endometrial stroma
- Endometriosis may be present
Adenofibroma:
- Widely spaced benign endometrioid glands associated with fibromatous stroma
- Endometriosis may be present
Areas of mucinous or serous differentiation can be seen (Histopathology 2021;78:445)

Microscopic (histologic) images

Contributed by Stephanie L. Skala, M.D.

Variably dilated endometrioid glands

Endometrioid glands, some ciliated

Predominantly cystic neoplasm

Attenuated cyst lining

Virtual slides

Images hosted on other servers:

Cystic ovarian tumor

Cytology description

Bland endometrioid cells (epithelial cells with moderate amounts of cytoplasm and bland, eccentrically placed nuclei) and fragments of ovarian type stroma (Diagn Cytopathol 2004 Jul;31:38)

Positive stains

PAX8, estrogen receptor, progesterone receptor
Nuclear beta catenin may be seen rarely; beta catenin alterations are better described in endometrioid borderline tumors (Int J Gynecol Pathol 2022 Feb 11 [Epub ahead of print], J Pathol 2006;208:708)

Negative stains

Sample pathology report

Ovary, right, oophorectomy:
- Right ovary with endometrioid adenofibroma arising in a background of endometriosis

Differential diagnosis

Endometriosis:
- Has associated endometrial type stroma with or without hemosiderin laden macrophages
Serous cystadenoma / adenofibroma:
- Glands show only tubal type differentiation
- WT1, ER diffusely positive
- Membranous beta catenin staining
Seromucinous cystadenoma:
- Glands show admixture of Müllerian epithelia with bland cytological features
  - Ciliated, endocervical type, mucinous, endometrioid (which may have squamous or mucinous differentiation)
- Also associated with endometriosis
- Some authors believe that a subset of seromucinous cystadenomas represent benign endometrioid neoplasms with foci of mucinous or serous differentiation (Histopathology 2021;78:445)

Additional references

WHO Classification of Tumours Editorial Board: Female Genital Tumours, 5th Edition, 2020

Board review style question #1

The image above shows a representative section of a 6 cm, solid and cystic ovarian mass. What is the diagnosis?

Endometrioid adenofibroma
Endometrioid borderline tumor
Endometrioid carcinoma
Endometriosis
Fibroma

Board review style answer #1

A. Endometrioid adenofibroma

Comment Here

Reference: Endometrioid cystadenoma / adenofibroma

Board review style question #2

What feature distinguishes endometrioid cystadenoma / adenofibroma from endometriosis?

Absence of endometrial type stroma
Epithelial lining
Location
Mucinous differentiation
Size

Board review style answer #2

A. Absence of endometrial type stroma

Comment Here

Reference: Endometrioid cystadenoma / adenofibroma

Endometriosis

Table of Contents

Definition / general

Presence of endometrial tissue outside of endometrium and myometrium, consisting of both endometrial glands and stroma

Essential features

Ectopically located endometrial tissue consisting of at least 2 of the following: endometrial type glands, endometrial type stroma or evidence of chronic hemorrhage
Endometriosis is associated with ovarian clear cell carcinoma and endometrioid carcinoma and shares similar molecular alterations
Endometriosis in patients without cancer harbors oncogenic mutations in ARID1A, PIK3CA, KRAS and PPP2R1A, suggesting a neoplastic nature in some cases (N Engl J Med 2017;376:1835)
CD10 immunohistochemistry can be used to confirm the presence of endometrial stroma

Terminology

Endometriotic cyst / endometrioma: cystic form of endometriosis
Atypical endometriosis: endometriosis with cytologic atypia or crowded glands lined by atypical epithelium resembling endometrial atypical hyperplasia (Adv Anat Pathol 2007;14:241)

ICD coding

ICD-10: N80 - endometriosis of uterus
- N80.0 - endometriosis of uterus
- N80.1 - endometriosis of ovary
- N80.2 - endometriosis of fallopian tube
- N80.3 - endometriosis of pelvic peritoneum
- N80.4 - endometriosis of rectovaginal septum and vagina
- N80.5 - endometriosis of intestine
- N80.6 - endometriosis in cutaneous scar
- N80.8 - other endometriosis
- N80.9 - endometriosis, unspecified

Epidemiology

Affects 5 - 15% women of reproductive age
Peak incidence: 30 - 45 years of age
Estrogen dependent; can rarely affect individuals assigned male at birth taking large doses of estrogen (Fertil Steril 2012;98:511)

Sites

Ovary (67%) > anterior and posterior cul de sac > posterior broad ligaments, uterosacral ligaments > uterus > fallopian tubes > sigmoid colon and appendix > round ligaments (Eur J Obstet Gynecol Reprod Biol 2018;230:36)
Also seen in bladder and cervix
Rarely in remote sites such as lung, regional lymph nodes or skin

Pathophysiology

Retrograde menstruation hypothesis: endometrial lining cells travel backwards through fallopian tubes during menses to reach peritoneal cavity, proliferate and cause chronic inflammation with formation of adhesions (Nat Rev Endocrinol 2014;10:261)
Coelomic metaplasia hypothesis: metaplastic transformation of coelomic cells lining the pelvic peritoneum (J Lab Physicians 2010;2:1)
Induction hypothesis: a combination of the first 2 theories (N Engl J Med 1993;328:1759)
Development of malignant neoplasm occurs in < 1% of cases; 75% of malignant neoplasms arise in ovarian endometriosis (J Lab Physicians 2010;2:1)

Etiology

Organochlorine pollutant exposure (Environ Int 2017;108:195)

Clinical features

Pelvic pain (Arch Gynecol Obstet 2015;292:1295)
Dyspareunia
Dysmenorrhea
Infertility
Rarely, infection or rupture of an endometriotic cyst with ascites or hemoperitoneum

Diagnosis

Laparoscopy required for definitive diagnosis, although ~50% laparoscopic biopsy specimens contain microscopic endometriosis (Am J Obstet Gynecol 2001;184:1407)
Endometriosis in pelvis categorized as superficial peritoneal, ovarian and deeply infiltrating

Radiology description

Ultrasound is mostly used for ovarian endometriotic cysts
Typically multilocular cysts with septations and hyperechoic mural nodules (Radiology 1999;210:739)

Prognostic factors

Risk of development of malignant neoplasm is estimated at 1% for premenopausal women and up to 2.5% for postmenopausal women
~75% neoplasms complicating endometriosis arise within the ovary; most common extraovarian site is rectovaginal septum
- Increased risk of endometrioid carcinoma followed by clear cell carcinoma (Clin Chim Acta 2019;493:63)
- Other associated neoplasms include seromucinous neoplasms (mainly borderline), endometrioid adenofibromas and borderline neoplasms, adenosarcomas and endometrial stromal sarcomas (Histopathology 2020;76:76)
Women with carcinoma arising in endometriosis tend to be premenopausal, obese and with history of unopposed estrogens (Gynecol Oncol 2000;79:18)
Endometriosis associated carcinomas (other than clear cell) tend to be lower grade and stage than similar ovarian carcinoma without associated endometriosis (Gynecol Oncol 2001;83:100)

Case reports

32 year old woman with ruptured endometrioma (J Med Case Rep 2022;16:161)
35 year old woman presenting with hematuria and abdominal pain (BMJ Case Rep 2018;11:e226927)
37 year old woman with history of pelvic surgery presenting with pelvic pain (Medicine (Baltimore) 2018;97:e0376)
37 year old woman with decidualized ovarian endometrioma in pregnancy (J Ovarian Res 2022;15:33)
40 year old woman with elevated CA125 and pelvic mass (Medicine (Baltimore) 2019;98:e15741)
42 year old woman with supernumerary ovary on rectosigmoid colon with associated endometriosis (Obstet Gynecol Sci 2018;61:702)
49 year old Japanese woman with abnormal vaginal bleeding and adenocarcinoma diagnosed by cervical cytology (J Obstet Gynaecol Res 2020;46:536)
55 year old woman with peritoneal endometriosis and smooth muscle metaplasia (Int J Clin Exp Pathol 2015;8:3370)
62 year old woman presenting with hematuria (Pathology 2017;49:441)

Treatment

Pain treated with NSAIDs, hormonal contraceptives, GnRH analogues and aromatase inhibitors (Arch Gynecol Obstet 2015;292:1295)
Surgical resection

Gross description

Ovarian endometriotic cysts (endometriomas) have fibrotic walls, a smooth lining and dark brown cyst contents (chocolate cyst), often adherent to adjacent organs
Polypoid endometriosis has a polypoid configuration that raises the differential diagnosis of a neoplasm on gross and intraoperative examination (Am J Surg Pathol 2004;28:285)
Red, brown, white plaques, sometimes with a gelatinous appearance (Arch Gynecol Obstet 2015;292:1295, Taiwan J Obstet Gynecol 2019;58:328)

Gross images

Contributed by University of Washington Medical Center and AFIP

Uterus with shaggy hemorrhagic adhesions

External surfaces of the ovarian wedges

Cyst contains chocolate colored fluid

Cyst has dark brown discoloration

Images hosted on other servers:

Small foci resembling powder burns

Chocolate cyst

Frozen section description

Presence of endometrial glands or endometrial stroma (Taiwan J Obstet Gynecol 2019;58:328)
- Sometimes only macrophages and hemosiderin are present (diagnose as consistent with clinical impression of endometriosis, as other causes are possible)
Can be associated with fibrous adhesions
Negative for neoplastic features such as glandular complexity

Frozen section images

Contributed by University of Washington Medical Center

Endometriosis involving omental nodule

Endometriosis in peritoneal nodule

Microscopic (histologic) description

At least 2 of the following 3 features
- Endometrial type glands
  - Müllerian type epithelium (can be atrophic to cycling endometrium)
  - Can show degenerative atypia (enlarged smudgy nuclei) or metaplasia
- Endometrial type stroma
  - Often contains fine capillary network
  - May undergo smooth muscle metaplasia, fibrosis (longstanding), decidual change
  - May be myxoid (particularly in pregnancy)
  - Stroma may be the only identifiable component (stromal endometriosis)
- Evidence of chronic hemorrhage (hemosiderin laden or foamy macrophages)
Other rare findings
- Necrotic pseudoxanthomatous nodules: central necrosis surrounded by histiocytes and outer fibrous zone
- Liesegang rings: eosinophilic acellular rings within necrotic tissue (Histopathology 2020;76:76)
- Burnt out endometriosis: this term has been proposed for changes suggestive of endometriosis, such as central necrosis with surrounding fibrosis and pseudoxanthoma cells but lacking confirmatory features as listed above
- Atypical endometriosis: this has been reported in 1.7 - 4.4% of endometriotic lesions and is considered the precursor lesion for endometriosis associated carcinomas (clear cell or endometrioid); may be in continuity with these tumors
  - Includes crowded glands lined by atypical epithelium resembling endometrial atypical hyperplasia; nuclear atypia is typically moderate or severe, with hobnailing (Histopathology 1997;30:249, Case Rep Oncol 2013;6:480, Int J Gynecol Pathol 2023 Mar 13 [Epub ahead of print])
  - Is associated with synchronous / subsequent neoplasia in 25% of cases and harbors genomic alterations seen in endometriosis associated tumors (Int J Gynecol Pathol 2023 Mar 13 [Epub ahead of print])

Microscopic (histologic) images

Contributed by University of Washington Medical Center and Aurelia Busca, M.D., Ph.D.

Uterine serosa with endometriosis

Endometriosis, partially denuded

Endometriosis with hemosiderin

Endometriosis involving appendix

Denuded hemorrhagic cyst

Endometriotic cyst

CD10

Virtual slides

Images hosted on other servers:

Ovarian endometriotic cyst

Cytology description

Reported in peritoneal fluid and fine needle aspiration of scar tissue following gynecologic procedure (e.g., Caesarean section) (J Cytol 2017;34:61)
Variably sized, 3 dimensional spherules with periphery of polygonal endometrial cells with larger, hyperchromatic nuclei and moderate amount of cytoplasm, often with a center of stromal cells with hyperchromatic nuclei, scant cytoplasm and indistinct cytoplasmic borders (Cancer Cytopathol 2013;121:582)
May have admixed hemosiderin laden macrophages

Cytology images

Contributed by Carmen Luz, M.D.

FNA from abdominal wall

Positive stains

CD10 is positive in endometrial stroma
ER, PR and PAX2 are often positive in endometrial glands and stroma (Am J Surg Pathol 2013;37:1342)

Molecular / cytogenetics description

Endometriosis and synchronous carcinoma share similar genetic alterations including ARID1A, PTEN and PIK3CA
Mutations in ARID1A, a tumor suppressor gene, identified in up to 57% of ovarian endometrioid carcinoma and up to 30% of clear cell carcinoma
- Multiple studies suggest ARID1A mutation occurs at early stage of canceration of endometriosis (Oncol Rep 2016;35:607)
- Endometriosis occurring distant from ARID1A deficient carcinomas are more likely to retain ARID1A expression
Other associated genetic alterations include loss of BAF250a, ER and PR and upregulation of hepatocyte nuclear factor - beta and SKP2
In one study, loss of DNA mismatch repair protein expression was found in 10% of patients with endometriosis associated ovarian carcinoma (Int J Gynecol Pathol 2012;31:524)

Videos

Causes, symptoms, diagnosis, treatment, pathology

Histopathology - ovary

Sample pathology report

Uterus, hysterectomy:
- Proliferative endometrium negative for hyperplasia or malignancy
- Unremarkable cervix
- Myometrium with leiomyomata
- Uterine serosa with multifocal endometriosis

Right ureterosacral peritoneum, excision:
- Fibrous tissue with focal endometrial type stroma and hemorrhage, suggestive of endometriosis

Differential diagnosis

Endocervicosis:
- Glandular component is endocervical mucinous type, no endometrial stroma, no hemorrhage
Endosalpingiosis:
- Glandular component is tubal (ciliated with peg / intercalated) cells, no endometrial stroma, no hemorrhage
Adenomyosis:
- Endometrial glands and stroma in myometrium
Endometrioid adenocarcinoma:
- Complex glandular growth and cytologic atypia
Metastatic carcinoma:
- Morphology varies by site of origin; however, no endometrial stroma
- Other features of neoplasm present, including crowded irregular glands, nuclear atypia or elevated mitotic activity

Additional references

Annu Rev Pathol 2020;15:71, Pathology 2018;50:190, Mutat Res 2018;809:1

Board review style question #1

A 39 year old woman presents with pelvic pain and menorrhagia. Hysterectomy was performed and the histologic findings shown in this photomicrograph were present on the serosal surface and right ovary. What malignant neoplasm is most associated with the lesion?

Clear cell sarcoma
Endometrial stromal sarcoma
High grade serous carcinoma
Immature teratoma
Ovarian endometrioid carcinoma

Board review style answer #1

E. Ovarian endometrioid carcinoma. Endometriosis can be associated with endometrioid and clear cell carcinoma, with the greatest association identified in the former neoplasm. Rare endometrial stromal sarcomas and adenosarcomas have also been reported to arise in association with endometriosis. Answer D is incorrect because there is no reported association between germ cell tumors and endometriosis. Answer C is incorrect because there is no reported association between high grade serous carcinoma and endometriosis. Answer A is incorrect because there is no reported association between clear cell sarcoma and endometriosis. Answer B is incorrect because even though some cases of adenosarcomas have been reported to arise in association with endometriosis, the association is less frequent than endometrioid carcinoma.

Comment Here

Reference: Endometriosis

Board review style question #2

Which of the following genes is most commonly altered in endometriosis associated carcinomas?

ARID1A
BRAF
CDKN2A (p16)
PTEN
TP53

Board review style answer #2

A. ARID1A. Of the 5 genes listed, mutations in tumor suppressor gene ARID1A are most commonly identified in endometriosis and endometriosis associated carcinomas. Many studies suggest that loss of ARID1A expression is an early driver mutation. Other common molecular alterations include mutations in PTEN, PIK3CA, KRAS and to a lesser extent, microsatellite instability with MMR protein loss. Answer D is incorrect because PTEN mutations are less frequent. Answers E and C are incorrect because TP53 and CDKN2A mutations are rare. Answer B is incorrect because BRAF mutations are not associated with endometriosis.

Comment Here

Reference: Endometriosis

Endosalpingiosis

Table of Contents

Definition / general

Presence of ectopic glands lined by fallopian tube type ciliated epithelium

Essential features

Defined as ectopic glands lined by fallopian tube type ciliated epithelium outside the fallopian tube
Incidental finding in resection specimens
Diagnosed by microscopic examination
Dilated glands measure less than 1 cm in size (if more than 1 cm, serous cystadenoma)

Epidemiology

Typically seen in women of reproductive age
In 33% of cases, endosalpingiosis is associated with endometriosis (Gynecol Oncol 2016;142:255)

Sites

Ovaries, omentum, fallopian tube serosa, uterine serosa, bladder, lymph nodes

Pathophysiology

Multiple hypotheses, including distal fallopian tube implants in the ovarian cortex during ovulation or metaplastic changes of the ovarian surface epithelium or peritoneal cells (Reprod Sci 2013;20:1030)
Papillary tubal hyperplasia (PTH) is a term that has been proposed to describe small rounded clusters of tubal epithelial cells and small papillae, with or without associated psammoma bodies, that are present within the tubal lumen; PTH has been linked to endosalpingiosis and serous tumor (Am J Surg Pathol 2011;35:1605)

Etiology

No specific etiology identified

Clinical features

Mostly asymptomatic and incidentally found in resection specimens
Rarely mass forming cystic lesion or mass related symptoms (BMJ Case Rep 2014;2014:bcr2013201645)

Diagnosis

By histopathological examination, with confirmation of morphology and exclusion of endometriosis

Radiology description

Typically no specific imaging findings
Multilocular cysts if mass forming (Abdom Imaging 2015;40:471)

Prognostic factors

Considered a benign finding
Relationship with development of epithelial malignancies is not clear but patients with endosalpingiosis have been found to be more likely to have concurrent endometriosis as well as uterine and ovarian cancer (Gynecol Oncol 2016;142:255)

Case reports

30 year old pregnant woman with cystic endosalpingiosis (Case Rep Obstet Gynecol 2016;2016:8621570)
31 year old woman with florid cystic endosalpingiosis, masquerading as a malignancy (BMJ Case Rep 2014;2014:bcr2013201645)
55 year old woman with florid cystic endosalpingiosis presenting as an ovarian cyst (Gynecol Minim Invasive Ther 2016;5:170)

Treatment

Surgery for the mass forming lesions

Gross description

Simple cysts on ovarian surface
Florid cystic endosalpingiosis can form a multicystic tumor-like mass (BMJ Case Rep 2014;2014:bcr2013201645)

Gross images

Images hosted on other servers:

Multiple lesions

Microscopic (histologic) description

Glands lined by ciliated tubal type epithelium
3 types of cells:
- Ciliated columnar cells
- Nonciliated columnar secretory mucous cells
- So called intercalated or peg cells
May have psammoma bodies
Absence of endometrial stroma
Glands can be cystically dilated; they are usually found in the superficial ovarian cortex, either scattered or in loose clusters
Reference: Clement: Atlas of Gynecologic Surgical Pathology, 4th edition, 2019

Microscopic (histologic) images

Contributed by Aurelia Busca, M.D., Ph.D.

Cystically dilated glands

Cystically dilated glands with tubal differentiation

Cystically dilated glands with stromal microcalcifications

Positive stains

PAX2, PAX8 (Am J Surg Pathol 2011;35:1837, Case Rep Obstet Gynecol 2016;2016:8621570)
WT1, ER, PR (Am J Surg Pathol 2014;38:1612, Abdom Imaging 2015;40:471)
Endosalpingiosis has a similar biomarker profile to normal fallopian tube and serous neoplasms (phospho-SMAD2, BCL2 and FOXJ1), which is distinct from ovarian surface epithelium (Gynecol Oncol 2014;132:316)

Negative stains

Calretinin, D2-40

Sample pathology report

Right and left ovaries, bilateral oophorectomies:
- Benign ovaries with focal endosalpingiosis
- Note: many pathologists do not report the finding of endosalpingiosis since it is common and benign

Differential diagnosis

Cystic ovarian neoplasms when mass forming:
- Other types of epithelial cysts (mucinous, peritoneal inclusion type, transitional type) have distinct epithelia
- Serous cystadenoma:
  - Lined by tubal type epithelium
  - Distinction relies (arbitrarily) on size > 1 cm for cystadenomas
Endometriosis:
- Has endometrial stroma and hemosiderin laden macrophages

Additional references

Int J Surg Pathol 2014;22:336

Board review style question #1

Which of the following is true about the finding illustrated in the photo of the ovary shown above?

It represents an indication for resection
Tubal differentiation distinguishes it from endometriosis
Typically PAX8 negative
Usually an incidental finding

Board review style answer #1

D. Usually an incidental finding. Endosalpingiosis is typically benign incidental finding in resection specimens, Müllerian derived (PAX8 positive). Absence of endometrial stroma distinguishes it from endometriosis, as tubal differentiation can be seen in both entities.

Comment Here

Reference: Endosalpingiosis

Board review style question #2

What feature below is most important to distinguish endosalpingiosis from endometriosis?

Location
Presence of endometrial stroma
Presence of tubal epithelium
Reactivity for PAX8

Board review style answer #2

B. Presence of endometrial stroma. Endometrial stroma is seen in endometriosis but not endosalpingiosis. Endometriosis can have tubal differentiation. It tends to have a similar anatomic distribution as endosalpingiosis and to express markers of Müllerian derivation, such as PAX8.

Comment Here

Reference: Endosalpingiosis

Epidermoid cyst

Table of Contents

Definition / general

Ovarian cyst lined exclusively by mature squamous epithelium

Terminology

Also called epidermal inclusion cyst
Do not confuse with dermoid cyst, which is a mature cystic teratoma (see differential diagnosis)

Epidemiology

Very rare

Etiology

Either monodermal teratoma or originating from surface epithelium (given the presence of Walthard nests in the wall of some) or rete ovarii

Clinical features

Often an incidental finding (Am J Obstet Gynecol 1976;124:523)

Prognostic factors

May be associated with squamous cell carcinoma (Clin Exp Obstet Gynecol 2005;32:265)

Case reports

With ovarian endometrioid carcinoma (Zentralbl Gynakol 2002;124:443)

Gross description

Cyst with creamy contents

Microscopic (histologic) description

Smooth inner lining of stratified squamous epithelium with no evidence of hair or a Rokitansky tubercle (Int J Gynecol Pathol 1996;15:69)
Also focally cystic nests within cyst wall containing mucin and keratin debris (Am J Clin Pathol 1980;73:272)

Microscopic (histologic) images

AFIP images

Keratinized material

Differential diagnosis

Mature cystic teratoma: also has skin adnexa or other tissues

Epithelial tumors-overview / molecular

Table of Contents

Definition / general

The ovary is a highly specialized organ physiologically dedicated to ovum production
It is composed mainly of stromal cells that support maturing germ cells, covered by a monolayer modified mesothelium (so called ovarian surface epithelium)
Most ovarian cancers are epithelial, but most testicular tumors derive from germ cells or sex cord stroma

Essential features

Ovarian carcinoma (previously called ovarian surface epithelial malignant tumors) is not a single entity, but a group of neoplasms with different histotypes, immunohistochemical characteristics, origins and biology
Although the WHO classification has not substantially changed from the first edition, recent molecular knowledge combined with epidemiological data has caused a considerable reevaluation of the pathogenesis, cell of origin and precursor lesions of ovarian carcinoma

Terminology

Serous / Endometrioid / Clear cell / Seromucinous / Mucinous / Brenner / Undifferentiated

Epidemiology

Epithelial cancers represent >90% of ovarian malignant tumors (Pathology 2011 Aug;43:420)

Tumor type	Acronym	Prevalence
High grade serous carcinoma	HGSC	70%
Low grade serous carcinoma	LGSC	5 %
Endometrioid carcinoma	EMC	10%
Clear cell carcinoma	CCC	10%
Seromucinous carcinoma	SMT	rare
Mucinous carcinoma	MC	3%
Malignant Brenner tumor	Malignant BT	rare
Undifferentiated carcinoma	UC	rare

Pathophysiology

Traditional pathogenetic view:

Cells of origin: ovarian surface epithelium (OSE)
Primary site of origin: ovary
Mechanism: OSE is a modified mesothelium which undergoes metaplasia, acquiring a Müllerian or non-Müllerian epithelial phenotype and successively undergoes neoplastic transformation
In 1925, Sampson hypothesized that ovarian carcinoma may arise from malignant transformation of endometriosis, thought to derive from OSE metaplasia or embryonic residuals
Fathalla’s theory of “incessant ovulation” identifies recurrent ovulation as a transforming event for OSE through direct damage, inflammation and exposure to sex hormone-rich follicular fluid (Lancet 1971;2:163)
- Therefore, incessant ovulation constitutes an index for individual ovarian cancer risk
- This theory assumes that all ovarian surface epithelial tumors have the same origin
For many years, pathologists diagnosed and classified ovarian epithelial tumors based on histological similarity, size, clinical information and apparent cell of origin; fallopian tubes were inadequately sampled and ignored

Controversies with the traditional view

No ovarian surface epithelial carcinomas (serous, endometrioid, clear cell, mucinous, seromucinous, transitional) resemble OSE
Metaplasia of OSE is difficult to demonstrate and almost never observed
There are no intermediate / hybrid phenotypes of OSE metaplasia tumors
Real mesotheliomas are rare
Most ovarian tumors do not express OSE molecular markers
In the testis, analogous surface (tunica albuginea) tumors are rare

Realities to consider

Recent advances in molecular genetics have found mutations in BRCA1 and BRCA2 tumor suppressor genes responsible for most hereditary ovarian cancer
When patients with mutations underwent prophylactic salpingo-oophorectomy, dysplastic precursor lesions were found in fallopian tubes (later named Serous Tubal Intraepithelial Carcinoma, STIC), but not in ovaries
Tubal ligation reduces the incidence of ovarian endometrioid, clear cell carcinoma and high grade serous carcinoma (Cancer Epidemiol Biomarkers Prev 1996;5:933, Int J Cancer 2016;138:1076)
Thorough examination of fallopian tubes using the SEE-FIM protocol (Sectioning and Extensively Examining the FIMbriated end), revealed early fallopian tube cancer in sporadic high grade serous carcinomas
- There are overlapping molecular alterations with STIC and high grade serous carcinoma regarding p53, p16, FAS, RSF1, CCNE1 and centrosome amplification, suggesting a clonal relationship (Mod Pathol 2016;29:1254)
Endometrioid (40%) and clear cell carcinoma (50-90%) are commonly associated with endometriosis, and patients with endometriosis have a 3-10x increased risk of developing ovarian endometrioid and clear cell carcinomas
- Molecular genetic alterations reveal a clonal relationship between endometriosis and endometrioid and clear cell carcinomas (ARID1A, KRAS, MET) (Int J Gynecol Cancer 2012;22:1310)
Primary mucinous ovarian carcinomas are uncommon: the real incidence of mucinous carcinomas is less than previously thought

Emerging pathogenetic views

Ovarian carcinoma (so called ovarian surface epithelial tumors) is not a single entity
Cells of origin: extra-ovarian Müllerian epithelia (endometrium or fallopian tube epithelium)
Primary site of origin: extra-ovarian Müllerian epithelia (endometrium or fallopian tube epithelium) or ovary (endometriosis or fallopian tube epithelium seeded on the ovary as inclusion cysts)
Mechanism: genetically normal or initially transformed epithelial cells from fallopian tube or endometrium seed the ovary, whose microenvironment promotes their neoplastic transformation
Mucinous carcinomas are composed of tumors with different genesis, including mature cystic teratoma and extra-ovarian Müllerian epithelium (Brenner tumors or endometriosis)

Etiology

The most significant risk factor is family history (Bethesda (MD): National Cancer Institute (US); 2002)
Contributing factors: excessive gonadotropins, androgen stimulation, pelvic inflammation, ovarian exposure to contaminants and carcinogens (talc and asbestos), nulliparity, refractory infertility, obesity
Protective factors: multiparity, tubal ligation, hysterectomy, oral contraceptives (use for 5+ years reduces risk 50% even for those with a family history, Cancer Epidemiol Biomarkers Prev. 2009 Feb;18:601)

Clinical features

Genetic syndromes and germline alterations

Hereditary Breast and Ovary Cancer syndrome from germline mutations in BRCA1 and BRCA2
Lynch syndrome from germline mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2)
Peutz-Jeghers syndrome from germline mutations in STK11
Cowden syndrome from germline mutations in PTEN
Coffin-Siris Syndrome from germline mutations in ARID1A
Li-Fraumeni syndrome from germline mutations in TP53 / p53
Other germline mutations that are correlated to ovarian carcinoma affect BRIP1, CHEK2, RAD51

Gross images

Contributed by Ayse Ayhan, M.D.

Clear cell carcinoma, case 1:

Schema

Outer appearance

Fixed pictures of surgical material

Cut surface

Clear cell carcinoma, case 2:

Outer appearance

Cut surface

Fixed cut surface

Bilateral endometrioid cancer:

Left, 730g, 14.5x12.6cm

Ovarian tumor:

Right, 70g, 7.5x3.5cm

Microscopic (histologic) description

Putative precursor lesions

Serous tubal intraepithelial carcinoma / low grade serous carcinoma: for high grade serous carcinoma
Serous borderline tumor: for low grade serous carcinoma and a few high grade serous carcinomas
Endometriosis / adenofibroma / borderline tumor: for endometrioid carcinoma, clear cell carcinoma, seromucinous carcinoma, mixed endometrioid-clear cell carcinoma
Endometriosis / mucinous borderline tumor: for mucinous carcinoma
Teratoma / Brenner tumor / mucinous borderline tumor: for mucinous carcinoma
Benign Brenner tumor: for borderline Brenner tumor

Positive stains

p53 (high grade serous carcinoma, high grade endometrioid carcinoma, mucinous carcinoma)
nuclear β catenin (endometrioid carcinoma)
HER2 (mucinous carcinoma)
Refer to histopathology for lineage specific markers

Negative stains

p53 (30% of high grade serous carcinoma)
MLH1, MSH2, MSH6, PMS2 (endometrioid carcinoma)
PTEN (endometrioid carcinoma)
ARID1A (endometrioid carcinoma, clear cell carcinoma, seromucinous carcinoma) (Int J Gynecol Cancer 2012;22:1310, Int J Gynecol Pathol 2012;31:297)
Refer to histopathology for lineage specific markers

Molecular / cytogenetics description

Common mutations

Tumor type	Acronym	Prevalence
High grade serous carcinoma	BRCA1	12%
	BRCA2	11%
	CSMD3	6%
	FAT3	6%
	TP53	95%
Low grade serous carcinoma	BRAF	38%
Low grade serous carcinoma	KRAS	19%
Endometrioid carcinoma	ARID1A	55%
	CTNNB1	60%
	KRAS	7%
	MLH1/MSH2/MSH6/PMS2	20%
	PIK3CA	35%
	PTEN	16%
	PPP2R1A	10-15%
	TP53	7%
Clear cell carcinoma	ARID1A	75%
	KRAS	10%
	PIK3CA	35%
	PPP2R1A	10%
	TERT	16%
Seromucinous tumor	ARID1A	33%
Seromucinous tumor	KRAS	69%
Mucinous carcinoma	BRAF	12%
	HER2	50%
	KRAS	54%
	RNF43	20%
	TP53	50%
Borderline Brenner tumors	KRAS	14%
Borderline Brenner tumors	PIK3CA	28%

NOTE: High grade serous carcinoma and low grade serous carcinomas have a mutually exclusive mutational signature

Germline/somatic mutations in BRCA1, BRCA2 and other genes predict:
- Platinum sensitivity and longer survival in women with high grade serous carcinoma
- Benefit from PARP inhibitors (Journal of Cancer 2016;7:1441)

Additional references

Kuhn E, Ayhan A., The non-ovarian origin and pathogenesis of ovarian carcinomas: update on the pathological and the molecular clues (PDF)
Kurman RJ, Shih IeM., The Dualistic Model of Ovarian Carcinogenesis: Revisited, Revised, and Expanded (Am J Pathol 2016 Apr;186:733)
Prat, J., Ovarian carcinomas: five distinct diseases with different origins, genetic alterations, and clinicopathological features (Virchows Arch 2012 Mar;460:237)
Lim D, Oliva E., Precursors and pathogenesis of ovarian carcinoma (Pathology 2013 Apr;45:229)

Features to report

Table of Contents

Definition / general | Additional references

Definition / general

Specimen type:
- Ovary (unilateral / bilateral), presence of fallopian tubes, uterus, cervix, omentum, peritoneum
Procedure done
Involvement of fallopian tube(s), opposite ovary and other tissues / organs (as mentioned in specimen type)
Specimen integrity
- Capsule intact, ruptured, fragmented, etc.
Ovarian surface involvement (present / absent)
Tumor site (within the ovary)
Tumor size
- Greatest dimension ____cm
- Additional dimensions ___X ____cm
Tumor appearance
- Smooth / papillary, solid / cystic / both, necrosis, hemorrhage, calcification
Histologic type (Refer to WHO classification of Ovarian neoplasms)
Histologic grade
Intratumoral T cells
Lymphovascular space involvement
Lymph nodes positive / number of nodes examined
Extranodal extension (present / absent)
Implants:
- Applicable to serous / seromucinous borderline tumors
- Not sampled / present / absent
- If present: noninvasive epithelial, noninvasive desmoplastic or invasive (mention sites)
Presence of endometriosis (ovarian / extraovarian), endosalpingosis or other findings
Treatment effect
- Applicable to carcinomas treated with neoadjuvant therapy
- Poor response / no response / marked response
Special studies
- Histochemistry, immunohistochemistry, hormone receptor studies, flow cytometry for DNA ploidy, etc.

Features to report by organization:

Additional references

Editor's note

Fibroma

Table of Contents

Definition / general

Benign stromal tumor composed of fibroblastic cells within a variably collagenous stroma

Essential features

Benign stromal tumor composed of spindled, ovoid to round cells within a variably collagenous stroma
Variants include fibroma with minor sex cord elements, cellular fibroma and mitotically active cellular fibroma
Important differential diagnoses for cellular fibroma include diffuse adult type granulosa cell tumor and fibrosarcoma
Gorlin syndrome should be suspected in young patients with bilateral ovarian fibroma
Long term follow up is recommended for cellular fibromas associated with rupture and adhesions due to increased risk of recurrence

ICD coding

ICD-O: 8810/0 - fibroma, NOS
ICD-10: D27 - benign neoplasm of ovary
ICD-11: 2F32.1 - ovarian fibroma

Epidemiology

Most common ovarian stromal tumor
- ~4% of all ovarian tumors (Cancer 1981;47:2663)
- Cellular fibromas represent ~10% of all ovarian fibromas
Mean age 48 years, uncommon before 30
Occurs in ~25% of patients with nevoid basal cell carcinoma syndrome (Gorlin syndrome) (J Med Genet 1993;30:460)
- Autosomal dominant disease due to mutations of the human homologue of the Drosophila gene PTCH (patched)

Sites

Ovary

Pathophysiology

Neoplastic transformation of ovarian stromal cells due to hereditary or sporadic genetic abnormalities (see Molecular / cytogenetics description)

Clinical features

Most commonly symptoms related to an ovarian mass, such as abdominal pain or distension and increased urinary frequency or may be incidental
Can be associated with ovarian torsion (BMC Surg 2014;14:38)
Rarely hormonal manifestations
Ascites in large (> 10 cm) tumors in 10% of cases (Am J Obstet Gynecol 1970;107:538)
Syndromic ovarian fibromas:
- Often diagnosed before the age of 30 years, including children
- Usually bilateral (75%), calcified and nodular, often overlapping medially (leading to misdiagnosis as calcified uterine leiomyoma) (Genet Med 2004;6:530)
- May be renin secreting, leading to gestational hypertension (Br J Obstet Gynaecol 1994;101:1015)
- May recur (Hum Reprod 2001;16:1261, Obstet Gynecol 1983;61:95S)
Meigs syndrome occurs in ~1% of cases (Am J Obstet Gynecol 1937;33:249, Eur J Obstet Gynecol Reprod Biol 2000;92:199)
- Characterized by the triad of benign adnexal mass, ascites and pleural effusion
- Due to seepage of fluid from ovary into peritoneal cavity and then into 1 or both pleural cavities either via lymphatics or through a communication between abdominal and pleural cavity (lumbocostal triangle)

Diagnosis

Histologic examination for definitive diagnosis
Tentative diagnosis can be made grossly and at frozen section evaluation (Semin Diagn Pathol 2002;19:237)

Laboratory

Can lead to nonspecific increase in serum CA125 (Gynecol Oncol 1995;59:405)

Radiology description

Ultrasonography:
- Usually solid, homogeneous and hypoechoic mass with posterior acoustic shadowing, similar to a pedunculated subserosal uterine leiomyoma (AJR Am J Roentgenol 1985;144:1239)
- Heterogeneous echogenicity in tumors with necrosis, hemorrhage or cystic degeneration
Computed tomography:
- Slightly hypoattenuating solid mass with poor, very slow contrast enhancement (Radiographics 2002;22:1305)
- Rarely calcifications
Magnetic resonance imaging (MRI):
- T1: homogeneous low signal intensity
- T2:
  - Well circumscribed mass with low signal intensity (J Magn Reson Imaging 1997;7:465)
  - Hyperintense areas due to edema or cystic degeneration
  - Characteristic feature is a band of T2 hypointensity separating the tumor from the uterus on all imaging planes
- Gadolinium: heterogeneous enhancement
- May mimic malignancy (Radiographics 2002;22:1305)

Radiology images

Images hosted on other servers:

Bilateral ovarian fibroma on MRI

Unilateral ovarian fibroma on MRI

Prognostic factors

Excellent in most cases
Ovarian surface involvement and extraovarian adhesions occur in 6% of cellular fibromas and 10% of mitotically active cellular fibromas (Am J Surg Pathol 2006;30:929)
Extraovarian spread at surgery in 11% of cellular fibromas and 13% of mitotically active cellular fibromas (Am J Surg Pathol 2006;30:929)
Cellular fibromas may recur, often after a long interval, warranting long term follow up (Cancer 1981;47:2663)

Case reports

15 year old girl with bilateral ovarian fibroma associated with Gorlin syndrome (J Pediatr Adolesc Gynecol 2011;24:e5)
19 year old woman with large ovarian fibroma presenting with spontaneous abdominal bleeding (Case Rep Obstet Gynecol 2019;2019:9834915)
34 year old woman with mitotically active cellular fibroma that recurred 16 years later (Int J Gynecol Pathol 2020 [Epub ahead of print])
40 year old woman with bilateral ovarian fibroma presenting as Meigs syndrome (J Obstet Gynaecol 2013;33:636)
66 year old woman with extraovarian fibroma with minor sex cord elements (Int J Surg Pathol 2017;25:472)

Treatment

Surgical excision (salpingo-oophorectomy, oophorectomy or ovarian sparing procedure with or without hysterectomy depending on patient’s age)
Cellular fibromas require long term follow up, particularly in the setting of ovarian surface involvement, intraoperative rupture or extraovarian spread (Cancer 1981;47:2663)

Gross description

Well circumscribed mass with smooth, lobulated surface
Firm, chalky, solid, white to yellow-white to tan-yellow cut surface that may be whorled
Frequent edema resulting in softer consistency
Mean size 6 cm (range 1 - 21.5)
Usually unilateral (< 10% bilateral)
Cystic degeneration in ~25% of cases
Calcifications in ~10% of cases
~20% present as pedunculated or polypoid growths on ovarian surface
With or without hemorrhage or necrosis
Cellular fibroma:
- Mean size 8 - 9 cm (range 1 - 19)
- Tan-yellow, soft and fleshy cut surface (Cancer 1981;47:2663)
- With or without surface adhesions
Fibroma associated with Gorlin syndrome:
- Bilateral, multinodular and calcified (J Pediatr Adolesc Gynecol 2011;24:e5)

Gross images

Contributed by Rex Bentley, M.D. and AFIP images

Chalky white surface

Edematous and focally hemorrhagic

Dense white mass

Images hosted on other servers:

Hard white tumor

Fibrothecoma

Frozen section description

Variably cellular spindle cell neoplasm with fascicular or storiform growth with or without hyaline plaques or calcifications

Frozen section images

Contributed by Gulisa Turashvili, M.D., Ph.D.

Spindle cell neoplasm

Bland spindle cells

Microscopic (histologic) description

Conventional fibroma:
- Recapitulates ovarian cortex
- Usually well circumscribed but nonencapsulated
- Variably cellular fascicular or less frequently, storiform growth of tumor cells within a variably collagenous stroma, sometimes with hyaline plaques (Cancer 1981;47:2663)
- Bland spindled to ovoid nuclei with pointy ends and scant eosinophilic cytoplasm blending with surrounding stroma
- Occasional mitoses (usually up to 3 mitoses per 10 high power fields)
- With or without Verocay-like areas (slightly wavy, parallel arrays of spindled nuclei), calcification, edema, hemorrhage, infarct type necrosis, rare groups of luteinized cells
- Rarely intracytoplasmic lipid (may be diagnosed as thecoma), eosinophilic hyaline globules, melanin pigment or bizarre nuclei (Int J Gynecol Pathol 2009;28:356, Int J Gynecol Pathol 2019;38:92, Int J Surg Pathol 2020 [Epub ahead of print])
Cellular fibroma (10% of cases):
- Resembles diffuse type of adult granulosa cell tumor
- Densely cellular with little intercellular collagen
- Bland spindled nuclei with up to 3 mitoses per 10 high power fields (Cancer 1981;47:2663)
- "Mitotically active cellular fibroma" has been proposed for cellular fibromas with ≥ 4 mitoses per 10 high power fields (Am J Surg Pathol 2006;30:929)
Fibroma with minor sex cord elements:
- Sex cord component accounting for < 10% of overall tumor volume
- No prognostic significance

Microscopic (histologic) images

Contributed by Gulisa Turashvili, M.D., Ph.D., Kyle C. Strickland, M.D., Ph.D. and Rex Bentley, M.D.

Cellular spindle cell neoplasm

Mild cytologic atypia

Mitotic activity

Small tubules

Variable cellularity

Bland spindle cells

Spindled to ovoid nuclei

Dense collagen

Cellular spindle cell neoplasm

Reticulin

Inhibin

Calretinin

Virtual slides

Images hosted on other servers:

Fibroma (conventional)

Reticulin stain in fibroma

Cellular fibroma

Reticulin stain in cellular fibroma

Fibroma (conventional)

Calretinin stain

Inhibin stain

Positive stains

WT1 (Am J Surg Pathol 2008;32:884)
SF1 (Am J Surg Pathol 2009;33:354)
FOXL2 (Am J Surg Pathol 2011;35:484)
Inhibin: 50% of cases, often focal or weak (Mod Pathol 1998;11:656, Mod Pathol 2003;16:584)
Vimentin (J Pathol 1987;152:253)
CD56 (Am J Surg Pathol 2008;32:884)
ER beta
PR
SMA (Am J Surg Pathol 2008;32:884)
Reticulin: differentiates fibroma (individual pericellular reticulin staining pattern) from diffuse type of adult granulosa cell tumor (nested reticulin staining pattern)

Negative stains

CD10 (Int J Gynecol Pathol 2007;26:359)
Desmin
Caldesmon
CD99 (Am J Surg Pathol 2009;33:354)
Calretinin: positive in 25% of cases, often focal or weak (Am J Surg Pathol 2009;33:354, Am J Surg Pathol 2011;35:484)
S100 and CD34: occasionally positive (Am J Surg Pathol 2008;32:884)

Electron microscopy description

Numerous thin, elongated cells with intercommunicating cytoplasmic processes admixed with abundant collagen fibrils (Cancer 1971;27:438)
- Fibrils appear grouped in bundles with a crossbanding pattern composed of a light band bound by two thin dark bands (recurring at intervals of 600 Å)
- Cells have indistinct cell borders and are compressed by collagenous stroma
- Elongated and thin nuclei with marked peripheral heterochromatin condensation
- Scant cytoplasm containing few mitochondria and scant endoplasmic reticulum

Molecular / cytogenetics description

Trisomy or tetrasomy 12 (Ann Pathol 2001;21:393, Genes Chromosomes Cancer 1990;2:48, Gynecol Oncol 1990;38:28)
Rarely, IDH1 mutations (Histopathology 2013;62:667)
Loss of heterozygosity at 9q22.3 (PTCH1) and 19p13.3 (STK11) in cellular fibromas (Hum Pathol 2005;36:792)
No or rare FOXL2 mutations (Am J Surg Pathol 2013;37:1450, Int J Gynecol Pathol 2018;37:305)

Sample pathology report

Right ovary and fallopian tube, salpingo-oophorectomy:
- Ovary: fibroma
- Fallopian tube: unremarkable

Differential diagnosis

Diffuse adult granulosa cell tumor (GCT):
- Typically see the other patterns of granulosa cell tumor
- Diffusely positive for inhibin and calretinin
- Nested reticulin staining pattern (Int J Gynecol Pathol 2018;37:305)
- FOXL2 mutations (Am J Surg Pathol 2011;35:484, N Engl J Med 2009;360:2719)
Thecoma:
- May present with estrogenic manifestations, including endometrial carcinoma
- Diffuse or rarely, lobulated or nested growth
- Uniform tumor cells with abundant pale gray cytoplasm and indistinct cell membranes imparting a syncytial appearance
- Ovoid to round nuclei, with or without nucleoli or nuclear grooves
- None to minimal mitotic activity
- With or without hyaline plaques, calcifications, adipose metaplasia, small clusters of steroid type cells with eosinophilic to clear cytoplasm (Am J Surg Pathol 2014;38:1023)
- Rarely, scattered pleomorphic bizarre nuclei due to degenerative changes (Int J Gynecol Pathol 1983;1:325, Am J Surg Pathol 2014;38:1023)
- Usually positive for inhibin, calretinin and other sex cord markers
Sclerosing stromal tumor:
- Often occurs in women in their third to fourth decades
- Alternating cellular and paucicellular areas with prominent staghorn vasculature
- Pseudolobulation and biphasic population of cells (luteinized and spindled)
- Usually positive for inhibin and calretinin
Leiomyoma:
- More prominent fascicular growth pattern with intersecting long fascicles of spindle cells with cigar shaped nuclei, eosinophilic cytoplasm and paranuclear vacuoles
- Positive for desmin and caldesmon
Endometrial stromal tumor, low grade:
- Typical features of low grade endometrial stromal neoplasia, including permeative growth and arteriole-like vessels
- Diffusely positive for CD10
- With or without characteristic gene fusions such as JAZF1-SUZ12 (Orphanet J Rare Dis 2016;11:15)
Metastatic gastrointestinal stromal tumor:
- Prior history or concomitant extraovarian disease
- With or without epithelioid or spindled to epithelioid morphology
- Pale cytoplasm, ill defined cell membranes, with or without skenoid fibers
- Positive for KIT and DOG1
Ovarian stromal hyperplasia:
- Bilateral
- Diffuse or multinodular proliferation of stromal cells
- Lacking collagenous stroma and hyaline plaques
Massive edema:
- Unilateral or bilateral
- No well defined mass
- Proliferation of stromal cells with marked intercellular edema
- Entrapment of preexisting ovarian structures (follicles, corpora lutea or albicantia)
Fibromatosis:
- Unilateral or bilateral
- No well defined mass
- Proliferation of stromal cells with abundant dense collagen
- Entrapment of preexisting ovarian structures
Fibrosarcoma:
- Exceptionally rare and no longer considered a distinct WHO entity
- Hypercellular, composed of disorderly fascicles of spindle cells with scant cytoplasm and moderate to marked nuclear atypia, elevated mitotic activity including atypical forms (Cancer 1981;47:2663)
- Presence of ≥ 4 mitoses per 10 high power fields is not sufficient to diagnose fibrosarcoma in the absence of significant cytologic atypia (Am J Surg Pathol 2006;30:929)
- With or without necrosis and hemorrhage
- Focally positive for calretinin or inhibin, negative for CD10 (Am J Surg Pathol 2002;26:1477, Int J Gynecol Pathol 2007;26:359)

Additional references

Radiographics 2021;41:289, Surg Pathol Clin 2009;2:731, Anticancer Res 2017;37:2557, Obstet Gynecol Int 2009;2009:803062, Eur J Obstet Gynecol Reprod Biol 2015;185:78

Board review style question #1

Microscopic examination of an 8 cm unilateral ovarian mass demonstrates a densely cellular neoplasm composed of intersecting fascicles of spindle cells with mild cytologic atypia and approximately 9 mitotic figures per 10 high power fields. Reticulin staining shows pericellular staining pattern and molecular testing is negative for FOXL2 mutation.

What is the most likely diagnosis?

Fibroma
Fibrosarcoma
Leiomyoma
Leiomyosarcoma
Mitotically active cellular fibroma

Board review style answer #1

E. Mitotically active cellular fibroma

Comment Here

Reference: Fibroma

Board review style question #2

You receive an intraoperative consultation for bilateral multinodular ovarian masses in a 16 year old patient. Microscopic examination demonstrates bland, monomorphic spindled cells within a collagenous stroma.

Mutation of which of the following genes is most likely associated with this entity?

FOXL2
HMGA2
JAZF1
PTCH
Vimentin

Board review style answer #2

D. PTCH. Bilateral ovarian fibroma in a young patient is most likely associated with Gorlin syndrome.

Comment Here

Reference: Fibroma

Fibromatosis and massive edema

Table of Contents

Definition / general

Tumor-like enlargement of ovary due to edema fluid
First described in 1969 (Obstet Gynecol 1969;34:564)
Patients present with pain, abdominal mass, menstrual irregularities, virilization, precocious puberty, Meigs syndrome (with ascites and pleural effusion, eMedicine: Meigs Syndrome)
May be due to partial torsion of mesovarium leading to interference of venous / lymphatic drainage
Usually young women
Right sided involvement is more common

Gross description

Marked ovarian enlargement, watery cut surface, no necrosis

Microscopic (histologic) description

Marked edema of stroma surrounding follicles and clusters of luteinized cells
Stroma around vessels and in superficial cortical zone is normal
Variable stromal luteinization

Microscopic (histologic) images

Contributed by Dr. Josehp Christopher Castillo

AFIP images

Clusters of lutein cells lie in the edematous stroma

Images hosted on other servers:

Loose stroma with occasional inflammatory cells

Differential diagnosis

Fibroma: circumscribed, tumor cells replace ovarian architecture
Krukenberg tumor: usually bilateral, signet ring cells present

Additional references

Am J Surg Pathol 1979;3:11, Arch Pathol Lab Med 1979;103:42

Fibrosarcoma

Table of Contents

Definition / general

Very rare (< 100 reported cases) aggressive tumor which arises directly from stromal cells or from preexisting cellular fibroma
More common in bone

Epidemiology

Median age 49 years, range 20 - 73 years

Clinical features

Pelvic pain, abdominal enlargement, awareness of abdominal mass (Cancer 1981;47:2663)

Laboratory

CA125 and CEA in normal range

Radiology description

MRI: solid mass (Anticancer Res 2007;27:4365)

Prognostic factors

FIGO stage (BMC Cancer 2010;10:585)

Case reports

8 year old girl with nevoid basal cell carcinoma syndrome (Am J Surg Pathol 1984;8:231)
32 year old woman (Anticancer Res 2007;27:4365)
52 year old woman (Int J Gynecol Cancer 2005;15:1142)

Treatment

Surgical resection with or without adjuvant chemotherapy or radiation

Gross description

5 - 23 cm solid mass, tan-yellow discoloration and partial necrosis (BMC Cancer 2010;10:585)

Gross images

Images hosted on other servers:

Capsular disruption and hemorrhage

Microscopic (histologic) description

Spindle cells arranged in sheets and intersecting fascicles creating a diffuse herringbone appearance
Mild to moderate nuclear atypia
Reticulin stain separates individual neoplastic cells
Mitotic activity > 4/10 HPF is most important criteria for diagnosing fibrosarcoma

Microscopic (histologic) images

AFIP images

Moderate cytologic atypia

Cytology description

Pleomorphic oval to spindle shaped cells with indistinct cell borders and atypical mitotic figures

Cytology images

Images hosted on other servers:

Clusters of pleomorphic spindle cells

Positive stains

Vimentin, CD34 (BMC Cancer 2010;10:585)

Negative stains

CD99, CD117, desmin, EMA, SMA, S100 (BMC Cancer 2010;10:585)

Molecular / cytogenetics description

Trisomy 8 present, may be helpful in distinguishing from cellular fibroma (Am J Surg Pathol 1997;21:52)

Differential diagnosis

Cellular fibroma: mitotic activity < 3/10 HPF, no trisomy 8 (Am J Surg Pathol 1997;21:52)

Follicle cyst

Table of Contents

Definition / general

Benign cyst measuring at least 3 cm and lined by an inner layer of granulosa cells with an outer layer of theca cells

Essential features

Benign cyst lined by an inner layer of granulosa cells with an outer layer of theca cells
Measures ≥ 3 cm, as opposed to cystic follicle, which measures < 3 cm
Should be differentiated from cystic granulosa cell tumor
May occur at any age, with a variable clinical presentation depending on age and etiology

Terminology

Follicular cyst

ICD coding

ICD-10: N83.0 - cyst, follicular (atretic) (hemorrhagic) (ovarian)
ICD-11: GA18.0 - follicular cyst of ovary

Epidemiology

Most common in nonpregnant women of reproductive age, especially near menarche or menopause
May occur at any age, including neonates and children (Acta Paediatr Scand 1987;76:91, Int J Gynecol Pathol 1984;3:318)
Affects 1 in 2,500 live female births (Obstet Gynecol Surv 1991;46:407)
Relatively rare in postmenopausal women and may present with hyperestrogenism
May be associated with McCune-Albright syndrome (Radiology 1988;168:817, Ann Endocrinol (Paris) 2016;77:7, Semin Pediatr Surg 2005;14:78)

Sites

Ovary

Pathophysiology

Physiologically:
- Ovarian follicle matures during proliferative phase of menstrual cycle, mature oocyte gets released due to luteinizing hormone (LH) surge at midcycle and follicle transforms to corpus luteum
- If no fertilization, corpus luteum atrophies and forms corpus albicans
Follicle may become cystic via 2 mechanisms:
- Gonadotropin independent:
  - McCune-Albright syndrome (N Engl J Med 1985;312:65)
  - Primary hypothyroidism
  - Isosexual pseudoprecocity
  - Idiopathic central precocious puberty
- Gonadotropin dependent due to hypothalamic pituitary gonadal axis dysfunction:
  - Central precocious puberty
  - No luteinizing hormone (LH) surge
  - Elevated follicle stimulating hormone (FSH)
  - No ovulation
  - Treatment with gonadotropin releasing hormone analogues, low dose phasic oral contraceptives and tamoxifen (Am J Obstet Gynecol 1987;156:1538, Fertil Steril 1990;53:1091, Gynecol Oncol 1999;72:202)
Cyst usually disappears within 2 - 3 menstrual cycles but may persist

Clinical features

Usually asymptomatic and incidental
May form adnexal or pelvic mass
Pelvic / abdominal pain, rarely hemoperitoneum, due to rupture or torsion (Am J Obstet Gynecol 1984;149:5)
May be multiple or bilateral and present with symptoms related to hyperestrogenism (isosexual precocity, pseudoprecocity, menstrual disturbances including amenorrhea and postmenopausal bleeding, endometrial hyperplasia) when associated with McCune-Albright syndrome
Rarely, central precocious puberty or isosexual precocity not related to McCune-Albright syndrome (Arch Dis Child 1999;81:53)
Most cysts regress during the first 4 months of life but may undergo torsion, hemorrhage and rupture during the neonatal period or in utero
May be associated with symptoms of primary hypothyroidism, including Van Wyk-Grumbach syndrome (juvenile hypothyroidism, precocious puberty with delayed bone age and ovarian cysts)
May be associated with FSH secreting pituitary adenoma and sometimes precedes clinical presentation of adenoma (Int J Gynecol Pathol 2019;38:562)
May be associated with ovarian remnant syndrome in 7% of cases (Acta Obstet Gynecol Scand 2012;91:965)
May be associated with autoimmune oophoritis (Obstet Gynecol 1989;74:492)

Diagnosis

Histologic examination of tissue

Radiology description

Ultrasound examination (J Ultrasound Med 1988;7:597):
- Thin walled unilocular cyst measuring at least 3 cm
- Posterior acoustic enhancement
- Absence of internal echoes
- No color flow, nodules or any solid components
- Fluid debris level or internal echoes, if torsion

Radiology images

Images hosted on other servers:

Follicle cyst on ultrasound

Prognostic factors

Usually regress spontaneously (Contraception 2002;66:153, Hum Reprod 2000;15:2567)
May undergo torsion requiring surgery
May recur when associated with McCune-Albright syndrome

Case reports

6 year old girl with precocious pseudopuberty due to ovarian follicle cyst (BMC Res Notes 2013;6:319)
13 year old girl with giant ovarian follicle cyst (J Clin Diagn Res 2014;8:OD03)
36 year old woman with pituitary adenoma and recurrent ovarian follicle cysts (BMC Res Notes 2013;6:408)
47 year old woman with IgG4 related disease associated with ovarian follicle cyst (Am J Case Rep 2020;21:e926803)

Treatment

Observation
High dose, combined estrogen progestogen preparations
LH releasing hormone agonists
Excision if symptomatic or persistent (Arch Pediatr 1994;1:903)
Cyst puncture if associated with isosexual pseudoprecocity

Gross description

Usually solitary
Ranging from at least 3 cm to up to 18.5 cm (Int J Gynecol Pathol 2021;40:359)
Larger size during pregnancy and puerperium
Thin walled cyst with smooth inner surface
Usually unilocular
No solid component
Clear to straw colored fluid contents
Serosanguinous or hemorrhagic fluid contents or clotted blood if torsion
Multiple or bilateral if associated with McCune-Albright syndrome

Gross images

AFIP images

Unilocular cyst with smooth lining

Images hosted on other servers:

Large follicle cysts

Frozen section description

Benign cystic structure lined by an inner layer of granulosa cells with an outer layer of theca cells
Either cell type may be luteinized

Microscopic (histologic) description

Inner layer (1 to several) of granulosa cells with or without luteinization
- May be focally denuded
- Uniform round nuclei lacking grooves (Int J Gynecol Pathol 2021;40:359)
- Moderate amounts of eosinophilic cytoplasm
- Variable mitotic activity ranging from 1 - 36 per 10 high power fields (Int J Gynecol Pathol 2021;40:359)
- Sparse or absent reticulum on reticulin stain
Outer layer of theca cells with or without luteinization
- Dense reticulum on reticulin stain
Luteinized cells have eosinophilic to clear cytoplasm and round nuclei with central nucleoli
Nonluteinized cysts are more common in patients with precocious puberty (Int J Gynecol Pathol 2021;40:359)
Dystrophic calcifications in neonatal cysts (Int J Gynecol Pathol 2021;40:359)
Multiple follicle cysts may be associated with eosinophil rich infiltrate (so called eosinophilic perifolliculitis) in autoimmune oophoritis (J Reprod Med 2006;51:141, Int J Gynecol Pathol 2021;40:359)

Microscopic (histologic) images

Contributed by Gulisa Turashvili, M.D., Ph.D.

Cyst wall

Cyst lining

Luteinized theca cells

Reticulin stain

Positive stains

Inhibin (J Clin Endocrinol Metab 1993;77:859)
Calretinin
SF1
Immunohistochemistry usually not required for diagnosis

Negative stains

Sample pathology report

Right ovary, cystectomy:
- Follicle cyst

Differential diagnosis

Cystic adult type granulosa cell tumor:
- May be virilizing
- Usually larger than follicular cysts
- Multiple layers of granulosa cells
- Typical architectural patterns within cyst wall (Call-Exner bodies, trabecular, corded)
- With or without invagination of granulosa cells into cyst wall (Int J Gynecol Pathol 2021;40:359)
- Nuclear grooves (may be inconspicuous in luteinized forms)
- Extensive sampling may be required
Cystic juvenile granulosa cell tumor:
- Pale to vacuolated cytoplasm
- Typical noncystic foci usually present
Cystadenoma:
- Usually 1 layer of epithelial cells with serous, mucinous, clear cell or endometrioid morphology
- Negative for inhibin and calretinin, positive for EMA
Endometriotic cyst:
- At least focally lined by endometrial-type epithelium
- Surrounded by endometrial stroma with or without hemorrhage or hemosiderin laden macrophages within wall
Cystic follicle:
- Considered physiologic
- Morphology identical to follicle cyst but measuring < 3 cm
Simple cyst:
- Denuded cyst without obvious lining or flattened lining
- No theca cells
Large solitary luteinized follicle cyst (Am J Surg Pathol 1980;4:431):
- Occurs during pregnancy or puerperium
- Larger than follicular cyst (median size 25 cm)
- 1 to several layers of markedly luteinized granulosa cells and theca cells that are usually indistinguishable
- Variable nuclear atypia ranging from small round nuclei with single nucleolus to enlarged nuclei with focal marked pleomorphism, hyperchromasia and smudgy chromatin (degenerative)
- Absent or rare mitotic figures
Hyperreactio luteinalis:
- Secondary to elevated human chorionic gonadotropin (hCG) levels due to gestational trophoblastic disease, fetal hydrops, multiple gestations, ovarian hyperstimulation syndrome
- Hyperandrogenism in 15%
- Bilateral, multiple, thin walled follicle cysts with distinct granulosa and theca cells
- More extensive luteinization in theca cells compared with granulosa cells
- Markedly edematous ovarian stroma and groups of luteinized stromal cells between cysts
- Corpora lutea in ovarian hyperstimulation syndrome
Corpus luteum cyst:
- Undulating border and inner fibrous lining with a zone of small blood vessels with involution (Int J Gynecol Pathol 2021;40:359)
- Markedly luteinized polygonal shaped granulosa cells with abundant eosinophilic cytoplasm
Cortical inclusion cyst:
- < 1 cm
- Lined by serous type ciliated epithelium or nonciliated nonmucinous flat epithelium

Additional references

Endocr Pract 2006;12:417

Board review style question #1

What entities are included in the differential diagnosis of this cystic lesion of the ovary?

Clear cell carcinoma, cystic follicle and cystic corpus luteum
Corpus luteum cyst, endometriotic cyst and endometrioid borderline tumor
Cystic adult type granulosa cell tumor, cystic follicle and corpus luteum cyst
Endometriotic cyst, corpus luteum cyst and clear cell carcinoma
Serous borderline tumor, cystic adult type granulosa cell tumor and cystic follicle

Board review style answer #1

C. Cystic adult type granulosa cell tumor, cystic follicle and corpus luteum cyst

Comment Here

Reference: Follicular cyst

Board review style question #2

What features would favor a cystic adult type granulosa cell tumor over a follicle cyst?

Large size (> 10 cm), 1 - 2 layers of granulosa cells with readily identifiable mitotic figures and without invagination into cyst wall or nuclear grooves
Large size (> 10 cm), markedly luteinized granulosa cell layer with readily identifiable mitotic figures
Large size (> 10 cm), thick granulosa cell layer with multiple architectural patterns, invagination into cyst wall and nuclear grooves
Small size (< 10 cm), 1 - 2 layers of granulosa cells without invagination into cyst wall or nuclear grooves
Small size (< 10 cm), 1 - 2 layers of granulosa cells without invagination into cyst wall or nuclear grooves and with external layer of luteinized theca cells

Board review style answer #2

C. Large size (> 10 cm), thick granulosa cell layer with multiple architectural patterns, invagination into cyst wall and nuclear grooves

Comment Here

Reference: Follicular cyst

Gonadoblastoma

Table of Contents

Definition / general

First described by Scully in 1953 (Cancer 1953;6:455)
Also called dysgenetic gonadoma
Mixture of germ cell tumor and sex-cord stromal tumor
Usually occurs in individuals with abnormal sexual development and indeterminate gonads; usually gonadal dysgenesis with Y chromosome (i.e. XY gonadal dysgenesis, XO-XY mosaicism, not XX gonadal dysgenesis); 25% risk of neoplasia in these gonads
Also present in phenotypically normal women, even during pregnancy, although ovary is never normal
Y chromosome material appears to participate in gonadoblastoma tumorigenesis (Am J Clin Pathol 1997;108:197, Birth Defects Res C Embryo Today 2009;87:114)
Associated with ataxia-telangiectasia
80% are phenotypic women, 20% are phenotypic men with undescended testicles and female internal secondary organs
50% have coexisting dysgerminoma
Excellent prognosis if completely excised; almost never malignant
Chromosomal analysis useful to diagnose androgen insensitivity / male pseudohermaphroditism (46,XY) and Turner syndrome (45,XO)
Imaging:
- Imaging studies useful to diagnose intersexuality and identify patients at risk of developing gonadoblastoma
- Flat abdominal radiograph may reveal gonadal calcification, a classic pathologic finding in gonadoblastoma

Pathophysiology

Gonadal differentiation starts after 5 weeks of gestation and depends on sex chromosome of fetus
Errors in this complex multistep process of sexual differentiation may cause dysgenetic gonads

Case reports

Two young patients with isochromosome 12p in dysgerminoma overgrowth component (Pathol Res Pract 2012;208:628)
Patient with Denys-Drash syndrome and early presentation of bilateral gonadoblastoma (J Pediatr Endocrinol Metab 2013;26:971)

Treatment

Pure Gonadoblastoma have excellent prognosis
Local excision is adequate treatment if no frankly malignant are present

Gross description

36% bilateral, tumors usually small and may be microscopic

Gross images

AFIP images

Bilateral tumor, with germinoma

With germinoma

Images hosted on other servers:

Gonadal dysgenesis

Microscopic (histologic) description

Primitive germ cells and sex cord stromal cells surrounded by ovarian type stroma
Nests of dysgerminoma-like germ cells and sex cord derivatives resemble immature Sertoli and granulosa cells
Arranged in nests surrounded by ovarian stroma containing Leydig or lutein type cells
Hyalinization and calcification are common
May be dysgerminoma if overgrowth of this component (Am J Clin Pathol 1997;108:197)

Microscopic (histologic) images

AFIP images

Nests of tumor

With germinoma

Small sex cord type cells

Positive stains

Anti-Müllerian hormone focally (Hum Pathol 2000;31:1202)
SALL4 and SF1 (Int J Gynecol Pathol 2013;32:379)
Occasional c-KIT mutations (PLoS One 2012;7:e43952)

Differential diagnosis

Incidental finding in ovaries of normal infants / children: associated with follicular cysts, microscopic foci resembling gonadoblastoma or sex cord tumor with annular tubules

Granulomatous inflammation

Table of Contents

Definition / general

Necrotizing or nonnecrotizing granulomatous inflammation of the ovary

Epidemiology

Cortical granulomas are common incidental findings with uncertain clinical significance
Primary ovarian tuberculosis and other primary ovarian granulomas are uncommon
Frequency of secondary ovarian granulomas depends on primary cause

Etiology

Tuberculosis: hematogenous spread to ovary or secondary to tuberculous salpingitis (Arch Gynecol Obstet 2008;278:359); may clinically resemble malignancy (Arch Gynecol Obstet 2010;282:643)
Actinomyces: associated with IUD (Am J Clin Pathol 1977;68:622)
Ascaris lumbricoides: J Coll Physicians Surg Pak 2009;19:663
Bowel contents via colo-ovarian fistula: Obstet Gynecol 1987;69:533
Crohn disease: usually extension from bowel (Am J Obstet Gynecol 1975;122:527)
Dysgerminoma: granulomatous reaction
Enterobius vermicularis: Eur J Gynaecol Oncol 2007;28:513
Foreign material: often postsurgical, including suture, talc, starch, lubricant and carbon (Obstet Gynecol 1985;66:701, Hum Pathol 1996;27:1008)
Keratin from cystic teratomas and squamous elements of endometrial and ovarian endometrioid adenocarcinomas
Malakoplakia: Obstet Gynecol 1987;69:537
Necrobiotic (palisading) granuloma: often with history of surgery or cauterization months to years previous
Sarcoidosis: rare (Am J Obstet Gynecol 1990;162:1284)
Schistosomiasis

Clinical features

Often an incidental finding or part of a systemic granulomatous disorder

Laboratory

May be associated with elevated CA 125, raising concern for cancer (Rom J Intern Med 2009;47:297)

Case reports

Due to microfibrillar collagen hemostat (avitene) used to control bleeding (Arch Pathol Lab Med 1995;119:1161)

Treatment

In secondary cases, treat primary cause

Gross description

May present as a mass and simulate a tumor

Microscopic (histologic) description

Tuberculosis is typically confined to the cortex

Microscopic (histologic) images

Contributed by Eman Abdelzaher, M.D., Ph.D. and AFIP

Actinomycosis: tubo-ovarian

Actinomycosis

Images hosted on other servers:

Central suppuration
and surrounding
giant cells in
Crohn's disease

Tuberculosis

Positive stains

AFB is typically positive in tuberculous oophoritis

Additional references

J Clin Pathol 1997;50:324

Granulosa cell tumor-adult

Table of Contents

Definition / general

Low grade indolent malignant neoplasm originating from granulosa cells of the ovarian follicles, accounting for approximately 10% of all sex cord stromal tumors of the ovary

Essential features

Low grade indolent sex cord stromal tumor of the ovary with 20 - 30% chance of local recurrence, 5 - 20 years after diagnosis
Should be considered in the differential diagnosis of solid / cystic and hemorrhagic ovarian mass in postmenopausal patients
FOXL2 mutation by immunohistochemistry or sequencing identified in > 95% (N Engl J Med 2009;360:2719)
Immunohistochemical panel could include inhibin, calretinin, FOXL2, SF1, EMA and reticulin special stain

ICD coding

ICD-O: 8620/1 - granulosa cell tumor, adult type (C56.9)
ICD-10:
- D39.10 - neoplasm of uncertain behavior of unspecified ovary
- D39.11 - neoplasm of uncertain behavior of right ovary
- D39.12 - neoplasm of uncertain behavior of left ovary

Epidemiology

Accounts for 2% of all ovarian tumors and is the second most common ovarian sex cord stromal tumors after fibroma / thecomas
Most granulosa cell tumors are adult type (95%) and 5% are juvenile type
Wide age range; most common in postmenopausal women with peak age 50 - 55

Sites

Ovary, often unilateral

Pathophysiology

Presumed to originate from the granulosa cells of the ovarian follicle; the histogenesis is unknown
Dimerization of mutant FOXL2 protein (402C → G, C134W) causes negative dominant effect, dysregulates gene expression and plays a major role in tumor pathogenesis (Endocrinology 2011;152:3917)

Clinical features

Mostly present with symptoms due to adnexal mass or endocrine manifestations
10% present with ovarian torsion, tumor rupture and hemoperitoneum
Most associated with hyperestrogenism, causing metrorrhagia, postmenopausal bleeding, endometrial hyperplasia / carcinoma (5%, usually FIGO grade 1 and superficial) in adults and if in children, associated with precocious puberty
Rarely associated with hyperandrogenism presenting with virilization or hirsutism
10 year survival > 90%; tends to recur locally in the abdomen / pelvis in 20 - 30% of cases, usually 5 years after diagnosis and up to 20 years later
Most are confined to the ovary (stage I); rarely distant metastasis to lung and liver
- Lymph node metastasis uncommon

Diagnosis

Surgical specimen: gross, frozen and permanent microscopic examination
Peritoneal cytology

Laboratory

Hyperestrogenism
Hyperandrogenism (rare)

Radiology description

Large unilateral solid and cystic ovarian mass, with or without torsion / rupture and associated hemoperitoneum

Radiology images

Images hosted on other servers:

Large pelvic mass

Prognostic factors

Stage (most important) and tumor rupture
Large size (> 15 cm) and bilaterality are considered unfavorable prognostic factors; size does not show significant difference if corrected for stage
No definitive correlation between mitotic activity or nuclear atypia and clinical outcome
Homozygous FOXL2 mutation and chromosomal imbalance are associated with early relapse and worse outcome (Oncotarget 2020;11:419)
Higher FOXL2 mRNA expression associated with worse outcome (Mod Pathol 2011;24:1360)
Higher levels of SMAD3 expression are associated with recurrence in early stage disease (Int J Gynecol Pathol 2017;36:240)
TERT promoter mutation (C228T) identified in 22% of primary and 41% of recurrent adult GCT (Mod Pathol 2018;31:1107)

Case reports

31 year old woman with hypertension and amenorrhea (AACE Clin Case Rep 2018;5:e168)
44 year old woman with luteinized adult type granulosa cell tumor and melanin pigment (Int J Gynecol Pathol 2019;38:92)
66 year old woman with mixed ovarian tumor composed of Brenner tumor and adult type granulosa cell tumor (Int J Surg Pathol 2018;26:382)
67 year old woman with aggressive adult granulosa cell tumor of the ovary without a FOXL2 mutation (J Obstet Gynaecol Res 2019;45:1404)
78 year old man with testicular adult type granulosa cell tumor and sarcomatous overgrowth (Diagn Pathol 2014;9:107)

Treatment

Surgical excision is the main treatment
Hormone modulator therapy, chemotherapy, radiation therapy, novel targeted treatments can be used in multiply recurrent or metastatic patients

Clinical images

Images hosted on other servers:

Hirsutism

Intraoperative mass

Gross description

> 95% unilateral and confined to the ovary
Variable size, average 10 - 12 cm
Encapsulated with smooth lobulated surface, tan or yellow (depending on the degree of luteinization and lipid content), soft to firm (depending on the amount of fibromatous component), usually solid and cystic with straw colored or mucoid fluid, can have areas of necrosis and hemorrhage
The more luteinized tumors are more yellow / orange
May resemble serous cystadenoma
Rare androgenic tumors tend to be large with thin walled cysts (Arch Pathol Lab Med 1984;108:786)

Gross images

Contributed by Shabnam Zarei, M.D. and AFIP

Solid, cystic and hemorrhagic mass

Solid and cystic mass

Solid yellow mass

Predominantly cystic mass

Solid and cystic tumor

Images hosted on other servers:

Solid cystic mass

Frozen section description

May be mistaken for endometrioid adenocarcinoma on frozen section
Characteristic nuclear features can be helpful in diagnosis

Frozen section images

Contributed by Shabnam Zarei, M.D.

Frozen section, angulated grooved nuclei

Microscopic (histologic) description

Small, bland, cuboidal to polygonal cells with scant cytoplasm and pale, uniform angulated and usually grooved nuclei (coffee bean)
Various patterns, including diffuse (the most common), trabecular and corded, insular, microfollicular (resembling Call-Exner bodies of the Graafian follicles: small follicle-like structures filled with eosinophilic material) and macrofollicular (the least common)
Usually a mixed growth pattern is seen
Rarely can be seen with juvenile type; classification should be based on the predominant histology
Luteinized adult type (such as during pregnancy): rare (1%) if extensive (> 50%), plump cells with moderate to abundant eosinophilic cytoplasm, conspicuous nucleoli, no nuclear grooves, myxoid or edematous stroma; may resemble steroid cell tumor
Mitotic activity is usually not brisk (< 3/10 high power fields)
Stroma is usually hypervascular with variable amounts of fibroblasts and theca cells
Theca cell proliferation is considered a stromal response rather than a second population of tumor cells (granulosa - theca cell tumor)
Can have a prominent fibrothecomatous stroma; need 10% granulosa cells to be classified as adult granulosa cell tumor, otherwise best classified as thecoma or fibroma with minor sex cord elements
Rarely show focal hepatic cell differentiation (large cells with abundant eosinophilic, slightly granular cytoplasm); HepPar1+, inhibin- (Am J Surg Pathol 1999;23:1089)
Rarely (2%) show focal or multifocal areas of atypical cells with enlarged hyperchromatic bizarre, some multinucleated, suggestive of degenerative change and not associated with adverse outcome (Int J Gynecol Pathol 1983;1:325)
Predominantly cystic granulosa cell tumor or macrofollicular pattern may mimic ovarian follicle
Small aggregates of nonneoplastic granulosa cells can be seen within vascular spaces adjacent to the follicles: probably a surgery related artifact

Microscopic (histologic) images

Contributed by Shabnam Zarei, M.D. and Sharon Bihlmeyer, M.D.

Classic diffuse pattern

Nuclear grooves

Luteinized

Luteinized with round nuclei

Luteinized

Calretinin

Reticulin

Diffuse pattern

Inhibin

Calretinin

CK7

AFIP images

Trabecular pattern

Insular pattern

Microfollicular pattern

Macrofollicular pattern

Watered silk (moiré silk) pattern

Gyriform pattern

Cystic tumor

Enlarged, hyperchromatic, bizarre nuclei

Theca cells

Virtual slides

Images hosted on other servers:

Diffuse pattern

Cytology description

Scant cytoplasm, naked nuclei, relatively uniform mildly convoluted nuclei with grooves, vacuolated cytoplasm (Diagn Cytopathol 2008;36:297)

Positive stains

FOXL2 immunostain is a sensitive (80%) and specific (99%) marker for sex cord stromal tumors (SCST), superior to α inhibin and calretinin and is positive in almost all SCST (98%) with FOXL2 mutation and a large number of those without mutation (67%); majority of adult GCTs (93%) are positive with FOXL2 stain and the immunostain cannot differentiate adult GCT from other SCSTs (Am J Surg Pathol 2011;35:484)
SF1: most sensitive marker for this as well as most common sex cord stromal tumors (Am J Surg Pathol 2009;33:354)
Inhibin A: more specific marker
Calretinin (Am J Surg Pathol 2002;26:1477)
Reticulin: shows lack of pericellular staining and highlights nests or large groups of granulosa cells and vessels, helps differentiate diffuse pattern from fibrothecoma (Int J Gynecol Pathol 2019;38:143)
Low molecular weight cytokeratin (CAM5.2, AE1 / AE3): 30 - 60%, usually dot-like or globoid perinuclear pattern (Hum Pathol 1994;25:60, Am J Surg Pathol 1992;16:962)
S100: 50% (Hum Pathol 1994;25:60)
CD99: 70% (Histopathology 1995;27:388, Mod Pathol 1998;11:769)
EGFR: 65% of primary and 85% of recurrent (Gynecol Oncol 2006;101:18)
Vimentin, WT1, CD56 and SMA

Negative stains

EMA (in contrast to juvenile type)
CK7

Molecular / cytogenetics description

FOXL2 402C → G (C134W) somatic mutation is highly sensitive and specific for diagnosis of adult GCT (N Engl J Med 2009;360:2719, PLoS One 2009;4:e7988, Am J Surg Pathol 2011;35:484)
More than half of cases show chromosomal imbalances (Gynecol Oncol 2005;97:68)
Most common chromosomal abnormalities are trisomy 12, trisomy 14, monosomy 16 / 16q deletion and monosomy 22 (Gynecol Oncol 2005;97:68)

Videos

Sex cord stromal tumors of the ovary and mimics

Histopathology of adult granulosa cell tumor

Granulosa cell tumor

Sample pathology report

Left ovary and fallopian tube, left salpingo-oophorectomy:
- Granulosa cell tumor, adult type (see synoptic report)

Differential diagnosis

Cellular fibroma or cellular thecoma versus diffuse pattern:
- Almost exclusively thin bland spindle cells in cellular fibroma and abundant pale cytoplasm in thecoma
- Reticulin: stains pericellular fibers
- Most are negative for FOXL2 mutation
Steroid cell tumor versus extensively luteinized pattern:
- Both inhibin+ but FOXL2-
Juvenile granulosa cell tumor (juvenile GCT) versus luteinized type:
- Both with moderate abundant pale cytoplasm, rounded nuclei and no nuclear grooves
- Has follicles with irregular size and shape, no Call-Exner bodies, brisk mitotic activity and can have areas of higher grade atypia
- 90% FOXL2 mutation negative (PLoS One 2009;4:e7988)
Endometrioid carcinoma (FIGO grade I and those resembling sex cord stromal tumor) versus microfollicular pattern:
- Usually have areas of typical endometrioid carcinoma with mucin producing glands or squamous differentiation
- Cytokeratin+, EMA+, calretinin-, inhibin-
Carcinoid tumor versus microfollicular and insular pattern:
- Similar insular and nested growth pattern
- May be seen co-existing with teratoma
- Classic salt and pepper chromatin pattern
- Synaptophysin+, chromogranin+
Sex cord tumors with annular tubules (SCTATs) versus microfollicular pattern:
- Have ring shaped simple and complex tubules, if bilateral and microscopic often associated with Peutz-Jeghers syndrome
- Usually have hyaline deposits larger than Call-Exner bodies and often calcified
Poorly differentiated ovarian surface epithelial carcinoma versus diffuse pattern:
- Higher grade cytological atypia
- EMA, HMWCK diffusely positive (Virchows Arch A Pathol Anat Histopathol 1989;414:439)
Endometrial stromal sarcoma, low grade versus diffuse pattern:
- Also with scant cytoplasm and diffuse growth pattern but with distinct periarteriolar swirling of tumor cells, no nuclear grooves
- CD10+, inhibin-
Metastatic breast carcinoma (lobular) versus diffuse pattern:
- History of breast carcinoma, bilaterality
- Intracellular mucin
- Inhibin-, GATA3+, ER+, EMA+, GCDFP-15+
Metastatic melanoma versus diffuse pattern:
- Presence of melanin pigment
- Inhibin-, S100+, HMB45+
Pregnancy related granulosa cell proliferation versus macrofollicular pattern:
- Usually incidental, microscopic, multifocal, lies within atretic follicles surrounded by a thick layer of luteinized theca cells (Hum Pathol 1988;19:657)

Additional references

Kurman: WHO Classification of Tumours of the Female Reproductive Organs (Medicine), 4th Edition, 2014, Pathology 2018;50:5, Mod Pathol 2013;26:860, Am J Surg Pathol 2013;37:1450, J Mol Diagn 2017;19:126, Gynecol Oncol 2017;146:285

Board review style question #1

A 59 year old woman underwent abdominal hysterectomy and salpingo-oophorectomy for ovarian torsion and endometrial atypical hyperplasia. You receive a 10 cm hemorrhagic cystic ovarian mass for intraoperative consultation. Frozen section is shown above. What is the most common mutation identified in this ovarian tumor?

CDH1
FOXL2
P53
STK11

Board review style answer #1

B. The FOXL2 somatic mutation has been identified in 94 - 97% of adult granulosa cell tumors and is thought to play an essential role in the pathogenesis of the disease.

Comment Here

Reference: Granulosa cell tumor - adult

Board review style question #2

Which of the following is associated with worse outcome in adult granulosa cell tumor?

Cytologic atypia
FOXL2 heterozygous mutation
Tumor necrosis
Tumor rupture

Board review style answer #2

D. The tumor rupture and disease stage are associated with adverse outcome in adult type granulosa cell tumor.

Comment Here

Reference: Granulosa cell tumor - adult

Granulosa cell tumor-juvenile

Table of Contents

Definition / general

Sex cord stromal tumor composed of primitive appearing granulosa cells with follicular and solid growth patterns

Essential features

Sex cord stromal tumor with primitive granulosa cell differentiation
Solid and follicular growth
Almost always occurs in patients younger than 30 years
Lacks the FOXL2 somatic mutation seen in adult granulosa cell tumor
Usually stage IA and associated with a favorable prognosis

ICD coding

ICD-O: 8622/1 - granulosa cell tumor, juvenile
ICD-10:
- C56.9 - malignant neoplasm of unspecified ovary
- D39.1 - neoplasm of uncertain behavior of ovary
ICD-11: 2F76 & XH2KH2 - granulosa cell tumor, juvenile

Epidemiology

Mean age 13 years; range 0 - 67 years
80% occur before age 20 and 97% before age 30 (Am J Surg Pathol 1984;8:575)

Sites

Ovary
Rarely extraovarian (Pediatr Hematol Oncol 2021;38:272)

Pathophysiology

Unknown

Etiology

Unknown

Clinical features

Most prepubertal patients present with sexual precocity due to excessive estrogen production and rarely produce androgens; older patients have nonspecific abdominal swelling and pain (J Endocrinol Invest 2006;29:653, Am J Surg Pathol 1984;8:575)
Rarely associated with enchondromatosis (Ollier disease), Maffucci syndrome, abnormal karyotype / ambiguous genitalia (Am J Surg Pathol 1984;8:575, Am J Surg Pathol 1985;9:737)

Diagnosis

Diagnosis is made at the time of removal of an adnexal mass
Possibility of juvenile granulosa cell tumor may be suspected if there are estrogenic manifestations in a prepubertal patient but histopathological examination is required for diagnosis

Radiology description

Typically appears on imaging as a large, unilateral, multicystic mass with occasional septae; most contain both solid and cystic components
Can have a sponge-like appearance on imaging (Radiographics 2014;34:2039)

Prognostic factors

Of low malignant potential, with a very favorable prognosis for patients with stage IA tumors (which account for a large majority of cases) but a guarded prognosis if there is spread beyond the ovary

Case reports

Fetus with an androgenic ovarian mass in the third trimester (J Obstet Gynaecol Res 2021;47:2220)
2 year old girl with precocious pseudopuberty (J Clin Res Pediatr Endocrinol 2021 Apr 14 [Epub ahead of print])
17 year old girl with gender dysphoria (Case Rep Oncol 2020;13:1330)
33 year old woman with adnexal mass and Maffucci syndrome (Clin Imaging 2019;56:77)
40 year old Japanese woman with late onset juvenile granulosa cell tumor (Acta Med Okayama 2020;74:159)

Treatment

Large majority of tumors are stage IA and surgical removal, with preservation of fertility if desired, is all that is required for treatment (Acta Obstet Gynecol Scand 2021 May 24 [Epub ahead of print])
With recurrent or advanced stage tumors, platinum based chemotherapy is typically offered (Acta Obstet Gynecol Scand 2021 May 24 [Epub ahead of print])

Gross description

Usually unilateral with a smooth surface
Mean size 12.5 cm (Am J Surg Pathol 1984;8:575)
Multiloculated, cystic and solid tumor with yellow-white solid areas
May have hemorrhage and necrosis

Gross images

AFIP Images

Solid and slightly lobulated

Large locules with smooth linings

Solid and cystic

Frozen section description

Smooth surfaced ovarian mass in a young patient
Presence of follicular differentiation is helpful but definitive diagnosis may have to be deferred to permanent sections

Microscopic (histologic) description

Diffuse or nodular appearance at low power
Macrofollicle and microfollicle formation containing eosinophilic secretions
Tumor cells are often luteinized
Round / oval hyperchromatic nuclei with small nucleoli, irregular nuclear contours
No / rare nuclear grooves; high mitotic rate (mean 11/10 high power fields) (Arch Pathol Lab Med 1989;113:40)
Bizarre / atypical nuclei are rarely present
May have pseudopapillary architecture (Am J Surg Pathol 2008;32:581)

Microscopic (histologic) images

Contributed by Jutta Huvila, M.D., Ph.D. and AFIP

Lobulated growth pattern

Follicular differentiation

Atypical cells lining follicle

Solid growth

Solid cellular neoplasm with focal follicle formation

Solid nodules

Mitotic figures

Hobnail nuclei

Bizarre nuclei

Virtual slides

Images hosted on other servers:

Lobulated architecture with follicle-like spaces

Positive stains

Inhibin
Calretinin
SF1
WT1
FOXL2
BRG1 (SMARCA4) (retained)
References: Mod Pathol 2003;16:584, Ann Diagn Pathol 2021;52:151721, J Obstet Gynaecol Res 2021 Apr 27 [Epub ahead of print], Am J Surg Pathol 2011;35:484

Negative stains

Molecular / cytogenetics description

Most have AKT1 mutations (EBioMedicine 2015;2:421)
GNAS mutations reported in 30% of cases (J Clin Endocrinol Metab 2006;91:1842)
Consistently negative for FOXL2 (402C > G) mutation, while 5 - 10% have a mutation in DICER1; the DICER1 mutations may be germline, i.e. associated with DICER1 syndrome (Am J Surg Pathol 2021;45:223)
Somatic mutations in IDH1 or IDH2 are associated with Ollier disease or Maffucci syndrome; juvenile granulosa cell tumor is an uncommon manifestation of both diseases (Am J Med Genet A 2020;182:1093)

Sample pathology report

Right ovary, oophorectomy:
- Juvenile granulosa cell tumor, negative for ovarian surface involvement or extraovarian spread

Differential diagnosis

Adult granulosa cell tumor:
- Older age at presentation (but there is some overlap in the age ranges)
- Small uniform cells resembling normal granulosa cells
- FOXL2 mutation in 95% of cases (N Engl J Med 2009;360:2719)
Small cell carcinoma, hypercalcemic type:
- More primitive appearing cells, with scant cytoplasm or rhabdoid cells
- Loss of BRG1 expression (protein encoded by SMARCA4) (J Pathol 2016;238:389)
- Mutation in SMARCA4 (Nat Genet 2014;46:427)
Sertoli-Leydig cell tumor:
- Tubules (in well differentiated tumors), cords (intermediate differentiation), sarcomatoid growth (poorly differentiated) or retiform architecture
- Follicle-like spaces occasionally seen admixed with typical sertoliform differentiation (Am J Surg Pathol 2021;45:59)
Gynandroblastoma:
- Typical Sertoli-Leydig cell tumor component coexisting with separate typical juvenile granulosa cell tumor (Am J Surg Pathol 2021;45:59)
Yolk sac tumor:
- Schiller-Duval bodies
- Enteric differentiation
- Hyaline globules
- Expresses SALL4 and AFP
Clear cell carcinoma:
- Older age
- Background endometriosis or adenofibroma
- Expression of CK7 and Napsin A
- Negative for inhibin, SF1 and FOXL2

Additional references

WHO Classification of Tumours Editorial Board: Female Genital Tumours, 5th Edition, 2020

Board review style question #1

A 2 year old girl presents with a unilateral ovarian tumor. Histology shows follicle-like spaces lined by cells with moderate amounts of cytoplasm and showing nuclear atypia and prominent nucleoli. What is the diagnosis?

Juvenile granulosa cell tumor
Sertoli-Leydig cell tumor
Teratoma
Yolk sac tumor

Board review style answer #1

A. Juvenile granulosa cell tumor

Comment Here

Reference: Granulosa cell tumor - juvenile

Gynandroblastoma

Table of Contents

Definition / general | Case reports | Microscopic (histologic) images

Definition / general

Sex cord stromal tumor with equal numbers of granulosa-theca cells and Sertoli-Leydig cells
Very rare; variable hormones

Case reports

24 year old woman with polycystic ovarian syndrome (Arch Pathol Lab Med 2006;130:225)

Microscopic (histologic) images

AFIP images

Well differentiated
ovarian and testicular
type cells

High grade serous carcinoma

Table of Contents

Definition / general

Epithelial carcinoma of serous cell lineage with papillary, glandular and solid growth patterns and high grade cytologic atypia

Essential features

Often bilateral, solid and cystic ovarian masses
Solid, pseudoendometrioid, transitional cell carcinoma-like (SET) appearance more common in BRCA1 mutations; need to refer to genetic testing
3 patterns of aberrant p53 expression correlate with TP53 mutation
Most important prognostic factor is stage, ~40% overall 5 year survival

Terminology

High grade serous adenocarcinoma

ICD coding

ICD-O: 8461/3 - malignant epithelial serous tumors, high grade serous carcinoma

Epidemiology

Accounts for majority of ovarian carcinoma diagnoses and related deaths
Affects women disproportionately in western nations
Increased risk in Caucasian as compared with African American women
Decreased risk with several menstrual and reproductive factors:
- Parity
- Later age at menarche
- Earlier age of menopause
- Oral contraceptive use
Increased risk with estrogen only hormonal therapy, combined estrogen and progestin regimens

Sites

Tubo-ovarian, peritoneum

Pathophysiology

Hereditary predisposition in 15 - 20% of cases involving BRCA genes (Am J Surg Pathol 2016;40:404):
- BRCA1 germline mutations cause 50% lifetime risk of ovarian cancer at average age of ~50 years
- BRCA2 germline mutations causes lower lifetime risk (10 - 35%) at a later age (average ~55 years)
Associated with homologous recombination defects
Hereditary predisposition in 6% of women with Fanconi anemia
A significant proportion arise in the fallopian tube and spread to the ovaries and peritoneum

Clinical features

Mean age: 63 years
Abdominal distension / bloating / pain
Nausea
Anorexia / early satiety
Back pain
Urinary incontinence
Advanced disease at presentation in ~80% of cases

Diagnosis

CT with contrast is the preferred imaging modality
Diagnosis is by surgical resection and histologic examination of resected tissue - may be associated with serous intraepithelial carcinoma (STIC) in fallopian tube (Histopathology 2014;65:149, Int J Gynecol Pathol 2017;36:230)

Laboratory

Elevated serum CA-125 level

Radiology description

Unilocular or multilocular, often bilateral, cystic and solid ovarian masses
Papillary projections identifiable
Peritoneal implantations and lymphadenopathy visible

Radiology images

Images hosted on other servers:

Cystic mass with papillary projections

Prognostic factors

Most important: stage, ~40% overall 5 year survival
In advanced stage disease, the amount of residual tumor present after staging and debulking is the most important factor
Low Ki67 proliferation index associated with platinum resistance and decreased survival
CD3+ or CD8+ tumor infiltrating lymphocytes confer favorable prognosis

Case reports

13 year old girl and 69 year old woman with normal sized ovarian carcinoma syndrome (Horm Mol Biol Clin Investig 2018;35:1)
22, 35 and 47 year old women with low grade serous neoplasms of the ovary with transformation to high grade carcinomas (Int J Gynecol Pathol 2012;31:423)
51 year old woman with high grade serous ovarian cancer 3 years after bilateral salpingectomy (Mol Clin Oncol 2017;6:201)
73 year old woman with serous carcinoma of the ovary that metastasized to the tail of the pancreas (Mol Clin Oncol 2016;5:41)

Treatment

Bilateral salpingo-oophorectomy with hysterectomy, debulking and staging biopsies
Chemotherapy (neoadjuvant and adjuvant)
Poly (ADP-ribose) polymerase (PARP) inhibitors with best response in patients with BRCA1 / BRCA2 mutations or other homologous recombination deficiency and platinum sensitivity (Cancer Chemother Pharmacol 2018;81:647, Invest New Drugs 2018;36:828)

Gross description

Often bilateral
Variable in size; often large, ~30% of cases with grossly normal ovary or surface nodules < 1 cm
Exophytic with solid or papillary growth
Solid areas tan to white with necrosis and hemorrhage
Serous / bloody fluid filled cysts
Fallopian tube can be grossly involved at fimbriated end

Gross images

Contributed by Erna Forgó, M.D. and Teri A. Longacre, M.D.

Cystic mass with papillary tumor growth

Frozen section description

Nuclear pleomorphism (> 3x variation in size)
Moderate to severe nuclear atypia
Can have large bizarre forms
Increased mitotic figures, can be atypical

Frozen section images

Contributed by Erna Forgó, M.D. and Teri A. Longacre, M.D.

SET pattern

Necrosis, nuclear pleomorphism

Nuclear atypia and pleomorphism

Microscopic (histologic) description

Solid masses of columnar to cuboidal cells with eosinophilic cytoplasm and slit-like spaces (fusion of papillae)
Solid, pseudoendometrioid, transitional cell carcinoma-like (SET) appearance (more common in BRCA1 mutations) (Mod Pathol 2012 Apr;25(4):625)
Hierarchical papillary branching, glandular and cribriform patterns common
Significant nuclear atypia
Significant nuclear pleomorphism (> 3x variation in size) with large, bizarre and multinucleated forms (Hum Pathol 2005;36:1049)
Prominent nucleolus, often large and eosinophilic
High mitotic index: ≥ 12 mitotic figures per 10 high power fields, often atypical
Necrosis is frequent
Can have increased CD3+ or CD8+ tumor infiltrating lymphocytes (more common in BRCA1 mutation)
Psammoma bodies are variable
Serous tubal intraepithelial carcinoma (STIC) (90% fimbria, 10% ampulla / isthmus) exhibits similar histologic features; may be bilateral (10 - 20%) and multifocal
Findings after neoadjuvant chemotherapy: single cells in a background of histiocytic reaction and fibrosis, clear cell change, decrease in mitotic figures, increased psammoma bodies

Microscopic (histologic) images

Contributed by Erna Forgó, M.D. and Teri A. Longacre, M.D.

Significant nuclear atypia and pleomorphism

Micropapillary growth pattern

SET pattern

PAX8 positive

ER positive

Variable PR (negative in this case)

WT1 positive

CK7 positive

CK20 negative

p53 overexpression

p53 null phenotype

Serous tubal intraepithelial carcinoma (STIC)

p53 overexpression in STIC

Contributed by Jijgee Munkhdelger, M.D., Ph.D. and Andrey Bychkov, M.D., Ph.D.

Ovarian serous carcinoma immunoprofile

Virtual slides

Contributed by Andrey Bychkov, M.D., Ph.D.

High grade serous carcinoma

Cytology description

3 dimensional clusters or single cells with scant cytoplasm
Significant nuclear pleomorphism (> 3x variation in size)
Prominent nucleoli

Cytology images

Contributed by Erna Forgó, M.D. and Teri A. Longacre, M.D.

Malignant glandular cells in 3D clusters and singly

Positive stains

PAX8, WT1, p16 (~60%), ER (80%), PR (30%), CK7, D2-40 (variable), calretinin (variable, may be focal)
Aberrant p53 expression that correlates with TP53 mutation, 3 patterns (J Pathol Clin Res 2016;2:247, Int J Gynecol Pathol 2019;38 Suppl 1:S123):
- Overexpression: strong, diffuse nuclear staining in > 80% of cells (missense mutation)
- Null phenotype: complete absence of staining (loss of function mutation)
- Cytoplasmic expression: Cytoplasmic p53 expression with intensity similar to that of internal nuclear controls (loss of function mutation disrupting nuclear localization domain)
High Ki67 proliferation index (> 75%) (Oncotarget 2016;8:107877)

Negative stains

CK20, Napsin A

Molecular / cytogenetics description

TP53 alterations in nearly all cases
Germline, somatic or promoter hypermethylation (inactivation) of BRCA1 and BRCA2 in ~50% of cases (Am J Surg Pathol 2016;40:404)
Prominent DNA copy number changes, including CCN1, MYC, NOTCH3, PIK3CA, AKT oncogenes

Sample pathology report

Ovary and fallopian tube, right, salpingo-oophorectomy:
- Ovary
  - High grade serous carcinoma (see comment and synoptic report)
- Fallopian tube
  - Intravascular involvement by high grade serous carcinoma
Ovary and fallopian tube, left, salpingo-oophorectomy:
- Ovary
  - High grade serous carcinoma
- Fallopian tube
  - Intravascular involvement by high grade serous carcinoma
  - Paratubal cysts
Comment: We reviewed the frozen sections and confirm the diagnosis rendered. Histologic sections of the right and left adnexa show a high grade neoplasm growing in a solid trabecular pattern that involves both ovaries without capsular disruption. Abundant tumor associated lymphocytes are present. The tumor cells are positive for CK7 and PAX8 with abnormal (overexpression) of p53 but negative for CK20. Estrogen receptor and progesterone receptor expression is negative. These features are best characterized as high grade serous carcinoma which displays a SET (solid, pseudoendometrioid or transitional) pattern. Ovarian carcinomas which show a SET pattern of high grade serous carcinoma may be associated with BRCA gene mutations (somatic or germline).

Differential diagnosis

Low grade serous carcinoma:
- Minimal nuclear pleomorphism (< 3x variation in size) (Hum Pathol 2005;36:1049)
- Low mitotic index (< 12 mitotic figures per 10 high power fields)
- p53 wild type expression
- p16 negative or patchy positive
Clear cell carcinoma:
- Associated with endometriosis
- Often lower stage at presentation
- Distinctive architecture with variable admixture of tubulocystic, papillary and solid growths
- Composed of clear, eosinophilic, cuboidal or hobnail cells
- WT1, ER negative
- HNF-1B, Napsin A positive
Undifferentiated carcinoma:
- Discohesive, often monomorphic cells
- Often decreased expression of keratins and EMA
- PAX8 often negative or weak
- Association with mismatch repair protein or SWI/SNF protein deficiency
Metastatic endometrioid serous carcinoma:
- Tumor mass, with or without endometrial intraepithelial carcinoma (precursor lesion) in the endometrium
- Usually WT1 negative or patchy
Endometrioid adenocarcinoma:
- Often lower stage at presentation
- Associated with endometriosis
- ER, PR diffusely positive
- WT1 variable, p16 patchy positive, p53 wild type expression
Malignant mesothelioma:
- Simple papillae lined by 1 cell layer without tufting
- Less severe nuclear atypia
- Low mitotic activity
- D2-40, calretinin positive
- ER negative

Board review style question #1

An ovarian tumor is shown. This particular pattern, called SET (solid, pseudoendometrioid, transitional cell carcinoma-like), is most commonly associated with which genetic mutation?

BRCA1
KRAS
P53
PIK3CA

Board review style answer #1

A. BRCA1. SET (solid, pseudoendometrioid or transitional) pattern has a strong correlation between the presence of BRCA1 mutation and ovarian high grade serous carcinoma phenotype. These tumors also tend to have a higher mitotic index, increased tumor infiltrating lymphocytes and necrosis that can be comedonecrosis or geographic necrosis, when compared with unassociated cases. Recognition of this architectural growth pattern allows for the initiation of appropriate genetic testing and referral into necessary screening programs.

Comment Here

Reference: High grade serous carcinoma

Board review style question #2

Which is the most important prognostic factor for overall survival of ovarian high grade serous carcinoma?

Grade
Histologic subtype
Mitotic index
Stage

Board review style answer #2

D. Stage. Stage is the most important prognostic factor in ovarian high grade serous carcinoma, with a ~40% overall survival at 5 years. In advanced stage disease, the amount of residual tumor present after staging and debulking is the most important factor for survival. Ovarian, tubal and peritoneal high grade serous carcinomas are staged the same. It has been proposed that ovarian disease in absence of serous intraepithelial carcinoma (STIC) be classified as ovarian in origin, ovarian disease in the presence of STIC be classified as tubal in origin and peritoneal disease in absence of ovarian or tubal involvement be classified as peritoneal in origin.

Comment Here

Reference: High grade serous carcinoma

Hyperreactio luteinalis

Table of Contents

Definition / general

Bilateral, ovarian enlargement due to multiple, luteinized follicle cysts

Epidemiology

Rare
Associated with hydatidiform mole, choriocarcinoma, fetal hydrops due to Rh sensitization and multiple gestations
Rarely seen in uncomplicated, single pregnancy

Etiology

Due to hCG stimulation or hypersensitivity to hCG

Clinical features

Usually no symptoms, may have pain from hemorrhage; rarely ascites
Virilization in 15% of mothers but not female infants in cases without gestational trophoblastic disease

Prognostic factors

Only rarely recurs (J Clin Pathol 2005;58:439)

Case reports

Associated with HELLP syndrome (Fertil Steril 2008;90:2008.e13)
With hirsutism (Gynecol Endocrinol 2007;23:248)
With marked virilization and hyperglycemia (Am J Perinatol 2006;23:85)

Treatment

Cysts typically involute within 6 months (Arch Pathol Lab Med 1989;113:921)
Operate only to remove infarcted tissue or to control hemorrhage

Gross description

Multiple, bilateral thin walled cysts, filled with clear or hemorrhagic fluid

Gross images

AFIP images

Both ovaries are
enlarged by
multiple thin
walled cysts

Microscopic (histologic) description

Follicular cysts with luteinization of theca interna or granulosa cells, edema of theca layer and stroma

Microscopic (histologic) images

AFIP images

Luteinized granulosa cells

Prominent edema
in the luteinized
theca cell layer

Ovarian stroma is markedly edematous

Large solitary luteinized follicular cyst of pregnancy and puerperium

Table of Contents

Definition / general

Rare solitary follicular cyst that occurs during pregnancy and puerperium, may be related to hCG
Palpable adnexal mass or seen at C section
No clinical endocrine disturbance

Treatment

Conservative, most regress during puerperium, may need to excise if symptomatic (Obstet Gynecol 2005;105:1218)

Gross description

Large, solitary, unilocular cyst, resembles follicular cyst but markedly larger (median size - 25 cm)

Gross images

AFIP images

25 cm unilocular cyst

Microscopic (histologic) description

Cyst lined by 1 or more layers of luteinized cells with clear to pink cytoplasm, no theca / granulosa distinction
Focal nuclear atypia (enlarged, pleomorphic and hyperchromatic nuclei) is probably degenerative
Also nests of luteinized cells within fibrous tissue of cyst wall (Pathol Res Pract 2006;202:471)
May have a few mitotic figures (Diagn Pathol 2011;6:3)

Microscopic (histologic) images

Contributed by Raul S. Gonzalez, M.D.

Solitary luteinized follicle cyst

Images hosted on other servers:

Microscopic features of ovarian cyst

Histologic characteristics of ovarian cyst

Differential diagnosis

Cystic ovarian neoplasm (low N/C ratio, sporadic atypia and clinical setting favor a solitary follicular cyst)

Additional references

Am J Surg Pathol 1980;4:431, Arch Pathol Lab Med 1986;110:928

Leiomyoma

Table of Contents

Definition / general

Accounts for 0.5 - 1% of all benign ovarian tumors
Associated with synchronous leiomyomas of uterus
Do not recur locally or metastasize, even if mitotically active

Epidemiology

Age varies between 20 and 65 years
About 16% occur after menopause (J Obstet Gynaecol Res 2005;31:257)

Pathophysiology

Arises from smooth muscle cells in ovarian hilar blood vessels
Other possible origins include cells in ovarian ligament, smooth muscle cells or multipotential cells in ovarian stroma, undifferentiated germ cells, or cortical smooth muscle metaplasia (Am J Surg Pathol 2004;28:1436)

Clinical features

Abdominal pain, mass, vaginal discharge

Laboratory

CA125, CA19-9 and CEA are within normal range

Radiology description

Transvaginal ultrasonography: solid mass
MRI T1 and T2 weighted images: well circumscribed low signal intensity mass (Eur Radiol 1998;8:1444)

Case reports

21 year old woman with bilateral massive ovarian leiomyomata (Mod Pathol 1992;5:586)
31 year old woman with primary ovarian leiomyoma associated with endometriotic cyst presenting with symptoms of acute appendicitis (Diagn Pathol 2009;4:25)
79 year old woman with leiomyoma of the ovary presenting with Meigs' syndrome (J Obstet Gynaecol Res 2005;31:257)

Treatment

Surgical resection

Gross description

Solid lobulated mass, median 3 cm (range 0.3 - 20 cm), often in hilar region
Cut surface is gray-white, whorled

Gross images

AFIP images

Lobulated sectioned surface

Images hosted on other servers:

Gray-white with whorled pattern

Ovary replaced with creamy mass

Microscopic (histologic) description

Irregular bundles and whorling of spindle shaped cells with no atypia or pleomorphism
Degenerative changes like hyaline degeneration and myxomatous changes can be seen
May be cellular, have prominent mitotic activity or occasionally have bizarre nuclei or myxoid stroma

Microscopic (histologic) images

AFIP images

Spindle cells arranged in intersecting fascicles

Images hosted on other servers:

Long fascicle of spindle shaped cells

H&E, desmin, α smooth muscle actin

Positive for SMA

Positive stains

α smooth muscle actin

Negative stains

α inhibin

Differential diagnosis

Leiomyosarcoma

Table of Contents

Definition / general

Rare tumor of teratomatous or nonteratomatous origin
"True" leiomyosarcoma if of nonteratomatous origin

Sites

Omentum, reteroperitoneum, mesentery

Pathophysiology

Arises from: malignant degeneration of ovarian leiomyoma; smooth muscle in blood vessel walls in cortical stroma and corpus luteum, muscular attachments of ovarian ligament, wolfian duct remnants, or totipotential ovarian mesenchyme; or from a teratoma

Clinical features

Mostly postmenopausal patients
Presents with abdominal pain and mass
62% die of disease within mean 24 months (Am J Surg Pathol 2004;28:1436)

Prognostic factors

Tumor stage, tumor size, grade, mitotic index (Obstet Gynecol Surv 2007;62:480)

Case reports

42 year old woman with epithelioid tumor (Gynecol Oncol 2005;97:697)
58 year old woman (Arch Pathol Lab Med 1991;115:941)
60 year old women (World J Oncol 2001;2:265, Online J Health Allied Scs 2009;8:16)

Treatment

Multimodality treatment: surgical debulking, postoperative radiotherapy or chemotherapy
FIGO staging and treatment of ovarian sarcoma is same as for epithelial ovarian carcinoma (Obstet Gynecol Surv 2007;62:480)

Gross description

Solitary, lobular, soft fleshy solid mass with hemorrhage and cystic degeneration

Microscopic (histologic) description

Usually 2 of 3: moderate / severe cytologic atypia, 10+ MF/10 HPF, tumor cell necrosis
Varies from well differentiated to highly pleomorphic sarcoma

Microscopic (histologic) images

AFIP images

Epithelioid tumor

Images hosted on other servers:

Pleomorphic tumor cells

H-Caldesmon, desmin and smooth muscle actin

Positive stains

desmin, H-Caldesmon, smooth muscle actin

Negative stains

CD34, Cytokeratin

Differential diagnosis

Cellular fibroma: low mitotic activity <10/10HPF
Krukenberg tumors have stromal reaction, history of GI primary, pan CK+
Mixed Müllerian tumors: pan CK+ areas
Sarcomatoid form of sex cord stromal tumors: sex cord elements present
Undifferentiated carcinomas: pan CK+, H caldesmon-

Leydig cell hyperplasia (pending)

[Pending]

Leydig cell tumor

Table of Contents

Definition / general

Rare, derived from hilar cells
Almost always benign
Call a nonhilar Leydig cell tumor if it occurs in ovarian cortical stroma
Symptoms: virilization, elevated 17-ketosteroid excretion and unresponsive to cortisol suppression

Treatment

Excision

Gross description

Unilateral

Gross images

AFIP images

Red-brown mass

Brown-black nodule

Microscopic (histologic) description

Large lipid laden cells with distinct borders; Reinke crystals common

Microscopic (histologic) images

AFIP images

Crystals of Reinke

Separated cellular areas

Prominent fibrous stroma

Fibrinoid replacement

Abundant, pale, vacuolated cytoplasm

Enlarged, hyperchromatic, bizarre nuclei

Low grade serous carcinoma

Table of Contents

Definition / general

Epithelial carcinoma of serous cell lineage, usually with distinctive patterns of invasion and low grade malignant cytologic atypia

Essential features

Often bilateral ovarian masses that are solid or solid and cystic with calcifications
Extraovarian spread at presentation associated with poor outcome
Precursor lesion is often a borderline serous tumor
KRAS and BRAF mutations in 50 - 60% of cases

Terminology

Low grade serous adenocarcinoma
Well differentiated serous carcinoma
Invasive micropapillary carcinoma

ICD coding

ICD-O: 8460/3 - malignant epithelial serous tumors, low grade serous carcinoma

Epidemiology

3.5% of all ovarian carcinomas; 5% of all serous tumors (Int J Gynecol Pathol 2010;29:203)
Mean age: fifth to sixth decades
Presents ~10 years earlier than patients with high grade serous carcinoma (Adv Anat Pathol 2009;16:267)

Sites

Ovary
Usually bilateral

Pathophysiology

Precursor lesion is often a borderline serous tumor (Am J Surg Pathol 2004;28:496, Int J Gynecol Pathol 2020;39:43)
- Both tumors can coexist in up to 85% of cases, in variable combinations (Am J Surg Pathol 2016;40:1165)
  - Can be synchronous, metachronous
  - Can be at same or different site
May rarely progress to high grade serous carcinoma, sarcomatoid carcinoma or carcinosarcoma (Histopathology 2019;74:638, Int J Gynecol Pathol 2012;31:423)

Clinical features

Abdominal pain / swelling
Incidental finding
Most patients present with advanced stage disease
Can manifest as recurrence following diagnosis of serous borderline tumor

Diagnosis

CT with contrast is the preferred imaging modality
Diagnosis is by surgical resection

Laboratory

Elevated serum CA-125 level (Gynecol Oncol 2014;132:560)

Radiology description

Ovarian masses are usually solid or solid and cystic
Can contain thick septae or nodular components with increased vascularity
Calcifications are often readily identifiable
Reference: Eur J Radiol Open 2015;2:39

Radiology images

Images hosted on other servers:

Solid pelvic mass with calcifications

Cystic pelvic mass with calcifications

Prognostic factors

Excellent with surgical excision alone if confined to the ovary
Extraovarian spread at presentation associated with poor outcome (Int J Gynecol Pathol 2013;32:529)
5 and 10 year survival rate in advanced stage is 80% and 50%, respectively
Better prognosis than high grade serous carcinoma when matched for stage

Case reports

29 year old woman with Rubinstein-Taybi syndrome and synchronous ovarian and endometrial carcinomas (Int J Gynecol Pathol 2015;34:132)
3 women, ages 33 - 50 years, with serous borderline tumor of the ovary with areas of serous low grade carcinoma and metastases (Am J Surg Pathol 2005;29:496)
39 year old woman with platinum resistance and extended response to bevacizumab (Anticancer Drugs 2013;24:986)
55 year old Japanese woman with a paraspinal bone metastasis after a 13 year disease free interval (Diagn Pathol 2018;13:43)
67 year old woman with BRAF V600E and TERT promoter mutations that transformed to carcinosarcoma in a lymph node (Int J Gynecol Pathol 2019;38:386)

Treatment

Bilateral salpingo-oophorectomy and hysterectomy with debulking and lymph node biopsies
Adjuvant chemotherapy or hormonal therapy
- Typically poor response to platinum / Taxol chemotherapy

Gross description

Often bilateral
Fine papillary, nodular growth
Little to no necrosis
Calcification in the ovary and extraovarian lesions can be extensive

Gross images

Contributed by Erna Forgó, M.D. and Teri A. Longacre, M.D.

Irregular papillary mass

Heterogeneous cystic yellow friable mass

Frozen section description

Uniform population of small cells with scant cytoplasm
Mild to moderate nuclear atypia at most (grade 1 or 2)
No nuclear pleomorphism (< 3x variation in size) (Hum Pathol 2005;36:1049)
May have a conspicuous nucleolus
Minimal necrosis

Microscopic (histologic) description

Uniform / homogeneous population of small cells with scant cytoplasm
Mild to moderate nuclear atypia at most (grade 1 or 2)
No nuclear pleomorphism (< 3x variation in size) (Hum Pathol 2005;36:1049)
May have a conspicuous nucleolus
Low mitotic index: < 12 mitotic figures per 10 high power fields
Little to no necrosis
Psammoma bodies are frequent
2 patterns, noninvasive and invasive:
- Noninvasive: nonhierarchical architecture with micropapillary or cribriform patterns with significant expansile growth
- Invasive (> 5 mm): micropapillary or complex papillae, compact cell nests, inverted macropapillae (with broad fibrovascular cores), cribriform, glandular or cystic, solid sheets with slit-like spaces and single cells
  - Multiple different invasive patterns can exist within one tumor

Microscopic (histologic) images

Contributed by Erna Forgó, M.D. and Teri A. Longacre, M.D.

Mild to moderate (low grade) cytologic atypia

Admixed glandular, micropapillary and cribriform invasive patterns

Cytology description

Malignant glandular cells in clusters and singly
Moderate amounts of finely vacuolated cytoplasm
Enlarged hyperchromatic nuclei
No significant nuclear pleomorphism (< 3x variation in size)
Prominent nucleoli

Cytology images

Contributed by Erna Forgó, M.D. and Teri A. Longacre, M.D.

Finely vacuolated cytoplasm

Hyperchromatic nuclei

Clusters of uniform cells

Prominent nucleoli

Micropapillary clusters

Positive stains

CK7, PAX8, WT1, ER (95%), PR (50%)
Low Ki67 proliferation index

Negative stains

p16 negative or patchy positive
p53 wild type expression pattern

Molecular / cytogenetics description

KRAS and BRAF mutations in 50 - 60% of cases (Am J Surg Pathol 2010;34:433, J Pathol 2012;226:413, Cancer 2013;119:548)
NRAS mutations (Histopathology 2019;74:638)
Few chromosomal abnormalities; 1p36 loss is most significant copy number alteration
BRAF mutations rare in advanced stage disease (Am J Pathol 2010;177:1611, Cancer 2013;119:548)

Sample pathology report

Fallopian tube and ovary, right, salpingo-oophorectomy:
- Ovary
  - Low grade serous carcinoma (see comment and synoptic report)
- Fallopian tube
  - Involved by low grade serous carcinoma
- Comment: Histologic sections show diffuse involvement by carcinoma with low to intermediate grade nuclei, prominent nucleoli, vesicular chromatin and moderate amounts of delicate cytoplasm. Mitotic count is 5 per 10 high power fields. Cells are arranged as solid nests and tightly packed papillary clusters. Immunohistochemical stains show that the tumor cells are positive for WT1, ER (2 - 3+, 90%) and PR (1+, 5%). Tumor cells demonstrate slightly elevated but patchy p53 wild type staining. p16 also demonstrates patchy staining. The findings are consistent with involvement by serous carcinoma of Müllerian origin and the overall morphologic features, low mitotic activity and wild type p53 and p16 staining support the diagnosis of low grade serous carcinoma.

Differential diagnosis

Serous borderline tumor:
- No or minimal (< 5 mm) invasion
- Absence of prominent nucleoli
High grade serous carcinoma:
- Increased nuclear pleomorphism with ≥ 12 mitotic figures/10 high power fields (Hum Pathol 2005;36:1049)
- Heterogeneous architecture
- Aberrant p53 expression (overexpression or null phenotype)
- p16 diffusely positive
Endometrioid carcinoma:
- Glandular architecture
- Squamous differentiation
- WT1 variably expressed
Malignant peritoneal mesothelioma with secondary involvement of ovary:
- Extensive disease
- D2-40, calretinin positive
- BerEp4, MOC31 negative

Board review style question #1

What is the best diagnosis for this ovarian mass in a 44 year old woman?

Low grade serous carcinoma
Mesothelioma
Psammocarcinoma
Serous borderline tumor

Board review style answer #1

A. Low grade serous carcinoma. Low grade serous carcinomas of the ovary exhibit minimal necrosis or apoptotic bodies. They demonstrate a low proliferation index and a low mitotic index (< 12 mitotic figures per 10 high power fields). This is in contrast to high grade ovarian serous carcinomas, which often display comedo or geographic necrosis, high mitotic index (≥ 12 mitotic figures per 10 high power fields) and increased Ki67 proliferation rate.

Comment Here

Reference: Low grade serous carcinoma

Board review style question #2

Which of the following is true about low grade serous carcinoma of the ovary?

KRAS and BRAF mutations are present in approximately half of the cases
Most tumors show aberrant p53 expression
Nearly all the tumors progress to high grade serous carcinomas
TP53 mutations are present in nearly all of the tumors

Board review style answer #2

A. KRAS and BRAF mutations are present in about half of the cases. Low grade serous carcinomas of the ovary have few point mutations. KRAS and BRAF mutations are present in 50 - 60% of the low grade serous carcinoma of the ovary. BRAF V600E mutation is associated with early stage disease and improved prognosis and it is rarely seen in advanced stage disease.

Comment Here

Reference: Low grade serous carcinoma

Luteinized thecoma associated with sclerosing peritonitis

Table of Contents

Definition / general

Uncommon syndrome characterized by presence of ovarian (mostly bilateral) stromal tumor(s) resembling theca cells and peritoneal fibrotic lesions

Essential features

Benign tumor
Usually bilateral (unilateral cases have been reported)
Ovarian theca cell proliferation involving the cortex with or without mass formation
Associated abnormal proliferation of fibroblasts and myofibroblasts in the peritoneum that results in an irreversible fibrosis
Leads to incarceration and strangulation of the abdominal organs, which is eventually fatal

Terminology

Luteinized thecomatosis associated with sclerosing (encapsulating) peritonitis

ICD coding

ICD-O: 8601/0 - thecoma, luteinized
ICD-10
- D27 - benign neoplasm of ovary
- K65.8 - other peritonitis
- K65.9 - peritonitis, nonspecific
ICD-11
- 2F32.Y & XH0Z30 - other specified benign neoplasm of ovary & thecoma, luteinized
- DC50.Z - peritonitis, unspecified

Epidemiology

Rare
Age ranges from 10 months to 85 years; median age is 27 (Am J Surg Pathol 2008;32:1273)

Sites

Ovary, predominantly confined to the ovarian cortex
Associated peritoneal fibroblastic proliferation
References: Expert Rev Anticancer Ther 2021;21:23, J Obstet Gynaecol Can 2016;38:41

Pathophysiology

Still unclear; debatable whether this is a neoplasm or nonneoplastic proliferation
Suggested that neoplastic theca cells are able to produce substances that, when released into the peritoneal cavity, stimulate fibroblastic proliferation
Has also been suggested that luteinized theca cells secrete steroid hormones (estrogen and progesterone) that would target submesothelial fibroblasts characterized by hormonal sensitivity
Among the substances produced are cytokines, in particular transforming growth factor beta (TGFβ), which induce a fibrotic reaction within the peritoneum and, rarely, even in distant anatomical sites
References: Expert Rev Anticancer Ther 2021;21:23

Etiology

Unknown

Clinical features

Abdominal pain
Ascites
Symptoms of small bowel obstruction (acute / subacute)
Hormonal symptoms are absent
Association with anticonvulsant therapy in some cases
References: Pathology 2018;50:5, Expert Rev Anticancer Ther 2021;21:23

Diagnosis

Histologic examination

Laboratory

Occasionally elevated serum CA125 (Expert Rev Anticancer Ther 2021;21:23)

Radiology description

Magnetic resonance imaging features
- Cystic, solid adnexal region mass
- Cystic component gives a homogeneous iso or hyperintense signal
- Solid component shows moderate enhancement
Computed tomography (CT) features
- Thickened contrast material enhanced abnormal peritoneal membrane, dilation of bowel loops with clump appearance
- Thickening or calcification of bowel walls, with or without loculated ascites
References: J Ovarian Res 2013;6:58, Radiographics 2019;39:62

Radiology images

Contributed by Rajesh Thampy, M.D.

Sclerosing encapsulating peritonitis, abdominopelvic CT

Images hosted on other servers:

Luteinized thecoma

Prognostic factors

Ovarian luteinized thecoma itself is a benign tumor without risk of recurrence or metastasis
However, associated peritoneal fibrosis may result in bowel incarceration and strangulation, causing potentially life threatening bowel obstruction
References: Expert Rev Anticancer Ther 2021;21:23, Pathology 2018;50:5

Case reports

18 year old woman presented with acute abdomen (Gynecol Oncol Rep 2019;28:44)
42 year old presented with progressive respiratory distress, increased abdominal girth and sudden weight gain (J Gynecol Obstet Hum Reprod 2021;50:101734)
52 year old woman with erythematous rash, coinciding with the rapid onset of ascites and peripheral edema (J Cutan Pathol 2017;44:898)

Treatment

Surgical management
- Bilateral salpingo-oophorectomy if localized to ovaries
- Oophorectomy or unilateral salpingo-oophorectomy if unilateral and preserved fertility is desired
- Total hysterectomy with bilateral salpingo-oophorectomy is indicated in postmenopausal patients
- Omentectomy in extensive disease
- Peritoneal biopsy in case of peritoneal nodules only
- Appendectomy or small bowel resection in case of involvement
Medical management (single or combined therapy)
- Cyclophosphamide, thalidomide, leuprorelin, tamoxifen, goserelin and corticosteroids
References: Expert Rev Anticancer Ther 2021;21:23, Gynecol Oncol Rep 2019;28:44

Gross description

Usually bilateral
Dimensions range from 2 - 31 cm
Outer surface is brown, red, purple, pink or gray
Cut surface is solid, yellow, pink or gray, very often characterized by cystic hemorrhagic or sometimes soft lobulated, cerebriform or polypoid cut surface
Peritoneum with brown to white fibrous adhesions
Omentum with lobulation, nodularities, indurations or thickening
Thick, white adherent membrane encasing the small bowel (partially or complete)
Reference: Am J Surg Pathol 2008;32:1273

Frozen section description

Sheets of bland spindle cell proliferation circumferentially involve the entire cortex, with sparing of the medulla in smaller lesions (Am J Surg Pathol 2008;32:1273)
Luteinized cells are arranged in small nests or singly with small to moderate amounts of clear or eosinophilic cytoplasm (Am J Surg Pathol 2008;32:1273)
Mitotic activity is typically prominent (Am J Surg Pathol 2008;32:1273)
Edema with extravasated erythrocytes, prominent small vessels and microcystic areas
Peritoneal / omental lesions have proliferation of bland spindled cells with variably fibrillar cytoplasm
While it is unlikely peritoneal samples are submitted for frozen section examination along with the ovarian tumor, it is very helpful to inquire from the surgeon about the presence of peritoneal lesions or seek this information from the patient's chart as this helps guide diagnosis

Frozen section images

Contributed by Rayan Sibira, M.D. and Mahmoud A. Khalifa, M.D., Ph.D.

Spindle cells with entrapped luteinized cells

Luteinized cells and mitoses

Peritoneal lesions

Microscopic (histologic) description

Highly cellular
Sheets of spindle cell proliferation circumferentially involves the entire cortex with sparing of the medulla
Proliferation arranged haphazardly in small fascicles or short cords and frequently includes pre-existing ovarian structures
Less cellular areas show edema with characteristic microcystic pattern
Larger lesions show prominent cellular lobules or vaguely nodular cellular aggregates, often highlighted by hemorrhage, separated by less cellular regions with varying amounts of edema which could give a microcystic appearance
Edematous areas contain extravasated erythrocytes and prominent small vessels
High power, the cells are rounded, fusiform or stellate and cytoplasm volume ranged from scant to moderate with pale or eosinophilic color
Ill defined aggregates of luteinized cells with rounded nuclei, eosinophilic to pale cytoplasm, in the background of bland spindle cells
Brisk mitotic activity may be seen
Sex cord-like differentiation in rare cases
Entrapped normal ovarian structures, usually follicles, rarely corpora albicans (Am J Surg Pathol 2008;32:1273)
Variable amount of hemorrhage, ischemic type necrosis and in rare cases fibrin thrombi in large vessels (Am J Surg Pathol 2008;32:1273)
Peritoneal lesions composed of a proliferation of fibroblastic spindled cells
Prominent omental lobulation in which the fibrosis expands between the septa of lobules with or without mild chronic inflammatory lymphocytic infiltrate

Microscopic (histologic) images

Contributed by Rayan Sibira, M.D. and Mahmoud A. Khalifa, M.D., Ph.D.

Spindled and luteinized cells

Luteinized cells

Luteinized cells with scarred mitosis

Sex cord-like differentiation

Peritoneal lesions

Reticulin stain

Calretinin IHC stain

Beta catenin IHC stain

Virtual slides

Images hosted on other servers:

LTSP, ovary, frozen section

LTSP, peritoneal lesions, frozen section

LTSP, ovary, permanent section

LTSP, peritoneal lesions, permanent section

Positive stains

SF1 (positive in spindle cells) (Am J Surg Pathol 2013;37:1458)
FOXL2 (positive in spindle cells) (Am J Surg Pathol 2013;37:1458)
Inhibin (positive in luteinized cells)
Calretinin (positive in luteinized cells)
CD56 (positive in luteinized cells)
Acetylglucosaminyltransferase B (MGAT5B) (positive in luteinized cells) (Medicine (Baltimore) 2023;102:e33911)
Nuclear receptor coactivator 3 (NCOA3) (positive in luteinized cells) (Medicine (Baltimore) 2023;102:e33911)
Reticulin stain highlights reticulin fibers separating individual theca cells and around nests in the luteinized cells

Negative stains

ER (22% positive) (Am J Surg Pathol 2008;32:1273)
PR (41% positive) (Am J Surg Pathol 2008;32:1273)
CD117 (33% positive) (Am J Surg Pathol 2008;32:1273)
Cytokeratin AE1 / AE3
EMA
CD34
Beta catenin (cytoplasmic staining in the luteinized cells)
TGF beta (Am J Surg Pathol 2008;32:1273)
WT1 (Medicine (Baltimore) 2023;102:e33911)
CD99 (Medicine (Baltimore) 2023;102:e33911)

Molecular / cytogenetics description

MGAT5B::NCOA3 fusion gene recently reported in luteinized thecoma associated with sclerosing peritonitis (LTSP), identified in the luteinized cells (Medicine (Baltimore) 2023;102:e33911)
Negative for FOXL2 mutation

Molecular / cytogenetics images

Images hosted on other servers:

MGAT5B::NCOA3 fusion gene

Sample pathology report

Right ovary and fallopian tube, right salpingo-oophorectomy:
- Ovarian luteinized thecoma, encased with fibrosis
- Fibrosis involving the surface of the ovary
- Unremarkable right fallopian tube
- Negative for malignancy

Anterior pelvic peritoneum, excision:
- Peritoneum with fibrosis and mesothelial cell hyperplasia (see comment)
- Negative for malignancy
- Comment: The given picture of peritoneal sclerosis (fibrosis) with hyperplasia of the submesothelial mesenchymal cells can result from a variety of stimuli. Given the finding of luteinized thecoma of the ovary, this favors the diagnosis of luteinized thecoma associated with sclerosing peritonitis (LTSP). LTSP is an uncommon syndrome characterized by the presence of a benign ovarian stromal tumor resembling theca cells and peritoneal fibrotic lesions. In some cases, peritoneal lesions lead to irreversible fibrosis with the incarceration and strangulation of abdominal organs, eventually proving fatal.
- Other causes of peritoneal sclerosis include chronic ambulatory peritoneal dialysis, the use of peritoneovenous shunt, bacterial or mycobacterial infection, sarcoidosis, carcinoid syndrome, familial Mediterranean fever and exposure to fibrogenic foreign materials. Idiopathic sclerosing peritonitis is diagnosed when all known causes are excluded, with supportive intraoperative and imaging findings.

Differential diagnosis

Thecoma (Am J Surg Pathol 2014;38:1023):
- Unilateral
- Commonly in perimenopausal and postmenopausal women
- No associated peritoneal lesions
- Associated hormonal manifestations and uterine bleeding
- Bland cytologic features with appreciable pale gray cytoplasm and low mitosis (≤ 4 mitoses/10 HPF)
- Reticulin surrounding individual cells
Fibroma (Am J Surg Pathol 2006;30:929):
- Mostly unilateral
- Fascicles of bland fibrous spindle cells in a variably collagenous stroma
- No or focal luteinized cells
- Focal weak inhibin and calretinin staining
Sclerosing stromal tumor (Int J Gynecol Pathol 2016;35:549):
- Pseudolobules contain epithelioid and spindled cells
- Alternating hypo and hypercellular areas
- Hemangiopericytoma-like vessels distributed throughout the tumor
Microcystic stromal tumor (Histopathology 2019;74:443):
- Small round to oval cystic spaces, in areas coalescing to form larger irregular channels
- Lobulated cellular masses with intervening fibrous or fibro-hyaline stroma
- Mutations in β catenin, with associated nuclear immunoreactivity
- Negative for inhibin and calretinin
Massive ovarian edema (Diagn Pathol 2016;11:18):
- Diffuse edema; uniformly hypocellular fibromatous stroma
- Preservation of the outer cortex
Stromal hyperthecosis (Gynecol Endocrinol 2021;37:677):
- No ascites or mass; low to absent mitoses
- Commonly in peri and postmenopausal women
- Androgenic manifestations

Additional references

Geburtshilfe Frauenheilkd 2021;81:1145, Kurman: Blaustein's Pathology of the Female Genital Tract, 7th Edition, 2019

Board review style question #1

A 37 year old woman presents with severe abdominal pain and distention. Laboratory investigations revealed a negative beta hCG and slightly elevated serum CA125. Radiologic images showed thick soft tissue of peritoneal sclerosis encasing the small bowel loops. Exploratory laparotomy reveals a 12.5 cm right ovarian mass and multiple peritoneal nodules, which are resected. Which of the following statements is true regarding the ovarian mass?

Associated with an unfavorable outcome in the small bowel
Associated with hormonal manifestations
Bilateral manifestation indicates metastasis of contralateral ovarian tumor
Peritoneal nodules are metastasized from the ovarian mass

Board review style answer #1

A. Associated with an unfavorable outcome in the small bowel. Axial abdominopelvic computed tomography (CT) shows peritoneal sclerosis encasing the small bowel loops with a characteristic clumped appearance of small bowel loops within a cocoon. The histopathology picture shows nodules of spindled and luteinized cells. Luteinized thecoma associated with sclerosing peritonitis (LTSP) may result in bowel incarceration and strangulation, causing potentially life threatening bowel obstruction. Answers C and D are incorrect because the ovarian tumor is benign and there is no recurrence or metastasis of the ovarian tumor after excision. Answer B is incorrect because this ovarian tumor usually is not hormonally active.

Comment Here

Reference: Luteinized thecoma associated with sclerosing peritonitis

Müllerian adenosarcoma

Table of Contents

Definition / general

Ovarian MMMT is either low grade (Müllerian adenosarcoma) or high grade (carcinosarcoma, mixed mesodermal tumor)
Müllerian adenonosarcoma is usually unilateral, more commonly seen in endometrium and cervix
67% have tumor rupture at or before excision
Poorer prognosis than uterine adenosarcoma, perhaps due to greater ease of peritoneal spread
Tends to recur as pure sarcoma or adenosarcoma (Am J Surg Pathol 2002;26:1243)

Epidemiology

Median age 54 years, range 30 - 84 years (Am J Surg Pathol 2002;26:1243)

Pathophysiology

Appears to have epithelial origin (Am J Surg Pathol 1990;14:317, Am J Surg Pathol 1995;19:666)

Clinical features

Abdominal or pelvic pain, abdominal swelling, may present as adnexal mass

Laboratory

No useful biochemical marker (Curr Opin Obstet Gynecol 2006;18:20)

Radiology description

MRI: solid pelvic mass, especially in patients with endometriosis
USG: very low resistive index (Ultrasound Q 2007;23:189)

Prognostic factors

Poor prognostic factors: extraovarian spread (high stage), tumor rupture, high grade, high grade sarcomatous overgrowth, age < 53 years
Survival: 5 year - 64%, 10 year - 46%

Case reports

34 year old woman with abdominal pain and a large right multicystic ovarian mass (Arch Pathol Lab Med 2004;128:1057)
Ovarian adenosarcoma with extensive deciduoid morphology arising in endometriosis (Int J Gynecol Pathol 2008;27:398)
Ovarian adenosarcoma arising from benign cystadenoma and associated intraoperative consultation pitfalls (Int J Gynecol Pathol 2010;29:415)

Treatment

Salphingopherectomy or panhysterectomy

Gross description

97% unilateral, mean 14 cm (range 5 - 50 cm)
Usually solid with occasional small cysts

Gross images

Images hosted on other servers:

Bilateral ovarian masses

Microscopic (histologic) description

Benign or atypical epithelial component and a low grade malignant stromal component
Conspicuous noninvasive Müllerian type glands within a predominant malignant stroma, either homologous or heterologous
Periglandular cuffs of cellular stroma (80%), intraglandular protrusions of cellular stroma (60%) or both
At least mild stromal atypia (33%)
Variable stromal mitotic count; usually marked stromal cellularity (resembling endometrial stromal sarcoma or cellular ovarian fibroma) but may also have hypocellular stromal areas
Other features: glands widely spaced throughout stroma (90%), occasional sarcomatous overgrowth (30%), sex cord-like elements (15%), heterologous elements (12%)

Microscopic (histologic) images

Images hosted on other servers:

Irregularly dilated endometrial glands

CD10, MIC2, calretinin, progesterone receptor, MIB1

Positive stains

Calretinin (focal), CD10 (focal), Ki67 (8 - 10%), MIC2 (cytoplasmic), PR (diffuse), vimentin (diffuse)

Differential diagnosis

Benign tumors (adenofibroma or endometriosis): lack periglandular cellular cuffs of cellular stroma, no stromal atypia
Endometrial stromal sarcoma: sample thoroughly to rule out glandular component
Immature teratoma: younger patient, usually embryonal neuroectodermal elements, no periglandular cellular cuffs of cellular stroma
Malignant mixed Müllerian tumor: glandular and stromal epithelium is obviously malignant versus at most atypical glands in stromal sarcoma

Mesonephric-like adenocarcinoma (uterus / ovary)

Table of Contents

Definition / general

Mesonephric-like adenocarcinoma (MLA) is a rare, recently recognized but frequently misdiagnosed subtype of gynecologic malignancy arising in the ovary and uterine corpus
MLA shares morphologic, immunophenotypic and molecular characteristics with mesonephric adenocarcinoma (MA) except that mesonephric remnants are not identified in the former
Entity is included in the 5th edition World Health Organization (WHO) classification of female genital tumors

Essential features

Rare subtype of gynecologic malignancy with high risk of recurrence and increased tendency to metastasize
Morphologic hallmark is the combination of architectural patterns in a tumor without squamous or mucinous differentiation; intraluminal dense eosinophilic secretions can be seen
Low grade morphology with negative ER and PR should prompt the pathologist to perform additional stains
PAX8, GATA3, TTF1, ER and PR are the main immunohistochemical stains that can be used to support the diagnosis
Usually mismatch repair (MMR) proficient and p53 wild type
KRAS mutation is commonly present

ICD coding

ICD-O: 9111/3 - mesonephric-like adenocarcinoma
ICD-11:
- 2C76.Y - other specified malignant neoplasms of corpus uteri
- 2C73.Y - other specified malignant neoplasms of the ovary

Epidemiology

Endometrial MLA accounts for < 1% of endometrial carcinomas; limited epidemiologic data on ovarian MLA (Am J Surg Pathol 2019;43:389)
Median age 61 years (range: 36 - 76), more commonly seen in postmenopausal patients (Mod Pathol 2021;34:1570)

Sites

Uterine corpus and ovary

Pathophysiology

Controversial whether MLA originates from mesonephric structures or represents Müllerian tumors that have acquired mesonephric characteristics
Evidence supporting Müllerian origin with mesonephric transdifferentiation
- Endometrial MLA arises from the endometrium rather than myometrium
- MLA is not associated with mesonephric remnants
- Ovarian MLA has been found to coexist with other Müllerian neoplasms such as low grade serous carcinoma (Int J Gynecol Pathol 2020;39:84)
- MA and MLA share KRAS mutations but concurrent PIK3CA mutations, which are described in endometrioid adenocarcinoma, are also documented in MLA
- NRAS mutations may occur (Int J Gynecol Pathol 2018;37:448)

Etiology

Unknown

Clinical features

Patients with endometrial MLA may present with abnormal vaginal bleeding
Patients with ovarian MLA may present with pelvic or abdominal pain and may be associated with endometriosis and other benign, borderline and malignant lesions of Müllerian origin (Am J Surg Pathol 2021;45:498)

Diagnosis

Definitive diagnosis of MLA requires a surgical specimen
Limited literature on the cytologic features of these tumors; may be identified on Pap test as atypical glandular cells (AGC) (Am J Surg Pathol 2021;45:498)
MLA of the uterine corpus was correctly diagnosed on initial biopsy in only 32% of the cases in one study (Am J Surg Pathol 2021;45:498)

Laboratory

Patient may have elevated tumor markers (CA125, CA19-9) (Int J Gynecol Pathol 2022;41:161)

Prognostic factors

Factors associated with development of metastasis in mesonephric adenocarcinoma of the uterine corpus (Am J Surg Pathol 2019;43:12)
- Large tumor size (> 4 cm)
- Ill defined tumor border
- Advanced FIGO stages (III - IV)
- Presence of coagulative tumor cell necrosis
- High mitotic activity (> 10/10 high power fields)
- Lymphovascular invasion (Am J Surg Pathol 2019;43:12)
Associated with aggressive clinical course (J Clin Med 2021;10:698)
- Tends to present with advanced stage (FIGO II or more)
- Increased risk of recurrent disease
- Increased tendency to metastasize to the lungs even for tumors with stage I disease
Compared with other endometrial adenocarcinomas (Am J Surg Pathol 2021;45:498)
- Better overall survival than carcinosarcoma and serous carcinoma
- Equal overall survival to endometrioid grade 3
- Worse overall survival than endometrioid grade 1 - 2 carcinomas

Case reports

32 year old woman with coexistent endometrial mesonephric-like adenocarcinoma and endometrioid carcinoma (Diagn Pathol 2019;14:54)
58 year old woman with endometrial mesonephric-like adenocarcinoma presenting as an ocular lesion (Int J Gynecol Pathol 2022;41:161)
69 year old woman with synchronous ovarian and uterine mesonephric-like carcinoma that potentially arose from endometrioid adenofibroma (J Obstet Gynaecol Res 2023;49:1052)
70 year old woman with mesonephric-like adenocarcinoma arising from the uterine body and mimicking follicular thyroid carcinoma (Histopathology 2019;74:651)
71 year old woman with corded and hyalinized mesonephric-like adenocarcinoma of the uterine corpus (Hum Pathol 2019;86:243)

Treatment

Surgical approach with total hysterectomy and bilateral salpingo-oophorectomy, with or without pelvic and para-aortic lymph node dissection, is the primary therapy
Adjuvant chemotherapy and radiation therapy have been used
Hormone therapy has been reported in 2 cases (Am J Surg Pathol 2020;44:429)
No tumor specific treatment options have been elucidated for MLA

Gross description

No distinctive macroscopic appearance compared to other endometrial or ovarian tumors
Areas of necrosis and hemorrhage can be present
Ovarian MLA is usually unilateral, ranging in size from 4 - 32 cm, with solid or mixed solid cystic, grey-white or yellow-tan appearance (Histopathology 2016;68:1013)

Microscopic (histologic) description

Variety of histologic patterns that may be present within the same tumor
- Most frequently small tubules with ductal / glandular growth
- Papillary, solid growth, trabecular, retiform, sex cord-like, sieve-like, glomeruloid and spindle cell areas have all been described
Luminal eosinophilic secretions are characteristic but not always identified
Tumor cells can be flattened, cuboidal or columnar with mild to moderate cytological atypia
- Clear cell features can be seen but are less common
- High grade cytological atypia is usually not a predominant feature
Nuclei show vesicular chromatin and nuclear grooves
Sarcomatoid transformation has been seen in rare instances
Squamous, ciliated or mucinous differentiation (metaplasia) are not present and there are no associated mesonephric remnants (J Clin Med 2021;10:698)

Microscopic (histologic) images

Contributed by Daniel Graham, M.D., Adele Wong, M.B., B.Ch., B.A.O. and Lucy Ma, M.D.

Glandular growth pattern

Variety of histologic patterns

Variable growth patterns

Glandular morphology

Glands

Multiple growth patterns

Glandular and cystic areas

Micropapillary architecture

Mitotic activity

Papillary architecture

Variable morphology

PAX8

GATA3

TTF1

CD10

Estrogen receptor

Progesterone receptor

p53

Ki67

WT1

Varied morphology

PTC-like nuclear features

Virtual slides

Images hosted on other servers:

MLA H&E and IHC

Positive stains

PAX8: usually diffusely positive
GATA3 and TTF1: focal or diffuse with inverse staining pattern described in several studies in the most recent WHO classification; cells positive for GATA3 are negative for TTF1 and vice versa (Am J Surg Pathol 2018;42:1596)
CD10: focal and apical / luminal
p53 wild type
MMR proficient

Negative stains

ER
PR (more reliable negative marker than ER)
Calretinin (usually negative may be focally positive)
Reference: J Clin Med 2021;10:698

Molecular / cytogenetics description

Majority of MLA shows KRAS mutation, most commonly G12V and G12D (Am J Surg Pathol 2020;44:429)
Concurrent ARID1A and PIK3CA mutations are quite common
PTEN mutation has been reported
CTNNB1 hotspot mutations have been reported
Copy number analysis: copy number gain of 1q and 10 are the most common, some have 1p loss (Mod Pathol 2021;34:1570)
Usually does not have the common molecular abnormalities described in endometrioid (p53, MMR and POLE) (Mod Pathol 2021;34:1570)
NRAS mutations may occur (Int J Gynecol Pathol 2018;37:448)

Videos

Mesonephric-like adenocarcinoma by Dr. Lewis Hassell

Sample pathology report

Uterus and cervix, bilateral fallopian tubes and ovaries, total hysterectomy and bilateral salpingo-oophorectomy:
- Endometrial adenocarcinoma, most consistent with mesonephric-like adenocarcinoma (see comment)
- Comment: The tumor exhibits various growth patterns including small tubular, glandular and papillary areas. Tumor cells show diffuse immunoreactivity for PAX8 and focal immunoreactivity for GATA3 and TTF1. Despite the predominant glandular architecture and low grade appearance, the tumor is negative for ER and PR. The cervix is benign and mesonephric remnants are not identified. All these findings are most consistent with endometrial adenocarcinoma, mesonephric-like subtype.

Differential diagnosis

Low grade endometrioid adenocarcinoma:
- ER and PR positive
- Small tubules with eosinophilic material are not commonly seen
- Lacks the heterogeneity of architectural patterns seen in MLA
- Squamous, ciliated or mucinous differentiation are not seen in MLA
- GATA3 or TTF1 expression are usually negative
- GATA3 expression can be seen in a 6% of endometrial carcinomas including endometrioid type but these cases were always TTF1 negative (Am J Surg Pathol 2015;39:1411)
Clear cell carcinoma:
- May show variable architectural patterns and cytological atypia
- Positive HNF-1B, napsin A or alpha methyacyl CoA racemase (AMACR)
- Napsin A and HNF-1B usually negative in MLA but can be positive (Int J Gynecol Pathol 2022;41:161)
- Abnormal p53 and MMR can be seen in clear cell carcinoma, in contrast to MLA
- GATA3 and TTF1 are usually negative
Serous carcinoma:
- Papillary architectural pattern in association with high grade nuclear atypia
- Abnormal p53 expression and block-like p16 staining
- ER and PR not helpful
Carcinosarcoma:
- Solid areas and spindled cell and sarcomatoid features
- Abnormal p53 expression
- Absence of KRAS mutations (Cancer Genomics Proteomics 2022;19:747)
Primary lung adenocarcinoma in metastatic setting:
- Positive TTF1 staining and negative hormone receptors
- PAX8 and GATA3 negative
Cervical mesonephric adenocarcinoma with the involvement of the uterine corpus:
- Both have negative ER and PR staining and express GATA3
- Primary cervical location of the tumor
- Mesonephric remnants / hyperplasia, while this should not be seen in MLA; most cases of MLA of the uterine body originate in the endometrium
- Usually lacks PTEN and PIK3CA mutations

Additional references

Front Oncol 2022;12:911695, Am J Surg Pathol 2022;46:921, Int J Environ Res Public Health 2022;19:14451

Board review style question #1

A 55 year old woman was recently diagnosed with endometrioid intraepithelial neoplasia on endometrial curettage. The entire endometrium is submitted for histologic evaluation. Histologic details from one section are shown in the image above. The tumor cells are diffusely positive for GATA3 and PAX8 and focally positive for TTF1. ER and PR are negative. Which of the following statements is true regarding this entity?

KRAS mutations, particularly G12V and G12D, are commonly identified
MMR deficiency is present in half of the cases
The tumor frequently shows p53 overexpression
The tumor has better prognosis compared to low grade endometrioid adenocarcinoma

Board review style answer #1

A. KRAS mutations, particularly G12V and G12D, are commonly identified. Despite the low grade morphology commonly encountered in mesonephric-like adenocarcinoma, the tumor has worse prognosis compared to low grade endometrioid adenocarcinoma. They do not show abnormal p53 expression and are usually MMR proficient. KRAS mutations are commonly seen, with G12V and G12D being the most common alterations identified.

Comment Here

Reference: Mesonephric-like adenocarcinoma

Board review style question #2

Which of the following statements is true regarding mesonephric-like adenocarcinoma occurring in the uterus?

The tumor commonly expresses GATA3 and TTF1 immunohistochemically
The tumor expresses hormone receptors similar to those seen in conventional endometrioid carcinoma
The tumor is most often seen in the myometrium without a surface connection to the endometrium
The tumor often shows DNA polymerase epsilon (POLE) mutation

Board review style answer #2

A. The tumor commonly expresses GATA3 and TTF1 immunohistochemically. The finding of a hormone receptor negative, PAX8, GATA3 and TTF1 positive tumor is highly supportive of the diagnosis of mesonephric-like adenocarcinoma. While mesonephric remnants and mesonephric derived tumors are often found in paracervical or adnexal locations, this is not true of the mesonephric-like tumors in the endometrium, which have a surface component in virtually all cases. Most such tumors are of no specific molecular type.

Comment Here

Reference: Mesonephric-like adenocarcinoma

Metastases to ovary

Table of Contents

Definition / general

Secondary involvement of ovary from malignant neoplasms of extraovarian primary sites

Essential features

Ovary is the most common site of metastasis within the gynecologic tract
Colorectal and breast carcinoma are the most common primary tumors to metastasize to the ovary
Usually bilateral, small (< 10 cm), multinodular tumors with extraovarian spread

Terminology

Krukenberg tumor
- Designation should be reserved for tumors with an appreciable component (> 10%) of signet ring cells (Gynecol Oncol 2006;101:152)
- Most commonly of gastric primary (Arch Pathol Lab Med 2006;130:1725)

ICD coding

ICD-10:
- C79.60 - secondary malignant neoplasm of unspecified ovary
- C79.61 - secondary malignant neoplasm of right ovary
- C79.62 - secondary malignant neoplasm of left ovary
ICD-11:
- 2E05.0 - malignant neoplasm metastasis in ovary

Epidemiology

~15% of ovarian malignancies are of metastatic origin (range: 3 - 30%) (Int J Gynecol Cancer 2009;19:1160)
Ovarian metastasis may present either synchronously or metachronously with primary tumor
Ovary is the most common site of metastasis within the gynecologic tract (Int J Gynecol Pathol 2019;38:363)
Colorectal carcinoma is the most common primary tumor to metastasize to the ovary, followed by breast carcinoma (Int J Gynecol Pathol 2023;42:414, Int J Gynecol Cancer 2009;19:1160)

Sites

Ovary and primary organ site, with or without other organs

Pathophysiology

Tumors can spread to the ovary by several pathways, depending on the primary
- Direct extension
- Lymphovascular / hematogeneous spread (Obstet Gynecol Int 2011;2011:612817)
- Transcoelomic / transperitoneal dissemination (e.g., Krukenberg tumors of gastric primary)
- Tumor cell exfoliation / transtubal spread (e.g., concurrent low grade endometrioid endometrial and ovarian carcinomas [FIGO stage IIIA endometrial carcinoma] simulating independent primary tumors) (Histopathology 2020;76:37)

Etiology

Malignant tumor of extraovarian primary site

Clinical features

Clinical features often relate to the primary tumor
Pelvic (ovarian) mass may be the first manifestation of the disease from a clinically occult primary (Virchows Arch 2017;470:69)

Diagnosis

Comprehensive medical history, physical evaluation, intraoperative evaluation, imaging, endoscopy
Final diagnosis is rendered by histopathology and immunohistochemistry (with or without molecular studies)

Laboratory

CA-125 is not a useful biomarker in the primary diagnostics of metastases to the ovary (Clin Exp Metastasis 2017;34:295)
CA-125/CEA ratio may be of clinical use in distinguishing primary ovarian tumors from colorectal carcinoma metastases (Tumour Biol 1992;13:18)

Radiology description

No specific imaging features differentiate primary ovarian malignancy from metastatic ovarian tumors (Magn Reson Imaging Clin N Am 2023;31:93)
MRI appearances that suggest a mucinous lesion should trigger a search on the scan for an alternative primary mass in the gastrointestinal tract

Radiology images

Images hosted on other servers:

Solid and cystic bilateral ovarian masses

Prognostic factors

Ovarian metastases from colorectal carcinoma are often unresponsive to chemotherapy and are associated with poor survival (Cancer 2017;123:1134)

Case reports

37 year old woman with primary jejunal adenocarcinoma presenting as bilateral ovarian metastasis (Gastroenterology Res 2017;10:366)
57 year old Japanese woman with malignant phyllodes tumor of the breast metastasizing to the ovary (Int J Surg Pathol 2022;30:427)
61 year old woman with metastatic angiosarcoma to an ovarian Brenner tumor (Int J Gynecol Pathol 2023;42:176)
64 year old woman with isolated ovarian metastasis from pancreatic adenocarcinoma and the role of molecular analysis in establishing diagnosis (J Pancreat Cancer 2021;7:74)
66 year old woman with primary colorectal carcinoma and metachronous ovarian metastasis (Am J Case Rep 2019;20:1515)

Treatment

Debulking surgery with or without chemotherapy

Gross description

Bilateral ovarian involvement (overall occurs in 40 - 80% of cases)
- Primary mucinous ovarian tumors, uncommonly bilateral
Size: usually < 10 cm
- Generally applied to metastatic mucinous tumors, though may be less reliable than previously reported (Gynecol Oncol 2006;101:152)
Multinodular, solid and cystic, or friable
Surface involvement
Hilar involvement (common in hematogenous spread)

Gross images

Images hosted on other servers:

Bilateral ovarian masses with multinodular cut surfaces

Microscopic (histologic) description

Morphology varies with appearance of primary tumor
General features
- Involvement of ovarian surface and superficial cortex
- Infiltrative growth pattern with stromal desmoplasia
- Heterogenous nodular invasive growth (Kurman: Blaustein's Pathology of the Female Genital Tract, 7th Edition, 2019)
- Metastatic tumors more often envelop preexisting normal ovarian structures than primary tumors
- Extensive lymphovascular invasion
Colorectal adenocarcinoma
- Dilated glands with cribriform epithelium draped along the periphery of luminal dirty necrosis (garland pattern)
Low grade appendiceal mucinous neoplasm
- Hypermucinous columnar epithelium with low grade cytologic atypia
- Retraction of epithelium from underlying stroma is commonly seen
- Abundant pseudomyxoma ovarii
Gastric carcinoma
- Frequently presents as Krukenberg tumor (composed predominantly of signet ring cells)
- Stroma may alternate from hypercellular to hypocellular (edematous)
Breast carcinoma
- Lobular or ductal differentiation
- Signet ring cells may be present
Endocervical adenocarcinoma
- HPV associated
  - Variety of glandular patterns
  - Epithelium with hyperchromatic nuclei, apical mitoses, basal apoptoses
- HPV independent, gastric type
  - Mucinous epithelium with clear / pale cytoplasm with distinct borders
  - Cytologic atypia may range from minimal to severe
Endometrial adenocarcinoma
- Endometrioid histotype is more common than serous
- Synchronous endometrial and ovarian endometrioid carcinomas
  - May apply Scully criteria, though recent studies suggest that these neoplasms are clonally related (J Natl Cancer Inst 2016;108:djv427, J Natl Cancer Inst 2016;108:djv428)
Melanoma
- Follicle-like spaces are frequently seen
- Diffuse or nodular growth is common
- Intracytoplasmic melanin pigment

Microscopic (histologic) images

Contributed by Lucy Ma, M.D.

Krukenberg tumor

Metastatic cervical adenosquamous carcinoma

Metastatic low
grade appendiceal
mucinous
neoplasm

Metastatic lobular breast carcinoma

Virtual slides

Images hosted on other servers:

Metastatic breast carcinoma to the ovary

Metastatic malignant melanoma to the ovary

Metastatic pancreatic adenocarcinoma to the ovary

Metastatic hepatocellular carcinoma to the ovary

Positive stains

Depends on the primary tumor
- Colorectal carcinoma and appendiceal neoplasms: CK20, SATB2, CDX2
- Breast carcinoma: CK7, GATA3, TRPS1, GCDFP-15, mammaglobin, ER, PR, SOX10 (if triple negative) (Semin Diagn Pathol 2022;39:313)
- Endocervical adenocarcinoma: CK7, PAX8, p16 (if HPV associated), high risk HPV ISH (if HPV associated)
References: J Clin Pathol 2012;65:596, Int J Gynecol Pathol 2015;34:257

Negative stains

Depends on the primary tumor
- Colorectal carcinoma and appendiceal neoplasms: CK7, PAX8, ER, PR
- Breast carcinoma: CK20, PAX8, WT1, CA-125
- Endocervical adenocarcinoma: CK20, ER, PR, vimentin
References: J Clin Pathol 2012;65:596, Int J Gynecol Pathol 2015;34:257

Molecular / cytogenetics description

KRAS, SMAD4 and NTKR1 mutations are more frequent in cases of ovarian metastasis from colorectal carcinoma than in cases of colorectal carcinoma without ovarian metastasis (Cancer 2017;123:1134)

Sample pathology report

Fallopian tube and ovary, right and left, bilateral salpingo-oophorectomy:
- Metastatic carcinoma, consistent with patient's known history of breast primary, involving bilateral ovaries (see comment)
- Bilateral fallopian tubes, negative for tumor
- Comment: On immunohistochemistry, the tumor cells are positive for GATA3, mammaglobin and GCDFP-15, while negative for PAX8. These findings support the diagnosis above.

Differential diagnosis

Primary ovarian mucinous cystic tumor:
- Differential diagnosis for metastatic low grade appendiceal mucinous neoplasm
- Typically unilateral
- Rarely associated with pseudomyxoma peritonei
- May be associated with Brenner tumor or mature cystic teratoma
- CK7+, CK20-, SATB2-
Primary ovarian endometrioid carcinoma:
- Differential diagnosis for metastatic colorectal adenocarcinoma
  - Commonly associated with endometriosis or adenofibromatous component
  - Squamous differentiation may be seen
  - CK7+, ER+, PAX8+
- Differential diagnosis for metastatic endometrial endometrioid carcinoma in cases of synchronous endometrial and ovarian endometrioid carcinomas
  - Scully criteria favoring primary ovarian endometrioid carcinoma (Scully: Tumors of the Ovary, Maldeveloped Gonads, Fallopian Tube, and Broad Ligament: Atlas of Tumor Pathology, 1st Edition, 1998)
    - Associated with endometriosis or endometriotic lesions, a subset of which are clonal and demonstrate cancer associated mutations (J Pathol 2015;236:201)
    - Low grade (FIGO grade 1 or 2)
    - Histologic dissimilarity between ovarian and endometrial tumors
    - No or superficial myometrial invasion of endometrial tumor
    - No vascular space invasion, surface implants,or predominantly hilar location in ovary
    - Ovarian tumor is unilateral
  - Regardless of histopathologic criteria, genomic studies suggest that most cases are clonally related (J Natl Cancer Inst 2016;108:djv427, J Natl Cancer Inst 2016;108:djv428)
    - Clonal relationship may not apply to Lynch syndrome patients (Mod Pathol 2021;34:994)
Signet ring stromal tumor of the ovary:
- Differential diagnosis for metastatic signet ring cell carcinoma
- Signet ring morphology in a background of fibromatous stroma
- Signet ring cells contain a single large nonmucinous intracytoplasmic vacuole
- Eosinophilic hyaline globules are common
- SF1+, calretinin+, EMA-

Board review style question #1

A 65 year old woman with an ovarian mass undergoes an oophorectomy. A representative section of the mass is shown above. Which of the following immunoprofiles best supports a diagnosis of metastatic colorectal adenocarcinoma?

CK7+, CK20+, PAX8-, GATA3+, CDX2-, SATB2-
CK7+, CK20-, PAX8+, GATA3-, CDX2+, SATB2-
CK7-, CK20+, PAX8-, GATA3-, CDX2+, SATB2+
CK7-, CK20-, PAX8-, GATA3-, CDX2-, SATB2-

Board review style answer #1

C. CK7-, CK20+, PAX8-, GATA3-, CDX2+, SATB2+. Compared with the other answer choices, this immunoprofile best supports a colorectal adenocarcinoma primary, which is typically CK7-, CK20+, PAX8-, GATA3-, CDX2+ and SATB2+. Answer A is incorrect as it fits the immunoprofile for a metastatic urothelial carcinoma. Answer B is incorrect as it is more consistent with a primary ovarian endometrioid carcinoma. Answer D is incorrect as it is not immunoreactive to any typical adenocarcinoma markers.

Comment Here

Reference: Metastases to ovary

Board review style question #2

Which of the following organs is the most common site of metastasis within the gynecologic tract?

Cervix
Endometrium
Fallopian tube
Ovary
Vulva

Board review style answer #2

D. Ovary. The ovary is the most common site of metastasis within the gynecologic tract. Answers A, B, C and E are incorrect because the vagina is the second most frequent site of metastasis within the gynecologic tract following the ovary (Cancer 1984;53:1978).

Comment Here

Reference: Metastases to ovary

Microcystic stromal tumor

Table of Contents

Definition / general

Benign ovarian neoplasm of presumed stromal origin
First described by Irving and Young in 2009 (Am J Surg Pathol 2009;33:367)

Essential features

Features to establish a diagnosis of microcystic stromal tumor in well sampled specimens include:
- A microcystic pattern and regions with lobulated cellular masses with intervening hyalinized, fibrous stroma
- No morphologic features enabling any other specific diagnosis in the sex cord stromal category
- No epithelial elements
- No teratomatous or other germ cell elements (Am J Surg Pathol 2009;33:367)

Epidemiology

Mean age of 45 years (range 26 - 63 years)

Pathophysiology / etiology

Deregulation of the Wnt/beta-catenin pathway has been suggested to play a role in the pathogenesis of microcystic stromal tumor (Am J Surg Pathol 2011;35:1429)
The ulrastructural features of this tumor support a stromal cell origin (Ultrastruct Pathol 2014;38:261)

Clinical features

Patients present with symptoms attributable to a pelvic mass
Not associated with manifestations related to hormonal excess
Usually unilateral
Often < 5 - 10 cm (range 2 - 27 cm)

Diagnosis

Histologic recognition, confirmed by immunophenotype

Laboratory

No specific laboratory findings

Prognostic factors

Benign behavior, no reports of recurrence or malignant transformation

Case reports

32 and 41 year old women with β-catenin S33C mutation (Am J Surg Pathol 2011;35:1429)
47 year old woman with overlap of microcystic stromal tumor and primary solid pseudopapillary neoplasm (Int J Clin Exp Pathol 2015;8:11792)
50 year old woman (Int J Gynecol Pathol 2015;34:541)
Ovarian microcystic stromal tumor (Ultrastruct Pathol 2014;38:261)

Treatment

Excision results in complete cure

Gross description

Well demarcated, solid-cystic tumor, however either solid or cystic areas can predominate
Solid component has tan-white cut surface
Foci of hemorrhage or necrosis can be present

Microscopic (histologic) description

Distinctive triad of histologic features:
- Microcysts: small round / oval cystic spaces that may coalesce to larger irregular channels
- Solid cellular regions
- Hyalinized fibrous stroma
- Cells have moderate, finely granular eosinophilic cytoplasm, bland round/oval nuclei with fine chromatin and indistinct nucleoli
- Foci of bizarre nuclei may be seen, low mitotic rate (up to 2/10HPF)

Microscopic (histologic) images

Images hosted on other servers:

Well demarcated mass

CD10, CD56, β-catenin, WT1, PR

Positive stains

CD10, vimentin, focal cytokeratin (25%)
β-catenin, FOXL2, WT1, Cyclin D1, SF1 (Am J Surg Pathol 2015;39:1420)

Negative stains

Inhibin, calretinin, EMA

Electron microscopy description

Tumor cells with predominantly spindle and stellate morphology with fewer epithelioid cells, arranged in a loose "microcystic" pattern
The cytoplasm shows intermediate filaments and variable amount of other organelles (Ultrastructural Pathol 2014;38:261)
The centrally placed nuclei are round with thin nuclear membranes and dispersed euchromatin
Some nuclei have prominent nucleoli

Molecular / cytogenetics description

Missense point mutations in exon 3 of CTNNB1 was recently described (Am J Surg Pathol 2015;39:1420)

Differential diagnosis

Adult granulosa cell tumor: oval cells with nuclear grooves, Call-Exner bodies, positive for inhibin and calretinin and FOXL2 gene mutation
Sertoli-Leydig tumor: positive for inhibin and calretinin
Steroid cell tumor: androgenic manifestations, positive for inhibin and calretinin
Thecoma: older women, estrogenic manifestations, positive for inhibin, calretinin and CD56
Yolk sac tumor: larger size, elevated serum AFP, Schiller-Duval bodies; positive for AFP immunostain

Mixed carcinoma (pending)

[Pending]

Mixed germ cell - sex cord stromal tumor, unclassified (pending)

Mixed germ cell tumor

Table of Contents

Gross images | Microscopic (histologic) images | Molecular / cytogenetics description

Gross images

AFIP images

Lobulated, focally hemorrhagic

Microscopic (histologic) images

AFIP images

Mixed malignant germ cell tumor

Diffuse embryoma

Molecular / cytogenetics description

Often isochromosome 12p in teratomatous and nonteratomatous components (Mod Pathol 2006;19:766)

Monodermal cystic teratoma

Table of Contents

Definition / general

Benign cystic tumor comprising mature tissues derived from a single germ layer (ectoderm or endoderm), except for struma ovarii, carcinoid and neuroectodermal type tumors (malignant tumors of central neuroectodermal derivation)

Essential features

Cystic tumor lined by benign keratinizing squamous epithelium or neuroectodermal tissues
May contain pituitary type adenomas
Benign with excellent prognosis

ICD coding

ICD-O: 9080/0 - cystic teratoma NOS
ICD-11: 2F32.0 - cystic teratoma

Epidemiology

Monodermal teratomas are rare (Pediatr Dev Pathol 2015;18:341)
Neuroectodermal cysts have been reported in children and young women
Epidermoid cysts occur across a wide age range

Sites

Ovary

Pathophysiology

Unknown

Etiology

Unknown

Clinical features

Abdominal distension or pain
Amenorrhea due to lactotroph adenoma (Obstet Gynecol 1990;75:540)
Central obesity and hirsutism due to corticotroph adenoma (Am J Surg Pathol 1987;11:218)

Diagnosis

Histologic examination

Laboratory

Elevated prolactin in lactotroph adenoma (JAMA 1990;263:2472)
Increased cortisol and lack of suppression of either low dose or high dose dexamethasone suppression test in corticotroph adenoma (Am J Surg Pathol 1987;11:218)

Radiology description

Wide spectrum of radiologic presentation ranging from a purely cystic to a complex cystic mass with a considerable solid component

Radiology images

Contributed by Azin Mashayekhi, M.D., M.B.A. and Gulisa Turashvili, M.D., Ph.D.

Magnetic resonance imaging (MRI) of pelvis

Prognostic factors

Benign with excellent prognosis

Case reports

2.5 year old girl with ovarian epidermoid cyst torsion associated with appendicitis (Int J Surg Case Rep 2022;100:107731)
10 year old girl with neurogenic ovarian cyst (Pediatr Dev Pathol 2015;18:341)
36 year old woman with epidermoid cyst treated with laparoscopic cystectomy (Gynecol Minim Invasive Ther 2018;7:40)
50 year old woman with a giant (17 cm) epidermoid cyst (J Clin Diagn Res 2012;6:1584)
65 year old woman with epidermoid cyst associated with stromal hyperplasia (J Cancer Res Ther 2015;11:1046)

Treatment

Ovarian cystectomy (Pediatr Dev Pathol 2015;18:341)
Oophorectomy

Gross description

Neuroectodermal cysts are thin walled, simple to multilocular cysts filled with clear yellow fluid, ranging from 8 - 15 cm (J Obstet Gynaecol Res 2001;27:21)
Epidermoid cysts are simple thin walled cysts, with white-grey cheesy material, ranging from 1 - 15 cm (Int J Gynecol Pathol 2009;28:193)

Gross images

Contributed by Azin Mashayekhi, M.D., M.B.A. and Gulisa Turashvili, M.D., Ph.D.

Cystic lesion

Frozen section description

Rarely performed but usually shows a cystic lesion lined by benign squamous epithelium or neuroectodermal tissues

Microscopic (histologic) description

Neuroectodermal cyst
- Lined by ependymal cells
- May show choroid plexus-like epithelium along the cyst lining
- Astrocytes, oligodendrocytes, microglia and ganglion cells may be present adjacent to the cyst lining (Histopathology 1994;24:477)
Epidermoid cyst
- Lined by mature, often keratinizing, stratified squamous epithelium
- Surrounded by a rim of collagenous stroma containing fibroblasts
- Keratinaceous debris fills the cyst lumen, with no evidence of hair or a Rokitansky tubercle (Int J Gynecol Pathol 1996;15:69)
Rarely, cysts are lined by respiratory type epithelium (Cancer 1979;43:383)
Lactotroph adenoma
- Closely packed nests of small cells with eosinophilic cytoplasm as seen in the anterior hypophysis (Obstet Gynecol 1990;75:540)
Corticotroph adenoma
- Monomorphic cells with round nuclei and vacuolated or eosinophilic cytoplasm, growing in nests or cords (Am J Surg Pathol 1987;11:218)

Microscopic (histologic) images

Contributed by Azin Mashayekhi, M.D., M.B.A. and Gulisa Turashvili, M.D., Ph.D.

Cystic lesion

Intracystic proliferation

GFAP

Positive stains

Immunohistochemistry has a limited role in diagnosis of monodermal cystic teratoma
Prolactin in lactotroph adenoma (Obstet Gynecol 1990;75:540)
ACTH in corticotroph adenoma (Am J Surg Pathol 1987;11:218)
GFAP in neuroectodermal cyst (Histopathology 1994;24:477)

Sample pathology report

Ovary, right, cystectomy:
- Epidermoid cyst (monodermal cystic teratoma)

Differential diagnosis

Mature teratoma:
- Mature tissue representing at least 2 germ layers (BMC Cancer 2019;19:217)
- Malignant transformation occurs rarely (most commonly squamous cell carcinoma)
Immature teratoma:
- Malignant germ cell tumor (Obstet Gynecol 2006;107:1075)
- Contains variable amounts of immature tissue (typically immature neuroepithelium comprising primitive appearing cells with scant cytoplasm, hyperchromatic nuclei and frequent mitoses)
Steroid cell tumor:
- Pituitary type adenomas may be mistaken for steroid cell tumors with eosinophilic (lipid poor) cells
- Association with ependymal lined neuroectodermal cyst as well as prolactin expression in lactotroph adenoma and ACTH expression in corticotroph adenoma along with negative sex cord stromal markers (inhibin, calretinin, SF1) are helpful clues

Additional references

WHO Classification of Tumours Editorial Board: Female Genital Tumours, 5th Edition, 2020

Board review style question #1

The image above is a representative section of an ovarian cyst from a 40 year old woman. What is the most likely diagnosis?

Epidermoid cyst
Immature cystic teratoma
Monodermal cystic teratoma with respiratory epithelium
Struma ovarii

Board review style answer #1

A. Epidermoid cyst. This ovarian cyst is lined by benign keratinizing squamous epithelium, consistent with epidermoid cyst. Answer D is incorrect because struma ovarii is exclusively composed of benign thyroid tissue. Answer C is incorrect because some monodermal cystic teratomas are lined by respiratory epithelium. Answer B is incorrect because immature cystic teratoma exhibits immature neuroepithelium in addition to endodermal, mesodermal and ectodermal elements.

Comment Here

Reference: Monodermal cystic teratoma

Mucinous borderline tumor

Table of Contents

Definition / general

Noninvasive mucinous neoplasm with complex architecture and gastrointestinal type differentiation

Essential features

Ovarian tumors with mucinous epithelium of gastrointestinal type and epithelial proliferation (tufting, stratification and villus formation) involving > 10% of tumor
Mild cytologic atypia, resembling low grade dysplasia of intestinal epithelium
May be associated with intraepithelial carcinoma (foci with high grade cytologic atypia) and microinvasion (stromal invasion by single cells or small nests, measuring < 5 mm)
> 90% of tumors are unilateral
KRAS mutations are the most frequent molecular alterations

Terminology

Mucinous borderline tumor
Previously classified as atypical proliferative mucinous tumor or mucinous tumor of low malignant potential

ICD coding

ICD-O: 8472/1 - mucinous cystic tumor of borderline malignancy

Epidemiology

Mean age: 45 years (Int J Gynecol Pathol 1995;14:198)
Second most common subtype of ovarian borderline tumor in Western countries and the most common subtype in Asia (Int J Gynecol Pathol 2011;30:218)

Sites

Ovary; less frequently in retroperitoneum

Pathophysiology

May arise from mucinous cystadenoma
Also associated with Brenner tumor and mature cystic teratoma (Mod Pathol 2020;33:722)

Clinical features

Symptoms most often are related to pelvic mass

Diagnosis

May be suggested by pelvic ultrasound
Definitive diagnosis deferred to oophorectomy

Laboratory

Patients may have increased CA 125, CEA or CA19-9 levels

Prognostic factors

Excellent prognosis; stage I at diagnosis
Mucinous borderline tumor with intraepithelial carcinoma: 95 - 100% overall survival rate (Am J Surg Pathol 2000;24:1447)
Recurrences may occur following cystectomy
Tumors with microinvasion are associated with recurrence rate of 5% (Am J Surg Pathol 2007;31:546)
Anaplastic carcinoma and sarcoma mural nodules are associated with adverse clinical behavior and increased mortality rate; however, anaplastic carcinoma in unruptured stage I tumors does not necessarily carry an adverse prognosis (Am J Surg Pathol 2008;32:383, Int J Gynecol Pathol 1994;13:62)
- Sarcoma-like mural nodule does not have effect on prognosis (Am J Surg Pathol 2002;26:1467)

Case reports

42 year old woman with ovarian borderline mucinous tumor accompanied by low grade endometrial stromal sarcoma with myxoid change (Eur J Med Res 2017;22:52)
53 year old woman with mucinous borderline tumor with pulmonary and pleural metastasis (Front Med (Lausanne) 2020;7:571348)
59 year old postmenopausal woman with primary signet ring cell carcinoma with neuroendocrine differentiation arising in mucinous borderline tumor (Gynecol Oncol Rep 2019;31:100522)

Treatment

Surgery with staging

Gross description

> 90% of the tumors are unilateral (Gynecol Oncol 2005;97:80)
Mean size: 22 cm; some tumors can measure as large as 50 cm (Am J Surg Pathol 2008;32:128)
Cysts are multiloculated with mucinous contents and smooth external surface
Solid areas and necrosis may be present

Gross images

Contributed by Russell Vang, M.D.

Multiloculated cyst

Frozen section description

Complex architecture with tufting and villus formation
- Glands with luminal mucin
- Mucinous epithelium of gastrointestinal type with goblet cells
- Mild cytologic atypia with nuclear stratification, hyperchromasia and mitotic activity

Frozen section images

Contributed by Neshat Nilforoushan, M.D. and Russell Vang, M.D.

Complex architecture with tufting and luminal mucin

Intestinal type mutinous epithelium

Microscopic (histologic) description

Complex architecture with tufting and villus formation
- Epithelium resembles low grade dysplasia of the intestine with goblet cells, neuroendocrine cells and occasional Paneth cells
- Neoplastic cells have hyperchromasia, crowding, stratification and mitotic activity
- Glands with luminal mucin
With intraepithelial carcinoma:
- Resembles high grade dysplasia of intestines
- No stromal invasion
With microinvasion:
- Foci of stromal invasion, measuring < 5 mm in the greatest dimension
- Degree of cytologic atypia is mild and similar to borderline tumor
- Areas of mucin extravasation with inflammatory response are not diagnostic of invasion
With mural nodule:
- Classified as sarcoma-like, anaplastic carcinoma and sarcoma (Cancer 1979;44:1327)
  - Sarcoma-like nodule (reactive): spindled and round cells, multinucleated giant cells and marked inflammation
  - Anaplastic carcinoma: rhabdoid, pleomorphic and spindle cells
  - Sarcoma: usually without specific differentiation but there are some reports of rhabdomyosarcomatous and leiomyosarcomatous differentiation (Int J Gynecol Pathol 1994;13:62)

Microscopic (histologic) images

Contributed by Neshat Nilforoushan, M.D. and Russell Vang, M.D.

Complex architecture, tufting and villus formation

Mucinous intestinal type epithelium

Intraepithelial carcinoma

Microinvasion

Cytology description

Clusters of epithelial cells with nuclear stratification, mild to moderate cytologic atypia and mucinous cytoplasm

Positive stains

CK7
CK20 (variable)
CDX2 (variable) [the extent of expression of CK7 is greater than that of CK20 or CDX2] (Am J Surg Pathol 2006;30:1130)
PAX8 (focal)
SATB2 is positive in a small subset of cases, including mucinous tumors associated with teratoma (Ann Diagn Pathol 2015;19:249, Mod Pathol 2019;32:1834)

Negative stains

Molecular / cytogenetics description

KRAS mutations are identified in 30 - 75% of the tumors (Genome Med 2015;7:87)
TP53 mutations are present in lower frequency

Sample pathology report

Ovary, left (oophorectomy):
- Mucinous borderline tumor
Ovary, right (oophorectomy):
- Mucinous borderline tumor with intraepithelial carcinoma
Ovary, left (oophorectomy):
- Mucinous borderline tumor with microinvasion

Differential diagnosis

Seromucinous borderline tumor:
- Admixture of Müllerian type epithelium with endocervical type mucinous epithelium, including serous or ciliated cells
- Associated with endometriosis
Low grade mucinous neoplasm of appendiceal origin:
- Mucinous epithelium with tall mucinous cells, scalloping, subepithelial clefts, dissecting mucin pools
Metastatic pancreatobiliary carcinoma:
- Diffuse intraepithelial carcinoma, foci of invasive carcinoma
Microinvasive carcinoma:
- Stromal invasion morphologically resembles invasive mucinous carcinoma but measuring < 5 mm
- Invasive component has complex architecture and high grade cytologic atypia
Mucinous cystadenoma:
- Cysts and glands with simple lining composed of nonstratified mucinous epithelium
Endometrioid adenocarcinoma with mucinous differentiation:
- Areas of endometrioid type glands and squamous differentiation also may be seen
- Positive for ER / PR (negative in mucinous tumors)
Mucinous carcinoma with expansile growth pattern:
- Confluent growth pattern with glandular crowding without intervening stroma, measuring ≥ 5 mm

Additional references

WHO Classification of Tumors Editorial Board: Female Genital Tumors, 5th Edition, 2020

Board review style question #1

What is the most common mutation associated with ovarian mucinous borderline tumors?

BRAF
CDKN2A
KRAS
TP53

Board review style answer #1

C. KRAS. KRAS mutations are present in 30 - 75% of mucinous borderline tumors.

Comment Here

Reference: Mucinous borderline tumor

Board review style question #2

Which of the following is true regarding microinvasion in mucinous borderline tumor?

Associated with adverse clinical behavior
Associated with mucin extravasation with inflammatory response and histiocytes
Cytologic atypia is severe and similar to intraepithelial carcinoma
Foci of stromal invasion measuring < 5 mm in the greatest dimension

Board review style answer #2

D. Foci of stromal invasion measuring < 5 mm in the greatest dimension. Cytologic atypia in microinvasion is mild to moderate, similar to adjacent borderline tumor. Presence of severe atypia warrants the diagnosis of microinvasive carcinoma. Mucin extravasation with inflammatory response and histiocytes is associated with gland rupture and not diagnostic of microinvasion. Overall, mucinous borderline tumors have excellent prognosis. Microinvasion is not associated with adverse behavior.

Comment Here

Reference: Mucinous borderline tumor

Mucinous carcinoma

Table of Contents

Definition / general

77% of ovarian mucinous carcinomas are metastases, 23% are ovarian primaries (Am J Surg Pathol 2003;27:985)
Of the ovarian primaries, most arise in a benign or borderline tumor; only 5-10% are pure
Features favoring primary ovarian carcinoma vs. metastasis are: unilateral, "expansile" pattern of invasion, complex papillary pattern, size > 10 cm, smooth external surface, microscopic cystic glands, necrotic luminal debris, mural nodules and accompanying teratoma, adenofibroma, endometriosis or Brenner tumor (Am J Surg Pathol 2003;27:281)
Stromal invasion > 10 mm² distinguishes these tumors from borderline tumors
Two types of invasion - expansile or infiltrative:
- Expansile tumors are usually stage I and behave "benign"
- Infiltrative tumors may demonstrate malignant behavior and cause death even if stage I (Am J Surg Pathol 2002;26:139)

Clinical features

Distant metastases are rare
Survival: 95% for stage I vs. 32% for stages II or greater

Prognostic factors

Poor prognostic factors for stage I tumors: infiltrative invasion (destructive stromal invasion, Mod Pathol 2005;18:903), high nuclear grade, tumor rupture
Anaplastic components in intact tumors do not affect prognosis (Am J Surg Pathol 2002;26:139)

Gross description

Primary tumors are usually unilateral, > 10 cm, smooth capsule, cystic and solid areas of tumor evenly distributed throughout ovary without discrete nodularity

Gross images

AFIP images

Mucinous
cystadenocarcinoma

Gelatinous with extensive hemorrhage and necrosis

Mucinous cystic
tumor with
various
components

Images hosted on other servers:

Mucinous
cystadenocarcinoma

Microscopic (histologic) description

Stromal invasion; also more solid growth, atypia, stratification, papillae, loss of glandular architecture, necrosis (resembles colon carcinoma), greater complexity of glands than borderline tumors
Stromal invasion may be infiltrative with disorderly penetration of stroma by neoplastic glands, single cells or cell clusters, may have desmoplastic response or expansile (confluent) with complex arrangement of glands, cysts or papillae lined by malignant epithelium with minimal or no intervening stroma with a broad, sharply defined border
Glands are almost always intestinal type
Endocervical type usually has other epithelial components (serous, endometrioid, squamous)
Carcinoma often merges with borderline or benign mucinous tumors
Rarely has signet ring cells, but differs from Krukenberg tumor (Am J Surg Pathol 2008;32:1373)
Grading:
- Not standardized and does not predict prognosis independent of stage (Am J Surg Pathol 2000;24:1447)
- Grade 1-no solid areas
- Grade 2-up to 50% solid foci
- Grade 3-more than 50% solid foci
- Severe nuclear atypia can increase raise grade I or II carcinomas by one grade

Microscopic (histologic) images

AFIP images

Cribriform pattern

Resembling endometrioid adenocarcinoma

Mostly apical
mucin, but several
goblet cells
with red mucin

With microinvasion of stroma

Disorderly
arrangement of
cysts and glands
of irregular shapes

Invasive small glands and small collections of signet ring cells

Cyst lined by cells with abundant mucin and highly stratified; nuclei highly atypical and presence of necrotic debris in lumen

Resembling
mucinous (colloid)
carcinoma
of intestine

Positive stains

CEA, CK7, CK20, CA125 (weak)

Molecular / cytogenetics description

K-ras mutations are common

Differential diagnosis

Endometrioid carcinoma
Metastatic tumor: bilateral tumors of any size, unilateral tumor < 10-12 cm, exceptions are often metastatic colorectal and endocervical carcinomas (Am J Surg Pathol 2008;32:128)

Additional references

Am J Surg Pathol 2002;26:1529

Mucinous cystadenoma and adenofibroma

Table of Contents

Definition / general

Benign mucinous neoplasm composed of cysts and glands lined by gastrointestinal or Müllerian type mucinous epithelium lacking architectural complexity or cytologic atypia

Essential features

Includes cystadenoma and adenofibroma
Usually unilateral and composed of variable amounts of cysts and glands lined by bland gastrointestinal or Müllerian type mucinous epithelium and variably cellular stroma
May be associated with mature teratoma or Brenner tumor
Excellent prognosis, with rare recurrences associated with cystectomy or rupture

ICD coding

ICD-O:
- 8470/0 - mucinous cystadenoma, NOS
- 9015/0 - mucinous adenofibroma, NOS
ICD-11:
- 2F32.Y & XH6H73 - other specified benign neoplasm of ovary and mucinous cystadenoma, NOS
- 2F32.Y & XH59X8 - other specified benign neoplasm of ovary and mucinous adenofibroma, NOS

Epidemiology

Accounts for 80% of primary ovarian mucinous neoplasms
Mucinous cystadenoma > adenofibroma (Int J Gynecol Pathol 2005;24:4, Cancer 1985;55:1958)
Median age 50 years (range 13 - 79) (Cancer 1985;55:1958)

Sites

Usually ovary
Less commonly, retroperitoneum (Int J Surg Case Rep 2012;3:486)

Pathophysiology

May arise from mature teratoma (possible germ cell origin) or Brenner tumor (Arch Pathol Lab Med 2008;132:1753)
KRAS mutations in 68% of cases (Cancer 1997;79:1581)

Etiology

Unknown

Clinical features

Abdominal distention with or without palpable mass
Abdominal or pelvic pain
Other symptoms related to abdominal / pelvic mass
Rarely, estrogenic or androgenic manifestations secondary to stromal luteinization (Int J Gynecol Pathol 2005;24:4)

Diagnosis

Microscopic examination

Laboratory

Rarely, elevated CA-125 (Cancer 1985;55:1958)

Radiology description

Ultrasonography:
- Usually large multilocular cystic adnexal mass with numerous thin septations
- Various degrees of echogenicity in different locules
- Low level internal echogenicity due to increased mucin content
Magnetic resonance imaging:
- Usually large multilocular cyst containing fluid of various viscosity resulting in variable signal intensities on both T1 and T2 sequences (stained glass appearance)
Reference: Radiographics 2000;20:1445, Radiographics 2019;39:982

Radiology images

Images hosted on other servers:

Palpable lower abdominal mass

Right pelvic pain

Prognostic factors

Excellent prognosis
Recurrences may occur after cystectomy or rupture and spillage (J Obstet Gynaecol Res 2006;32:615, Am J Obstet Gynecol 2010;202:142.e1)

Case reports

13 year old girl with recurrent ovarian mucinous cystadenoma after cystectomy (Int J Surg Case Rep 2021;83:106006)
22 year old woman with metachronous ipsilateral recurrent ovarian mucinous cystadenoma in initial pregnancy and mature teratoma in subsequent pregnancy (Cureus 2019;11:e3818)
40 year old woman with an ovarian mixed Brenner tumor and mucinous cystadenoma (J Clin Imaging Sci 2020;10:22)
71 year old woman with postmenopausal hyperandrogenism associated with ovarian mucinous cystadenoma (BMJ Case Rep 2021;14:e237505)

Treatment

Oophorectomy or cystectomy

Gross description

Usually unilateral (95%)
Smooth or bosselated surface
Cystadenoma:
- Uni or multilocular cyst with variably sized smooth walled locules
- Filled with dense, viscous, sticky, gelatinous material
- No solid areas or papillary excrescences
- Mean size 10 cm, rarely > 30 cm
Adenofibroma:
- Usually smaller
- Predominantly white and solid with variable amounts of small cysts (Int J Gynecol Pathol 2005;24:4, Surg Pathol Clin 2019;12:565)

Gross images

AFIP images

Mucinous cystadenoma

Associated with dermoid cyst

Frozen section description

Benign cystic neoplasm lined by a single layer of bland mucinous epithelium (cystadenoma) or solid and cystic neoplasm composed of small glands or cysts lined by a single layer of bland mucinous epithelium set in a fibromatous stroma (adenofibroma)

Frozen section images

Contributed by Gulisa Turashvili, M.D., Ph.D.

Unilocular cyst

Bland mucinous epithelium

Microscopic (histologic) description

Mucinous cystadenoma:
- Uni or multilocular cystic neoplasm composed of multiple cysts and glands lined by a single layer of bland mucinous epithelium
Mucinous adenofibroma:
- Solid and cystic neoplasm composed of small cysts or glands lined by a single layer of bland mucinous epithelium
- Stroma is fibromatous and variably cellular with or without luteinization
- Focal extravasated mucin or mucin granulomas with numerous histiocytes may be present secondary to cyst / gland rupture
General features:
- Simple nonstratified mucinous epithelium resembling Müllerian, intestinal or gastric foveolar type epithelium
- > 80% are intestinal type containing goblet cells
- Epithelium may be undulating but usually no epithelial stratification or tufting
- Columnar, cuboidal to flat nonciliated cells
- Variable amounts of mucinous cytoplasm
- Small basally located nuclei lacking cytological atypia
- Absent or minimal mitotic activity and apoptotic bodies
- Spiculated calcifications (62.5%) (Arch Pathol Lab Med 2008;132:1753)
Rare features:
- Tubular crypt-like outpouchings or papillary infoldings at the periphery of cysts
- Focal mild cytologic atypia and mitoses
- Goblet cells with or without neuroendocrine cells or Paneth cells
- Periglandular stromal condensation and luteinization (more common in pregnancy) (40%) (Arch Pathol Lab Med 2008;132:1753)
- Sex cord-like differentiation
- Necrosis (12.5%) (Arch Pathol Lab Med 2008;132:1753)
- Pseudoxanthoma cells (47.5%) (Arch Pathol Lab Med 2008;132:1753)
- Muciphages (42.5%) (Arch Pathol Lab Med 2008;132:1753)
- Pseudomyxoma ovarii (stromal dissecting mucin) and giant cell reaction (10%) (Arch Pathol Lab Med 2008;132:1753)
May be associated with:
- Brenner tumor (18%) (Arch Pathol Lab Med 2008;132:1753)
- Mature teratoma (2 - 11%)
- Mural nodules (Indian J Med Sci 2005;59:499, Cancer 1979;44:1327, J Korean Med Sci 1998;13:680)
- Clear cell carcinoma (J Clin Pathol 2000;53:938, J Pak Med Assoc 2007;57:373, Int J Gynecol Pathol 2009;28:584)
- Large cell neuroendocrine carcinoma (Int J Gynecol Pathol 1996;15:167)
- Endometrioid carcinoma (Ann Diagn Pathol 2003;7:300)
- Sex cord stromal tumors, such as granulosa cell tumor and Sertoli-Leydig cell tumor (Arch Pathol Lab Med 1986;110:528, Int J Gynecol Pathol 2005;24:224)

Microscopic (histologic) images

Contributed by Gulisa Turashvili, M.D., Ph.D. and AFIP images

Unilocular cyst

Bland mucinous epithelium

Mucinous adenofibroma

Mucinous cystic tumor

Virtual slides

Images hosted on other servers:

Mucinous cystic neoplasm

Mucinous cystadenoma associated with Brenner tumor

Mucinous cystadenoma with functioning stroma

Mucinous cystadenoma, intestinal type

PAX8

CK7

CK20

Cytology description

Usually negative cytology or reactive mesothelial cells

Positive stains

CK7 (Am J Clin Pathol 2002;117:944)
PAX8: variable, may be focal
CK20: variable (Am J Clin Pathol 2002;117:944)
CDX2: variable

Negative stains

Molecular / cytogenetics description

KRAS mutations in 68% of cases (Cancer 1997;79:1581)

Sample pathology report

Right fallopian tube and ovary, salpingo-oophorectomy:
- Ovary: mucinous cystadenoma
- Fallopian tube: benign

Differential diagnosis

Mucinous tumor with focal atypia / proliferation (Hum Pathol 2004;35:949, Hum Pathol 2004;35:918, Am J Surg Pathol 1991;15:227):
- Focal (< 10%) architectural complexity, including papillae and tufting or nuclear pseudostratification and crowding
Mucinous borderline tumor:
- Architectural complexity with variable degrees of epithelial stratification, tufting and villous or slender filiform papillae in at least 10% of tumor
Metastatic low grade appendiceal mucinous neoplasm:
- Mucin on ovarian and extraovarian surfaces (pseudomyxoma peritonei)
- Bilateral ovarian involvement
- Detachment of mucinous epithelium from stroma (cleft-like space)
- Hypermucinous (highly differentiated, tall, mucin rich) cells
- Positive for CK20, CDX2 and SATB2; negative for PAX8, usually negative for CK7
Metastatic adenocarcinoma:
- Variable differentiation with high grade nuclear atypia and mitotic activity (gastrointestinal and pancreatico-hepatobiliary tract)
- Nuclear pseudostratification, apical mitoses and apoptotic bodies (human papillomavirus associated endocervical adenocarcinoma)
- Often bilateral, multinodular, with surface involvement, at least focal infiltrative growth and lack of correlation between architecture and cytology (Anticancer Res 2018;38:5465)

Board review style question #1

Which immunohistochemical markers are useful for differentiating this primary ovarian tumor from a low grade appendiceal mucinous neoplasm involving the ovary?

CK7, CK20, CDX2, SATB2 and PAX8
CK7, CK20, CDX2, WT1 and SATB2
CK7, CK20, PAX8, ER and SATB2
CK7, CK20, SATB2, ER and PR
CK7, CK20, SATB2, WT1 and PAX8

Board review style answer #1

A. CK7, CK20, CDX2, SATB2 and PAX8. Low grade appendiceal mucinous neoplasm is usually positive for CK20, CDX2 and SATB2 and negative for CK7 and PAX8.

Comment Here

Reference: Mucinous cystadenoma / adenofibroma

Board review style question #2

Which of the following is true for ovarian mucinous cystadenoma?

Always positive for PAX8
May be associated with mature teratoma or Brenner tumor
Most common in postmenopausal women
Usually bilateral ovarian involvement
Usually positive for ER and PR

Board review style answer #2

B. May be associated with mature teratoma or Brenner tumor

Comment Here

Reference: Mucinous cystadenoma / adenofibroma

Mural nodules in mucinous cystic neoplasms

Table of Contents

Definition / general

Grossly circumscribed nodules, most associated with primary ovarian mucinous neoplasms (less frequently other ovarian tumor types)
May be microscopically invasive but still separate / distinct from the associated mucinous tumor (Int J Gynecol Pathol 1994;13:62)

Essential features

May be reactive (sarcoma-like), benign neoplastic (leiomyomatous) or malignant (anaplastic carcinoma, sarcoma, carcinosarcoma)
Associated mucinous tumor may be benign, borderline or malignant
Can present a diagnostic challenge as the discrimination between truly malignant versus reactive mural nodules can be difficult

Terminology

General term: ovarian mucinous neoplasm with mural nodule
Various classification schema used (Int J Gynecol Pathol 1994;13:62, Cancer 1979;44:1332, Am J Surg Pathol 2008;32:383):
- Reactive (sarcoma-like mural nodules)
  - Pleomorphic and epulis-like
  - Pleomorphic and spindle celled
  - Giant cell histiocytic
- Benign neoplastic
- Malignant neoplastic
  - Anaplastic carcinoma: rhabdoid, spindled or pleomorphic
  - Sarcoma
  - Carcinosarcoma

ICD coding

ICD-10: C56 - Malignant neoplasm of ovary (C56.1: right; C56.2: left; C56.9: unspecified)
ICD-10: D27 - Benign neoplasm of ovary (D27.0: right; D27.1: left; D27.9: unspecified)
ICD-10: D39.1 - Neoplasm of uncertain behavior of ovary (D39.11: right; D39.12: left; D39.10: unspecified)

Epidemiology

Females of varying ages and parity
Sarcomatous nodules generally in older patients compared to sarcoma-like nodules (Am J Surg Pathol 2002;26:1467)
Sarcoma-like mural nodules: 18 - 83 years (mean 39 years) (Cancer 1979;44:1332, Am J Surg Pathol 2002;26:1467)
Sarcomatous mural nodules: 49 - 72 years (mean 61 years) (Int J Gynecol Pathol 1994;13:62)
Anaplastic carcinoma mural nodules: 15 - 93 years (mean 44 years) (Am J Surg Pathol 2008;32:383)
Carcinosarcoma mural nodules: 27 - 44 years (mean 33 years) (Int J Gynecol Pathol 1994;13:62)

Sites

Ovary (almost always unilateral)

Pathophysiology / etiology

Unclear histogenesis; however, may evolve through divergent differentiation of mucinous neoplasm or through a collision phenomenon (Int J Gynecol Pathol 2015;34:19)
Sarcoma-like mural nodules: likely common histogenesis for different subtypes, favored to be reactive and of histiocytic origin (Cancer 1979;44:1332, Am J Surg Pathol 2002;26:1467)
Malignant mural nodules clonally related to accompanying mucinous tumor and may represent dedifferentiation (Am J Surg Pathol 2017;41:1261)
Targeted next generation sequencing has shown a clonal relationship between carcinomatous mural nodules and the ovarian mucinous tumor, indicating a dedifferentiation process (Am J Surg Pathol 2017;41:1261)

Clinical features

Majority of patients present with abdominal enlargement or pain (Cancer 1979;44:1332, Cancer 1979;44:1327, Am J Surg Pathol 2008;32:383)
Less common presentations: menometrorrhagia, vomiting, intestinal obstruction, vaginal bleeding (Cancer 1979;44:1332, Am J Surg Pathol 2002;26:1467, Am J Surg Pathol 1991;15:1055)
Stage at presentation:
- Sarcoma-like mural nodules: all FIGO stage Ia (Cancer 1979;44:1332, Am J Surg Pathol 2002;26:1467)
- Anaplastic carcinoma mural nodules: 68% stage I (Ia or Ic), 32% stage II or higher (Am J Surg Pathol 2008;32:383)
- Sarcomatous mural nodules: 60% stage I, 40% stage III or IV (Int J Gynecol Pathol 1994;13:62)
- Carcinosarcoma mural nodules: 75% stage I, 25% stage III (Int J Gynecol Pathol 1994;13:62)

Radiology images

Images hosted on other servers:

Mural anaplastic carcinoma

Mural leiomyoma

Prognostic factors

Sarcoma-like mural nodules behave in benign fashion with no effect on prognosis of associated mucinous tumor (Cancer 1979;44:1332, Am J Surg Pathol 2002;26:1467)
Overt sarcoma and anaplastic carcinoma carry a much worse prognosis:
- For malignant mural nodules overall: 39% mortality (3 months to 1.5 years) (Am J Surg Pathol 2002;26:1467)
- Anaplastic carcinoma mural nodules: 33% mortality (median 8 months) (Am J Surg Pathol 2008;32:383)
- Sarcoma mural nodules: 67% mortality (within 4 years) (Int J Gynecol Pathol 1994;13:62)
Among anaplastic carcinomas, FIGO stage is the only significant prognostic factor (stage Ia tumors do not necessarily carry an adverse prognosis) (Am J Surg Pathol 2008;32:383)

Case reports

18 and 34 year old women, both with osteosarcomatous mural nodules (Int J Gynecol Pathol 2015;34:369)
29 year old woman with solid mural leiomyoma associated with mucinous cystadenoma (Sultan Qaboos Univ Med J 2013;13:127)
30 year old woman with borderline mucinous tumor and sarcoma-like mural nodule (J Midlife Health 2014;5:192)
36 year old woman with anaplastic carcinoma mural nodule associated with rapid and fatal outcome (Int J Gynecol Pathol 2016;35:348)
45 year old woman with mural nodule of anaplastic spindle cell carcinoma within a mucinous borderline tumor (J Ovarian Res 2013;6:86)
48 year old woman with multifocal anaplastic carcinoma and sarcoma-like mural nodules (Int J Clin Exp Pathol 2013;6:1688)
48 year old woman with anaplastic carcinoma nodule and 60 year old woman with sarcomatous mural nodule (Medicine (Baltimore) 2017;96:e8636)
53 year old woman with borderline ovarian seromucinous cystic tumor and anaplastic carcinoma mural nodule (J Ovarian Res 2018;11:77)

Treatment

Appropriate treatment depends on nature of mural nodule (benign / reactive versus malignant) as well as type of associated mucinous tumor and stage at presentation
Tumors with sarcoma-like nodules can be followed after oophorectomy
Staging surgery can be considered in malignant mural nodules, as well as systemic treatment (particularly in patients with extra-ovarian tumor spread)
Reported cases have been variably treated (Cancer 1979;44:1332, Am J Surg Pathol 2002;26:1467, Am J Surg Pathol 2008;32:383)
- Surgical treatment: unilateral salpingo-oophorectomy, bilateral salpingo-oophorectomy or bilateral salpingo-oophorectomy with hysterectomy
- Subset of patients also underwent omentectomy, appendectomy or lymphadenectomy
- Subset of patients treated with adjuvant chemotherapy, especially in cases of malignant nodules

Gross description

Typically unilateral, large, unilocular or multilocular cystic mass with smooth external surface (7 - 62 cm, mean ~20 cm) (Am J Surg Pathol 2008;32:383, Cancer 1979;44:1332, Am J Surg Pathol 2002;26:1467)
1 or more well circumscribed nodules protruding into lumen
May be dark brown, hemorrhagic and soft, or firm and yellow-tan; can have necrosis (Am J Surg Pathol 2008;32:383, Cancer 1979;44:1332, Cancer 1982;50:300)

Gross images

Images hosted on other servers:

Mural leiomyoma

Sarcoma-like mural nodule

Anaplastic carcinoma mural nodule

Clear cell mural nodule

Microscopic (histologic) description

Associated mucinous tumor: endocervical or intestinal type; cystadenoma, borderline tumor or carcinoma (Am J Surg Pathol 2002;26:1467, Cancer 1979;44:1332)
Mural nodules: sharply circumscribed, separated from overlying cyst lining by a layer of hypocellular stroma (Am J Surg Pathol 2002;26:1467)
Sarcoma-like mural nodules: 3 types (Cancer 1979;44:1332, Am J Surg Pathol 2002;26:1467)
- Pleomorphic and epulis-like type (resemble giant cell reparative granuloma / giant cell epulis of gingiva):
  - Loose network of oval to spindled mononucleate cells with marked nuclear pleomorphism
  - Uniformly distributed, multinucleated osteoclast-like giant cells, some with phagocytized red blood cells and debris
  - Blood filled spaces
  - Variable mitotic activity, can have atypical forms
- Pleomorphic and spindle cell type:
  - Fascicles of spindle cells with elongated hyperchromatic nuclei and prominent nucleoli
  - Multinucleated giant cells similar to epulis-like type
  - Diffuse extravasation of red blood cells; blood filled spaces
  - Variable mitotic activity, can have atypical forms
  - Mitotic index ranges from 5 to 10/10 HPF (usually in the most cellular areas)
- Giant cell histiocytic type:
  - Round mononucleate giant cells in closely packed aggregates separated by delicate fibrous septa
  - Cells with vesicular nuclei, ill defined borders, abundant ground glass eosinophilic cytoplasm and minute vacuoles
  - No multinucleated giant cells as in other types
  - Mitoses rare
- Variable but often marked mixed inflammatory infiltrate in all types of nodules
- Some nodules contain scattered cuboidal epithelium lined glands (likely entrapped)
- Most cases have multiple nodules within the tumor
- Associated mucinous tumor is carcinoma in 50% of cases, the rest being benign and borderline in nature
Anaplastic carcinoma mural nodules (Am J Surg Pathol 2008;32:383):
- In general, characterized by poor circumscription, tumor infiltration into adjacent stroma and vessels, and necrosis
- Can have scattered multinucleated giant cells of epulis type
- Divided into 3 types:
  - Rhabdoid: diffusely arranged cells with abundant bright pink cytoplasm and atypical, eccentrically placed nuclei
  - Spindled: spindle cells with atypical vesicular nuclei and moderate eosinophilic cytoplasm, often in herringbone pattern; areas of obvious epithelial differentiation
  - Pleomorphic: admixture of above types, more variegated
Sarcomatous mural nodules: various types of sarcoma described, including fibrosarcoma, rhabdomyosarcoma, undifferentiated sarcoma (Cancer 1979;44:1327, Int J Gynecol Pathol 1994;13:62)
Other mural nodule types described:
- Other carcinomas (clear cell, neuroendocrine, giant cell) (Int J Gynecol Pathol 2015;34:19)
- Carcinosarcoma (Int J Gynecol Cancer 2005;15:549, Histopathology 1991;18:268)
- Leiomyoma (Int J Gynecol Pathol 1990;9:80, Am J Surg Pathol 1991;15:1055)
Multiple or mixed types of nodules may occur in same tumor (Am J Surg Pathol 2002;26:1467)

Microscopic (histologic) images

Contributed by Kruti P. Maniar, M.D. and Jian-Jun Wei, M.D.

Mural carcinosarcoma

Stromal invasion

Atypical spindled and epithelial cells

CK7

Vimentin

Mural neuroendocrine carcinoma

Stromal invasion

Marked atypia

Synaptophysin

Mural anaplastic carcinoma

Marked atypia

Vascular / stromal invasion

Metastasis

Mural carcinosarcoma

Stromal invasion

Malignant cells

Images hosted on other servers:

Rhabdomyoblastic

Sarcomatoid anaplastic

Virtual slides

Images hosted on other servers:

Anaplastic carcinoma

Positive stains

Sarcoma-like mural nodules (Am J Surg Pathol 2002;26:1467):
- Vimentin
- CD68 (in most)
- Variable calretinin, smooth muscle actin, muscle specific actin
Sarcomatous mural nodules: vimentin (Int J Gynecol Pathol 1994;13:62)
Anaplastic carcinoma mural nodule:
- Pankeratin is positive in many cases (Int J Gynecol Pathol 1994;13:62)
- However, staining can be focal
- Moreover, a negative result does not exclude anaplastic carcinoma
Leiomyomatous mural nodule: vimentin, desmin, smooth muscle actin, muscle specific actin (Int J Gynecol Pathol 1990;9:80, Am J Surg Pathol 1991;15:1055)

Negative stains

Sarcoma-like mural nodules (Am J Surg Pathol 2002;26:1467):
- Pankeratin (but can have focal / weak expression)
- ALK, CD34, desmin
Sarcomatous mural nodule: pankeratin (Int J Gynecol Pathol 1994;13:62)
Leiomyomatous mural nodule: pankeratin (Int J Gynecol Pathol 1990;9:80, Am J Surg Pathol 1991;15:1055)

Molecular / cytogenetics description

Recent next generation sequencing study found identical KRAS mutations in paired mucinous tumors and carcinomatous mural nodules (Am J Surg Pathol 2017;41:1261, Int J Gynecol Pathol 2015;34:19)
- Identical CDH1 and p53 mutations may also be seen in both components
- Unpaired p53 and PTEN mutations detected in 2 mural nodules
One case of different KRAS mutations in sarcomatous mural nodule and associated mucinous tumor - suggests different clones of same tumor (Int J Gynecol Pathol 2014;33:186)
Overall findings support neoplastic nature of carcinomatous mural nodules and clonal relationship with better differentiated mucinous tumor; acquisition of additional mutations within the mucinous neoplasm may result in transformation to anaplastic morphology (Am J Surg Pathol 2017;41:1261)
Further larger molecular studies still needed to clearly elucidate the mechanisms and molecular alterations underlying the different types of mural nodules

Differential diagnosis

Distinguishing different types of mural nodules:
- Sarcoma-like mural nodules versus anaplastic carcinoma:
  - Irregular borders, epithelioid and cohesive areas are indicative of carcinoma
  - Keratins are useful if positive; however, a negative result should be interpreted with caution (Virchows Arch A Pathol Anat Histopathol 1991;419:89)
- Sarcoma-like mural nodules versus true sarcomatous nodules:
  - Immunohistochemistry not useful (both keratin-, vimentin+) (Virchows Arch A Pathol Anat Histopathol 1991;419:89)
  - Features favoring true sarcoma: irregular or infiltrative nodule borders, monotonous population of spindle cells, significant nuclear atypia, evidence of vascular or stromal invasion, presence of atypical heterologous elements, older patient age, large nodule size (Virchows Arch A Pathol Anat Histopathol 1991;419:89, Int J Gynecol Pathol 1994;13:62)
Other differential diagnoses:
- Carcinosarcoma: carcinoma component usually not mucinous; carcinoma and sarcoma elements more intimately admixed
- Pure sarcoma: no associated epithelial component
- Inflammatory myofibroblastic tumor: larger, less circumscribed, often immunohistochemical positivity for ALK

Board review style question #1

Which of the following features favors diagnosis as a true sarcomatous mural nodule?

Monotonous spindle cells with infiltration into stroma
Positivity for CD68
Positivity for pankeratin AE1 / AE3
Presence of extravasated red blood cells and blood lakes
Scattered osteoclast-like multinucleated giant cells

Board review style answer #1

A. Monotonous spindle cells with infiltration into stroma

Comment Here

Reference: Mural nodules in mucinous cystic neoplasms

Board review style question #2

60 year old patient had a 30 cm mucinous ovarian tumor removed. Gross exam demonstrated a 5 cm mural nodule. Based on the histologic image of the mural nodule (right) and the overlying mucinous tumor (left), which of the following is most likely true regarding tumor behavior?

Absence of vascular invasion indicates that the tumor is benign
Presence of cytologic atypia within the mural nodule indicates that it is malignant
Presence of a fibrous layer between the nodule and the mucinous tumor indicates that the mural nodule is benign
Presence of infiltrative tumor nests between the nodule and the mucinous tumor indicates that the mural nodule is malignant
Tumor behavior will be driven by the mucinous tumor, which appears benign

Board review style answer #2

D. Presence of infiltrative tumor nests between the nodule and the mucinous tumor indicates that the mural nodule is malignant

All mural nodules are characterized by the presence of a fibrous stromal layer between the nodule and the mucinous tumor. However, tumor invasion into this stroma is indicative of malignancy. Vascular invasion may also be seen in malignant mural nodules but is not required for diagnosis as such. Cytologic atypia may be seen in both malignant mural nodules and benign sarcoma-like mural nodules. A malignant mural nodule can be associated with poor prognosis regardless of the benignity of the associated mucinous tumor.

Comment Here

Reference: Mural nodules in mucinous cystic neoplasms

Neuroectodermal type tumors (pending)

[Pending]

Olaparib

Table of Contents

Definition / general

Apoly (ADP-ribose) polymerase (PARP) inhibitor blocks PARP1, PARP2, PARP3, which are involved in DNA transcription and DNA repair
Developed by KuDOS Pharmaceuticals and acquired and developed later by AstraZeneca Pharmaceuticals LP and Merck & Co
Synonym: AZD2281, MK-7339, Lynparza, PARP inhibitor AZD2281

Trade name

Lynparza®

Indications

Advanced ovarian cancer with BRCA1 and BRCA2 germ line mutations, has been treated with other types of chemotherapy (U.S. FDA approved, 12/19/2014) (Drugs.com: Olaparib [Accessed 5 May 2020])
Previously treated or metastatic breast cancer that is HER2 negative and has germ line mutations in BRCA1 and BRCA2 genes (U.S. FDA approved, 1/12/2018)
Advanced or recurrent ovarian epithelial, fallopian tube or primary peritoneal cancer with germ line / somatic mutations in BRCA1 and BRCA2 genes and partial or complete response to platinum chemotherapy (U.S. FDA approved, 12/9/2018)
Metastatic pancreatic cancer with germ line mutations in BRCA1 and BRCA2 genes and has been treated with platinum chemotherapy (U.S. FDA approved, 12/27/2019)
Reference: National Cancer Institute: Cancer Drugs [Accessed 5 May 2020]

Pathophysiology

In normal cells, base excision repair and homologous recombination mediated double strand breaks repair responsible for damaged DNA repair (Figure 1, panel A)
In cells with BRCA1 or BRCA2 mutation, base excision repair and other DNA repair systems compensate for the nonfunctional homologous recombination (Figure 1, panel B)
In cells with nonfunctioning base excision repair because of PARP1 inhibition and at least one copy of BRCA1 and BRCA2, homologous recombination can repair the DNA (Figure 1, panel C)
In cancer cells with BRCA1 or BRCA2 mutation, PARP1 inhibitor (olaparib) blocks the base excision repair leading to cell death (Figure 1, panel D)
Mechanism of drug resistance (Ann Oncol 2019;30:1437)
- Secondary mutations resulting in somatic reversion or restoration of open reading frame of homologous recombination genes including BRCA1/2
- Expression of functional hypomorphic variants of BRCA1/2
- Stabilization of BRCA1/2 variants by HSP90
- Reversion of BRCA1 epigenetic silencing by demethylation process
- Removal of barriers to DNA end resection via loss of 53BP1 or proteins from shieldin complex
- Oncogenic signaling that promotes expression of homologous recombination repair genes
- Protection of the replication fork and decrease in cell cycle progression
Reference: N Engl J Med 2009;361:189, see diagram below

Diagrams / tables

Images hosted on other servers:

Mechanism of PARP1 inhibitor in cancer cells

Clinical information

BRCA1/2 aberrations occur in ovarian and breast cancers and 5% of other cancers including prostate, skin (nonmelanoma), endometrial, pancreatic and biliary duct cancers (Ann Oncol 2019;30:1437)
Efficacy of olaparib in BRCA mutated advanced ovarian cancer with prior treatment: objective response rate 34%, complete response 2%, partial response 32% (FDA: LYNPARZA (Olaparib) Tablets [Accessed 6 May 2020])
Efficacy in BRCA1/2 mutated HER2 negative metastatic breast cancer: objective response rate 52% (olaparib) versus 23% (nonolaparib chemotherapy)
Olaparib in patients with metastatic castration resistant prostate cancer with DNA repair gene aberrations: TOPARP-B, phase II clinical trial (Lancet Oncol 2020;21:162)
- 161 of 711 patients with DNA damage repair gene aberrations
- Decrease in PSA of 50%: 37% of patients received 400 mg; 30.2% with 300 mg
- Circulating tumor cell count conversion: 53.6% of patients received 400 mg; 48.1% with 300 mg
Olaparib in patients with metastatic castration resistant prostate cancer with BRCA1/2 or ATM mutations: PROfound, phase III trial (Cancer Discov 2019;9:1638)
- 245 patients with BRCA1/2 or ATM mutations
- Objective response rate of 33.3% compared with 2.3% of patients who received enzalutamide or abiraterone plus prednisone
Restored DNA repair capacities found in resistant clones of carcinoma cells (Clin Cancer Res 2013;19:5485)
Myelodysplastic syndrome / acute myeloid leukemia occurred in < 1.5% with fatal outcome; discontinue if it is confirmed (Gynecol Oncol 2018;151:190)
Pneumonitis occurred in < 1% with some fatal outcome; discontinue if it occurs (FDA: LYNPARZA (Olaparib) Tablets [Accessed 6 May 2020])
Embryo / fetal toxicity: potential hazard to a fetus
Clinical pharmacokinetics (FDA: LYNPARZA (Olaparib) Tablets [Accessed 6 May 2020])
- Absorption: rapid, peak median plasma concentrations peak at 1.5 hours after dosing, co-administration of a high fat meal slowed the rate
- Distribution:
  - Mean volume of distribution 158 ± 136 L after a single dose of 300 mg
  - In vitro protein binding approximately 82%
- Metabolism: mainly by CYP3A4/5 in vitro
- Excretion: 44% via urine and 42% via feces
  - Mean terminal plasma half life of 14.9 ± 8.2 hours
  - Plasma clearance of 7.4 ± 3.9 L/h, after a single dose of 300 mg
Drug interactions: avoid concurrent use of strong or moderate CYP3A inhibitors such as itraconazole, clarithromycin, ketoconazole, ritonavir, indinavir, ciprofloxacin, diltiazem, erythromycin, fluconazole (FDA: LYNPARZA (Olaparib) Tablets [Accessed 6 May 2020])
Olaparib costs about $3,000 per month

Uses by pathologists

Anti-BRCA1 mouse monoclonal clone MS110, most effective antibody to detect mutated BRCA1
- Positive BRCA1 mutation if < 10% nuclear staining ovarian carcinoma cells (J Clin Pathol 2020;73:191)
Normal BRCA1: retained BRCA1 staining
Abnormal BRCA1: equivocal and loss of BRCA1 staining (Am J Surg Pathol 2013;37:138)

Side effects

Anemia
Nausea
Vomiting
Diarrhea
Stomatitis
Infections and infestations
Nasopharyngitis / sinusitis / rhinitis / influenza
Fatigue including asthenia
Metabolism and nutrition disorders
Decreased appetite
Arthralgia / myalgia
Dysgeusia
Headache
Neutropenia
Reference: N Engl J Med 2009;361:123

Drug administration

300 mg taken orally, twice daily for 2 years of treatment
Continued treatment until disease progression or intolerable drug toxicity

Additional references

J Adv Pract Oncol 2019;10:167, Cells 2019;8:E860, Curr Treat Options Oncol 2018;19:21, Curr Treat Options Oncol 2018;19:1, Genes Dev 2020;34:360, Mol Cancer 2020;19:49, Nature 2012;481:287, N Engl J Med 2012;366:1382, N Engl J Med 2015;373:1697, N Engl J Med 2018;379:2495, N Engl J Med 2019;381:2416, Pancreas (Fairfax) 2019;3:e5

Board review style question #1

Which of the following is true about olaparib?

Olaparib is used to treat breast and ovarian cancers with BRAF mutation
Olaparib is used to treat breast and ovarian cancers with BRCA1/2 mutation
Olaparib is used to treat breast and ovarian cancers with HER2 mutation
Olaparib is used to treat breast and ovarian cancers with RAS mutation

Board review style answer #1

B. Olaparib is used to treat breast and ovarian cancers with BRCA1/2 mutation

Comment Here

Reference: Olaparib

Ovarian myxoma (pending)

[Pending]

Ovotesticular DSD

Table of Contents

Definition / general

Ovarian and testicular tissue in the same individual (either bilateral or unilateral ovatestes or separate testis and ovary) with or without abnormal genitalia

Terminology

Ovotesticular disorder of sex development (DSD) in the new terminology (Best Pract Res Clin Endocrinol Metab 2010;24:187)

Epidemiology

Very rare, with only about 500 cases identified worldwide

Clinical features

All have uterus, most have fallopian tubes, some have vas deferens
Usually ambiguous genitalia (J Pediatr Endocrinol Metab 2001;14:421)
At puberty, 80% have gynecomastia, 50% menstruate
May be associated with transexualism (Urologiia 2008;2:14)
All true hermaphrodites who have successfully completed pregnancy have had male offspring to date (Obstet Gynecol 2009;113:534)

Laboratory

Hormone levels are typically normal

Prognostic factors

Important to assign gender as soon as possible (in infants, before age 2 - 4), since: (a) usually no other developmental anomalies and (b) patients will have a better chance for normal psychological, sexual and reproductive lives if gonad inappropriate for gender assignment is removed
Dysplastic gonads are at risk for developing germ cell malignancy; risk of gonadal malignancy increases if Y chromosome is present

Case reports

16 year old phenotypic boy with gynecomastia and pubertal arrest (Horm Res 2007;68:261)
Due to tetragametic chimerism (fertilization of two ova by two sperm, followed by the fusion of the zygotes and the development of an organism with intermingled cell lines, Urology 2009;73:293)

Treatment

Plastic surgery is the mainstay after gender is assigned, based on genetic sex, gonadal sex, social sex, psychologic sex and patient request
Conservative gonadal surgery with long term followup (J Urol 2007;177:726)
Case series on surgical treatment of 25 cases of hermaphroditism, 4 of whom were true hermaphrodites who had female gender assignment (Ann Plast Surg 2009;63:543)

Microscopic (histologic) description

Ovary usually normal (prepubertal ovary has primordial follicles with primary oocytes with a few primary or antral follicles)
Prepubertal testis has immature seminiferous tubules lined by immature Sertoli cells and primitive germ cells, usually without spermatogonia
Ovotestis often has normal ovarian tissue with atrophic testicular tissue (Obstet Gynecol 2009;113:534)

Microscopic (histologic) images

Contributed by @drraajul on Twitter

Ovotesticular DSD

Positive stains

Placental-like alkaline phosphatase (PLAP) stained gonocytes indicates higher risk of malignant transformation (Int J Gynecol Pathol 2010;29:33)

Molecular / cytogenetics description

70% are 46,XX; 10% are 46,XY; 20% show various forms of mosaicism; less than 1% show 46,XX / 46, XY chimerism or two or more cell lines of different genetic origins
80% have chromatin positive Barr bodies
60% are 46,XX only in blood cells with Y chromosome present in most of rest of cells

Differential diagnosis

Mixed gonadal dysgenesis:
- Ovarian tissue, if present, lacks primordial follicles; internal / external genitalia are not relevant for distinguishing these 2 conditions

Polycystic ovary disease

Table of Contents

Definition / general

Polycystic ovarian syndrome (PCOS) is a clinicopathologic syndrome comprising polycystic ovaries and characteristic clinical features
Polycystic ovaries resembling PCOS may be seen in prepubertal period or puberty without clinical manifestations

Essential features

Most common cause of anovulatory infertility
Presents with a variety of clinical and radiologic findings
Grossly enlarged, multicystic ovaries, although may not be enlarged in adolescent patients
Microscopically: ovaries with multiple cysts, hyperthecosis and atretic follicles
Associated with endometrial hyperplasia and endometrial neoplasia

Terminology

Formerly called Stein-Leventhal syndrome

ICD coding

ICD-10: E28.2 - polycystic ovarian syndrome
ICD-11: 5A80.1 - polycystic ovary syndrome

Epidemiology

Affects 4 - 12% of women in the U.S., usually of teenage or childbearing ages (Clin Med Res 2004;2:13)

Pathophysiology

Development of insulin resistance and hyperandrogenism in polycystic ovary disease is not fully understood
Familial clustering of cases has been observed, strongly suggesting a genetic basis for polycystic ovary disease; however, no specific genetic abnormality has been shown to be the sole culprit in the development of polycystic ovary disease

Clinical features

Presents with menstrual disorders (from amenorrhea to menorrhagia) and infertility
Can cause acne, obesity, hirsutism, insulin resistance and diabetes
3 different diagnostic criteria:
- National Institutes of Health (NIH) (1990): androgen excess, oligoovulation and exclusion of other entities that cause polycystic ovaries
- European Society of Human Reproduction and Embryology / American Society of Reproductive Medicine (ESHRE / ASRM) in Rotterdam (2003) (2 of 3 present):
  - Oligoovulation or anovulation
  - Excess androgen activity (clinical or biochemical signs)
  - Polycystic ovaries present (by ultrasound) but no other endocrine disorders
- Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society criteria (2006):
  - Hyperandrogenism and any 1 or 2 of:
    - Ovulatory dysfunction
    - Polycystic ovarian morphology (PCOM)
90% of endometrial cancers arise in a background of chronic estrogen stimulation
- Obesity (associated with PCOS), which encourages the conversion of androstenedione to estrone in adipose tissue via aromatase activity, is strongly associated with this subset of endometrial tumors
Reference: Crum: Diagnostic Gynecologic and Obstetric Pathology, 3rd Edition, 2017

Diagnosis

Clinical symptoms:
- Oligo or anovulation
- Androgen excess (hirsutism, acne)
Radiologic findings:
- Ultrasound is gold standard
- MRI may be used but is not generally indicated
Reference: Crum: Diagnostic Gynecologic and Obstetric Pathology, 3rd Edition, 2017

Radiology description

Transvaginal ultrasound:
- Increased ovarian volume with size > 10 mL
- Presence of at least 12 follicles that are between 2 and 9 mm in a single ovary (Hum Reprod 2003;18:598)
- Peripheral distribution of multiple follicles, giving a string of pearls appearance

Case reports

18 year old woman with hirsutism and oligomenorrhea (Gynecol Endocrinol 2013;29:273)
31 year old woman with polycystic ovary syndrome and increasing ovarian cyst size (Medicine (Baltimore) 2021;100:e28261)
32 year old woman with a few year history of hirsutism, menstrual disorders and T1DM (Endocr J 2016;63:193)

Treatment

Lifestyle modifications, weight loss
Treatment of hirsutism and insulin resistance
Infertility:
- Letrozole (aromatase inhibitors) is associated with increased ovulation rate to clomiphene citrate (N Engl J Med 2014;371:119)
- Ovarian drilling puncture of small follicles with electrocautery, although effectiveness has been questioned (Hum Reprod 2002;17:2851, Cochrane Database Syst Rev 2007;3:CD001122)

Gross description

Enlarged ovaries, with numerous subcortical cysts (cysts may be immature follicles)

Gross images

AFIP images

Enlarged ovary is
pearly white

Microscopic (histologic) description

Increased ovarian size, including thickness of cortical and subcortical stroma
Thickened collagenized tunica
Normal numbers of primordial follicles
Twice the expected number of ripening and atretic follicles
Multiple cystic follicles (1 - 2 mm) with luteinized theca layer (theca lutein hyperplasia)
Reference: Crum: Diagnostic Gynecologic and Obstetric Pathology, 3rd Edition, 2017

Microscopic (histologic) images

Contributed by Krisztina Lengyel, M.D. and AFIP

Multiple variably sized cysts and cystic follicles

Atretic follicle with bands of luteinized theca cells

Bands of luteinized theca cells with hemorrhage

Outer cortex is
collagenized with
several follicle
cysts

Sample pathology report

Ovary, left, oophorectomy:
- Benign ovary with collagenized tunica, theca lutein hyperplasia of cystic follicles and atretic follicles with residual theca lutein hyperplasia, consistent with polycystic ovary

Differential diagnosis

Endocrine disorders:
- Androgen secreting tumors:
  - Symptoms of hirsutism, acne, deepening of voice
  - Laboratory results: high blood testosterone, DHEA sulfate levels and urine 17 ketosteroids
- Exogenous androgen:
  - Laboratory results: high blood testosterone
- Cushing syndrome:
  - Adrenal adenoma (ACTH independent Cushing syndrome)
  - Symptoms include male pattern baldness, clitoromegaly and deepening of voice
  - High cortisol levels, low ACTH level
- Nonclassical congenital adrenal hyperplasia:
  - Due to either 21 hydroxylase deficiency (most common), 11β hydroxylase deficiency or 3β hydroxysteroid dehydrogenase deficiency
  - Most common biochemical abnormality is adrenal androgen excess
  - Measure 17 hydroxyprogesterone, serum cortisol, serum androstenedione
  - Analysis of CYP21A2 gene, which encodes 21 hydroxylase, may be used to confirm diagnosis of nonclassic congenital adrenal hyperplasia (Hum Reprod Update 2017;23:580)
- Primary ovarian failure:
  - Characterized by high levels of gonadotropins, particularly FSH
    - Exceptions are prepubertal age or menopausal transition

Additional references

eMedicine: Polycystic Ovarian Syndrome [Accessed 2 November 2022], eMedicine: Imaging in Polycystic Ovary Disease [Accessed 2 November 2022], ACOG: Polycystic Ovary Syndrome [Accessed 2 November 2022], Nurs Clin North Am 2018;53:407, Semin Reprod Med 2008;26:62

Board review style question #1

A 34 year old woman presents with years of irregular menstrual cycles and infertility. On physical examination, she's noted to have hirsutism, central obesity (BMI of 35) and acne. Her bloodwork is noted to have elevated total testosterone and an abnormal glucose tolerance test (GTT). What is she at increased risk of?

Cardiovascular disease
Endometrial hyperplasia / adenocarcinoma
Hypothyroidism
Primary ovarian failure

Board review style answer #1

B. Endometrial hyperplasia / adenocarcinoma. The vignette describes a patient presenting with polycystic ovary disease (reproductive age woman with hirsutism and infertility). She had biochemical changes indicating polycystic ovary disease, such as elevated testosterone and an abnormal glucose tolerance test suggesting insulin resistance. She is at increased risk for endometrial hyperplasia / adenocarcinoma due to frequent anovulation.

Comment Here

Reference: Polycystic ovary disease

Board review style question #2

Which of the common histologic features of polycystic ovary syndrome is shown in the image above?

Cortical stromal hyperplasia
Cystic follicles
Fibrotic ovarian cortex
Hilar cell hyperplasia
Stromal hyperthecosis

Board review style answer #2

C. Fibrotic ovarian cortex. Polycystic ovary syndrome has multiple histologic hallmarks, one of which is the fibrotic ovarian cortex / collagenized tunica. The other features include twice the expected ripening and atretic follicles, multiple cystic follicles with luteinized theca layer (theca lutein hyperplasia).

Comment Here

Reference: Polycystic ovary disease

Pregnancy luteoma

Table of Contents

Definition / general

Pregnancy luteoma falls under the tumor-like lesions category of the WHO 2020 classification of tumors
Self limited, hyperplastic (nonneoplastic) proliferation of large, luteinized ovarian cells during pregnancy, resulting in a tumor-like mass of the ovary that regresses spontaneously during puerperium

Essential features

Pregnancy luteomas are nonneoplastic (hyperplastic) proliferations of luteinized cells, occurring, by definition, during pregnancy
Regress spontaneously after delivery
Microscopic features include diffuse sheets of round cells with abundant eosinophilic cytoplasm and round nuclei
Some luteomas may show brisk mitoses
- This may be a diagnostic pitfall, especially during intraoperative evaluation
- Presence of uniform bland cells, despite the high mitotic rate and a supportive clinical history, is the key to making a diagnosis in these cases

Terminology

Luteoma of pregnancy

ICD coding

ICD-O: 8610/0 - luteoma, NOS
ICD-11: 2F32.Y & XH40J2 - other specified benign neoplasm of ovary & luteoma, NOS

Epidemiology

Age group: 15 - 44 years; by definition, during pregnancy (Int J Gynecol Pathol 1993;12:108)
Commonly seen in mid to late pregnancy (Int J Gynaecol Obstet 2022 Feb 25 [Epub ahead of print])
80% of patients are multiparous; luteomas are rare in primiparous women
80% of patients are African Americans
Rarely, may recur in consecutive pregnancies

Sites

Ovary

Pathophysiology

Occurs due to nodular hyperplasia of theca interna cells
Previously, elevated hCG was implicated as a direct causative agent of luteomas, due to the finding of elevated hCG levels in luteoma patients and spontaneous regression after pregnancy
hCG shares a common alpha subunit with luteinizing hormone (LH) and is thus able to bind to the LH-hCG receptor on the ovarian stromal cells; this causes proliferation and luteinization of ovarian stromal cells
Factors against hCG being the sole causative agent in luteoma pathogenesis:
- There are other conditions (such as trophoblastic tumors) that are more common, that have elevated hCG levels; luteomas have not been found to be associated with trophoblastic tumors
- Luteomas occur in mid to late pregnancy, while hCG levels are higher in the first trimester
- Therefore, factors other than hCG are also involved in the pathogenesis; exact pathogenesis is unknown (Am J Obstet Gynecol 1969;104:871)
Pre-existent endocrinopathy, such as stromal hyperthecosis or polycystic ovarian syndrome (PCOS), may predispose to the development of luteomas in some patients

Etiology

Elevated hCG levels have been implicated in causing hyperplasia of luteinized cells

Clinical features

Usually asymptomatic, with the mass being incidentally detected at cesarean section or tubal ligation at the end of pregnancy
Pelvic mass: rarely seen, can rarely cause obstruction of birth canal
Virilization (Obstet Gynecol 1982;59:105S):
- Seen in 25% of patients, appearing or increasing in the third trimester of pregnancy
- Androgen levels are increased up to 70 times normal
- High androgen levels may be seen in women who do not exhibit virilizing symptoms; this is due to the androgen blunting effect of sex hormone binding globulin (SHBG)
- Virilization symptoms seen with luteomas include:
  - Hirsutism
  - Deepening of voice
  - Acne
  - Frontal baldness
  - Clitoral hypertrophy, etc.
- Virilization features can be seen in up to 70% of female infants born to women that exhibit virilization features under the influence of androgens, leading to clitoromegaly and labial fusion (Obstet Gynecol 1982;59:105S)
- Androgen levels are high in female infants but lower than maternal levels
- Other uncommon symptoms include:
  - Abdominal pain
  - Abdominal mass
  - Ascites
Regression of luteomas:
- Regression occurs spontaneously, several weeks after delivery (starts within days after delivery)
- Androgen levels fall to baseline 2 weeks after delivery
- Symptoms of virilization disappear during first 2 weeks after delivery

Diagnosis

Excisional biopsy, frozen section examination

Laboratory

Elevated hCG levels
Elevated androgen levels

Radiology description

Ultrasound and MRI show a predominantly solid, heterogenous mass

Radiology images

Images hosted on other servers:

Peripherally located multinodular ovarian masses

Prognostic factors

All pregnancy luteomas invariably regress spontaneously after pregnancy

Case reports

28 year old woman, gravida 2, para 1 (G2P1), with large ovarian mass causing hirsutism identified intraoperatively (Case Rep Obstet Gynecol 2021;2021:6695117)
30 year old woman with pregnancy luteoma associated with ectopic pregnancy (J Reprod Infertil 2017;18:333)
33 year old woman with enlarged ovaries discovered incidentally during cesarean section (Int J Appl Basic Med Res 2016;6:282)

Treatment

Treatment is usually not necessary as these are spontaneously resolving lesions

Gross description

Mostly unilateral; bilateral in 33% of cases (Am J Surg Pathol 2014;38:239)
Multiple lesions are seen in 50% of cases
Usually measure 5 - 10 cm but can be smaller or rarely larger, up to 20 cm
Cut surface:
- Well circumscribed, multinodular or multiple lesions, brown with focal hemorrhage, without areas of necrosis
- When necrosis is seen (rarely), it is central and due to infarction

Gross images

Images hosted on other servers:

Bilaterally enlarged ovaries

Multicentric and bilateral tumor

Frozen section description

Similar to permanent sections, frozen sections show round to oval cells with abundant eosinophilic cytoplasm, arranged in diffuse sheets
Caution is advised in interpreting mitoses
- Historically, some luteomas may show brisk mitoses misleading a pathologist into making a diagnosis of malignancy on intraoperative evaluation
- Even with brisk mitoses, cells are uniform and stroma is rarely prominent (Am J Surg Pathol 2014;38:239)

Frozen section images

Contributed by Swati Bhardwaj, M.B.B.S., M.D. and Tamara Kalir, M.D., Ph.D.

Eosinophilic luteoma cells in sheets

Brisk mitoses

Microscopic (histologic) description

Arrangement:
- Lesion is well circumscribed; even when there are multiple nodules, they are sharply circumscribed from the stroma
- Cells are arranged in sheets
- Occasionally, stromal edema may result in separation of cell clusters giving rise to a vaguely nested appearance (Am J Surg Pathol 2014;38:239)
- There may be follicle-like spaces that give rise to a thyroid-like or (when smaller), acinus-like appearance
- Sometimes, a vague reticular or nested pattern may be seen (Am J Surg Pathol 2014;38:239)
Cells are round to oval with abundant eosinophilic cytoplasm, round nuclei with prominent nucleoli
- Sometimes, cells may have pale, frothy cytoplasm instead of eosinophilic cytoplasm; nuclei are uniform (no nuclear pleomorphism)
Mitoses: mitoses are infrequent; in some cases, brisk mitoses can be seen, as high as 2 - 3/10 high power fields (Am J Surg Pathol 2014;38:239)
Necrosis: not usually seen; can be seen in very large tumors, in a central location, due to infarction of the tumor as it outgrows its blood supply
Stroma: usually scant; some cases may show stromal edema or fibrosis giving rise to a vaguely nested arrangement of tumor cells
Additional features: some authors have described the presence of granulosa cell proliferations of pregnancy in the ovary uninvolved by pregnancy luteoma (Am J Surg Pathol 2014;38:239)
- Granulosa cell proliferations of pregnancy may be observed in the ovary involved by luteoma

Microscopic (histologic) images

Contributed by Swati Bhardwaj, M.B.B.S., M.D., Tamara Kalir, M.D., Ph.D. and AFIP images

Multinodular,
well circumscribed
pregnancy
luteoma

Uniform, round, eosinophilic luteoma cells

Luteoma with brisk mitoses

Stromal edema

Stromal edema with nested appearance of luteoma cells

Reticular pattern

Granulosa cell proliferations adjacent to luteoma

Groups of cells surrounded by reticulin fibers

Mitoses

Cytology description

Moderate to large cells with abundant eosinophilic cytoplasm and uniform, round nuclei

Positive stains

Inhibin: strong positivity in tumor cells
Reticulin: positive staining fibers enclosing groups of cells, rather than individual cells

Negative stains

Electron microscopy description

Electron microscopy shows features of steroid hormone producing cells (Hum Pathol 1976;7:205, Pathol Res Pract 1999;195:859):
- Lipid droplets
- Mitochondria with tubular cristae
- Abundant smooth endoplasmic reticulum
- Dispersed golgi apparatus
No crystalloid lattice structures are seen

Sample pathology report

Ovary, oophorectomy specimen:
- Pregnancy luteoma (see comment)
- Comment: Reticulin staining revealed reticulin fibers encircling groups of luteinized cells, consistent with the diagnosis.
- Microscopic description: There are sheets of uniform, round to oval cells with abundant eosinophilic cytoplasm with round nuclei. Background stromal luteosis is seen.

Ovary, oophorectomy specimen:
- Pregnancy luteoma (see comment)
- Comment: Mitotic activity is brisk but attributed to the hormonal milieu of pregnancy.
- Microscopic description: There are sheets of uniform, round to oval cells with abundant eosinophilic cytoplasm with round nuclei. 5 - 6 mitoses are seen per 10 high power fields. Brisk mitotic activity has been described in pregnancy luteomas. The presence of bland and uniform cells is compatible with a luteoma, despite the brisk mitoses.

Differential diagnosis

Steroid cell tumor:
- Rarely bilateral
- Grossly, yellow in color
- Cells are smaller than luteoma cells (cells of pregnancy luteoma are 1.5 - 2 times larger than the cells of steroid cell tumor)
- Eosinophilic cells may be accompanied by pale staining lipid rich cells
- Follicle-like spaces are rarely seen
- Distinction between steroid cell tumor and luteomas is important; a subset of steroid cell tumors are clinically malignant
- Dense reticulum pattern and the presence of lipochrome pigment are other features favoring a diagnosis of steroid cell tumor
- In Leydig cell tumors, a hilar location and the presence of Reinke crystals are helpful
Luteinized thecoma:
- Shows at least focal classical thecoma cells with oval to round cells with spindled nuclei
Luteinized granulosa cell tumor:
- Shows at least focal areas of granulosa cell tumor with classical morphology
- Can retain evidence of epithelial differentiation
- Even when they are luteinized, adult granulosa cell tumor do not show luteinization to the extent seen in pregnancy luteomas
- FOXL2 402C → G (C134W) somatic mutation is highly sensitive and specific for diagnosis of adult granulosa cell tumor (N Engl J Med 2009;360:2719, PLoS One 2009;4:e7988, Am J Surg Pathol 2011;35:484)
Malignant melanoma:
- Shows much greater atypia and higher mitotic rate than that seen in pregnancy luteomas
- IHC is positive for MelanA, HMB45, S100, SOX10 (Case Rep Oncol Med 2020;2020:7206786)

Additional references

Kurman: Blaustein's Pathology of the Female Genital Tract, 6th Edition, 2011, WHO Classification of Tumours Editorial Board: Female Genital Tumours, 5th Edition, 2020

Board review style question #1

Which of the following features is characteristic of pregnancy luteoma?

AFP staining
Brisk mitotic activity
Necrosis even in small tumors
Reticulin staining fibers enclosing groups of cells, rather than individual cells

Board review style answer #1

D. Reticulin staining fibers enclosing groups of cells, rather than individual cells

Comment Here

Reference: Pregnancy luteoma

Board review style question #2

Which of the following features favors a diagnosis of steroid cell tumor over a pregnancy luteoma?

Bilaterality and multinodularity
Brisk mitoses
Follicle-like spaces
Lipid rich cells and dense reticulum pattern

Board review style answer #2

D. Lipid rich cells and dense reticulum pattern. Lipid rich cells and dense reticulum patterns favor a diagnosis of steroid cell tumors over pregnancy luteoma. Other features are commonly seen in pregnancy luteomas.

Comment Here

Reference: Pregnancy luteoma

Rete cystadenoma, adenoma and adenocarcinoma

Table of Contents

Definition / general

Also called adenoma of rete ovarii
Rare; mean age 59 years

Case reports

11 year old girl (J Pediatr Surg 2005;40:e17)

Gross description

Mean 9 cm, usually hilar

Microscopic (histologic) description

Tubulopapillary proliferations of columnar cells with clear cytoplasm; stroma has extensive polygonal, Leydig-like cells
Rete and hilar mesonephric remnants found in vicinity of the lesion

Microscopic (histologic) images

AFIP images

Small cyst in hilus

Numerous small crevices

Positive stains

CAM 5.2, vimentin, EMA, progesterone receptor

Additional references

Int J Gynecol Pathol 1988;7:330, Hum Pathol 1997;28:1428

Sclerosing stromal tumor

Table of Contents

Definition / general

Sclerosing stromal tumor is a benign stromal tumor that has a pseudolobular appearance resulting from alternating cellular and hypocellular areas

Essential features

Alternating cellular and hypocellular areas impart a pseudolobular appearance
Pseudolobules contain a haphazard arrangement of epithelioid (lutein) and spindled cells
Hemangiopericytoma-like vessels are conspicuous in both components
Positive for sex cord markers but negative for EMA and cytokeratin

ICD coding

ICD-10: D27.9 - benign neoplasm of unspecified ovary
ICD-11: 2F32 - benign neoplasm of ovary

Epidemiology

Most common in the first 3 decades (mean: 29 years; median: 26 years) (Histopathology 2022;80:360)

Sites

Ovary

Pathophysiology

FHL2-GLI2 fusions activate the Sonic hedgehog (SHH) pathway (Nat Commun 2020;11:44)

Etiology

Unknown

Clinical features

Most patients present with menstrual irregularities or abdominopelvic pain; subset is incidental
Typically nonfunctioning but androgenic or estrogenic manifestations can occur
Rarely associated with Meigs syndrome (Eur J Gynaecol Oncol 2004;25:528, J Obstet Gynaecol 2010;30:747, World J Clin Cases 2020;8:6364)

Diagnosis

Mass is often observed on imaging
Diagnosis is made by histological examination

Laboratory

CA-125 often within normal limits but elevated levels have been reported (Eur J Gynaecol Oncol 2004;25:528, World J Clin Cases 2020;8:6364)

Radiology description

CT:
- Plain: nonhomogeneous density
- Contrast: peripheral ring enhancement; may see enhancement of central patch or internal septa
- Venous phase: enhancement decreases but increases with centripetal progression; no enhancement of cystic component (Oncol Lett 2016;11:3817)
MRI:
- T1 weighted: slight hyperintense periphery, irregular hypointense center
- T2 weighted: hyperintense cystic components or heterogeneous solid mass with intermediate to high intensity
- T1 with contrast: early peripheral enhancement with centripetal progression (AJR Am J Roentgenol 2005;185:207)

Radiology images

Images hosted on other servers:

CT ovarian mass

MRI ovarian mass

Prognostic factors

Benign tumors; 2 have locally recurred (Int J Gynecol Pathol 2016;35:549, Histopathology 2022;80:360)

Case reports

17 year old virilized girl presents with Meigs syndrome (World J Clin Cases 2020;8:6364)
22 year old pregnant woman with a 12 cm ovarian mass on imaging (Case Rep Obstet Gynecol 2019;2019:3927971)
5 young women (≤ 30 years) with different presentations of an ovarian mass (Indian J Surg Oncol 2018;9:581)

Treatment

Complete surgical excision (oophorectomy)

Clinical images

Images hosted on other servers:

Laparoscopy

Large mass

Gross description

Typically unilateral and well circumscribed, ranging from 1.0 - 23 cm (mean: 8.4 cm) (Histopathology 2022;80:360)
White-yellow variegated solid mass, often edema and cysts
Hemorrhage, calcifications and rarely necrosis may be seen

Gross images

Contributed by Jennifer Bennett, M.D.

Yellow-white mass

Frozen section description

Alternating cellular and hypocellular areas that impart a pseudolobular appearance may be seen in Krukenberg tumors; carefully examine for incipient metastases

Frozen section images

Contributed by Jennifer Bennett, M.D.

Alternating cellularity

Hypercellular pseudolobule

Microscopic (histologic) description

Alternating cellular and hypocellular areas impart a pseudolobular appearance
Hypocellular foci may be ill defined in pregnancy due to expansion of the pseudolobules by lutein cells (Int J Gynecol Pathol 2015;34:357)
Thin, dilated and branching hemangiopericytoma-like vasculature is often conspicuous in both components
Pseudolobules comprised of a jumbled admixture of epithelioid (lutein) and spindled cells with minimal atypia
- Epithelioid cells: round nuclei with prominent nucleoli, vesicular chromatin and clear to vacuolated cytoplasm
  - Abundant eosinophilic cytoplasm often seen in pregnancy (Int J Gynecol Pathol 2015;34:357)
  - Occasionally have a signet ring-like appearance
- Spindled cells: elongated nuclei with indistinct nucleoli, bland chromatin and scant eosinophilic cytoplasm
  - Typically round to ovoid but may show angulation if edema is striking
Hypocellular areas can be edematous, collagenous (variably keloid-like) or myxoid
Mitoses are often inconspicuous but rarely can be up to 12/10 high power fields, no atypical forms (Int J Gynecol Pathol 2016;35:549)
Infarct type necrosis and calcification infrequent
References: Cancer 1973;31:664, Histopathology 2022;80:360

Microscopic (histologic) images

Contributed by Jennifer Bennett, M.D.

Alternating cellularity

Pseudolobule

Collagenous background

Abundant eosinophilic cytoplasm

Inhibin

Virtual slides

Images hosted on other servers:

Sclerosing stromal tumor

Positive stains

Inhibin, calretinin, FOXL2
CD10, smooth muscle actin
Diffuse TFE3 expression in a subset of tumors (Anticancer Res 2017;37:5441)

Negative stains

Cytokeratin, EMA

Electron microscopy description

3 cell types (Int J Gynecol Pathol 1988;7:280):
- Epithelioid cells: membrane bound cytoplasmic lipid, well developed Golgi
- Spindled cells: fibroblast-like, prominent rough endoplasmic reticulum
- Undifferentiated primitive mesenchymal cells (in hypocellular areas): few organelles, rare cilia and basal lamina
Smooth muscle differentiation supported by aggregates of cytoplasmic filaments with interspersed dense bodies, pinocytotic vesicles and basal lamina (Ultrastruct Pathol 1992;16:363)

Molecular / cytogenetics description

GLI2 rearrangements in 81% (Nat Commun 2020;11:44)
- FHL2 is the most common gene partner

Sample pathology report

Right ovary, oophorectomy:
- Sclerosing stromal tumor (5.0 cm)

Differential diagnosis

Thecoma (Am J Surg Pathol 2014;38:1023):
- Typically postmenopausal (mean: 50 - 60 years)
- Hormonal manifestations common
- Indistinct cell borders
- Pale gray cytoplasm
Steroid cell tumor:
- Older (mean: 43 years)
- Hormonal manifestations common
- Staghorn vessels absent
- No spindled cells
Fibroma:
- Older (mean: 48 years)
- Often have a uniform white cut surface
- Hyalinized plaques
Metastatic signet ring cell carcinoma (Krukenberg tumor) (Am J Surg Pathol 2006;30:277):
- Clinical history
- Bilateral in > 50%, often with extraovarian disease at presentation
- Staghorn vessels absent
- Admixed with glands, nests or cords of malignant cells (may be very focal)
- Cytokeratin, EMA and mucicarmine positive
Pregnancy luteoma:
- Often bilateral and multifocal
- Brown and hemorrhagic cut surface
- No admixture of cells
Solitary fibrous tumor (Histopathology 2018;72:749, Am J Surg Pathol 2022;46:363):
- Patternless architecture
- STAT6 typically strong and diffuse
- Inhibin negative
Microcystic stromal tumor (Histopathology 2022;80:898):
- Triad of microcysts, solid areas and fibrous stroma
- No admixture of cells
- Subset with bizarre nuclei
- Beta catenin (nuclear and cytoplasmic) and cyclin D1 positive
- Inhibin and calretinin negative
- CTNNB1 or APC mutations

Board review style question #1

A 30 year old woman presented with pelvic pain; ultrasound detected a 10 cm mass in the left ovary. She underwent an oophorectomy. You receive the intact specimen with a 10 cm well circumscribed yellow-white edematous lesion with multiple cysts that replaces the entire ovary. Histologic examination shows cellular areas that alternate with hypocellular edematous foci. Staghorn vessels are prominent. What is the likely diagnosis?

Pregnancy luteoma
Sclerosing stromal tumor
Solitary fibrous tumor
Steroid cell tumor
Thecoma

Board review style answer #1

B. Sclerosing stromal tumor

Comment Here

Reference: Sclerosing stromal tumor

Board review style question #2

Which of the following is true regarding the ovarian lesion pictured above?

It is characterized by a recurring mutation
It is only seen in pregnancy
It is typically white, firm and uniform on cut surface
Marked cytologic atypia, tumor cell necrosis and atypical mitoses are common
The cellular foci are composed of lutein and spindled cells

Board review style answer #2

E. The cellular foci are composed of lutein and spindled cells

Comment Here

Reference: Sclerosing stromal tumor

Seromucinous borderline tumor

Table of Contents

Definition / general

Ovarian seromucinous borderline tumor is a papillary neoplasm of the ovary that is associated with endometriosis and has an excellent prognosis

Essential features

Papilla with hierarchical branching lined by a mix of Müllerian cell types
No evidence of stromal invasion

Terminology

Historic terms that are no longer used: endocervical type mucinous borderline tumor, Müllerian mucinous borderline tumor, Müllerian mucinous papillary borderline tumor, mixed epithelial papillary borderline tumor of Müllerian type

ICD coding

ICD-O: 8474/1 - seromucinous borderline tumor
ICD-11: 2C73.Y & XH0RB9 - other specified malignant neoplasms of the ovary & seromucinous borderline tumor

Epidemiology

Uncommon (Am J Surg Pathol 2002;26:1529)
Associated with endometriosis (Am J Surg Pathol 2002;26:1529, Am J Surg Pathol 2004;28:1311)
Presents over a wide age range (mean age is 34 - 39 years) (Cancer 1988;61:546, Cancer 1988;61:340, Am J Surg Pathol 2004;28:1311)

Sites

Ovary

Pathophysiology

Subset with loss of ARID1A expression (Int J Gynecol Pathol 2012;31:297)

Etiology

Associated with endometriosis
Many arise from endometriotic cysts

Clinical features

Incidental finding on imaging or may present with signs and symptoms of pelvic mass
Considered to be endometriosis related ovarian neoplasm, along with endometrioid and clear cell tumors

Diagnosis

Tumor can be identified via ultrasound or other imaging studies
Removal of the ovary is then needed for histologic evaluation

Laboratory

Generally not useful

Radiology description

Cystic or solid mass

Prognostic factors

Generally excellent prognosis

Case reports

23 year old woman with no history of pregnancy presented to the emergency room with lower abdominal pain (Gynecol Oncol Rep 2021;37:100839)
25 year old woman with complex cyst in the left ovary suggesting an endometriotic origin (Int J Womens Health 2020;12:601)
39 year old woman who was initially thought to have malignant transformation of endometriosis (Medicine (Baltimore) 2019;98:e15707)
65 year old woman with a previous history of bilateral salpingo-oophorectomy had peritoneal cysts increasing in size over 15 years and an increasing CA 19-9 level (BMJ Case Rep 2020;13:e234692)

Treatment

Surgical management
- Treatment is surgical with the extent of surgery dependent on the stage
- Depending on patient's desire to preserve fertility, a conservative approach may be taken in younger patients (Ann Oncol 2016;27:i20)

Gross description

Tumors range in size from 1.8 - 18 cm; mean size is 9 cm (Am J Surg Pathol 2015;39:983, Am J Surg Pathol 2002;26:1529)
Up to 33% of cases are bilateral (Am J Surg Pathol 2002;26:1529)
Typically a cyst with smooth outer lining and internal papillary excrescences

Frozen section description

Frozen sections of ovarian tumors are common
Frozen section will usually show architecture consistent with a borderline tumor with epithelium showing mixed cell types

Microscopic (histologic) description

Papillary tumor with hierarchical branching
Epithelial lining composed of cytologically bland cells of mixed Müllerian types: endometrioid, squamous, endocervical type, ciliated, hobnail, clear and indifferent (nondescript) eosinophilic cells
Stromal cores with edema or fibrosis with conspicuous inflammatory cells (neutrophils or eosinophils)
Background endometriosis or endometriotic cyst
Microinvasion has been described
References: Cancer 1988;61:546, Cancer 1988;61:340, Am J Surg Pathol 2002;26:1529, Am J Surg Pathol 2004;28:1311

Microscopic (histologic) images

Contributed by Shannon Mingo Welter, M.D.

Endometriotic cyst

Squamous and endocervical

Stromal cores with edema or fibrosis

Papillary tumor

Fibrous cores with inflammation

Variable cell types

Hobnail and endocervical

Endocervical cell lining

Nondescript eosinophilic cells

Positive stains

CK7, PAX8, ER, PR (Int J Gynecol Pathol 2016;35:78)

Negative stains

WT1 (can be positive patchy but generally not diffuse)
CK20, CDX2 (Int J Gynecol Pathol 2016;35:78, In Vivo 2020;34:1341)

Videos

Ovary tumors associated with endometriosis

Sample pathology report

Right ovary, oophorectomy:
- Seromucinous borderline tumor, size 9 cm (see synoptic report)

Differential diagnosis

Serous borderline tumor:
- Similar morphology as papillary architecture but has single cell type and lacks other defined Müllerian cell types
- Usually WT1 positive
Mucinous borderline tumor:
- Gastrointestinal differentiation (Int J Gynecol Pathol 2006;25:83)
- Older age, larger size, less likely to be bilateral, not associated with endometriosis (In Vivo 2020;34:1341)

Additional references

WHO Classification of Tumours Editorial Board: Female Genital Tumours, 5th Edition, 2020

Board review style question #1

A 37 year old woman is found to have a 13.5 cm left ovarian cystic mass with smooth outer surface and internal papillary excrescences. On frozen section, the tumor has papillary, hierarchical branching. The epithelial lining is composed of cytologically bland cells of mixed Müllerian types. Endometriosis background is present but there is no stromal invasion. What is the most likely immunohistochemical profile of this tumor?

CK7+, CK20-, PAX8-, WT1-
CK7+, CK20+, PAX8-, WT1-
CK7+, CK20-, PAX8+, WT1-
CK7-, CK20+, PAX8-, WT1+
CK7-, CK20-, PAX8+, WT1-

Board review style answer #1

C. CK7+, CK20-, PAX8+, WT1-. Answers A, B, D and E are incorrect because seromucinous borderline tumors are positive for CK7 and PAX8. They are negative for CK20 and usually negative for WT1. Serous tumors of the ovary are usually positive for WT1.

Comment Here

Reference: Seromucinous borderline tumor

Board review style question #2

A 35 year old woman is found to have an 8.2 cm right ovarian mass. Histologic sections show a cyst lined by bland columnar epithelium with underlying spindle stroma. What tumors are known to be associated with this type of benign cyst?

Clear cell carcinoma, mucinous carcinoma, low grade serous carcinoma
Endometrioid carcinoma, seromucinous borderline tumor, clear cell carcinoma
Seromucinous borderline tumor, clear cell tumor, mucinous borderline tumor
Serous borderline tumor, mucinous borderline tumor, endometrioid carcinoma

Board review style answer #2

B. Endometrioid carcinoma, seromucinous borderline tumor, clear cell carcinoma. The picture shows an endometriotic cyst. Endometriosis associated malignancies include clear cell carcinoma, endometrioid carcinoma and seromucinous borderline tumors. Answers A, C and D are incorrect because serous and mucinous tumors are not associated with endometriosis.

Comment Here

Reference: Seromucinous borderline tumor

Seromucinous cystadenoma and adenofibroma

Table of Contents

Definition / general

Rare, benign ovarian epithelial tumors exhibiting admixture of 2 or more Müllerian type epithelia (mucinous, serous and endometrioid), each accounting for at least 10% of the epithelium

Essential features

Benign ovarian neoplasms with admixture of 2 or more Müllerian type epithelia, each accounting for 10% or more
Mucinous, serous and endometrioid cell types
Mean age 62 years (Histopathology 2021;78:445)
Association with endometriosis

Terminology

Müllerian mucinous cystadenoma (preferred by some authors to reflect association with endometriosis, endometrioid and clear cell tumors rather than serous tumors of the ovary)

ICD coding

ICD-10: D27 - benign neoplasm of ovary

Epidemiology

Rare tumors

Clinical features

Detected incidentally during work up of other gynecological diseases
May present with an abdominal mass, abdominal pain or swelling
Unilateral / bilateral (bilateral in 40% of cases) (Int J Gynecol Pathol 2022;41:68)
Mean size is 9 cm, generally smaller than intestinal type neoplasms (Int J Gynecol Pathol 2022;41:68)

Diagnosis

Microscopic examination

Radiology description

Unilocular / multilocular cystic masses (J Comput Assist Tomogr 2019;43:119)

Treatment

Surgery (cystectomy or oophorectomy)

Gross description

Cystic masses (unilocular or multilocular)
Seromucinous cystadenofibroma are solid with a fibrous cut surface

Microscopic (histologic) description

Single layered epithelial lining with occasional stratification
Cell types: mucinous (endocervical in appearance), serous (ciliated), endometrioid (nonserous, nonciliated), hybrid morphology (serous and mucinous) (Histopathology 2021;78:445)
Variable degree of papillae (epithelial papillary tufting or broader papillae with fibrovascular core) (Int J Gynecol Pathol 2022;41:68)
Neutrophilic infiltrate may be present
Endometrioid epithelium may have squamous metaplasia
Some tumors have a prominent fibrous stromal component (classified as seromucinous adenofibroma)
Associated with endometriosis in 27 - 36% of cases (Histopathology 2021;78:445, Int J Gynecol Pathol 2022;41:68)

Microscopic (histologic) images

Contributed by Gulisa Turashvili, M.D., Ph.D.

Cyst wall lined by simple epithelium

Cyst wall lined by simple epithelium consisting of serous type ciliated cells admixed with endocervical type mucinous cells

Sample pathology report

Right ovary, cystectomy / oophorectomy:
- Seromucinous cystadenoma

Differential diagnosis

Serous cystadenoma:
- Lined by nonstratified tubal type epithelium
Mucinous cystadenoma:
- Lined by nonstratified mucinous epithelium with intestinal differentiation (goblet cells)
Seromucinous borderline tumor:
- Epithelial proliferation > 10%, complex architecture, papillae with hierarchical branching, edematous papillae with neutrophils
Metastatic tumors:
- Low grade appendiceal mucinous neoplasms, pancreatic adenocarcinoma, endocervical adenocarcinoma, etc.
  - Morphology and immunohistochemical panels are helpful

Additional references

Histopathology 2022;80:255, Akush Ginekol 2018;7:84

Board review style question #1

Seromucinous cystadenoma of ovary is associated with which of the following conditions?

Endometriosis
Hypercalcemia
Isochromosome 12p
Peutz-Jeghers syndrome

Board review style answer #1

A. Endometriosis

Comment Here

Reference: Seromucinous cystadenoma

Serous borderline tumor

Table of Contents

Definition / general

Ovarian serous borderline tumor (SBT) is a low grade epithelial neoplasm of generally younger women with a favorable prognosis when diagnosed at an early stage
Defined, nonobligate precursor to low grade serous carcinoma (LGSC)
As a borderline tumor, can give rise to extra-ovarian abdominoperitoneal or lymph node implants

Essential features

2 morphologic subtypes:
- Conventional SBT shows hierarchically branching papillae lined by stratified, heterogenous epithelium with up to moderate atypia
- Micropapillary / cribriform SBT shows multiple nonbranching filiform structures without fibrovascular cores that are 5 times longer than they are wide, originating directly from bulbous central stalks
When making distinction between SBT and LGSC in a properly sampled resection, numerous stipulations are in place regarding invasion (size and cytomorphology) and features of extra-ovarian implants (noninvasive versus invasive)

Terminology

Serous borderline tumor is currently the sole recommended term for primary ovarian tumor (WHO female genital tumors, 2014 and 2020)
Implant references extra-ovarian nonnodal disease rather than metastasis
Involvement of lymph node by SBT is preferred over lymph node metastasis
Micropapillary / cribriform SBT no longer considered definitionally synonymous with noninvasive LGSC per 2020 WHO
SBT with microinvasion (as defined) is no longer, by definition, synonymous with LGSC per 2020 WHO
Obsolete terminology no longer recommended:
- Atypical proliferative serous tumor
- Serous tumor of low malignant potential
- Semimalignant serous tumor
- Noninvasive LGSC / micropapillary SBT

ICD coding

ICD-O: 8442/1 - serous cystadenoma, borderline malignancy (ICD-10: C56.9), serous tumor, NOS, of low malignant potential (C56.9), atypical proliferating serous tumor (C56.9)
ICD-O: 8462/1 - serous papillary cystic tumor of borderline malignancy (C56.9), atypical proliferative papillary serous tumor (C56.9), papillary serous cystadenoma, borderline malignancy (C56.9), papillary serous tumor of low malignant potential (C56.9)
ICD-O: 8463/1 - serous surface papillary tumor of borderline malignancy (C56.9)
ICD-O: 9014/1 - serous adenofibroma of borderline malignancy, serous cystadenofibroma of borderline malignancy
ICD-10: D39.1 - neoplasm of uncertain behavior of ovary

Epidemiology

Up to 15% of ovarian serous neoplasms are of the borderline type (Hum Pathol 2000;31:539)
Median age is fifth decade, with a range from the second to ninth decades; i.e. younger than high grade serous carcinoma (HGSC) demographic
Nulliparity and unopposed estrogen therapy confer risk, which decreases with increasing parity (Gynecol Oncol 2017;144:571)
Unlike most other ovarian borderline histotypes (endometrioid, clear cell, seromucinous), SBT is not associated with endometriosis

Sites

Primary tumor:
- Ovaries, fallopian tube (lumen and paratubal serosa - extremely rare) and peritoneal surfaces
- When ovarian, frequently bilateral (up to 33%) (Gynecol Oncol 2017;144:174)
- Rarely encountered in males; in the paratestis, is thought to derive from either multipotent mesodermal epithelium or Müllerian ductular remnants (Am J Surg Pathol 2001;25:373)
Implants (all subtypes):
- Ipsilateral ovarian surface (autoimplant), contralateral ovarian surface, omentum, diaphragm, abdominal wall, serosal surface of other abdominopelvic organs

Pathophysiology

There is data to suggest progression from serous cystadenoma / cystadenofibroma with BRAF / KRAS mutations → SBT → LGSC; however, this is still controversial (Ann Oncol 2016;27:i16)
Alternative theory suggests that SBT directly arises from papillary hyperplasia of the fallopian tube, which exfoliates and travels through the lumen to implant on ovarian and peritoneal surfaces (Am J Surg Pathol 2011;35:1605)

Etiology

High incidence of microinvasion in SBTs of pregnant patients

Clinical features

About a third are asymptomatic; otherwise present with nonspecific pelvic / abdominal pain (Oncologist 2012;17:1515)
Mass / compression effect on adjacent tissues (constipation, dysuria)
Uncommonly abdominal bloating, ascites / distention, associated early satiety

Diagnosis

Definitive diagnosis is made only after both adequate sampling of resection specimen and classification of any synchronous abdominoperitoneal implants (Pathology 2018;50:205)
Frozen section diagnosis of SBT often dictates subsequent intraoperative staging protocols (ie, more extensive resection, omental and peritoneal biopsies / washings, extent of lymph node dissections)

Laboratory

Preoperative serum levels of CA 125 are usually elevated (less frequently, CEA and CA19-9)
- Neither sensitive nor specific and cannot distinguish SBT from benign or frankly malignant neoplasms / conditions (Eur J Obstet Gynecol Reprod Biol 2014;183:5, Med Sci Monit 2020;26:e924497)
- Trended postoperatively as qualitative indicator of residual / recurrent disease (not evidence based)

Radiology description

Radiologically challenging (with any modality) to distinguish between SBT and LGSC
Pelvic ultrasound (Abdom Radiol (NY) 2020 Aug 29 [Epub ahead of print])
- Primary modality of imaging evaluation - both transvaginal / abdominal components useful to characterize primary mass and appraise extrapelvic disease
- Spectrum of features from serous borderline to LGSC (former has fewer / smaller papillary projections, lower proportion of solid components, thinner septations / wall thicknesses and fewer microcalcifications)
MRI
- Used to further characterize indeterminate masses or those too large to visualize on ultrasound (Jpn J Radiol 2020;38:782, J Magn Reson Imaging 2014;40:151)
- Variably multicystic to solid, bilateral irregularly enhancing masses with internal septations, fibrous branching and closely packed to loose papillations
CT or PET / CT
- Used to further characterize enhancing solid components or qualities of extra-ovarian disease (Abdom Radiol (NY) 2020 Aug 29 [Epub ahead of print])
- Presence of nodularity and microcalcifications within peritoneal deposits more likely to indicate invasive (versus noninvasive) implants

Radiology images

Contributed by Aarti Sharma M.D. and Ricardo R. Lastra, M.D.

26 cm mass

Prognostic factors

Prognosis largely stage dependent (FIGO / TNM):
- Early stage disease (ovary confined, constituting a majority of patients) has survival comparable to that of general population (Gynecol Oncol 2014;134:267)
- Advanced stage at presentation (i.e. extra-ovarian disease) associated with decreased survival; however, prognosis of advanced stage SBT hinges on presence of established poor prognosticators (invasive versus noninvasive implants, micropapillary / cribriform histotype) not reflected in conventional TNM staging

Case reports

50 and 61 year old women with early recurrence of ovarian serous borderline tumor as high grade carcinoma (Int J Gynecol Pathol 2004;23:265)
61 year old woman with ovarian mesonephric-like adenocarcinoma arising in serous borderline tumor (Diagn Pathol 2020;15:91)

Treatment

Primary treatment is surgical and subsequently stage dependent:
- Hysterectomy and bilateral salpingo-oophorectomy with complete staging; if fertility desired, then unilateral salpingo-oophorectomy with complete staging (both only if early stage preoperatively)
- With bulky disease or advanced preoperative stage: neoadjuvant chemotherapy followed by cytoreductive surgery
Advanced postoperative stage, incomplete staging, quality of implants (invasive or noninvasive) and desire for fertility dictates postoperative management
- Observation, completion surgery, adjuvant platinum / taxane based or hormonal chemotherapy (or combination thereof)
- In contrast to high grade serous carcinoma, SBT / LGSC is suboptimally sensitive to platinum based chemotherapy (NCCN: Clinical Practice Guidelines in Oncology (NCCN Guidelines®) [Accessed 11 February 2021])

Gross description

Received from surgery (often for frozen section) as distended, lobulated bulbous ovarian, adnexal or pelvic mass
Upon receipt and prior to inking, crucial to document:
- Presence of surface autoimplants (plaque-like deposits, suspicious adhesions)
- Integrity of surface / capsule - intact or focally / diffusely ruptured
Cut surface:
- Multiloculated cystic to solid mass with variably thick dissecting septations
- Firm to friable tan-yellow edematous papillary outgrowths from inner wall - resembling clusters of small berries (Am J Surg Pathol 2002;26:1111)
- Can be either subtle, inconspicuous foci in an overall smooth walled cyst or solid proliferations overtaking entire cavity
- Serosanguinous fluid contents
- Gross coagulative necrosis rare
Proper sampling for permanent sections to exclude areas of destructive invasion, atypia or solid growth that would merit promotion to LGSC
- At least 2 representative sections per centimeter of greatest gross tumor dimension (i.e. solid or papillary areas, not the overall simple cyst)
- Grossly normal omentum: 5 - 10 sections total

Gross images

Contributed by Aarti Sharma M.D. and Ricardo R. Lastra, M.D.

Papillary clusters

Excrescences

Frozen section description

Request for frozen section anticipated preoperatively based on imaging and results of peritoneal cytopathology
Gross intraoperative evaluation:
- Representative sections of any papillary excrescences or solid areas should be evaluated histologically
- Unless focally thickened, uniform smooth walled areas are not grossly concerning and do not merit freezing
Histologic intraoperative evaluation:
- After concerning histology is judiciously followed up with additional representative sections, report concerning features that would impact subsequent intraoperative course:
  - Ambiguous volume of epithelial proliferation
  - Micropapillary or cribriform / foci
  - True invasion (microinvasion, as defined below, is not an adverse prognosticator and does not influence management)
Correlation between frozen and permanent sections in SBT (up to 93% consistent) better than other borderline histotypes, e.g. endometrioid or mucinous (Gynecol Oncol 2011;123:517, Gynecol Oncol 2007;107:248)
- Risk of underdiagnosis of SBT (frozen) and subsequently LGSC (permanents) increases with larger tumor size (≥ 8 cm)

Frozen section images

Contributed by Aarti Sharma M.D. and Ricardo R. Lastra, M.D.

Conventional SBT

Micropapillary SBT

Microscopic (histologic) description

Conventional SBT
- Architecture:
  - Numerous slender to bulbous, irregularly contoured papillae with fibrous, hyaline or myxoid cores
  - Hierarchical branching pattern - larger papillae arborize to sequentially smaller papillae terminating in epithelial clusters or single cells
  - Pseudostratified, crowded lining with hobnailing or epithelial tufting, which exfoliate from papillae
  - Psammomatous (concentrically lamellated) or dystrophic calcifications
- Cytologic features:
  - Heterogenous cellular population - cuboidal to columnar ciliated, secretory or eosinophilic cells (latter can have baseline atypia, are more numerous during pregnancy)
  - Up to moderate atypia - mild cellular enlargement, chromatin coarsening, small nucleoli
  - Minimal, nonatypical mitotic activity
Micropapillary / cribriform SBT
- Often admixed with areas of conventional SBT
  - Micropapillary / cribriform subtype defined as SBT harboring a focus of ≥ 5 mm (confluent linear extent) of pure micropapillary / cribriform growth
  - Some experts also cite 10 mm² (2 dimensional area) towards this definition but this is not recognized in 2020 WHO (Am J Surg Pathol 1999;23:397, Am J Surg Pathol 2002;26:1111)
- Architecture - often combination of both patterns:
  - Micropapillary:
    - Thread-like extensions lacking true fibrovascular cores, radiating directly from cyst walls or central bulbous and smooth contoured prominences with fibromatous / myxoid stroma
    - Micropapillae appear 5 times longer than they are wide, resembling mythical snakes of Medusa’s head
    - Low power appearance of labyrinthine spaces created by complex micropapillary interweaving
  - Cribriform: confluent sieve-like microacini (occasionally appearing solid), formed by fusion of micropapillae
- Cytologic features distinct from those of conventional SBT:
  - Epithelial population is uniform rather than heterogenous - low cuboidal monotonous cells with high nuclear to cytoplasmic (N/C) ratio and small, prominent nucleoli
  - Rare to absent ciliation or cytoplasmic eosinophilia
  - Minimal, nonatypical mitotic activity and up to moderate atypia
SBT with microinvasion
- Distinction from LGSC in this context is made on size and cytoarchitectural features of the area of concern:
  - Foci of microinvasion with cytoarchitecture of SBT actually represent senescent cells and confer no prognostic detriment (Am J Surg Pathol 2014;38:743)
    - Individual cells to rounded clusters invading papillary or intracystic stroma with retraction clefting
    - Minimally atypical cells with cytoplasmic hypereosinophilia, scant nonatypical mitoses (< 3 - 4/10 high power fields) and lower Ki67 index than surrounding tumor
    - Surrounding stroma is unremarkable to minimally reactive (fibroblastic reaction, edema)
    - Often multiple foci within same tumor (cutoff for progression to LGSC not defined) but any individual one must be < 5 mm in greatest dimension (otherwise defined as invasive LGSC arising in background of SBT)
  - Foci of microinvasion with cytoarchitecture of LGSC are defined as microinvasive LGSC or SBT with microinvasive LGSC only after proper sampling to exclude frankly invasive LGSC
    - Micropapillae, inverted micropapillae or confluent cribriform structures haphazardly infiltrating papillary or intracystic stroma in a fashion similar to conventional invasive LGSC (Am J Surg Pathol 2006;30:1209)
    - Monotonous hyperchromatic cells with scant cytoplasm and prominent nucleoli
    - Must measure < 5 mm (confluent linear growth) in greatest dimension in any single focus, otherwise defined as frankly invasive LGSC
- Implants
  - 2 types of implants: noninvasive and invasive, latter now classified as extra-ovarian LGSC
  - Noninvasive implant:
    - Grossly, both epithelial and desmoplastic noninvasive implants appear plastered onto peritoneal surface
    - 2 histologic subtypes of no clinical bearing but important to recognize each in the differential of invasive implants
    - Epithelial:
      - Hierarchical papillary proliferations or cellular tufts without associated underlying stroma
      - Planted on mesothelial surface or within cystic mesothelial invaginations, with overall smooth epithelial stromal interface
      - Cytologic features similar to conventional SBT
    - Desmoplastic:
      - True papillae with clusters of or single hypereosinophilic cells blending into (compressed by) inflamed fibroblastic, granulation tissue-like stroma
      - Despite reactive stroma, neoplastic groups remain serosa based, retain smooth and sharply delineated contours at stromal interface and invade without underlying stromal destruction
      - In omentum, desmoplastic implants can create infiltrative inflammatory fibrous septation but do not engulf or extend into adipose tissue
      - Autoimplant: deposit of tumor on ovarian surface, often of desmoplastic noninvasive histomorphology
  - Peritoneal extra-ovarian LGSC (formerly known as invasive implant) - epithelial predominant lesions:
    - Invasive implant defines said focus as extra-ovarian LGSC (even if primary tumor remains as borderline - uncommon situation in which sufficient sampling must be ensured, to exclude histologic features meriting upgrade of the primary)
    - Most critical histologic feature of invasion in the context of an SBT implant is presence of destructive stromal growth evident at low magnification (should not be present in desmoplastic noninvasive implants)
    - Haphazard infiltration of solid epithelial nests with peripheral retraction clefting / halos resembling lymphatic channels
    - In omentum, invasive implants have expansile to infiltrative borders with interruption of normal lobulated fibroadipose architecture
- Lymph node involvement
  - Does not portend worse prognosis but retroperitoneal nodes with involvement of SBT still staged per usual (as N1), not as an extra-ovarian implant
  - Composed of single cells, small clusters, micropapillae or macropapillae and cribriform glands located in nodal subcapsular sinuses or parenchyma
  - Cytologically similar to conventional SBT
  - Adjacent endosalpingiosis is common

Microscopic (histologic) images

Contributed by Aarti Sharma M.D., Ricardo R. Lastra, M.D. and Carlos Parra-Herran, M.D.

Conventional SBT

Micropapillary SBT

Lymph node involvement

Noninvasive implants

Microinvasion

Cytology description

Peritoneal / pelvic washings for ovarian or pelvic masses are taken immediately post entry into the abdominal cavity (during primary resection operation) to minimize contamination from potential intraoperative tumor rupture
Rarely can be taken along with preoperative peritoneal or omental biopsies for advanced stage disease
Positive washings upgrade FIGO / TNM stage of both SBT and LGSC:
- Implies presence of any of the following: ovarian surface involvement, occult extra-ovarian disease (i.e. microscopic invasive / noninvasive implants) or pre/intraoperative tumor rupture
- No reliable cytologic features to distinguish between the above scenarios or between involvement by SBT versus LGSC
Cytologic features of SBT in washings (Diagn Cytopathol 2004;30:313, Cancer Cytopathol 2012;120:238):
- 3 dimensional clusters with smooth or irregular contours, papillations (more prominent on cell block) or other architecturally complex structures
- 2 cell population of minimally atypical cuboidal nonciliated cells with high N/C ratio and frequent cytoplasmic vacuolization
- Psammomatous calcifications can be seen in any of the following: endosalpingiosis, SBT and serous carcinoma (low or high grade)

Cytology images

Contributed by Aarti Sharma M.D. and Ricardo R. Lastra, M.D.

Clusters of cells with irregular contours

High N/C ratio in clusters

Positive stains

PAX8, CK7, ER / PR, WT1

Negative stains

p53 wild type (patchy and weak expression in scattered nuclei)
- To be considered aberrant (aka mutation type), p53 must be either diffusely positive in > 80% of nuclei, completely negative (null type mutant pattern) or any amount of unequivocal cytoplasmic staining (blush does not qualify)
p16 mosaic (patchy and weak nuclear / cytoplasmic expression)
- To be considered positive, p16 must have strong, diffuse, block-like nuclear and cytoplasmic positivity throughout the area of interest
CK20, HNF-1B, Napsin A negative

Molecular / cytogenetics description

KRAS mutations implicated in the progression from SBT to LGSC and are associated with higher risk of recurrence as LGSC (Cancer Res 2004;64:6915, J Pathol 2013;231:449)
BRAF mutations implicated in the progression from serous cystadenoma to SBT but these are rarely associated with advanced stage SBT or progression to LGSC
Molecular studies (X inactivation, loss of heterozygosity, KRAS / BRAF sequencing) conflict in regards to clonal versus multifocal versus metaplastic origin of SBT implants (Ann Oncol 2016;27:i16)

Sample pathology report

Sample report 1:
- Right adnexal mass, excision:
  - Ovarian serous borderline tumor (7.5 cm) with surface involvement (see synoptic report)
- Cecal nodule, excision:
  - Low grade serous carcinoma (invasive implant)
Sample report 2:
- Left fallopian tube and ovary, left salpingo-oophorectomy:
  - Serous ovarian borderline tumor, without ovarian surface involvement (see comment and synoptic report)
  - Fallopian tube without diagnostic abnormality
  - Comment: Immunohistochemical stains performed with adequate controls on sections of the right ovarian tumor show the tumor cells to be diffusely positive for PAX8, WT1, ER and PR, with focal / weak expression of p53 (wild type expression) and patchy positivity for p16. The combined morphologic and immunohistochemical findings support the above diagnosis.

Differential diagnosis

With ovarian SBT
- Serous cystadenoma / cystadenofibroma:
  - Should not harbor architectural complexity in the form of papillae, micropapillae, cribriforming or nesting - otherwise:
    - If proliferation constitutes < 10% of overall tumor: serous cystadenoma / cystadenofibroma with focal epithelial proliferation
    - If > 10% of overall tumor: serous borderline tumor
  - Similar heterogenous population of secretory / ciliated cells but without atypia or mitoses
- Low grade serous carcinoma:
  - Any single focus of invasion with nuclear features of borderline tumor measuring ≥ 5 mm in greatest linear extent (invasive LGSC)
  - Any single focus of invasion with nuclear features of low grade serous carcinoma:
    - < 5 mm in greatest linear extent - microinvasive LGSC
    - > 5 mm - invasive LGSC
  - Noninvasive LGSC and SBT often coexist and can be challenging to distinguish in the absence of invasion
    - SBT should not have architecturally confluent cribriform or micropapillary growth - i.e. solid, florid proliferation of low grade cells (amount required to define carcinoma over borderline not defined)
- Endometrioid borderline tumor:
  - Arises from / associated with endometriosis (unlike SBT)
  - Can have papillary structures but not in hierarchically branching configuration
  - Luminal surface of endometrioid glands is nonciliated and crisp / linear, not exfoliative, hobnailing or tufting like SBT
  - Squamous, squamous morular or mucinous metaplasia (extremely rare in both low and high grade serous neoplasms)
- Seromucinous borderline tumor (formerly endocervical type mucinous borderline tumor):
  - Arises from / associated with endometriosis (unlike SBT)
  - Has hierarchically branching edematous papillae but in contrast to SBT, these have a prominent stromal acute inflammatory infiltrate
  - Lined by endocervical type mucinous but occasionally ciliated to indifferent cells (unclassifiable cells unique to seromucinous tumors - abundant eosinophilic cytoplasm and prominent nucleoli)
With SBT autoimplant
- Invasive LGSC arising in SBT (Am J Surg Pathol 2006;30:457):
  - As autoimplants are usually identical in morphology to peritoneal noninvasive desmoplastic implants, can mimic invasive LGSC arising in the borderline tumor if they are situated between papillae of exophytic or intracystic tumor
  - Autoimplants are more stromal dominant with a more prominent inflammatory infiltrate
  - Epithelial component of autoimplants appears compressed by desmoplastic reaction, rigid structural retention like the nests of microinvasive LGSC
With noninvasive peritoneal implant of SBT
- Mesothelial hyperplasia:
  - Diffuse sheets to papillary proliferations of monotonous mesothelial cells restricted to serosa and demarcated from underlying stroma
  - Variable cellular atypia with rare mitoses
  - Both can be PAX8, WT1 positive but SBT is negative for calretinin, D2-40
- Well differentiated papillary mesothelioma:
  - Tubulopapillary architecture (uniformly short / blunted rather than hierarchically branching papillae) with bland cuboidal monolayered mesothelial lining
  - Psammoma bodies associated with both
  - Immunoprofile similar to mesothelial hyperplasia (above)
- Endosalpingiosis:
  - Endosalpingiosis is limited to simple glandular structures lined by a monolayer of cells similar to fallopian tube epithelium with neither atypia nor cellular crowding / tufting
- Primary peritoneal SBT:
  - Can be multifocal and is histomorphologically identical to either epithelial or desmoplastic noninvasive implants of ovarian SBT
    - Defined as primary peritoneal SBT only when a primary ovarian SBT is excluded

Additional references

WHO Classification of Tumours Editorial Board: Female Genital Tumours, 5th Edition, 2020

Board review style question #1

The ovarian neoplasm in the image above is associated with which of the following?

Endometriosis
Increased risk of extra-ovarian peritoneal implants
Lynch syndrome
Progression to high grade serous carcinoma
Serous tubal intraepithelial neoplasia

Board review style answer #1

B. Increased risk of extra-ovarian peritoneal implants

Comment Here

Reference: Serous borderline tumor

Board review style question #2

Which of the following features, if present, increases the TNM stage of a serous borderline tumor?

Lymphovascular invasion
Positive pelvic washings
Presence of frank destructive invasion
Presence of microinvasion
Tumor size ≥ 10 cm

Board review style answer #2

B. Positive pelvic washings

Comment Here

Reference: Serous borderline tumor

Serous cystadenoma, adenofibroma and surface papilloma

Table of Contents

Definition / general

Benign partially or completely cystic lesion measuring > 1 cm in size and composed of cells resembling fallopian tube epithelium or cuboidal nonciliated epithelium resembling ovarian surface epithelium

Essential features

Benign; > 1 cm in size (< 1 cm signifies a cortical inclusion cyst); composed of cells resembling fallopian tube epithelium
Presents over a broad age range and are generally asymptomatic
Usually small, uni to multilocular cysts lined by a single layer of tall, columnar, ciliated cells
Adenofibromas and cystadenofibromas are composed predominantly of fibrous stroma, with glands and cysts forming a minor component

Terminology

Includes cystadenoma, cystadenofibroma, adenofibroma, papillary cystadenoma, papillary cystadenofibroma, papillary adenofibroma
Term used depends on the relative amount of fibrous stroma but distinctions are often arbitrary

ICD coding

ICD-11: 2F32.3 - serous ovarian cystadenoma

Epidemiology

Patients present over a broad age range
Most often found in adult women of reproductive age

Sites

Ovary, less commonly fallopian tube

Pathophysiology

DNA copy number changes may be seen in stromal fibromatous cells and epithelial cells (Clin Cancer Res 2011;17:7273, Lab Invest 2004;84:778)

Etiology

Unknown

Clinical features

Generally asymptomatic
Symptoms related to an ovarian mass
One of the more common ovarian tumors to undergo torsion

Diagnosis

Cystectomy or oophorectomy

Laboratory

CA-125 levels may be mildly elevated (rarely marked) (Arch Gynecol Obstet 2007;276:559)

Radiology description

Typically anechoic with thin, smooth walls and posterior acoustic enhancement; unilocular cysts, thin walls, minimal septations and absence of papillary projections (Radiographics 2000;20:1445)
Imaging modality: pelvic ultrasound or CT scan

Prognostic factors

May recur after incomplete excision

Case reports

63 year old woman with ruptured benign serous ovarian cystadenoma mimicking ovarian malignancy with peritoneal carcinomatosis (Diagn Interv Imaging 2016;97:1187)
64 year old woman with bilateral ovarian fibromas and concomitant unilateral serous cystadenoma (J Obstet Gynaecol 2019;39:1027)
65 year old woman with ovarian serous cystadenoma with ectopic adrenal tissue (Int J Surg Case Rep 2017;33:89)

Treatment

Surgery (cystectomy or oophorectomy)

Gross description

Cystadenoma:
- Usually 3 - 10 cm (but can be up to 30 cm), oval to round, smooth glistening surface
- Usually watery clear to pale yellow cyst fluid but can be viscous and mucoid
- Rarely papillary excrescences are seen on outer surface
Cystadenofibroma:
- Varies from solid areas with knobby papillae to firm confluent areas
Adenofibroma:
- Entirely solid with small cysts
Reference: Kurman: Blaustein's Pathology of the Female Genital Tract (Springer Reference), 7th Edition, 2019

Gross images

Images hosted on other servers:

Serous cystadenoma

Cystadenofibroma

Frozen section description

Uni or multiloculated cysts with single layer of cuboidal or columnar epithelium and simple papillary projections, if present
Bland appearing fibrous stroma in varying amounts
No invasion, architectural complexity or atypia

Microscopic (histologic) description

Usually small, uni to multilocular cysts lined by a single layer of tall, columnar, ciliated cells resembling normal tubal epithelium or cuboidal nonciliated epithelium resembling ovarian surface epithelium
Stroma contains spindle fibroblasts
If papillae are present, they are simple
Adenofibromas and cystadenofibromas are composed predominantly of fibrous stroma, with glands and cysts forming a minor component
If < 10% of the total tumor volume shows epithelial proliferation within the cysts that would otherwise qualify as serous borderline tumor, the tumor is designated as serous cystadenoma with focal epithelial proliferation
Reference: Kurman: Blaustein's Pathology of the Female Genital Tract (Springer Reference), 7th Edition, 2019

Microscopic (histologic) images

Contributed by Catherine J. Roe, M.D. and Krisztina Hanley, M.D.

Serous cystadenofibroma

Serous cystadenoma

Serous cystadenoma with focal epithelial proliferation

Papillary tufting

Cytologic features

Focal epithelial proliferation

Cytology description

Groups, strips or clusters of epithelial cells with small, bland, round to oval nuclei and variable cytoplasm with or without cilia
Background cyst contents, including histiocytes and proteinaceous debris
Cannot definitively diagnose on a cytology specimen; histologic examination is required for classification

Cytology images

Images hosted on other servers:

Small epithelial cell cluster

CD68

Positive stains

Epithelial cells: cytokeratins (i.e. AE1 / AE3, CK7), WT1, PAX8, ER, PR
Stromal cells: ER, PR

Sample pathology report

Right ovary, oophorectomy:
- Serous cystadenofibroma (3.3 cm)
Left ovary, oophorectomy:
- Serous cystadenoma with focal epithelial proliferation (see comment)
- Comment: The 8.3 cm cystic ovarian mass was extensively sampled. Focal epithelial proliferation (small, noncomplex papillae) is noted, which represents less than 10% of sampled cyst wall. These finding represent a benign serous cystadenoma with focal epithelial proliferation.

Differential diagnosis

Rete cyst / cystadenoma:
- Located in ovarian hilus, undulating epithelium, smooth muscle wall, cyst lining is a single layer of flat cuboidal cells
- Nests of Leydig cells may be present in the wall
Paratubal Müllerian cyst (hydatid cyst of Morgagni):
- Paramesonephric cyst attached to fimbria, thin fallopian tube type epithelium with small epithelial plicae projecting into the lumen, may have smooth muscle in the wall
Peritoneal cyst:
- Lined by mesothelial cells, often associated with ovarian surface adhesions
Mesonephric cyst:
- Lined by cuboidal cells and usually surrounded by smooth muscle
Mucinous cystadenoma:
- Lined by a single layer of mucin containing tall columnar epithelium
Hydrosalpinx:
- Dilated fallopian tube lumen, lined by ciliated epithelium, attenuated or rare plicae, well developed smooth muscle in the wall
Cortical / epithelial inclusion cyst:
- < 1 cm
- Lined by simple cuboidal to columnar epithelium with ciliated cells, sometimes admixed with nonciliated cells
Serous borderline tumor:
- Epithelial proliferation with architectural complexity, including branching of irregularly shaped papillae
Seromucinous cystadenoma:
- Lined by epithelium with 2 or more Müllerian cell types each accounting for at least 10% of the epithelium (Histopathology 2021;78:445)
- Frequently associated with endometriosis (Int J Gynecol Pathol 2021 Feb 11 [Epub ahead of print])

Additional references

WHO Classification of Tumours Editorial Board: Female Genital Tumours, 5th Edition, 2020, Crum: Diagnostic Gynecologic and Obstetric Pathology, 1st Edition, 2011

Board review style question #1

Serous cystadenoma / adenofibroma / surface papilloma

This image is a representative section of a 4.3 cm solid and cystic ovarian mass. What is the diagnosis?

Fibroma
Hydrosalpinx
Mucinous cystadenoma
Paratubal cyst
Serous cystadenoma

Board review style answer #1

E. Serous cystadenoma

Comment Here

Reference: Serous cystadenoma / adenofibroma

Board review style question #2

What feature distinguishes cystadenoma from cortical inclusion cyst?

Epithelial lining
Location
Presence of psammoma bodies
Relationship to ovarian serosa
Size

Board review style answer #2

E. Size

Comment Here

Reference: Serous cystadenoma / adenofibroma

Sertoli cell tumor

Table of Contents

Definition / general

Pure sex cord neoplasm of the ovary composed of Sertoli cells most commonly arranged in a tubular pattern
Rare to no Leydig cells present
Many have hormone manifestations (most commonly estrogenic)

Essential features

Solid or hollow tubules with or without other histologic patterns containing cuboidal cells that are positive for sex cord markers

ICD coding

ICD-O: 8640/1 - Sertoli cell tumor, NOS
ICD-11: 2F32.Z & XH4H24 - benign neoplasm of ovary, unspecified & Sertoli cell tumor, NOS

Epidemiology

Rare tumor
Occurs at any age (mean: 30) (Am J Surg Pathol 2005;29:143)

Sites

Ovary

Pathophysiology

Subset have DICER1 mutation (Mod Pathol 2015;28:1603)

Etiology

No known causative agents

Diagrams / tables

Contributed by Mahmoud A. Khalifa, M.D., Ph.D.

Sex cord classification

Clinical features

Incidental finding or may present with signs and symptoms of pelvic mass
Hormonal manifestations
- Most commonly due to estrogen
- Less commonly due to production of androgens, renin, progesterone or aldosterone
Associations
- Peutz-Jeghers syndrome (lipid rich and oxyphilic variants) (Int J Surg Pathol 2016;24:269)
- DICER mutation
Reference: Cancer 1980;46:2281

Diagnosis

Tumor can be identified via ultrasound or other imaging studies
Removal of the ovary is then needed for histologic evaluation

Laboratory

Generally not useful although hormonal manifestations are seen and suggest a possible steroid producing tumor

Radiology description

Predominantly solid mass in the ovarian parenchyma

Prognostic factors

Excellent in the vast majority of cases
Features of malignancy
- Severe cytologic atypia
- Necrosis
- Mitotic rate > 5/10 high power fields
Tumor size > 5 cm
Reference: Am J Surg Pathol 2005;29:143

Case reports

29 year old woman, previously diagnosed with polycystic ovarian syndrome, presented with complaints of amenorrhea for the past 3 years (Medicina (Kaunas) 2022;58:1638)
32 year old woman with rapidly growing pelvic tumors and widespread bulky peritoneal disseminations (Gynecol Oncol Rep 2018;24:54)
46 year old regularly menstruating woman presented with complaints of dull aching, recurrent pain in the suprapubic region (Clin Case Rep 2022;10:e05892)

Treatment

Oophorectomy
Chemotherapy with or without radiation if malignant

Gross description

Unilateral, solid, tan to yellow
Mean size is 8 cm

Gross images

AFIP images

Yellow and lobulated

Frozen section description

Frozen sections of ovarian tumors are common
Frozen section will usually show a bland tumor composed of tubules
History of hormone activity, unilaterality and young age are helpful features to recognize the tumor as likely benign
Reference: Arch Pathol Lab Med 2019;143:47

Microscopic (histologic) description

Tubular pattern (most common and usually present at least focally) with solid or hollow tubules
Cuboidal or columnar cells
Bland oval to round, monotonous nuclei
Pale cytoplasm
Lipid rich or oxyphilic variants may be associated with Peutz-Jeghers syndrome
Other patterns: trabecular, diffuse, alveolar, pseudopapillary, reniform, pseudoendometrioid, spindled
Absent to very rare Leydig cells
Pathologic features predictive of malignant behavior include 5 mitoses per 10 high power fields, severe cytologic atypia, necrosis and size > 5 cm
Reference: Am J Surg Pathol 2005;29:143

Microscopic (histologic) images

Contributed by Shannon Mingo Welter, M.D.

Hollow and solid tubules

Tubules with hyalinized stroma

Tubular and trabecular

Trabecular

Diffuse with tubules

Mixed patterns

Positive stains

Inhibin, SF1, calretinin
Frequently positive: CD99, WT1, AE1 / AE3
Reference: Am J Surg Pathol 2007;31:255

Negative stains

EMA, CK7, PAX8, GATA3, chromogranin

Molecular / cytogenetics description

DICER1 mutations can be seen in some of these tumors

Sample pathology report

Ovary, right, oophorectomy:
- Sertoli cell tumor

Differential diagnosis

Sertoli-Leydig cell tumor:
- Abundant Leydig cell component (MelanA positive)
Endometrioid carcinoma:
- Luminal / cytoplasmic mucin or squamous differentiation
- EMA and PAX8 positive
- Inhibin and SF1 negative
Carcinoid tumor:
- Associated teratoma or mucinous tumor
- Chromogranin positive
- Inhibin and SF1 negative
Female adnexal tumor of probable Wolffian origin:
- Variable inhibin staining
- SF1 negative
Hilar Sertoli cell proliferation:
- Located in the hilum
- Microscopic

Additional references

WHO Classification of Tumours Editorial Board: Female Genital Tumours, 5th Edition, 2020

Board review style question #1

A 40 year old woman is seen in the clinic with complaints of irregular uterine bleeding and pelvic fullness. Transvaginal ultrasound shows a 9 cm right ovarian mass. The mass is surgically removed and a pathologic examination shows the features in the picture above. The mass is positive for inhibin and SF1. The tumor is negative for EMA, PAX8, MelanA and chromogranin. In which of the following general categories does this tumor belong?

Epithelial
Neuroendocrine tumor
Pure sex cord tumor
Sex cord stromal tumor

Board review style answer #1

C. Pure sex cord tumor. Sertoli cell tumor is a pure sex cord neoplasm of the ovary composed of Sertoli cells most commonly arranged in a tubular pattern. Sertoli cells are positive for inhibin and SF1. Answer D is incorrect because no Leydig cells, which are positive for MelanA and are stromal in nature, are present. Answer B is incorrect because the tumor is negative for neuroendocrine markers. Answer A is incorrect because the tumor is negative for EMA and PAX8.

Comment Here

Reference: Sertoli cell tumor

Sertoli-Leydig cell tumor

Table of Contents

Definition / general

Rare ovarian tumor composed of sex cord (Sertoli cells) and stromal (Leydig cells) elements, accounting for < 0.5% of all ovarian neoplasms

Essential features

Rare ovarian tumor composed of sex cord (Sertoli cells) and stromal (Leydig cells) elements
May occur sporadically or in patients with DICER1 syndrome
3 molecular subtypes (Am J Surg Pathol 2019;43:628):
- DICER1 mutant: younger age, moderately / poorly differentiated, retiform or heterologous elements
- FOXL2 c.402C>G (p.Cys134Trp) mutant: postmenopausal patients, moderately / poorly differentiated, no retiform or heterologous elements
- DICER1 / FOXL2 wildtype: intermediate age, no retiform or heterologous elements, including all well differentiated tumors
Express general sex cord markers (inhibin, calretinin, SF1, FOXL2 and CD56); CK7 and EMA immunostains are negative
Behavior correlates with tumor grade and histologic subtype

Terminology

Sertoli-Leydig cell tumor
- Well differentiated
- Moderately differentiated / intermediate grade
- Poorly differentiated
Sertoli-Leydig cell tumor with heterologous elements
Sertoli-Leydig cell tumor, retiform variant
Histologic grade and subtype correlates with clinical behavior (see Prognostic factors)

ICD coding

ICD-O:
- 8631/1 - Sertoli-Leydig cell tumor, NOS
ICD-11:
- XH0UP7 - Sertoli-Leydig cell tumor of intermediate differentiation
- XH6FQ9 - Sertoli-Leydig cell tumor, NOS
- XH8U56 - Sertoli-Leydig cell tumor, intermediate differentiation, with heterologous elements
- XH6XB6 - Sertoli-Leydig cell tumor, retiform
- XH3PN1 - Sertoli-Leydig cell tumor, retiform, with heterologous elements

Epidemiology

Rare, accounting for < 0.5% of all ovarian neoplasms and 1 - 2% of pediatric ovarian cancers
Most common in young patients with a mean age of 25 years (Am J Surg Pathol 1985;9:543)
May also present after menopause (Eur J Gynaecol Oncol 2017;38:214)
Tumors with a retiform pattern or germline DICER1 mutation occur at a younger age (Gynecol Oncol 2017;147:521)
Nearly all pediatric Sertoli-Leydig cell tumors are moderately or poorly differentiated, are DICER1 syndrome associated and often show a retiform pattern or heterologous elements

Sites

Ovary

Pathophysiology

May occur sporadically or in patients with DICER1 syndrome (OMIM: Pleuropulmonary Blastoma; PPB [Accessed 16 August 2021])
- Rare tumor predisposition syndrome caused by germline mutations in DICER1, a gene encoding the RNase III enzyme in the microRNA maturation pathway (N Engl J Med 2012;366:234, Br J Cancer 2013;109:2744)
- Other tumors and disorders associated with DICER1 syndrome include pleuropulmonary blastoma, cystic nephroma, multinodular goiter and botryoid embryonal rhabdomyosarcoma, among others (Nat Rev Cancer 2014;14:662)
- Germline mutation is generally a truncating mutation; may occur anywhere in the gene
- Second hit somatic mutation is a focused hotspot missense mutation affecting the RNase IIIb domain of DICER1 (Histopathology 2016;69:903)
- Sporadic Sertoli-Leydig cell tumors (moderately and poorly differentiated) harbor somatic mutations at the same hotspot of DICER1 gene (Am J Surg Pathol 2017;41:1178)
- Somatic hotspot DICER1 mutations are present in approximately half of all cases (range: 15 - 97%), 61 - 69% of which also have germline DICER1 mutations (Am J Surg Pathol 2017;41:1178, Gynecol Oncol 2017;147:521, Histopathology 2016;68:279)

Etiology

May occur sporadically or in patients with DICER1 syndrome (see Pathophysiology) (OMIM: Pleuropulmonary Blastoma; PPB [Accessed 16 August 2021])

Clinical features

Clinical presentation may include pelvic pain or a pelvic mass, rarely with ascites and tumor rupture
Androgenic hormonal symptoms (virilization) are common and present in approximately 50% of patients; they include hirsutism, clitoromegaly, breast atrophy and menstrual irregularity or amenorrhea (Am J Surg Pathol 1985;9:543)
Estrogenic hormonal manifestations are rare

Diagnosis

May be suspected clinically in a young patient presenting with a combination of virilization, elevated testosterone levels and ovarian / pelvic mass on imaging studies
Clinical presentation often overlaps with other, more common entities, as nearly half of patients with Sertoli-Leydig cell tumors lack the characteristic androgenic symptoms and may be older (peri or postmenopausal, expanding the clinical differential diagnosis) (Eur J Gynaecol Oncol 2017;38:214)
Intraoperative frozen section evaluation is helpful to confirm the clinical suspicion and guide the surgical management

Laboratory

May have elevated testosterone (Eur J Gynaecol Oncol 2017;38:214)

Radiology description

Ultrasound, pelvic CT or MRI can show a solid or solid and cystic adnexal mass

Radiology images

Images hosted on other servers:

Large tumor

Prognostic factors

Behavior correlates with tumor grade and histologic subtype
Well differentiated Sertoli-Leydig cell tumors are essentially benign
Approximately 10% of moderately differentiated and 13 - 59% of poorly differentiated tumors have malignant behavior (Gynecol Oncol 2012;125:673, Gynecol Oncol 2012;127:384, J Obstet Gynaecol Res 2013;39:305)
Heterologous elements, retiform pattern, tumor rupture and spread outside the ovary (stage II or higher tumor stage) are adverse prognostic factors (J Obstet Gynaecol Res 2013;39:305, Gynecol Oncol 2012;125:673)
Patients with germline DICER1 mutations have a favorable prognosis compared with those with somatic DICER1 mutations only (Gynecol Oncol 2017;147:521)

Case reports

15 year old girl with Sertoli-Leydig cell tumor and DICER1 mutation (Case Rep Obstet Gynecol 2018;2018:7927362)
20 and 21 year old sisters with Sertoli-Leydig cell tumor and DICER1 syndrome (Medicine (Baltimore) 2020;99:e20806)
68 year old woman with ovarian Sertoli-Leydig cell tumor with heterologous hepatocytes and a hepatocellular carcinomatous element (Int J Gynecol Pathol 2019;38:247)
3 cases of bilateral ovarian Sertoli-Leydig cell tumors in patients with DICER1 syndrome (Histopathology 2020;77:223)
9 of 16 cases of familial multinodular goiter and Sertoli-Leydig cell tumors are associated with a large intragenic in frame DICER1 deletion (Eur J Endocrinol 2018;178:K11)

Treatment

Conservative fertility sparing surgery (unilateral salpingo-oophorectomy) and staging procedure (with or without lymphadenectomy) is usually performed in young patients with stage I tumors (Gynecol Oncol 2012;125:673, Gynecol Oncol 2012;127:384, J Obstet Gynaecol Res 2013;39:305)
Older patients who do not wish to preserve fertility typically undergo bilateral salpingo-oophorectomy, total hysterectomy and complete surgical staging
Platinum based adjuvant chemotherapy has also been reported in patients with moderately and poorly differentiated tumors, heterologous mesenchymal elements, advanced stage or rupture (J Obstet Gynaecol Res 2013;39:305, Eur J Gynaecol Oncol 2017;38:214)
Genetic counseling and germline DICER1 mutation testing is recommended (Am J Surg Pathol 2017;41:1178)

Gross description

Almost always unilateral (Am J Surg Pathol 1985;9:543)
Tumor size ranges widely from < 1 cm to 35 cm (mean 12 - 14 cm) (Am J Surg Pathol 1985;9:543)
Cut surface is typically solid, tan-yellow
Cystic component may also be seen, especially in tumors with heterologous elements or with a retiform morphologic pattern
Poorly differentiated tumor may show grossly identifiable foci of necrosis

Gross images

Contributed by Natalia Buza, M.D.

Intermediate grade tumor

Frozen section description

Most critical issue is differentiation from epithelial ovarian malignancies
- Unlike epithelial malignancies, Sertoli-Leydig cell tumor is almost always unilateral and typically occurs in younger patients
- Clinical history of hormonal (androgenic) symptoms is helpful and should be actively sought from the surgical team
- Key microscopic features on frozen section include admixture of Sertoli cell tubules or compressed cords with variable amount of Leydig cell clusters
- Intracytoplasmic Reinke crystals may be better preserved compared to formalin fixed paraffin embedded permanent sections
- Sertoli-Leydig cell tumor: fertility sparing surgery is typically performed in younger patients
- Epithelial ovarian malignancies: generally requires complete surgical staging and the role of fertility preserving surgery is more controversial (Hui: Atlas of Intraoperative Frozen Section Diagnosis in Gynecologic Pathology, 1st Edition, 2015, Mod Pathol 1999;12:933, J Obstet Gynaecol Res 2013;39:305, Gynecol Oncol 2012;125:673)

Frozen section images

Contributed by Natalia Buza, M.D.

Well differentiated tumor

Moderately differentiated tumor

Poorly differentiated tumor

Heterologous elements

Microscopic (histologic) description

Difficulty of histologic diagnosis increases with tumor grade
While Sertoli and Leydig components can be readily identified in well differentiated tumors, less differentiated tumors lack well formed Sertoli cell tubules and have fewer Leydig cells
Well differentiated
- Open or compressed Sertoli cell tubules, admixed with clusters of Leydig cells in the intervening stroma
- Sertoli cells are low columnar to cuboidal with oval to round nuclei, which often show nuclear grooves and small nucleoli
- Leydig cells can be recognized by their round nuclei and abundant eosinophilic cytoplasm with characteristic Reinke crystals and lipofuscin pigment
- No significant atypia or mitotic activity
Moderately differentiated
- Typically has a diffuse or lobulated architectural pattern and may show alternating hypo and hypercellularity on low magnification
- Sertoli cells form compressed tubules, cords or diffuse sheets and have hyperchromatic, oval or spindled nuclei with mild to moderate atypia and occasional mitotic figures (average 5 per 10 high power fields)
- Rare small clusters of Leydig cells are admixed with the Sertoli cell component
- Follicular differentiation may be seen in moderately and poorly differentiated tumors and may resemble juvenile granulosa cell tumor (Am J Surg Pathol 2021;45:59)
Poorly differentiated
- Diffuse sheets of immature, sarcomatoid Sertoli cells with moderate to marked nuclear atypia and only rare foci of vague cord formation
- Increased mitotic activity, up to 20 mitoses per 10 high power fields
- Leydig cells are difficult to find; a few small clusters are typically located at the periphery of tumor nodules
Sertoli-Leydig cell tumor with heterologous elements
- Heterologous (epithelial or mesenchymal) elements may be seen in approximately 20% of moderately or poorly differentiated tumors and in retiform Sertoli-Leydig cell tumor (Am J Surg Pathol 1985;9:543)
- Most common heterologous element is mucinous (intestinal or gastric type) epithelium, which may be benign, borderline or malignant (Cancer 1982;50:2448)
- Carcinoid tumor (trabecular or goblet cell) has also been described arising from heterologous mucinous epithelial elements (Cancer 1982;50:2448)
- Heterologous mesenchymal (cartilage or skeletal muscle) elements are less common (Cancer 1982;50:2465)
- Rare focal hepatocyte differentiation has also been reported and may be associated with increased serum AFP (Hum Pathol 1999;30:611)
Sertoli-Leydig cell tumor, retiform variant
- Approximately 15% of Sertoli-Leydig cell tumors demonstrate focal or diffuse retiform pattern, forming anastomosing, slit-like, irregular spaces or multicystic, sieve-like or papillary architecture (Am J Surg Pathol 1985;9:543, Am J Surg Pathol 1983;7:755)

Microscopic (histologic) images

Contributed by Natalia Buza, M.D.

Well differentiated tumor

Moderately differentiated tumor

Poorly differentiated tumor

Retiform pattern

Heterologous elements

Positive stains

General sex cord proteins, such as inhibin, calretinin, SF1, FOXL2, CD56, WT1 and CD99 (Am J Surg Pathol 1997;21:583, Arch Pathol Lab Med 2017;141:1052)
Vimentin and pancytokeratin (Am J Surg Pathol 2007;31:592)
MelanA / MART1 in Leydig cells (Am J Surg Pathol 2011;35:484)
CK20 and CDX2 in heterologous intestinal type mucinous epithelium
AFP, arginase and HepPar1 in hepatoid elements
Reticulin histochemical staining may be helpful in differentiating Sertoli-Leydig cell tumor (completely absent or nested pattern) from fibromas and thecomas (individual pericellular reticulin network)
- Absence of reticulin staining is not specific for Sertoli-Leydig cell tumors, as adult granulosa cell tumors and epithelial ovarian tumors also show the same staining pattern (Int J Gynecol Pathol 2018;37:305)

Negative stains

CK7 and EMA immunostains are negative; helpful in distinguishing Sertoli-Leydig cell tumors from ovarian epithelial tumors (Arch Pathol Lab Med 2017;141:1052)
Reticulin is absent (highlights the individual pericellular reticulin network in ovarian fibromas / thecomas; also absent in adult granulosa cell tumors and epithelial ovarian tumors) (Int J Gynecol Pathol 2018;37:305)

Molecular / cytogenetics description

3 molecular subtypes (Am J Surg Pathol 2019;43:628):
- DICER1 mutant: younger age, moderately / poorly differentiated, retiform or heterologous elements
- FOXL2 c.402C>G (p.Cys134Trp) mutant: postmenopausal patients, moderately / poorly differentiated, no retiform or heterologous elements
- DICER1 / FOXL2 wildtype: intermediate age, no retiform or heterologous elements, including all well differentiated tumors
Somatic hotspot DICER1 mutations are present in approximately half of all cases (range: 15 - 97%), 61 - 69% of which also have germline DICER1 mutations (Gynecol Oncol 2017;147:521, Am J Surg Pathol 2017;41:1178, Histopathology 2016;68:279, Mod Pathol 2015;28:1603)
More recent study identified DICER1 mutations in all of their moderately and poorly differentiated tumors, whereas none of the well differentiated tumors had DICER1 mutations, raising the possibility that well differentiated Sertoli-Leydig cell tumors may represent a different pathogenetic entity (Am J Surg Pathol 2017;41:1178)
FOXL2 mutation has been reported in up to 22% of ovarian Sertoli-Leydig cell tumors and is mutually exclusive with DICER1 mutations (Histopathology 2016;68:279, J Pathol 2010;221:147, Int J Gynecol Pathol 2018;37:305)

Sample pathology report

Ovary and fallopian tube, right, salpingo-oophorectomy:
- Sertoli-Leydig cell tumor of the ovary, poorly differentiated, with heterologous elements (embryonal rhabdomyosarcoma) (see comment)
- Tumor size: 28 cm
- Tumor ruptured intraoperatively (see surgeon's operative report)
- Ovarian surface involvement: not definitely identified
- Fallopian tube: negative for tumor
- TNM stage (AJCC 8th edition): pT1c1 Nx, at least stage IC1
- Comment: Pelvic wash cytology is negative. Referral for genetic counseling is recommended.

Differential diagnosis

Sertoli-Leydig cell tumor:
- Endometrioid adenocarcinoma, especially sertoliform variant (Mod Pathol 1999;12:933):
  - Positive for CK7 and EMA and negative for sex cord markers (Arch Pathol Lab Med 2017;141:1052)
  - Presence of squamous differentiation is helpful
- Adult granulosa cell tumor:
  - Lacks Leydig cell component
  - Majority of tumors have FOXL2 mutations (Histopathology 2016;68:279, J Pathol 2010;221:147, Int J Gynecol Pathol 2018;37:305)
- Fibroma:
  - Lacks Leydig cell component
  - Reticulin stain shows individual pericellular network (Int J Gynecol Pathol 2018;37:305)
- Tubular Krukenberg tumor (i.e. tubular variant of metastatic signet ring cell carcinoma):
  - Bilaterality, presence of signet ring cells and positive EMA favor metastasis
  - Depending on the primary site, the tumor is also positive for CK7 or CK20
  - May be positive for CDX2
Retiform Sertoli-Leydig cell tumors:
- Yolk sac tumor:
  - Lacks Leydig cell component
  - Positive for AFP and SALL4 (Histopathology 2014;65:51)
- Low grade serous tumors (borderline tumor and low grade serous carcinoma):
  - Positive for CK7
  - Lacks Leydig cell component
  - Often bilateral
Sertoli-Leydig cell tumors with heterologous elements:
- Carcinosarcoma:
  - Marked nuclear atypicality in both components
  - Positive for epithelial markers (EMA, CK7), at least in the carcinoma component
- Mucinous tumors (primary ovarian and metastatic):
  - Lack of the surrounding atypical sex cord (Sertoli cell) and Leydig cell component
- Teratoma:
  - Lack of atypical sex cord (Sertoli cell) and Leydig cell component
  - Usually predominant ectodermal component

Board review style question #1

The ovarian tumor in this image most commonly harbors mutations in which gene?

ARID1A
DICER1
FOXL2
SMARCA4
STK11

Board review style answer #1

B. DICER1. Somatic hotspot missense mutation affecting the RNase IIIb domain of DICER1 gene are common in Sertoli-Leydig cell tumors. In a recent large case series, all moderately and poorly differentiated Sertoli-Leydig cell tumors harbored DICER1 mutations.

Comment Here

Reference: Sertoli-Leydig cell tumor

Board review style question #2

Sertoli-Leydig cell tumors of the ovary typically show which of the following immunoprofiles?

CK7+ / EMA+ / inhibin- / calretinin+
CK7- / EMA+ / inhibin+ / calretinin-
CK7- / EMA- / inhibin+ / calretinin+
CK7- / EMA- / inhibin+ / calretinin-

Board review style answer #2

C. CK7- / EMA- / inhibin+ / calretinin+. Sertoli-Leydig cell tumors express general sex cord immunohistochemical markers, such as inhibin and calretinin. CK7 and EMA immunostains are negative and can help differentiate Sertoli-Leydig cell tumors from sertoliform endometrioid adenocarcinoma of the ovary, which is typically positive for both CK7 and EMA.

Comment Here

Reference: Sertoli-Leydig cell tumor

Sex chromosome DSD

Table of Contents

Mixed gonadal dysgenesis | Turner syndrome

Mixed gonadal dysgenesis

Definition / general

Mixed gonadal dysgenesis refers to an individual who usually has a differentiated gonad on one side and a streak gonad or streak testis on the other side
Either (a) testis plus contralateral streak gonad, (b) testis and contralateral gonadal agenesis, (c) hypoplastic gonads with tubules in one gonad or (d) streak gonad with contralateral tumor
A type of asymmetrical gonadal dysgenesis due to chromosomal abnormality
Often mosaicism: 45X / 46XY, 45X / 46XX or 45X / 47XXY; may also have 46XX but missing part of one X chromosome

Terminology

In 2005, the Chicago Consensus of Intersex Disorders proposed the term "mixed gonadal dysgenesis" to substitute for disorders of sex development, defined by congenital conditions in which the development of chromosomal, gonadal or anatomical sex is altered
There is much confusion about the nomenclature for patients with gonadal dysgenesis
Asymmetrical gonadal dysgenesis is the term used if one gonad displays more complete development and can be identified as a testis or ovary (usually is a testis) and the other gonad is a streak
Streak testis: streak tissue identified at periphery of differentiated testis
Streak gonad: ovarian type stroma without differentiated gonadal structures

Etiology

Reproductive system developmental disorder characterized by progressive loss of primordial cells on the developing glands of an embryo
This loss leads to extremely hypoplastic and dysfuctioning gonads, which are mainly composed of fibrous tissue, hence the name streak glands
During embryogenesis, the reproductive system is intrinsically conditioned to give rise to a female, unless altered by hormone production
As a result, if a gonad cannot express hormones, as occurrs with gonadal dysgenesis, the affected person will still develop both internal and external genitalia
In gonadal dysgenesis, the accompanying hormonal failure prevents the development of secondary sex characteristics in either sex, resulting in the appearance of a sexually infantile female and infertility

Clinical features

Phenotype may be ambiguous, male, female, Turner-like syndrome or intersex
Müllerian structures present since no / minimal anti-Müllerian hormone is produced
Usually bilateral fallopian tubes are present, occasionally vas deferens
Females may exhibit clitoromegaly; no breast development except with tumors
Phenotypic males may have short stature, 90 degree penile torsion, undescended testis, chordae without hypospadias, hypospadias or no obvious abnormalities
Patients with 45X mosaicism are often considered to have a variant of Turner syndrome
Phenotypic females may develop virilization at puberty, often complete
High risk for gonadoblastoma (30%) if Y chromosome material is present, which may obliterate testicular elements and cause incorrect diagnosis
Higher risk for other medical problems, including deficient immunoglobulin levels, aberrant bony development of inner ear structures, cardiovascular and renal anomalies (horseshoe kidney)

Laboratory

Elevated FSH
Chomatin negative Barr bodies
Low immunoglobulins levels

Prognostic factors

High risk for gonadoblastoma (30%) if Y chromosome material is present, which may obliterate testicular elements and cause incorrect diagnosis

Case reports

Short stature in phenotypic male with 45X0 / 46XY mosaicism (Nat Clin Pract Endocrinol Metab 2008;4:524)
Mistaken diagnosis of testicular dysgenesis (Arq Bras Endocrinol Metabol 2010;54:331)

Treatment

Excise gonads early to prevent tumors
Hormone replacement therapy

Microscopic (histologic) description

Prepubertal patients show normal immature testis
At / after puberty, tubules exhibit mild hypospermatogenesis to total sclerosis
Streak gonad has ovarian stroma without primordial ovarian follicles
Streak ovary is streak gonad with primordial follicles and primitive sex cord-like structures with or without germ cell components within the ovarian type stroma, mimicking gonadoblastoma, granulosa cell tumor or Sertoli cell tumors

Microscopic (histologic) images

AFIP images

Mixed gonadal dysgenesis

Molecular / cytogenetics description

FISH may be helpful (Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2008;25:570)
Usually no mutations of SRY (Eur J Obstet Gynecol Reprod Biol 2004;115:55) but see J Med Genet 1993;30:655

Differential diagnosis

True hermaphroditism:
- Ovary has numerous primordial follicles containing primary oocytes, nature of internal or external genitalia is not relevant (Mod Pathol 2002;15:1013)

Additional references

Ann Saudi Med 1994;14:267

Turner syndrome

Definition / general

Describes females with a variety of features (most commonly short stature and gonadal insufficiency) associated with loss of an entire X chromosome (45,X0) in about 50%, mosaicism in 15 - 25% and the rest with loss of only a portion of the X chromosome containing the tip of its short arm

Terminology

Also called Ullrich-Turner syndrome

Epidemiology

Occurs in about 1:4000 live births
Increased frequency in abortuses or women with short stature

Etiology

Haploinsufficiency of genes that are normally expressed by both X chromosomes including:
- "Short stature homeobox containing gene on the X chromosome" (SHOX) in chondrocytes
- Lymphatic gene, leading to absence or hypoplasia of lymphatics, which causes lymphedema, cystic hygroma, webbed neck, low posterior hairline, nail dysplasia and lymphedematous hands and feet at birth
- Multiple genes involved in ovarian function, leading to gonadal dysgenesis and accelerated loss of oocytes at 15 weeks gestation

Clinical features

Growth failure: short stature with cubitus valgus, genu valgum and short fourth metacarpals (Wikipedia: Cubitus Valgus [Accessed 15 January 2024], Wikipedia: Genu Valgum [Accessed 15 January 2024])
High palate, prominent ears, chronic otitis media, obstructive sleep apnea, increased sensitivity to noise and problems learning how to suck, blow, eat and articulate (Wikipedia: Turner Syndrome [Accessed 15 January 2024])
Cardiovascular disease: including bicuspid aortic valve, coarctation of the aorta, partial anomalous pulmonary venous return (PAPVR) and atrial and ventricular septal defects
Gonadal failure: have female ducts and external genitalia but usually no pubertal development
Learning disabilities: deficits in visuomotor skills, visual spatial skills, visual and working memory, visual attention, executive functions and social skills
Associated with nongonadal neoplasms: including atypical polypoid adenomyoma of uterus, endometrial adenocarcinoma, leukemia and soft tissue tumors

Laboratory

Diagnosis requires a standard 30 cell karyotype
Markedly elevated serum FSH, reduced serum estrogen

Case reports

Mother and daughter with nonmosaic Turner syndrome (Fertil Steril 2004;82:923)

Treatment

Growth hormone (to increase stature) as soon as growth failure occurs
Cardiac imaging (MRI) at diagnosis and repeated in 5 - 10 year intervals to assess for congenital heart abnormalities and the emergence of aortic dilatation (precursor to aortic dissection)
Aggressive treatment of hypertension
Hormone replacement therapy (transdermal estradiol) beginning at normal pubertal age continued to age 50
Routine neuropsychological testing and family support, including special education
Also search for hidden Y chromosome mosaicism (J Pediatr Endocrinol Metab 2006;19:1113)
Follow up medical care for various conditions in adulthood (Endocr Rev 2002;23:120, J Clin Endocrinol Metab 2010;95:1487)

Clinical images

Images hosted on other servers:

Various images

Microscopic (histologic) description

Streak gonad with fibrous tissue resembling ovarian stroma

Molecular / cytogenetics images

Images hosted on other servers:

45,X0 karyotype

Sex cord stromal tumor NOS (pending)

[Pending]

Sex cord tumor with annular tubules

Table of Contents

Definition / general

Sex cord tumor with annular tubules (SCTAT) is a distinctive variant of sex cord stromal tumor that histologically exhibits a unique morphology, characterized by sharply circumscribed nests composed of ring-like tubules that encircle basement membrane-like material

Essential features

Presence of characteristic tubular pattern, with antipodal distribution of nuclei and basement membrane-like material
Rare tumor, < 1% of all sex cord stromal tumors
2 types: sporadic and syndromic, the latter is associated with Peutz-Jeghers syndrome
Peak incidence between third and fourth decade
Uncertain clinical behavior: syndromic types usually have a benign clinical course, up to 20% of sporadic type exhibit extraovarian spread

ICD coding

ICD-O: 8623/1 - sex cord tumor with annular tubules
ICD-10: D39.1 - neoplasm of uncertain behavior of ovary
ICD-11: 2F76 & XH5BV8 - neoplasms of uncertain behavior of female genital organs & sex cord tumor with annular tubules

Epidemiology

Overall rare tumor (accounting for < 1% of all sex cord tumors)
Syndromic: associated with germline STK11 mutations on chromosome 19p13.3 (Peutz-Jeghers syndrome), incidental finding
Nonsyndromic: mean age at presentation is 36 years of age (range: 6 - 76 years)
References: Cancer 1982;50:1384, Crum: Diagnostic Gynecologic and Obstetric Pathology, 3rd Edition, 2017

Sites

Peutz-Jeghers syndrome associated cases occur as bilateral ovarian lesions, sometimes multifocal
Nonsyndromic / sporadic cases are unilateral ovarian lesions

Pathophysiology

Peutz-Jeghers syndrome associated lesions harbor germline STK11 mutations

Etiology

Unknown

Clinical features

Lesions may be seen at any age, mainly in the third and fourth decade
Incidental finding in a patient with Peutz-Jeghers syndrome
Nonsyndromic
- Associated with nonspecific symptoms and signs
- Menstrual irregularities
- Premenstrual girls often have precocious pseudopuberty (Fletcher: Diagnostic Histopathology of Tumors, 5th Edition, 2020)
Older women may have menstrual dysfunction or postmenopausal bleeding (Fletcher: Diagnostic Histopathology of Tumors, 5th Edition, 2020)
Rarely, nonsyndromic cases may be associated with signs related to progesterone production

Diagnosis

Histologic evaluation

Radiology description

Ultrasound imaging (Pediatr Radiol 2007;37:1270)
- Multiple small, lobulated, discrete high echogenicity masses or tumorlets
- Occasionally may have calcifications

Prognostic factors

Syndrome associated tumors are typically benign
Nonsyndromic / sporadic cases may exhibit extraovarian spread in ~20% of patients
Malignant potential of SCTAT cannot be reliably assessed on histologic evaluation as high risk features such as mitotic rate, lymphovascular invasion or ovarian surface involvement are not consistently associated with poor outcomes (Crum: Diagnostic Gynecologic and Obstetric Pathology, 3rd Edition, 2017)
Malignant SCTAT may have early or late recurrences decades after initial presentation (Crum: Diagnostic Gynecologic and Obstetric Pathology, 3rd Edition, 2017)
Sites of metastasis include pelvic peritoneum, retroperitoneum and lung (Crum: Diagnostic Gynecologic and Obstetric Pathology, 3rd Edition, 2017)

Case reports

11 year old girl with Peutz-Jeghers syndrome and unilateral ovarian tumor most consistent with Sertoli cell tumor associated SCTAT (Int J Surg Pathol 2016;24:269)
14 year old girl without Peutz-Jeghers syndrome and with stage III A1 malignant SCTAT (J Obstet Gynaecol Res 2016;42:224)
35 and 36 year old women with minimal deviation adenocarcinoma of the cervix, tumorlets of sex cord tumor with annular tubules of the ovaries and Peutz-Jeghers syndrome (J Gynecol Oncol 2013;24:92)
60 year old woman with primary diagnosis of granulosa cell tumor with SCTAT (J Obstet Gynaecol Can 2021;43:361)

Treatment

Surgical management (salpingo-oophorectomy) is a feasible treatment option for nonsyndromic cases
Complete resection in recurrent cases is advised
Prognosis is overall favorable
Reference: BMC Cancer 2015;15:270

Gross description

Nonsyndromic tumors
- Unilateral masses ranging in size from several millimeters to 3 cm
- Solid, tan to yellow
- Cysts may be seen and occasionally may predominate (Pathology 2018;50:5)
Syndromic tumors
- Bilateral and multifocal lesions
- Often microscopic; may not be grossly visible
- Gritty texture may be noted if there is a mass

Gross images

AFIP images

Predominantly solid tumor

Microscopic (histologic) description

Syndromic and nonsyndromic tumors have similar morphology
- Variably size round nests of sharply delineated simple and complex tubules containing basement membrane-like material, which may also be present around the tubules
- Sertoliform tubules are classified as annular by their arrangement as small concentric secondary ring shaped acini peripherally arranged around the circumference of a larger tubule
- Tall cells with ample amount of pale cytoplasm and basally located round nuclei
- Often with antipodal nuclear distribution within the tubules
Tumors associated with Peutz-Jeghers syndrome
- Calcifications within the tubules may be seen (Pathology 2018;50:5)
- May be associated with endocervical gastric type adenocarcinoma (adenoma malignum)
Nonsyndromic / sporadic tumors
- May focally transition to granulosa or Sertoli cell morphology
- Cytologic atypia and mitotic activity may rarely be seen
- May be hyalinized
Reference: Crum: Diagnostic Gynecologic and Obstetric Pathology, 3rd Edition, 2017

Microscopic (histologic) images

Contributed by Krisztina Lengyel, M.D. and AFIP

Sharply delineated bland nests

Variably sized nests

Variably sized discrete nests

Numerous and variable nests

Multiple cysts and nests in young patient

Multiple nests of cells

Positive stains

Negative stains

Molecular / cytogenetics description

If syndromic, associated with a germline STK11 gene mutations on chromosome 19p13.3 (BMC Med Genet 2016;17:77)

Sample pathology report

Right ovary, oophorectomy:
- Sex cord tumor with annular tubules (SCTAT), single 9 mm focus (see comment)
- Comment: This neoplasm is an incidental finding. There is no mitotic activity, cytologic atypia, lymphovascular invasion or ovarian surface involvement noted.

Ovaries and fallopian tubes, bilateral salpingo-oophorectomy:
- Ovaries: bilateral multifocal sex cord tumor with annular tubules (SCTAT), ranging in size from 1.2 mm to 28 mm (see comment)
- Fallopian tubes: benign fimbriated, histologically unremarkable
- Comment: Given the presence of bilateral ovarian involvement and multifocal disease, a possibility of Peutz-Jeghers syndrome associated SCTAT should be considered and excluded. Germline testing for STK11 mutation is recommended.

Differential diagnosis

Gonadoblastoma:
- Multiple variably sized round nests are distributed in a fibrous to cellular gonadal stroma
- Nests contain 3 components
  - Germ cells
  - Small sex cord cells
  - Globular basement membrane deposits
- Sex cord cells may palisade at the periphery of nests and may resemble the appearance of SCTAT
Adult granulosa cell tumor:
- Tumor cells of round to oval nuclei with irregular nuclear membrane and nuclear grooves (coffee bean nuclei) and scant cytoplasm
- May form small spaces containing eosinophilic material (Call-Exner bodies) in a microfollicular pattern
- Associated with FOXL2 point mutation (N Engl J Med 2009;360:2719)
Sertoli cell tumor:
- Cuboidal or columnar cells with pale, at times lipid rich to eosinophilic cytoplasm
- Bland oval to round nuclei, with small nucleoli
- Lipid rich and oxyphilic tumors may be associated with Peutz-Jeghers syndrome
- Areas strongly resembling SCTAT may be seen, especially in patients with Peutz-Jeghers syndrome
- Subset may harbor DICER1 mutations (Mod Pathol 2015;28:1603)

Additional references

WHO Classification of Tumours Editorial Board: Female Genital Tumours, 5th Edition, 2020, Arch Pathol Lab Med 2018;142:1459

Board review style question #1

A 47 year old woman with mucocutaneous oral pigmentations and a history of prior gastrointestinal (GI) polyp resections (multiple hamartomatous polyps) presents for a total abdominal hysterectomy with bilateral salpingo-oophorectomy for menorrhagia. Patient's hysterectomy specimen has no significant histopathologic abnormalities, however, lesion is found in bilateral ovaries. The ovaries were grossly unremarkable. The patient harbors a germline mutation in which of the following genes?

DICER1
MMR deficiency
PTEN
STK11

Board review style answer #1

D. STK11. The patient has characteristic findings and history of Peutz-Jeghers syndrome. This includes mucocutaneous pigmentation, previous hamartomatous gastrointestinal (GI) polyps. The incidental ovarian findings resemble sex cord tumor with annular tubules (SCTAT). This entity is frequently associated with Peutz-Jeghers syndrome and is often an incidental finding. They are grossly unremarkable and usually involve bilateral ovaries.

Answer A is not correct as DICER1 is associated with Sertoli-Leydig cell tumor, sarcoma and gynandroblastoma, as well as other nongynecologic tumors. Answer B is incorrect because MMR loss is associated with Lynch syndrome. Lynch syndrome predisposes to endometrioid endometrial adenocarcinoma, gastric and intestinal cancers to name a few. Answer C is incorrect because PTEN gene mutations are part of Cowden syndrome, which is associated with high prevalance of thyroid, breast and endometrial neoplasias.

Comment Here

Reference: Sex cord tumor with annular tubules

Signet ring stromal tumor

Table of Contents

Definition / general

Rare, benign ovarian stromal tumor with signet ring cells

Essential features

Primary ovarian stromal neoplasm comprised of various proportions of signet ring and spindle cells
Cytoplasmic vacuoles in signet ring cells are negative for lipid, mucin and glycogen
Usually positive, at least focally, for 1 or more sex cord markers (SF1, inhibin, calretinin) but typically negative for epithelial membrane antigen (EMA)

Terminology

Signet ring stromal cell tumor (SRSCT)
Signet ring stromal tumor (SRST)

ICD coding

ICD-O: 8590/1, C56 - sex cord gonadal stromal tumor, NOS
ICD-10: D27.9 - benign neoplasm of unspecified ovary

Epidemiology

~20 cases reported to date
No age predilection (range: 28 - 70 years; mean: 49 years) (Am J Surg Pathol 2022;46:1599)

Sites

Ovary

Pathophysiology

Unknown; hypothesized to arise from ovarian stromal cells or multifocal conversion of a fibroma (Adv Anat Pathol 2014;21:443)

Etiology

Unknown

Clinical features

Nonspecific including abdominopelvic pain, abnormal uterine bleeding or incidental finding on imaging

Diagnosis

Oophorectomy

Laboratory

CA-125 typically within normal limits
- Mildly elevated (76.1 U/mL; normal < 46 U/mL) in one report (Int J Gynecol Pathol 2020;39:193)

Radiology description

No defining features to distinguish from other ovarian neoplasms on imaging
Solid or cystic, may appear complex

Prognostic factors

No reports of metastasis or recurrence but overall limited follow up data

Case reports

44 year old woman with polymenorrhea and 4 cm right adnexal mass (J Turk Ger Gynecol Assoc 2011;12:59)
69 year old obese woman with bilateral adnexal masses on imaging (Obstet Gynecol 2010;116:556)
70 year old woman with abdominal distention, rectal bleeding and bilateral ovarian masses (Int J Gynecol Pathol 2020;39:193)
76 year old woman with incidental complex adnexal mass (Med Mol Morphol 2008;41:165)

Treatment

Surgical excision (oophorectomy)

Gross description

Most are unilateral
Typically well circumscribed and unencapsulated
Yellow to tan and soft to firm cut surface
- May show white fibromatous areas
- Variable hemorrhage, necrosis and cystic spaces
Range: 3.0 - 20 cm (mean: 12.8 cm) (Am J Surg Pathol 2022;46:1599)

Microscopic (histologic) description

2 cell populations in variable proportions
- Diffuse growth of round cells with single to occasionally multiple intracytoplasmic, optically clear vacuoles, which peripherally displace and indent nuclei into a crescent shape (signet ring cells)
- Fusiform cells with eosinophilic cytoplasm and ovoid nucleus
May have fibroma-like areas that merge with signet ring component
Absent to minimal cellular atypia, mitotic activity and necrosis
- Rarely show brisk mitoses (13/10 and 16/10 high power fields) (Ultrastruct Pathol 1995;19:401, Int J Gynecol Pathol 2004;23:45)
PAS+ intracytoplasmic hyaline globules noted in ~50% (Ultrastruct Pathol 1995;19:401, Virchows Arch A Pathol Anat Histopathol 1993;422:333, Int J Gynecol Pathol 2004;23:45, Int J Surg Pathol 2008;16:180, Pathol Oncol Res 2008;14:333, Med Mol Morphol 2008;41:165, J Turk Ger Gynecol Assoc 2011;12:59, Int J Gynecol Pathol 2020;39:193)

Microscopic (histologic) images

Contributed by Glenn McCluggage, M.D.

Spindled and signet ring cells

Signet ring cells

Positive stains

Usually positive, at least focally for 1 or more sex cord markers (SF1, calretinin, inhibin, WT1) (Am J Surg Pathol 2022;46:1599)
Variable expression for CD10 (usually focal), AE1 / AE3 and CAM5.2

Negative stains

Hallmark is negativity of intracytoplasmic vacuoles for
- Mucins (mucicarmine, PASD, Alcian blue)
- Glycogen (PAS, Alcian blue)
- Lipid (Sudan III, Oil Red O)
Usually negative for cyclin D1, with cytoplasmic beta catenin expression (not nuclear)
EMA, CK7, CK20
Reference: Am J Surg Pathol 2022;46:1599

Electron microscopy description

Cytoplasmic vacuoles result from (Ultrastruct Pathol 1995;19:401)
- Generalized edema of cytoplasmic matrix
- Dilatation of mitochondria
- Invagination of cell membranes (pseudoinclusions) by extracellular matrix
No basement membrane formation and abundant free ribosomes (Cancer 1976;38:166, Gynecol Oncol 2000;77:323)
Hyaline globules show features of lysosomes or degenerating erythrocytes (Med Mol Morphol 2008;41:165, Ultrastruct Pathol 1995;19:401)

Molecular / cytogenetics description

Negative for FOXL2 and CTNNB1 mutations (Int J Gynecol Pathol 2020;39:193, Am J Surg Pathol 2022;46:1599)

Sample pathology report

Right ovary, oophorectomy:
- Signet ring stromal tumor (5.0 cm)

Differential diagnosis

Krukenberg tumor (Am J Surg Pathol 2006;30:277):
- Bilateral in > 50%, often with extraovarian disease at presentation
- Nodular growth
- Admixed with glands, nests or cords of malignant cells (may be very focal)
- Cytokeratin strongly and diffusely positive
- Vacuoles are positive for PASD and mucicarmine
- Similar to SRST, it might have prominent fibromatous component
Microcystic stromal tumor (Am J Surg Pathol 2009;33:367, Am J Surg Pathol 2015;39:1420, Am J Surg Pathol 2018;42:137, Am J Surg Pathol 2022;46:1599):
- Often separated into lobules by hyalinized bands
- Admixture of microcysts, solid cellular areas and fibrous stroma
- Up to 60% have bizarre nuclei
- Diffuse cyclin D1 and CD10
- Aberrant (nuclear) beta catenin
- Negative for calretinin and inhibin
- Characterized by CTNNB1 or APC mutations
Signet ring cell change (Adv Anat Pathol 2014;21:443):
- Recent study suggests that some signet ring stromal tumors are fibromas with signet ring cell change (Am J Surg Pathol 2022;46:1599)
- Described in adult granulosa cell tumor (n=1), Brenner tumor (n=1) and serous cystadenofibroma (n=2)

Board review style question #1

Which of the following is true regarding the ovarian lesion pictured above?

It has a poor prognosis
It is negative for epithelial membrane antigen (EMA)
It is positive for mucicarmine
It is typically bilateral
Treatment involves local excision with adjuvant chemotherapy

Board review style answer #1

B. It is negative for EMA. This is a signet ring stromal tumor. Answers A and E are incorrect as this is a benign entity for which excision is curative. Answer D is incorrect because the tumor is usually unilateral but may rarely be bilateral. Answer C is incorrect as it is negative for mucicarmine. Given the signet ring cell morphology and cytokeratin expression, there may be concern for a metastatic mucinous carcinoma with signet ring cells (i.e., Krukenberg tumor). However, EMA helps to distinguish between the 2 entities as it is negative in signet ring stromal tumor but positive in Krukenberg tumor.

Comment Here

Reference: Signet ring stromal tumor

Board review style question #2

A 32 year old woman without significant medical history presents with abdominal pain. Workup reveals a 2 cm right adnexal mass on ultrasound and she undergoes salpingo-oophorectomy. Histologic examination of the ovarian tumor reveals sheets of cells with crescent shaped nuclei and intracytoplasmic vacuoles. The vacuoles are negative for mucicarmine and periodic acid Schiff (PAS). The cells are positive for inhibin and steroidogenic factor 1 (SF1) but negative for cyclin D1 and epithelial membrane antigen (EMA). Beta catenin shows cytoplasmic expression. What is the likely diagnosis?

Adult granulosa cell tumor
Brenner tumor
Krukenberg tumor
Microcystic stromal tumor
Signet ring stromal tumor

Board review style answer #2

E. Signet ring stromal tumor. All of the answers above are reasonable considerations for which clinicopathologic and immunohistochemical features should aid towards the diagnosis; however, in contrast to the other options, signet ring stromal tumors should present as a unilateral mass with expression of sex cord markers and negativity for cyclin D1 and beta catenin (membranous positivity only). Answer A is incorrect because adult granulosa cell tumor usually occurs in postmenopausal females who present with estrogenic manifestations. Histologically, multiple growth patterns are common and cells are usually small with coffee bean nuclei, longitudinal nuclear grooves and scant cytoplasm. Answer C is incorrect because Krukenberg tumor also presents in older females, usually as bilateral ovarian masses, with positivity for cytokeratin and negativity for sex cord markers. Answer D is incorrect because microcystic stromal tumor can show signet ring cells along with variably thick collagenous septations and strong nuclear expression of beta catenin and cyclin D1. Answer B is incorrect because Brenner tumor usually shows a nested architecture of transitional type cells embedded in a fibromatous stroma and should be positive for CK7 and EMA.

Comment Here

Reference: Signet ring stromal tumor

Small cell carcinoma of ovary, hypercalcemic type

Table of Contents

Definition / general

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and highly aggressive ovarian malignancy defined by an inactivating mutation of the SMARCA4 gene, that occurs in young women and is commonly associated with hypercalcemia

Essential features

Small cell neoplasm with undifferentiated morphology (monomorphic, discohesive and mitotically active) with or without follicle-like spaces, rhabdoid morphology or large cell component
Loss of nuclear SMARCA4 / BRG1 immunohistochemical expression (> 93% of cases)

Terminology

SMARCA4 deficient carcinoma of ovary
Malignant rhabdoid tumor of the ovary
This lesion is unrelated to small cell neuroendocrine (pulmonary) carcinoma, which refers to a neuroendocrine neoplasm of the ovary

ICD coding

ICD-O: 8044/3 - small cell carcinoma, intermediate cell
ICD-11: 2C73.0Y & XH8ZR8 - other specified carcinomas of ovary & small cell carcinoma, hypercalcemic type

Epidemiology

Adolescent and young adult women (median: 25 years) (Gynecol Oncol 2016;141:454, Nat Genet 2014;46:427)
Cases associated with germline mutations may occur in younger patients (Gynecol Oncol 2016;141:454, Nat Genet 2014;46:427)
Very rare cases reported in postmenopausal women

Sites

Ovary

Pathophysiology

Inactivating mutation (germline or somatic) of the SMARCA4 gene, a core subunit of the SWI / SNF complex, drives oncogenesis (Gynecol Oncol 2016;141:454)
SWI / SNF complex is an important regulator of the chromatin remodeling process

Etiology

Predisposition factor: rhabdoid tumor predisposition syndrome 2 (RTPS2)
Exact cellular origin remains unknown
- Although SCCOHT was initially believed to be of epithelial origin, studies have suggested a primitive germ cell, neural or mesenchymal progenitor (Hum Pathol 1987;18:175, Histopathology 2017;70:1147, J Pathol 2017;242:371)
- Studies have shown distinct DNA methylation signatures in SCCOHT that are distinct from ovarian epithelial neoplasms (J Pathol 2022;257:140)

Clinical features

Poor clinical outcome (Gynecol Oncol 2016;141:454)
Most patients present at an advanced stage (Gynecol Oncol 2016;141:454)
Nonspecific symptoms may include abdominal pain, distention and signs related to intestinal obstruction
A minority of patients may show symptoms of hypercalcemia (N Engl J Med 2010;362:1031)
Patients may harbor SMARCA4 germline mutation which is associated with the rhabdoid tumor predisposition syndrome 2 (RTPS2) and also predisposes for other undifferentiated malignancies such as atypical teratoid / rhabdoid tumors (ATRT) and other extracranial malignant rhabdoid tumors (OMIM: Rhabdoid Tumor Predisposition Syndrome 2; RTPS2 [Accessed 22 February 2023])

Diagnosis

There are no established tests to screen for SCCOHT
When clinical suspicion arises, abdominal ultrasound and computed tomography scans are useful adjuncts
Definitive diagnosis requires biopsy
All patients diagnosed with SCCOHT should be referred to clinical genetics services and offered testing for germline SMARCA4 pathogenic variants
At risk family member surveillance
- In patient's family members with germline SMARCA4 mutation, surveillance may include clinical examination and ultrasound, as well as whole body and CNS MRI
- Furthermore risk reducing bilateral salpingo-oophorectomy (RRBSO) may be considered; however, the benefits of early detection using imaging and RRBSO remain unproven
- Guidelines are provided by the International SCCOHT Consortium (ISC) (Clin Cancer Res 2020;26:3908)

Laboratory

Hypercalcemia can be detected in a majority of patients, likely from parathyroid hormone related peptide secretion by the tumor cells
Most of these patients will not present with symptoms of hypercalcemia (N Engl J Med 2010;362:1031, Cancer 1994;73:1878, Gynecol Oncol 2016;141:454)

Prognostic factors

Stage is the most important parameter (Gynecol Oncol 2016;141:454)
- FIGO stage I: 55% 5 year overall survival
- FIGO stage II: 40% 5 year overall survival
- FIGO stage III: 29% 5 year overall survival
- FIGO stage IV: 0% 5 year overall survival
Favorable prognostic factors include
- Older patient age at diagnosis (> 40 years) (Gynecol Oncol 2016;141:454)
- Small tumor size (< 10 cm) and absence of large cell component (Am J Surg Pathol 1994;18:1102)

Case reports

18 - 29 year old women with small cell carcinoma of the ovary of hypercalcemic type with responses to anti-PD1 immunotherapy (J Natl Cancer Inst 2018;110:787)
21 year old pregnant woman with small cell carcinoma of the ovary of hypercalcemic type (Medicine (Baltimore) 2020;99:e20387)
24 year old woman with an abdominal mass (Case Rep Oncol 2016;9:305)

Treatment

No established standard treatment
Patients are usually treated by a combination of surgery, chemotherapy and radiation
Treatment guidelines are provided by the International SCCOHT Consortium (ISC) (Clin Cancer Res 2020;26:3908)
Following complete response to initial chemotherapy, high dose chemotherapy with autologous stem cell rescue (HDC-aSCR) may be considered (Gynecol Oncol 2016;141:454)
There is active research looking at epigenetic modulators, kinase inhibitors and immunotherapy as potential treatment alternatives

Gross description

Unilateral (vast majority of cases), solid or cystic mass with lobulated or nodular surface
Mean size of 15 cm (range: 6 - 26 cm)
Fleshy and tan to white to gray cut surface
Hemorrhage and necrosis are common
Familial cases are more often bilateral (Arch Pathol Lab Med 1995;119:523, J Med Genet 1996;33:333)

Gross images

AFIP images

Fleshy cream colored tissue

Microscopic (histologic) description

Small round cells with scant cytoplasm, small nucleoli and brisk mitotic activity
Diffuse growth of tightly packed cells, sometimes in a nested or corded architecture
Follicle-like spaces (80%), usually containing eosinophilic or basophilic fluid
Necrosis seen in most tumors
Focal myxoid stroma is common
Most show a large cell component, often with rhabdoid features, of varying extent (if > 50% of the tumor, it is referred to as a small cell carcinoma of the ovary hypercalcemic, large cell variant)
Intermixed mucinous glands are reported in some cases (Arch Pathol Lab Med 1995;119:523)

Microscopic (histologic) images

Contributed by Basile Tessier-Cloutier, M.D. and AFIP

Follicle-like spaces and myxoid stroma

Solid and corded architecture

Rhabdoid morphology

SMARCA4 / BRG1 loss of expression

Reduced SMARCA4 / BRG1 expression

Diffuse growth of small cells with scanty cytoplasm

Hyperchromatic nuclei

Growing in nests

Large cell variant

Follicle-like structures with eosinophilic material

Several mucinous glands

Signet ring cells in basophilic mucin

Several glands lined by tumor cells, some with mucin

Positive stains

WT1 (86 - 93%) (Int J Gynecol Pathol 2004;23:330, Histopathology 2007;51:305)
CD10 (93%) (Int J Gynecol Pathol 2004;23:330)
Calretinin (73%) (Int J Gynecol Pathol 2004;23:330)
EMA (87%) (Int J Gynecol Pathol 2004;23:330)
AE1 / AE3 (60%) (Int J Gynecol Pathol 2004;23:330)
p53 wild type pattern (Histopathology 2023;83:154)

Negative stains

Loss of nuclear SMARCA4 / BRG1 expression (Pol J Pathol 2013;64:238, Nat Genet 2014;46:427, Nat Genet 2014;46:438, Nat Genet 2014;46:424)
Loss of nuclear SMARCA2 / BRM expression (J Pathol 2016;238:389)
CAM5.2 (20%) (Int J Gynecol Pathol 2004;23:330)
Inhibin (Int J Gynecol Pathol 2004;23:330)
CD99 (Int J Gynecol Pathol 2004;23:330)
TTF1 (Histopathology 2007;51:305)
OCT3/4 (Histopathology 2007;51:305)
Loss of nuclear SMARCB1 / INI1 staining has been reported in rare cases of SMARCA4 proficient tumors (J Pathol 2016;238:389)
FOXL2

Molecular / cytogenetics description

Almost all SCCOHTs harbor inactivating somatic or germline mutations in SMARCA4 (Pol J Pathol 2013;64:238, Nat Genet 2014;46:427, Nat Genet 2014;46:438, Nat Genet 2014;46:424)
SCCOHTs show SMARCA2 loss of expression likely due to transcriptional / posttranscriptional silencing (J Pathol 2016;238:389)
SCCOHTs are chromosomally stable cancers (Orphanet J Rare Dis 2013;8:33, Oncotarget 2016;7:1732, J Pathol 2022;257:140)
SCCOHTs harbor distinct DNA methylation profiles, which distinguish them from other SWI / SNF deficient cancers (Oncotarget 2016;7:1732, Acta Neuropathol 2021;141:291, J Pathol 2022;257:140)

Sample pathology report

Ovary, oophorectomy:
- Small cell carcinoma of the ovary hypercalcemic type (see comment and synoptic report)
- Comment: Immunohistochemical tests for SMARCA4 / BRG1 and SMARCA2 / BRM show loss of expression. Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) can be associated with the rhabdoid tumor predisposition syndrome 2 (RTPS2); referral to medical genetics is recommended.

Differential diagnosis

Undifferentiated and dedifferentiated carcinomas of the ovary:
- Older age (median: 53 years)
- May be associated with a differentiated ovarian carcinoma (dedifferentiated carcinoma)
- Mismatch repair deficiency is common
- Loss of nuclear expression of SMARCA4 / BRG1, SMARCB1 / INI1 or ARID1B
- Associated with other genetic alterations (PTEN, ARID1A, PIK3CA, KRAS, CTNNB1, NRAS, TP53)
Granulosa cell tumor, adult and juvenile:
- Prominent follicle-like spaces (juvenile)
- Small cells usually not present (juvenile)
- Prominent nuclear grooves (adult)
- Usually, no brisk mitotic activity of small cells (adult)
- Intact nuclear expression of SMARCA4 / BRG1 (J Pathol 2016;238:389)
- Positive for FOXL2
Small cell carcinoma, pulmonary type (primary or metastatic):
- Usually lacks follicle-like spaces
- Positive for TTF1
- May show dot-like positivity for CK20
- Intact nuclear expression of SMARCA4 / BRG1 (J Pathol 2016;238:389)
Dysgerminoma:
- Usually lacks follicle-like spaces
- Large, uniform cells with clear or eosinophilic cytoplasm and distinct membranes
- May show granulomatous reaction
- Positive for OCT4, PLAP, KIT and SALL4
- Intact nuclear expression of SMARCA4 / BRG1 (J Pathol 2016;238:389)
Embryonal rhabdomyosarcoma:
- Moderately cellular with both hyper and hypocellular areas
- May show conspicuous strap cells with bright eosinophilic stroma
- May show nodules of cartilage (may be DICER1 associated)
- Positive for desmin, myogenin or MyoD1 (can be focal)
Primitive neuroectodermal tumor (central type or peripheral type):
- Associated with ovarian teratoma (central type)
- Positive for FLI1 and GFAP
- EWSR1 rearrangement (peripheral type)
Melanoma (primary or metastatic):
- May be associated with ovarian teratoma (primary)
- Often bilateral (metastatic)
- May show cytoplasmatic melanin pigment
- Intact nuclear expression of SMARCA4 / BRG1 (J Pathol 2016;238:389)
- Positive for S100, HMB45, MelanA
- Negative for cytokeratin and WT1
Lymphoma:
- Lacks follicle-like spaces
- Negative for cytokeratin and WT1
- Positive for lymphoid markers (subtype specific)

Board review style question #1

A 27 year old woman presented with a 5 cm unilateral ovarian mass. SMARCA4 / BRG1 IHC image is provided above. What is the most likely diagnosis?

Dysgerminoma
Granulosa cell tumor, adult type
Granulosa cell tumor, juvenile type
Metastatic melanoma
Small cell carcinoma of the ovary, hypercalcemic type

Board review style answer #1

E. Small cell carcinoma of the ovary, hypercalcemic type. The H&E image shows a solid and corded undifferentiated tumor with follicle-like spaces and focal myxoid stroma. The immunohistochemical test for SMARCA4 / BRG1 shows aberrant expression (loss of nuclear staining). The morphology and immunophenotype are consistent with the diagnosis of SCCOHT. All 4 other options may have some overlapping morphologic features with SCCOHT but retain SMARCA4 / BRG1 expression.

Comment Here

Reference: Small cell carcinoma of ovary, hypercalcemic type

Board review style question #2

Which of the following immunohistochemical tests shows aberrant expression in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT)?

BAP1
MDM2
MLH1
p53
SMARCA4 / BRG1

Board review style answer #2

E. SMARCA4 / BRG1. SCCOHT is molecularly defined by inactivating SMARCA4 mutations, which are associated with SMARCA4 / BRG1 nuclear loss of expression. The other options are in other entities such as mesothelioma (BAP1 loss of expression), malignant Brenner tumor (MDM2 overexpression), ovarian undifferentiated and dedifferentiated carcinoma (MLH1 loss of expression) and high grade serous carcinoma (aberrant p53 expression).

Comment Here

Reference: Small cell carcinoma of ovary, hypercalcemic type

Solid pseudopapillary tumor

Table of Contents

Definition / general

Ovarian tumor that is morphologically, immunohistochemically and genetically identical to pancreatic solid pseudopapillary neoplasm
Categorized as miscellaneous tumor of ovary in WHO classification (Kurman: WHO Classification of Tumours of the Female Reproductive Organs, 4th Edition, 2014)

Essential features

Rare tumor of reproductive age group; 10 reported cases
Possible origin from genital ridge related cells, presumed epithelial / neuroendocrine nature
Solid nests with pseudopapillary architecture, cysts with colloid-like material, papillae with myxoid stroma and tumor cell nuclei oriented away from the papillae
Abnormal nuclear β catenin immunohistochemical staining and E-cadherin (negative NCH-38 clone)
Limited cases with followup, presumed to be of low malignant potential, like pancreatic solid pseudopapillary neoplasm

Terminology

Primary ovarian solid pseudopapillary neoplasm
Extrapancreatic solid pseudopapillary neoplasm
Miscellaneous ovarian tumors (Kurman: WHO Classification of Tumours of the Female Reproductive Organs, 4th Edition, 2014)

ICD coding

ICD-10: C56.9 - Malignant neoplasm of unspecified ovary

Epidemiology

Rare tumor
Females of reproductive age, range 17 - 57 years
10 reported cases: 6 from U.S., 2 from China, 1 each from India and Japan (Am J Surg Pathol 2010;34:1514, Hum Pathol 2012;43:1339, Ann Diagn Pathol 2012;16:498, Int J Gynecol Pathol 2018;37:110, Int J Clin Exp Pathol 2015;8:8645, Int J Gynecol Pathol 2011;30:539, Indian J Pathol Microbiol 2016;59:348, Pathol Int 2014;64:460)

Sites

Ovary

Clinical features

Abdominal mass, fullness, swelling or pain (6 cases)
Pelvic pain (2 cases)
Incidental radiologic finding (2 cases)
Postmenopausal bleeding (1 case)

Diagnosis

Exclude metastasis of solid pseudopapillary neoplasm from extraovarian site

Radiology description

Ultrasound: solid and cystic complex adnexal mass with high density in cyst (Int J Clin Exp Pathol 2015;8:8645)
Multiloculated heterogeneous ovarian cystic mass (Hum Pathol 2012;43:1339)

Radiology images

Images hosted on other servers:

Solid pseudopapillary neoplasm

Prognostic factors

Unknown due to limited number of cases
Only patient who died of disease was stage IV
- Tumor showed high mitotic rate (62/50 high powered fields), necrosis and lymphovascular invasion (Ann Diagn Pathol 2012;16:498)
6 patients had no evidence of disease at followup, including a stage IIIC case at 18 months followup

Case reports

17, 21 and 57 year old women; first reported cases (Am J Surg Pathol 2010;34:1514)
22 and 47 year old women with metastasis from pancreas to ovary (Mol Clin Oncol 2016;4:845)
47 year old woman with overlap of microcystic stromal tumor and SPN (Int J Clin Exp Pathol 2015;8:11792) 
48 year old woman with clinically aggressive tumor (Hum Pathol 2012;43:1339)
49 year old woman with CTNNB1 point mutation (Int J Gynecol Pathol 2018;37:110)

Treatment

Surgery is mainstay of treatment

Gross description

Circumscribed ovarian / adnexal mass with solid and cystic hemorrhagic cut surface

Microscopic (histologic) description

Well circumscribed tumor
Tumor cell sheets, nests and bands surrounded by fibrous septa
Thin delicate capillary sized vessels forming myxohyaline pseudopapillary cores; nuclei located away from the papillary core
Moderate amount of pale eosinophilic cytoplasm with central / eccentric round to oval nuclei with uniform chromatin
Inconspicuous mitoses, usually no necrosis, no significant nuclear atypia
Abundant foamy cytoplasm, paranuclear vacuoles, nuclear grooves and intra / extracellular PAS+ diastase resistant eosinophilic globules can be present
Microcysts with colloid-like material
Infarction can be present

Microscopic (histologic) images

Contributed by Kamaljeet Singh, M.D.

Circumscribed mass

Nests with fibrous septa

Pseudopapillae

Intracytoplasmic vacuoles

β catenin

c-kit

CAM5.2

CD10

CD99

Synaptophysin

Vimentin

WT1

E-cadherin

Ki67

Positive stains

β catenin: nuclear and cytoplasmic
Keratin: variable for CAM5.2 and AE1 / AE3; can be negative
Vimentin
Synaptophysin: cytoplasmic
Progesterone receptor: nuclear, can be focal or negative
Cyclin D1, MelanA, CD117, CD10, CD99, WT1 (cytoplasmic) and CD56

Negative stains

E-cadherin: no staining with NCH-38 clone
Chromogranin: usually negative
Calretinin, inhibin, S100, desmin, TTF1, GFAP and HMB45

Electron microscopy description

Tumor cells with numerous pleomorphic mitochondria interspersed among short strands of rough endoplasmic reticulum (Ann Diagn Pathol 2012;16:498)

Molecular / cytogenetics description

c.110C > T point mutation in CTNNB1 exon 3 (Pathol Int 2014;64:460) 
c.98C > G point mutation in CTNNB1 exon 3 (Int J Gynecol Pathol 2018;37:110)

Differential diagnosis

Granulosa cell tumor:
- Cuboidal to polygonal cells with Call-Exner bodies arranged in macrofollicular, trabecular, solid and insular patterns
- Inhibin+ and calretinin+
Steroid cell tumor:
- Sheets and nests of large vacuolated cells with clear or eosinophilic cytoplasm; minimal to no nuclear atypia
- Inhibin+ and calretinin+
Metastatic pancreatic solid pseudopapillary neoplasm (Mol Clin Oncol 2016;4:845):
- Similar morphologically
- Clinical correlation and pancreatic / abdominal imaging required
Metastatic neuroendocrine tumor:
- Cells arranged in nests, sheets and ribbons separated by thin walled vessels
- Salt and pepper chromatin and moderate granular cytoplasm
- Keratin+, chromogranin+ and synaptophysin+
Struma ovarii:
- Mature thyroid tissue with variable sized follicles lined by cuboidal cells
- TTF1+ and thyroglobulin+
Paraganglioma / pheochromocytoma:
- Zellballen pattern with supporting vessels and spindle sustentacular cells
- S100+ sustentacular cells, chromogranin+ and synaptophysin+
Melanoma:
- Variable histology, noncohesive epithelioid to spindle cells with abundant cytoplasm; prominent nucleoli
- Melanin pigment may be present
- S100+, HMB45+ and MelanA+
Gastrointestinal stromal tumor:
- Spindle or epithelioid cells in fascicles and sheets; mitotically active lesion, with cystic change and hemorrhage
- CD34+, CD117+ and DOG1+
Ependymoma:
- Monomorphic bland cells with coarse chromatin, perivascular and ependymal rosettes
- GFAP+ and EMA+

Board review style question #1

The most characteristic immunohistochemical staining pattern of solid pseudopapillary neoplasm of the ovary is

c-kit-
Consistent keratin expression
Consistent positive expression of both chromogranin and synaptophysin
Nuclear β catenin+ and E-cadherin-
S100+ and HMB45+

Board review style answer #1

D. Nuclear β catenin+ and E-cadherin-

Comment Here

Reference: Solid pseudopapillary neoplasm

Board review style question #2

The image below is taken from an H&E stained section of a 3.0 cm circumscribed hemorrhagic left ovarian lesion of a 48 year old woman. Plasma inhibin levels were normal. Tumor cells expressed CAM5.2, vimentin and synaptophysin and were negative for S100, inhibin, FOXL2, E-cadherin and chromogranin. Genetic analysis showed c.98C > G point mutation in CTNNB1 exon 3. The diagnosis is

Ependymoma
Granulosa cell tumor
Microcystic stromal tumor
Solid pseudopapillary neoplasm
Strumal carcinoid

Board review style answer #2

D. Solid pseudopapillary neoplasm

Comment Here

Reference: Solid pseudopapillary neoplasm

Somatic neoplasms arising from teratomas (pending)

[Pending]

Staging

Table of Contents

Definition / general

All primary tumors (malignant or potentially malignant [borderline] of the ovary and fallopian tube) and primary peritoneal carcinoma are covered by this staging system
The following topics are not covered: metastatic tumors to the ovary and fallopian tube, hematopoietic malignancies, peritoneal primaries other than primary peritoneal carcinoma (i.e., mesothelioma, gastrointestinal stromal tumor)

Essential features

AJCC 7th edition staging was sunset on December 31, 2017; as of January 1, 2018, use of the 8th edition is mandatory

ICD coding

ICD-10:
- D39.10 - neoplasm of uncertain behavior of unspecified ovary
- D39.11 - neoplasm of uncertain behavior of right ovary
- D39.12 - neoplasm of uncertain behavior of left ovary
- C56.1 - malignant neoplasm of right ovary
- C56.2 - malignant neoplasm of left ovary
- C56.9 - malignant neoplasm of unspecified ovary
- C57.00 - malignant neoplasm of unspecified fallopian tube
- C57.01 - malignant neoplasm of right fallopian tube
- C57.02 - malignant neoplasm of left fallopian tube
- C48.1 - malignant neoplasm of specified parts of peritoneum
- C48.2 - malignant neoplasm of peritoneum, unspecified
- C48.8 - malignant neoplasm of overlapping sites of retroperitoneum and peritoneum

Primary tumor (pT) and FIGO stages in ( )

pTX: primary tumor cannot be assessed
pT0: no evidence of primary tumor
pT1a (IA): tumor limited to 1 ovary (capsule intact) or fallopian tube; no tumor on ovarian or fallopian tube surface; no malignant cells in ascites or peritoneal washings
pT1b (IB): tumor limited to both ovaries (capsules intact) or fallopian tubes; no tumor on ovarian or fallopian tube surface; no malignant cells in ascites or peritoneal washings
pT1c (IC): tumor limited to 1 or both ovaries or fallopian tubes, with any of following:
- pT1c1 (IC1): surgical spill
- pT1c2 (IC2): capsule ruptured before surgery or tumor on ovarian or fallopian tube surface
- pT1c3 (IC3): malignant cells in ascites or peritoneal washings
pT2a (IIA): extension or implants on the uterus or fallopian tube(s) or ovaries
pT2b (IIB): extension to or implants on other pelvic tissues
pT3a (IIIA2): microscopic extrapelvic (above the pelvic brim) peritoneal involvement with or without positive retroperitoneal lymph nodes
pT3b (IIIB): macroscopic peritoneal metastasis beyond pelvis ≤ 2 cm with or without retroperitoneal lymph node metastasis
pT3c (IIIC): macroscopic peritoneal metastasis beyond pelvis > 2 cm with or without retroperitoneal lymph node metastasis (includes extension of tumor to capsule of liver and spleen without parenchymal involvement of either organ)

Regional lymph nodes (pN) and FIGO stages in ( )

pNX: regional lymph nodes cannot be assessed
pN0: no regional lymph node metastasis
pN0(i+): isolated tumor cells in regional lymph node(s) ≤ 0.2 mm
pN1a (IIIA1i): lymph node metastatic deposit > 0.2 mm to ≤ 10 mm
pN1b (IIIA1ii): lymph node metastatic deposit > 10 mm

Note:

Regional lymph nodes include the following: external iliac, internal iliac (hypogastric), obturator, common iliac, para-aortic, pelvic NOS and retroperitoneal NOS lymph nodes

Distant metastasis (pM) and FIGO stages in ( )

pM0: no distant metastasis
pM1a (IVA): pleural effusion with positive cytology
pM1b (IVB): liver or splenic parenchymal metastases; metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside the abdominal cavity); transmural involvement of intestine

Prefixes

cTNM: clinical classification
pTNM: pathological classification
ypTNM: post therapy pathological classification
rTNM: recurrence or retreatment classification
aTNM: autopsy classification

AJCC prognostic stage groups


Stage I:	pT1	N0	M0
Stage IA:	pT1a	N0	M0
Stage IB:	pT1b	N0	M0
Stage IC:	pT1c	N0	M0
Stage II:	pT2	N0	M0
Stage IIA:	pT2a	N0	M0
Stage IIB:	pT2b	N0	M0
Stage IIIA1:	pT1/2	N1	M0
Stage IIIA2:	pT3a	any N	M0
Stage IIIB:	pT3b	any N	M0
Stage IIIC:	pT3c	any N	M0
Stage IV:	any T	any N	M1
Stage IVA:	any T	any N	M1a
Stage IVB:	any T	any N	M1b

Registry data collection variables

FIGO stage
Preoperative CA125 level
Gross residual tumor after primary cytoreductive surgery
Residual tumor volume after primary cytoreductive surgery
Residual tumor location following primary cytoreductive surgery

Histologic grade (G)

GX: grade cannot be assessed
GB: borderline tumor
G1: well differentiated
G2: moderately differentiated
G3: poorly differentiated

Histopathologic type

Epithelial tumors (borderline or malignant)
- Serous tumors
  - Serous borderline tumor
  - Low grade serous carcinoma
  - High grade serous carcinoma
- Mucinous tumors
  - Mucinous borderline tumor
  - Mucinous carcinoma
- Endometrioid tumors
  - Endometrioid borderline tumor
  - Endometrioid carcinoma
- Clear cell tumors
  - Clear cell borderline tumor
  - Clear cell carcinoma
- Seromucinous tumors
  - Seromucinous borderline tumor
  - (Seromucinous carcinoma - now considered a subtype of endometrioid carcinoma, according to WHO 5th edition)
- Brenner tumors
  - Borderline Brenner tumor
  - Malignant Brenner tumor
- Other carcinomas
  - Mesonephric-like adenocarcinoma
  - Undifferentiated and dedifferentiated carcinoma
  - Carcinosarcoma
  - Mixed carcinoma
Sex cord - stromal tumors (malignant or potentially malignant)
- Adult granulosa cell tumor
- Juvenile granulosa cell tumor
- Sertoli-Leydig cell tumor
- Gynandroblastoma
- Steroid cell tumor, NOS
- Fibrosarcoma
Germ cell tumors (malignant)
- Dysgerminoma
- Yolk sac tumor
- Immature teratoma
- Choriocarcinoma (nongestational)
- Embryonal carcinoma
- Mixed germ cell tumor
- Somatic neoplasms arising from teratomas
Miscellaneous tumors
- Small cell carcinoma, hypercalcemic type
- Adenocarcinoma of rete ovarii

Gross images

Contributed by Natalia Buza, M.D.

Ovarian surface involvement (pT1c2)

Rectosigmoid colon (pT2b)

Splenic hilum and parenchyma (pM1b)

Microscopic (histologic) images

Contributed by Natalia Buza, M.D.

Ovarian surface involvement (pT1c2)

Uterine serosal (pT2a)

Appendiceal serosal (pT3b)

Splenic capsule (pT3c)

Splenic parenchyma (pM1b)

Additional references

Int J Gynaecol Obstet 2014;124:1

Board review style question #1

Which of the following is the pTNM stage (per the AJCC 8th edition) of a malignant ovarian tumor involving the right ovarian parenchyma and surface, omentum and splenic capsule (for which the largest tumor focus in the omentum and splenic capsule exceeds 2 cm) and no lymph node or parenchymal spleen metastases?

pT1c N0 M0, stage IC
pT1c N0 M1b, stage IVB
pT3b N0 M0, stage IIIB
pT3c N0 M1b, stage IVB
pT3c N0 M0, stage IIIC

Board review style answer #1

E. pT3c N0 M0, stage IIIC. Macroscopic peritoneal metastasis beyond the pelvis (including capsule of liver and spleen without parenchymal involvement) measuring more than 2 cm in greatest dimension is pT3c. Parenchymal metastasis to the liver or spleen is pM1b, which would yield stage IVB.

Comment Here

Reference: Staging - ovary

Steroid cell tumor

Table of Contents

Definition / general

Ovarian stromal tumor composed of steroid cells with malignant potential

Essential features

Mostly unilateral
Half of cases have androgenic manifestations
Microscopic features include diffuse sheets of polygonal to rounded tumor cells with moderate to abundant cytoplasm (Am J Surg Pathol 1987;11:835)

Terminology

Steroid cell tumor, not otherwise specified (NOS)

ICD coding

ICD-O
- 8670/0 - steroid cell tumor, NOS
- 8670/3 - steroid cell tumor, malignant
ICD-11: 2C73.Y & XH4L39 - other specified malignant neoplasms of the ovary & steroid cell tumor, malignant

Epidemiology

Rare (< 1% of ovarian tumors)
Average age in general: 43 year old
Average age in von Hippel-Lindau: 27 years old (Int J Clin Exp Pathol 2022;15:332)
In an analysis of 63 cases, patients with clinically malignant tumors were 16 years older than patients with benign tumor (Am J Surg Pathol 1987;11:835)

Sites

Ovary
Extraovarian origin (very rare) (Int J Gynecol Pathol 2019;38:151)

Pathophysiology

Tumors are presumed to be of ovarian stromal cell origin

Etiology

Dysregulation in the hypoxia signaling pathway (Endocr Relat Cancer 2023;30:e230179)
VHL aberration in von Hippel-Lindau (Int J Clin Exp Pathol 2022;15:332)
Genomic instability, MDM1 / CDK4 coamplification, ATRX rearrangement, MDM2 / CDK4 copy number gain, BAP1 mutation in malignant tumors
In nonmalignant tumors: mutation in FH, CTTNB1, CASP10 and P53 (Am J Surg Pathol 2023;47:1398)

Clinical features

Androgenic (~50%), estrogenic changes including rare examples of isosexual pseudoprecocity (~10%), occasional progestogenic changes, Cushing syndrome or elevated cortisol levels (uncommon)
Rarely with hypercalcemia, erythrocytosis, ascites or acute heart failure
Reported in von Hippel-Lindau (both types I and II), with the most common presentation including abnormal uterine bleeding, amenorrhea and infertility (Int J Clin Exp Pathol 2022;15:332)

Diagnosis

Histologic examination

Laboratory

In patients with androgenic changes, Cushing syndrome or both: elevated urinary levels of 17-ketosteroids and 17-hydroxycorticosteroids, serum testosterone and androstenedione
In Cushing syndrome: elevated free cortisol in the blood or urine

Radiology description

Ultrasound: hypoechoic / isoechoic, homogenous or heterogeneous texture, characterized by abundant blood flow signals (Oncol Lett 2022;24:370)
Computed tomography (CT): low density area, consistent with lipid content within the mass (AJR Am J Roentgenol 2007;188:W393, Magn Reson Med Sci 2019;18:251)
Magnetic resonance imaging (MRI): intermediate signal intensity on T2 weighted images and avid contrast enhancement (indicating hypervascularity of the tumor); signal loss on out of phase MR imaging, consistent with lipid content within the mass (AJR Am J Roentgenol 2007;188:W393, Magn Reson Med Sci 2019;18:251)
Overall CT and MRI findings are variable, owing to the amount of lipid component and fibrous stroma (AJR Am J Roentgenol 2007;188:W393, Magn Reson Med Sci 2019;18:251)

Radiology images

Images hosted on other servers:

Enhancing adnexal mass

Fat containing pelvic mass

Homogeneous isoechoic mass

Solid adnexal mass

Prognostic factors

Clinically malignant in 25 - 43% of cases (Am J Surg Pathol 1987;11:835)
Patients with clinically malignant tumor were on average 16 years older than patients with benign tumors in one series (Am J Surg Pathol 1987;11:835)
No malignant steroid cell tumors have been reported in patients in their first 2 decades
Rare tumors have recurred up to 19 years postoperatively (Am J Surg Pathol 1987;11:835)
Extraovarian spread of tumor is present at the time of operation in a small minority of cases; 3 cases with Cushing disease with extensive intra-abdominal spread of tumor (Int J Gynecol Pathol 1987;6:40)
Features associated with malignancy (Am J Surg Pathol 1987;11:835)
- 2+ mitoses per 10 high power fields (92% malignant)
- Necrosis (86% malignant)
- 7 cm or larger (78% malignant)
- Intratumoral hemorrhage (77% malignant)
- Grade 2 or 3 nuclear atypia (64% malignant)
Aggressive behavior with 4 or more malignant features (Am J Surg Pathol 2023;47:1398)

Case reports

16 year old girl with history of von Hippel-Lindau (VHL) syndrome and a 3 cm well defined nodule in right ovary (Int J Gynecol Pathol 2020;39:473)
21 and 23 year old women with malignant and benign steroid cell tumors, NOS (J Ovarian Res 2013;6:53)
28 year old woman with acute heart failure, virilization and 7 cm right adnexal mass (J Obstet Gynaecol Res 2020;46:1211)
35 year old woman with virilization and a pelvic mass (Arch Pathol Lab Med 2006;130:113)
56 and 74 year old women with mixed steroid cell tumor and fibroma in extraovarian and ovarian tissue, respectively (Int J Gynecol Pathol 2019;38:151)
64 year old woman with collision signet ring stromal tumor and steroid cell tumor of the ovary (Int J Gynecol Pathol 2017;36:261)

Treatment

Unilateral salpingo-oophorectomy if fertility sparing is desired; otherwise, total hysterectomy and bilateral salpingo-oophorectomy
Adjuvant chemotherapy has been used for cases with malignant type; however, there is no consensus (Case Rep Oncol 2020;13:358, Case Rep Obstet Gynecol 2016;2016:6184573)
Tumor excision, chemotherapy and gonadotropin releasing hormone (GnRH) analog therapy are reported for disease recurrence or progression (BMC Endocr Disord 2022;22:265, Gynecol Oncol Rep 2023;46:101169)

Clinical images

Images hosted on other servers:

Hirsutism

Male pattern baldness

Gross description

Wide size range (mean size: 8.4 cm) (Am J Surg Pathol 1987;11:835)
Unilateral (95%)
Solid, well circumscribed, occasionally lobulated
Sections from yellow-orange (lipid rich) to red-brown (lipid poor) to dark brown-black (abundant lipochrome pigment)
Occasionally with necrosis, hemorrhage and cystic degeneration

Gross images

Images hosted on other servers:

Yellow cut surface

Metastatic steroid cell tumor

Lobulated cut surface

Nodular solid tumor

Tan-brown, well circumscribed tumor with hemorrhage

Frozen section description

Diffuse or nested arrangement of tumor cells
Cells with abundant eosinophilic or clear, foamy cytoplasm

Frozen section images

Contributed by Fatemeh Ghazanfari Amlashi, M.D. and Tamara Kalir, M.D., Ph.D.

Monotonous sheets of cells

Abundant cytoplasm

Microscopic (histologic) description

Architectural pattern: diffuse (most common) but occasionally in nests, cords, pseudoglandular and follicle-like arrangements (Am J Surg Pathol 1987;11:835)
Stroma: usually sparse (85%) but may be fibrotic or hyalinized, rarely edematous or myxoid, exceptionally with calcification and psammoma body formation
Polygonal to rounded tumor cells with distinct cell borders, central nuclei and moderate to abundant cytoplasm
Tumor cell cytoplasm: eosinophilic and granular (lipid poor) to vacuolated and spongy (lipid rich); tumors with a mixture of 2 cell types are also present
More lipid rich cytoplasm in this tumor compared to other subtypes of steroid cell tumor
Lipochrome pigment present (40%)
Rarely, signet ring appearance
Adipocytic metaplasia and hyaline globule (unusual) (Am J Surg Pathol 2023;47:1398)
Usually absent / slight nuclear atypia along with low mitotic activity (< 2 mitotic figures/10 high power fields); those with grades 1 - 3 nuclear atypia associated with increased mitotic activity (up to 15 mitotic figures/10 high power fields)
Necrosis and hemorrhage are occasionally present, particularly in tumors with significant cytologic atypia
Metastatic tumor is similar to the primary tumor in some cases but more poorly differentiated in others
Stromal hyperthecosis may be seen in the adjacent ovarian stroma and contralateral ovary, particularly in small tumors

Microscopic (histologic) images

Contributed by Fatemeh Ghazanfari Amlashi, M.D., Tamara Kalir, M.D., Ph.D. and AFIP

Well defined tumor

Sparse stroma

Diffuse sheets

Moderate to abundant cytoplasm

Round to polygonal cells

Distinct cell borders

Spongy and eosinophilic cytoplasm

2 atypical mitotic figures

Inhibin

Calretinin

MelanA

Abundant lipid (oil red O stain)

Virtual slides

Images hosted on other servers:

Lipid rich tumor cells

Cytology description

Large polygonal to round cells
Arranged in sheets and attached with vascular stromal tissue fragments (J Cytol 2015;32:284)
Cells with small central round nuclei with conspicuous nucleoli and abundant granular to pale foamy cytoplasm
Ascites in malignant steroid cell tumor: isolated tumor cells or clusters with slight overlapping and cannibalism formation (Acta Cytol 2017;61:165)

Cytology images

Images hosted on other servers:

Large polygonal cells

Positive stains

Inhibin
Calretinin
SF1
MelanA (A103 clone) (Int J Gynecol Pathol 2003;22:162)
Androgen receptor (64%) (Int J Gynecol Pathol 2010;29:315)
Vimentin (75%) (Int J Gynecol Pathol 1995;14:331)
CD99 (Int J Gynecol Pathol 2010;29:315)

Negative stains

Molecular / cytogenetics description

Pathogenic variants in several hypoxia related genes, including HIF1A, VHL, SDHB, SRC, IDH2 and FOXO4 (Endocr Relat Cancer 2023;30:e230179)
Mutation in FH, CTTNB1, CASP10 and P53 (Am J Surg Pathol 2023;47:1398)
Malignant steroid cell tumor with genomic instability, MDM1 / CDK4 coamplification, ATRX rearrangement, MDM2 / CDK4 copy number gain, BAP1 mutation (Am J Surg Pathol 2023;47:1398)

Videos

Steroid cell tumor

Sample pathology report

Right ovary and fallopian tube, salpingo-oophorectomy:
- Ovarian steroid cell tumor, not otherwise specified (6 cm size) (see comment)
- Fallopian tube with no significant pathologic change
- Comment: Sections show a well circumscribed neoplasm composed of abundant clear cytoplasm. There is mild nuclear atypia. No mitosis or necrosis identified. Immunostains show the tumor cells are positive for inhibin, calretinin and negative for CD10, supporting the diagnosis.

Left ovary and fallopian tube, salpingo-oophorectomy:
- Ovarian steroid cell tumor, not otherwise specified (12 cm size) (see comment)
- Fallopian tube with no significant pathologic change
- Comment: Sections show a well circumscribed neoplasm composed of sheets of round cells with abundant eosinophilic granular cytoplasm. Intratumoral hemorrhage and focal necrosis is present. Moderate nuclear atypia and mitoses (4/10 high power fields) are seen. The ovarian capsule is intact and uninvolved by the tumor cells. Immunostains show the tumor cells are positive for calretinin and inhibin, supporting the diagnosis.

Differential diagnosis

Ovarian clear cell carcinoma:
- Periodic acid-Schiff (PAS) positive, diastase sensitive, glycogen rich cytoplasm and eccentric nuclei
- Variety of architectural patterns (Int J Gynecol Pathol 2019;38:S40)
- Almost always accompanied by a variable component of clear and hobnail cells
Metastatic renal cell carcinoma:
- Glycogen rich cytoplasm and eccentric nuclei
- Prominent sinusoidal vascular framework (Int J Gynecol Pathol 2018;37:525)
- Areas with tubular differentiation
- History of a prior or concurrent renal mass
- No endocrine manifestation
- CD10 positive
Pregnancy luteoma:
- Third trimester of pregnancy
- Bilateral (33%) (Am J Surg Pathol 2014;38:239)
- Multiple (50%)
- Abundant eosinophilic cytoplasm containing little or no lipid
- Mitotic figures may be numerous, up to 2 - 3/10 high power fields
Leydig cell tumor:
- Reinke crystalloids (Am J Surg Pathol 2023;47:1398)
- Acellular eosinophilic zone
- Nuclear clustering
- Fibrinoid material within vessel walls
- Located in ovarian hilum
Sertoli cell tumor (lipid rich):
- At least focal tubular differentiation in adequately sampled tumors
- Absence of lipochrome pigments
Metastatic melanoma:
- Bilateral (40%)
- No endocrinologic manifestation
- More malignant nuclear features than steroid cell tumors
- MelanA, S100 positive (Am J Surg Pathol 2004;28:771)
- Inhibin, calretinin, SF1 negative
Oxyphilic struma ovarii:
- Association with other teratomatous elements (Endocr Pathol 2015;26:342)
- Presence of colloid
- Thyroglobulin positive
Hepatoid yolk sac tumor:
- Elevated serum alpha fetoprotein (Am J Surg Pathol 2022;46:309)
- Glandular lumens may be seen
- AFP positive (Cancer 1982;50:2355)

Additional references

Kurman: Blaustein's Pathology of the Female Genital Tract, 7th Edition, 2019

Board review style question #1

Which of the following statements is correct regarding steroid cell tumor, not otherwise specified (NOS) of the ovary?

Inhibin+, calretinin+, MelanA+, PAX8-
Less than 1% risk of malignancy
Mostly bilateral
Various architectural patterns

Board review style answer #1

A. Inhibin+, calretinin+, MelanA+, PAX8-. Steroid cell tumor, NOS shows positive inhibin, calretinin and MelanA and negative PAX8. Note that MelanA (A103 clone) can be expressed in steroid cell tumor and the presence of it should not necessarily prompt the diagnosis of melanoma. Answer B is incorrect because steroid cell tumor has a 30% risk of malignancy. Answer C is incorrect because steroid cell tumors are mostly unilateral. Answer D is incorrect because having various architectural patterns is a feature of ovarian clear cell carcinoma.

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Reference: Steroid cell tumor

Board review style question #2

A 40 year old woman presented with 5 cm, solid, well defined adnexal mass. Which of the following features is in favor of steroid cell tumor, NOS?

Acellular eosinophilic material and nuclear clustering
Location in hilum
Reinke crystal
Sheets of tumor cells with distinct cell borders and clear to foamy cytoplasm

Board review style answer #2

D. Sheets of tumor cells with distinct cell borders and clear to foamy cytoplasm. Steroid cell tumor, NOS is mostly seen as sheets of tumor cells with distinct cell borders and can have clear to foamy cytoplasm in lipid rich tumor. Answers A, B and C are incorrect because these are features of Leydig cell tumor.

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Reference: Steroid cell tumor

Stromal hyperplasia and hyperthecosis

Table of Contents

Definition / general

Ovarian stromal hyperplasia is a nonneoplastic functional disorder resulting in nodular or diffuse proliferation of ovarian stroma
Hyperthecosis is characterized by proliferation of ovarian stroma along with luteinization of stromal cells (J Turk Ger Gynecol Assoc 2013;14:182)

Essential features

Ovarian stromal hyperplasia and hyperthecosis are nonneoplastic conditions resulting in diffuse or nodular proliferation of ovarian stroma as single cells, clusters or nodules of luteinized cells
Patients can present with bleeding due to endometrial pathology or symptoms of hyperandrogenism, principally androgenetic alopecia or hirsutism, along with elevated testosterone levels
Both show an excess of androgen production leading to increased testosterone
Ovaries with stromal hyperplasia and hyperthecosis secrete more androstenedione than normal ovaries that can be converted to estradiol by peripheral aromatization (BJOG 2003;110:690)

ICD coding

ICD-11: 5A80.Y - other specified ovarian dysfunction

Epidemiology

Generally encountered in postmenopausal women with an average age of 55 years (age range: 51 - 64 years) (J Menopausal Med 2020;26:39)
Rare in women of reproductive age (< 1%) (Case Rep Obstet Gynecol 2023;2023:2783464)

Sites

Ovarian stroma

Pathophysiology

Studies have shown that ovaries with stromal hyperplasia and hyperthecosis secrete more androstenedione and estradiol than normal ovaries
- Most patients with stromal hyperplasia and hyperthecosis have normal gonadotrophin levels, unlike patients with polycystic ovary syndrome (Histopathology 1989;14:369)
Some in vitro incubation studies show that stromal proliferation in premenopausal and postmenopausal women is increased by luteinizing hormone
- Luteinizing hormone also increases androgen production in ovaries with or without stromal hyperplasia (Am J Obstet Gynecol 1980;136:997, J Clin Endocrinol Metab 1992;74:172)
Most patients with stromal hyperplasia and hyperthecosis show hyperinsulinemia or insulin resistance that likely plays a role in pathogenesis (Am J Obstet Gynecol 1986;154:384)

Etiology

Etiology is not completely known (J Menopausal Med 2020;26:39)
Some studies suggest genetic etiology (Medicina (Kaunas) 2023;59:1097)
There may be an association with hyperandrogenism, insulin resistance and acanthosis nigricans (HAIR AN) syndrome

Clinical features

Symptoms and signs of hyperandrogenism, such as deepening voice, acne, hirsutism, frontal alopecia, clitoromegaly
Other features include obesity, hyperinsulinemia, acanthosis nigricans and metabolic syndrome
There is an increased risk of vaginal bleeding, endometrial hyperplasia and carcinoma, cardiovascular pathology and diabetes mellitus (J Menopausal Med 2020;26:39)
May be associated with HAIR AN syndrome in a few patients

Diagnosis

Initial investigation is usually done to rule out adrenal tumors and androgen secreting ovarian tumors
Clinical assessment for hirsutism, alopecia, deepening of voice, etc.
Serological assessment: elevated testosterone, androgen and estrogen levels, normal or suppressed luteinizing hormone, normal dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), 17 hydroxyprogesterone (17 OHP), normal progesterone and prolactin levels
Imaging: enlarged ovaries without hypervascularization on imaging (J Menopausal Med 2020;26:39)
Histology: the gold standard diagnostic test used for confirmation (and subsequent treatment) consists of histological investigation performed after bilateral salpingo-oophorectomy (J Menopausal Med 2020;26:39)

Laboratory

Increased androgen, testosterone and estrogen levels
Normal or suppressed LH and FSH
Normal serum androstenedione or dehydroepiandrosterone sulfate (DHEAS) concentrations
Unfavorable lipid profiles (i.e., increase in low density lipoprotein [LDL] and triglycerides, along with decrease in high density lipoprotein [HDL] associated with the hyperandrogenemia)

Radiology description

Imaging: enlarged ovaries without hypervascularization on ultrasonography (J Menopausal Med 2020;26:39)
In severe cases, bilateral expansion of ovarian stroma with more solid ovaries (J Turk Ger Gynecol Assoc 2013;14:182)
Increased ovarian volume for the age group or nodules / cysts, however, unlike polycystic ovary syndrome, the number of follicles tends to be normal (Case Rep Obstet Gynecol 2023;2023:2783464)
Magnetic resonance can show homogeneous T2 hypointensity and mild enhancement of the ovaries (Endocrinol Diabetes Metab Case Rep 2021;2021:20)

Radiology images

Images hosted on other servers:

Ovarian stromal hyperplasia

Prognostic factors

Although it is a benign nonneoplastic condition, ovarian stromal hyperplasia / increased ovarian volume is believed to be associated with an increased risk of endometrial cancer; hence, malignancy should be excluded and patient should be treated to reduce the neoplastic risk (Ann Saudi Med 2012;32:588, Cancer Epidemiol Biomarkers Prev 2006;15:1550, Case Rep Obstet Gynecol 2023;2023:2783464)

Case reports

55 year old multiparous woman presented with bilateral ovarian hyperthecosis and endometrial intraepithelial neoplasia (EIN) (J Turk Ger Gynecol Assoc 2013;14:182)
62 year woman presented with bilateral ovarian stromal hyperplasia (Endocrinol Diabetes Metab Case Rep 2021;2021:20)
64 year old woman presented with serous cystadenoma and hyperthecosis (Case Rep Obstet Gynecol 2023;2023:2783464)
64 year old woman presented with virilizing symptoms and ovarian stromal hyperplasia (Postgrad Med J 1991;67:304)

Treatment

Bilateral oophorectomy in postmenopausal women, however, if the patient has multiple comorbidities and is not fit for surgical option, then long term gonadotropin releasing hormone agonist treatment may be an option (J Turk Ger Gynecol Assoc 2013;14:182)
In young females, long term gonadotropin releasing hormone agonist is an alternative to preserve fertility (Endocrinol Diabetes Metab Case Rep 2021;2021:20)

Gross description

Mostly involves bilateral ovaries with increase in size
May be nodular or diffuse with solid, firm, homogeneous white to yellow cut surface

Gross images

AFIP images

Enlarged ovaries

Microscopic (histologic) description

Diffuse or nodular proliferation of ovarian stroma in cortex, medulla or both
Stromal proliferation of spindle cells with scant intervening collagen
May be diffuse or present as a nodule with coalescent nodules (Endocrinol Diabetes Metab Case Rep 2021;2021:20)
Entrapped follicular derivatives may be present
In hyperthecosis, single cells, nests or nodules of polygonal luteinized theca cells with eosinophilic or clear cytoplasm < 1 cm are present

Microscopic (histologic) images

Contributed by Hafza Asma Adnan, M.B.B.S. and AFIP

Diffuse stromal hyperplasia

Ovarian stromal hyperplasia

Nests of vacuolated, luteinized cells

Large nodule of luteinized cells

Lutein cells contain abundant lipid (oil red O stain)

Positive stains

CD56, WT1, vimentin, ER, PR, calretinin in luteinized cells, inhibin in luteinized cells (Am J Surg Pathol 2008;32:884)
FOXL2

Negative stains

AE1 / AE3, EMA, cytokeratin MNF 116 and CD10

Sample pathology report

Right ovary, oophorectomy:
- Ovarian stroma hyperplasia / hyperthecosis (see comment)
- Comment: This ovarian tissue shows expansion of ovarian stroma as diffuse proliferation of stromal cells. In between these stromal cells, few clusters of eosinophilic luteinized cells are also present. No evidence of epithelial elements, increased mitosis, pleomorphism or necrosis is identified.
- Clinicopathological correlation: Correlation with serological markers and endometrial thickness is recommended as this condition is frequently associated with hyperandrogenism and endometrial hyperplasia.

Differential diagnosis

Fibroma:
- Mostly unilateral mass
- Usually well circumscribed and composed of variable cellular spindle to oval cells with scant cytoplasm, arranged as intersecting fascicles with intervening collagen; sometimes hyaline plaques are also present
- Cellular fibroma is densely cellular with little intervening collagen that may be mitotically active
Steroid cell tumor, NOS:
- This tumor is comprised of expansile diffuse proliferation of large polygonal cells with eosinophilic, pale or vacuolated cytoplasm
- Steroid cells nodules > 1 cm arising in a background of stromal hyperthecosis are now best diagnosed as steroid cell tumor, NOS, as the previous diagnostic category of stromal luteoma is no longer recognized as a distinct entity
Luteinized thecoma associated with sclerosing peritonitis:
- Extremely rare lesion, patient presents with abdominal swelling, ascites and bowel obstruction
- Almost always bilateral, ovaries have tan to red sectioned surface
- Microscopically, ovaries are hypercellular and show microcystic appearance due to edema
- Cells are predominantly spindled with minority component of small luteinized cells
- SF1 and FOXL2 are positive in spindle cells while calretinin and inhibin are positive in luteinized cells
Normal ovary:
- Normal appearance of cortex and medulla
- Cortex is the hypercellular outer zone having majority of follicles in premenopausal women; medulla is the hypocellular central area containing blood vessels and diffuse or nodular population of spindle cells
- Young women have thick cortex and contain follicles in various stages of development, while this is atrophied in old age and mainly contain corpus albicans
- Diagnosis of stromal hyperplasia and hyperthecosis is a subjective estimation of cortex and medullary cellularity with respect to age
Sex cord stromal tumor, NOS:
- Both sex cord and stromal components are present
- Stromal component highlighted by reticulin staining
Pregnancy luteoma:
- Associated with pregnancy
- Comprised of oval to round uniform cells with abundant eosinophilic cytoplasm
Massive ovarian edema and fibromatosis:
- Prominent edema of stroma sparing cortex
- Clusters of luteinized cells may be present
Krukenberg tumor:
- Isolated atypical cells with signet ring cell morphology in ovarian stroma
- AE1 / AE3 positive
Low grade endometrial stromal sarcoma:
- Oval to spindle cells with minimal atypia and associated arterioles
- CD10 positive

Additional references

Adv Anat Pathol 2007;14:305, Obstet Gynecol 1985;66:545, Int J Gynecol Pathol 1985;4:24

Board review style question #1

A specimen for bilateral oophorectomy is received with enlarged ovaries. One ovary measures 44 x 30 x 25 mm while the second measures 35 x 30 x 25 mm. Sectioning shows homogeneous solid areas with a single 3 mm cyst. Microscopy shows a diffuse population of spindle cells with no pleomorphism, mitosis or necrosis. What is the likely diagnosis?

Adult granulosa cell tumor
Fibroma
Metastatic tumor
Sex cord stromal tumor, NOS
Stromal hyperplasia

Board review style answer #1

E. Stromal hyperplasia. There is a homogeneous population of spindle cells with no atypia. Answer A is incorrect because adult granulosa cell tumor will show atypia with variable patterns and nuclear grooving. Answer B is incorrect because no hyalinized areas with intersecting fascicles are present. Answer C is incorrect because no epithelial elements are present in this tumor. Answer D is incorrect because no sex cord-like areas or biphasic cell populations are identified.

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Reference: Stromal hyperplasia and hyperthecosis

Board review style question #2

A 57 year old woman presents with postmenopausal bleeding. Endometrial biopsy showed FIGO grade 1 endometrioid type endometrial cancer and hysterectomy revealed stage IA endometrioid type endometrial carcinoma with enlarged bilateral ovaries. Microscopic findings are shown in the image above. What is the diagnosis?

Fibroma
Leydig cell tumor
Metastatic endometrioid type endometrial cancer
Sex cord stromal tumor
Stromal hyperplasia and hyperthecosis

Board review style answer #2

E. Stromal hyperplasia and hyperthecosis. Clusters of luteinized cells are present in stromal hyperplasia. Answer A is incorrect because no hyalinized areas with intersecting fascicles are present. Answer B is incorrect because no Leydig cell population is identified and the cells do not contain Reinke crystals. Answer C is incorrect because no epithelial elements are identified. Answer D is incorrect because no tumor-like mass or epithelial elements are identified.

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Reference: Stromal hyperplasia and hyperthecosis

Struma ovarii

Table of Contents

Definition / general

Monodermal ovarian teratoma primarily (> 50%) or exclusively composed of benign thyroid tissue
Any mature teratoma with malignant thyroid tissue

Essential features

Ovarian teratoma either composed predominantly or exclusively of benign thyroid tissue or with any amount of malignant thyroid tissue
Most common thyroid malignancy to occur in struma ovarii is papillary thyroid carcinoma, followed by follicular carcinoma

ICD coding

ICD-10: D27.9 - benign neoplasm of unspecified ovary
ICD-10: C56 - malignant neoplasm of ovary

Epidemiology

Most common type of monodermal teratoma
Accounts for 3% of ovarian teratomas (Pathol 2007;39:139)
Usually presents in the fifth decade

Sites

Ovary

Pathophysiology / etiology

Unknown at this time

Clinical features

Most often an incidental and asymptomatic finding but may present as a pelvic mass with abdominal pain (Pathology 2007;39:139)
Uncommonly presents as hyperthyroidism or pseudo-Meigs syndrome (with ascites and pleural effusion) (Pathology 2007;39:139)
Seen in association with Brenner tumor, serous and mucinous cystadenoma and fibrothecoma (Endocr Pathol 2015;26:342)

Diagnosis

Diagnosis is made by microscopic examination of resected tissue

Laboratory

Mildly increased CA125 levels in up to 30% of cases (J Gynecol Oncol 2008;19:135)

Radiology description

Typically a lobulated and multiloculated solid cystic lesion on imaging (Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2015;37:309, Abdom Imaging 2012;37:904)
MRI is more specific, showing high and low signal intensity on T1 and T2 weighted images from the colloid (J Med Imaging Radiat Oncol 2009;53:480)

Radiology images

Images hosted on other servers:

Left adnexal mass

Prognostic factors

Most cases have a good prognosis, even when malignancy is present

Case reports

10 year old girl with tachycardia, normal thyroid and thyrotoxicosis with papillary thyroid carcinoma arising from a struma ovarii (Int J Surg Case Rep 2018;51:218)
48 year old woman with malignant struma ovarii presenting 14 years after oophorectomy and chemotherapy (Medicine (Baltimore) 2018;97:e13867)
52 year old woman with clinical features of advanced ovarian carcinoma found to have a struma ovarii (Oncol Lett 2015;9:1739)
61 year old woman with insular carcinoma (90%) and adjacent papillary thyroid carcinoma arising in a struma ovarii (Gynecol Oncol Rep 2016;18:1)
62 year old woman with 2 different types of RAS mutations in a papillary thyroid carcinoma from a struma ovarii and papillary thyroid microcarcinoma of the thyroid (J Endocr Soc 2018;2:944)
74 year old woman with a mixed ovarian tumor composed of elements of Brenner tumor, mucinous cystadenoma and struma ovarii (Int J Gynecol Pathol 2019;38:576)

Treatment

Oophorectomy
Surgery for malignant struma ovarii may include total abdominal hysterectomy and bilateral salpingo-oophorectomy with complete staging (Gynecol Oncol 2004;94:835)

Gross description

Typically unilateral and solid with a gelatinous, red-brown to green cut surface; may show goiter-like multinodular or cystic change (Am J Surg Pathol 1994;18:785)

Gross images

Contributed by Kseniya Korchagina, M.D. and AFIP

Cystic teratoma

Solid and cystic

Reddish brown solid mass

Cystic tumor

Frozen section description

Frozen section sample usually shows a mature teratoma or benign thyroid tissue; rarely, a possible malignant component may be detected

Microscopic (histologic) description

Variably sized macro and microfollicles often containing colloid
Other architectural patterns include solid areas composed of cells with clear to oxyphilic cytoplasm, trabeculae, cords and pseudotubular structures
Rarely, stroma in between follicles may be fibrotic or edematous; peripheral stromal leutinization may also be seen
Adenomatous hyperplasia or proliferative changes may be seen, such as areas of densely packed follicles or papillary formations lacking nuclear features of papillary thyroid carcinoma
Birefringent calcium oxalate crystals may be seen in colloid
Most commonly associated malignancy is papillary thyroid carcinoma, cytologically characterized by crowded and overlapping elongated nuclei with irregular contours and chromatin clearing, usually with papillary or follicular architecture
Follicular carcinoma is the second most common malignancy; since ovarian lesions typically lack capsule, demonstration of tumor invasion into surrounding ovarian tissue, vascular invasion or metastases is needed as evidence of malignancy
Uncommonly associated with the more recently described highly differentiated follicular carcinoma of ovarian origin, characterized by extraovarian spread of thyroid elements histologically resembling nonneoplastic thyroid tissue (Int J Gynecol Pathol 2008;27:213)
Undifferentiated (anaplastic) carcinoma and medullary carcinoma have also been described in association with struma ovarii

Microscopic (histologic) images

Contributed by Sharon Song, M.S., M.D., Kseniya Korchagina, M.D. and AFIP

Follicular variant PTC

Capsular invasion

TTF1 stain

Papillary thyroid carcinoma in struma ovarii

Macrofollicular, microfollicular and solid areas

Solid tubular pattern

Oxyphilic cells arranged in nests

With peripheral formation of lutein cells

Resembling clear cell carcinoma

Cystic tumor

Thyroglobulin

With papillary carcinoma

Cytology description

Flattened to cuboidal / columnar cells with small round to oval nuclei, even chromatin and pale to eosinophilic cytoplasm (Crum: Gynecologic and Obstetric Pathology, 3rd Edition, 2017)
Clear cell change may occasionally be seen

Positive stains

TTF1, thyroglobulin, PAX8, CK7, AE1 / AE3 (Semin Diagn Pathol 2005;22:3)

Negative stains

HNF1β, Napsin A, AMACR, inhibin A, calretinin, SF1, S100, MelanA, HMB45

Molecular / cytogenetics description

BRAF mutations and RET / PTC rearrangements may be seen in papillary thyroid carcinomas arising from a struma ovarii (Am J Surg Pathol 2007;31:1337, Endocr Pathol 2007;18:182)

Sample pathology report

Ovary and fallopian tube, left, salpingo-oophorectomy:
- Struma ovarii, 4.5 cm
Ovary and fallopian tube, left, salpingo-oophorectomy:
- Papillary thyroid carcinoma, follicular and papillary growth patterns, 1.1 cm, arising in a background of struma ovarii

Differential diagnosis

Metastatic thyroid carcinoma to the ovary:
- Clinical history of primary thyroid carcinoma
Strumal carcinoid:
- Corded, trabecular or follicular architecture with salt and pepper nuclear chromatin pattern and occasional eosinophilic granules
- Positive staining for TTF1, PAX8, thyroglobulin (in follicular component) and neuroendocrine markers chromogranin, synaptophysin, CD56 and neuron specific enolase
Ovarian clear cell carcinoma:
- Tubulocystic, papillary and solid growth patterns with cytologically atypical cells, often hobnailing into cysts
- Positive staining for HNF1β, Napsin A and AMACR
- Negative for TTF1, thyroglobulin
Sex cord stromal tumor:
- Tubular, trabecular or corded growth without eosinophilic secretions
- Positive staining for inhibin A, calretinin and SF1
- Negative for TTF1, PAX8 (usually negative, Appl Immunohistochem Mol Morphol 2011;19:293), thyroglobulin
Melanoma:
- Nested growth with eosinophilic cytoplasm
- Positive staining for typical melanoma markers such as S100, MelanA and HMB45
- Negative for keratin (AE1 / AE3)

Board review style question #1

What type of crystals may be seen in struma ovarii?

Calcium carbonate
Calcium oxalate
Calcium phosphate
Triple phosphate
Tyrosine

Board review style answer #1

B. Calcium oxalate crystals may be identified in colloid

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Reference: Struma ovarii

Board review style question #2

Which laboratory marker may be elevated with struma ovarii?

Alpha-fetoprotein (AFP)
CA125
CEA
hCG
PLAP

Board review style answer #2

B. CA125 is a widely accepted biomarker for ovarian cancers that can also be elevated in many other conditions, such as menstruation, endometriosis, pregnancy, pelvic inflammatory disease, fibroids, liver disease and tumors of the endometrium, breasts and lungs. It can be increased in up to 30% of struma ovarii.

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Reference: Struma ovarii

Strumal carcinoid

Table of Contents

Definition / general

Has features of carcinoid tumor and struma ovarii
Associated with MEN IIA / III

Case reports

Associated with MEN IIA (Arch Pathol Lab Med 1992;116:200)

Gross images

AFIP images

4 cm, rounded, brown nodule (bottom)

Microscopic (histologic) description

Often other teratomatous elements

Microscopic (histologic) images

AFIP images

Admixed: struma (right) merges with trabecular carcinoid (left)

Admixed: trabecular
carcinoid with
microfollicles
containing colloid

Chromogranin (top), thyroglobulin (bottom)

With formation of
layer of steroid cells
in adjacent ovarian
stroma

Positive stains

Neuron specific enolase, chromogranin, synaptophysin, thyroglobulin and PAP (similar to rectal carcinoids)

Negative stains

Calcitonin

Electron microscopy description

Numerous electron-dense neurosecretory granules (Am J Clin Pathol 1978;69:356)

Teratoma-immature

Table of Contents

Definition / general

A malignant germ cell tumor consisting of a teratoma containing variable amounts of immature tissue (typically primitive neuroectodermal)

Essential features

Malignant germ cell tumor of the ovary composed of cells from the 3 germ layers and containing variable amounts of mature and immature tissue
Affects mostly young females < 20 years old
Grossly solid ovarian tumor mass with necrosis and hemorrhage on cut sections
Grading is based on the amount of immature neuroepithelium
Can have associated nodal or peritoneal gliomatosis (presence of mature neural tissue), which increases risk of recurrence
Grading and stage are the most important factors for prognosis and prognosis is greatly improved after chemotherapy

Terminology

Immature teratoma

ICD coding

ICD-O: 9080/3 - teratoma, malignant, NOS

Epidemiology

Immature teratomas constitute about a third of malignant germ cell tumors (Cancer 1976;37:2359, Obstet Gynecol 2006;107:1075)
Mean age at diagnosis is 20.6; only 4 of 244 patients with immature teratoma were older than 40 (Int J Gynecol Pathol 1994;13:283)

Sites

Ovary

Pathophysiology

Abnormal differentiation of fetal germ cells
2 pathogenetic models for ovarian teratomas, similar to their testicular counterparts
- Pure mature and immature teratomas are not derived from transformed ovarian germ cells
- Teratomatous components of mixed germ cell tumors derived from their associated nonteratomatous components
Pure mature and immature teratomas do not have i(12p) or 12p amplification, abnormalities that are identified in both teratomatous and nonteratomatous components of mixed germ cell tumors; this supports a different pathogenesis for pure versus mixed tumors (Mod Pathol 2006;19:766)
25% of cases with immature teratoma have peritoneal implants composed of mature glial tissue (gliomatosis peritonei); this phenomenon is thought to arise from metaplasia of submesothelial cells in response to growth factors secreted by the ovarian tumor, rather than a true metastatic process (Hum Pathol 1976;7:625, Hum Pathol 2004;35:685, Int J Gynecol Cancer 2015;25:244, Mod Pathol 2015;28:1613)
Rarely, mature glial tissue is also present in lymph nodes (nodal gliomatosis), usually with associated gliomatosis peritonei
Prognosis is good and the presence of nodal gliomatosis does not warrant chemotherapy (J Ovarian Res 2016;9:45, Mod Pathol 2015;28:1613)

Etiology

No known causative agents

Clinical features

Associated with symptoms of rapidly growing abdominal mass, pain, distention and torsion
Growing teratoma syndrome: immature teratoma status postneoadjuvant chemotherapy consists of persistent or enlarging ovarian tumor with normalization of serum markers
- Thought to represent conversion of deposits of immature teratoma into mature teratoma as a result of chemotherapy (chemotherapeutic retroconversion) (Int J Gynecol Pathol 2015;34:465, Medicine (Baltimore) 2016;95:e2647)
- Histologic examination shows only mature teratoma

Diagnosis

A combination of clinical, radiological and laboratory findings: rapidly enlarging adnexal mass in a young patient with mildly elevated alpha fetoprotein (AFP) and typical radiological findings raises the possibility of immature teratoma
Requires histological examination for confirmation of diagnosis and grading
Reference: Int J Gynecol Pathol 1994;13:283

Laboratory

Low level increase of AFP
High levels of AFP suggest the presence of a yolk sac tumor component (mixed germ cell tumor)

Radiology description

On CT imaging, the solid component appears large and irregular, with coarse calcifications and small foci of fat scattered throughout the lesion rather than localized, as seen in dermoid cyst (J Med Imaging Radiat Oncol 2009;53:480, Eur J Radiol 2009;72:454)

Radiology images

Images hosted on other servers:

Complex ovarian mass

Prognostic factors

Older age at diagnosis, higher stage and grade confer worse prognosis but overall improved after chemotherapy, with 72% survival for stage IV disease (Gynecol Oncol 2016;142:261, Gynecol Oncol 2016;142:446)
Grade is the most important risk factor for relapse across all age groups
In a study of 98 pediatric patients and 81 adult patients, there were no relapses in grade 1 patients, irrespective of stage or age; only 1 adult patient with a grade 2 tumor relapsed (Cancer 2016;122:230)
In patients with grade 3 tumors, recurrence rate was 21% in the pediatric cohort and 20% in the adult cohort and was significantly associated with stage (Cancer 2016;122:230)
Higher risk of recurrence with presence of gliomatosis peritonei or lymph node gliomatosis but similar overall survival (Virchows Arch 2012;461:299, J Ovarian Res 2016;9:45)

Case reports

5 year old girl with ruptured immature teratoma at initial presentation (IJAR 2017;5:1811)
12 year old girl with grade 1 immature teratoma in the left ovary that presented as growing teratoma syndrome of the ovary (Medicine (Baltimore) 2020;99:e22297)
12 year old monozygotic twin girls with simultaneous presentation of ovarian mature and immature teratomas (Case Rep Obstet Gynecol 2017;2017:5810515)
13 year old girl with growing teratoma syndrome after treatment for immature teratoma (J Obstet Gynaecol India 2017;67:295)
31 year old woman with immature teratoma in pregnancy (Open Access Maced J Med Sci 2019;7:1016)
46 year old woman presented with simultaneous immature teratoma in the endometrium and mature teratomas in the ovary associated with gliomatosis peritonei (Int J Gynecol Pathol 2017;36:222)

Treatment

Surgery plus chemotherapy for grade 2 or 3 lesions in adult women (Cancer 2016;122:230, Gynecol Oncol 2011;123:50)
Patients with stage I, grade 1 tumors can be followed by surveillance (Gynecol Oncol 2011;123:50)
Primarily surgical treatment for pediatric population (J Clin Oncol 2008;26:3590)

Gross description

Usually unilateral ovarian masses with a mean size of 16 cm (range: 5 - 42 cm) (Int J Gynecol Pathol 1994;13:283)
Solid with cystic areas or mostly solid; hemorrhage and necrosis on cut sections
Contralateral ovary with mature teratoma in 9% of cases

Gross images

Images hosted on other servers:

Solid ovarian mass with variegated appearance

Frozen section description

Extensive sampling may be needed to include areas of immature teratoma at the time of frozen section in cases where a preoperative diagnosis of immature teratoma is suspected; sample nodular, soft appearing and mass forming areas

Microscopic (histologic) description

Variable amounts of mature elements from all 3 germ layers, admixed with immature elements, mostly neuroectodermal
Immature neuroepithelium
- Immature neuroepithelium can be spindled (sarcomatoid) or with rosette, pseudorosette and primitive tubule formation; the latter is easier to recognize
- Cells appear primitive with scant cytoplasm, hyperchromatic nuclei and frequent mitoses, which helps differentiate the immature elements from mature brain tissue
- Only immature neuroepithelium is used for grading, so it is important to recognize as such on histological slides
- Grading is based on the number of low power microscopic fields containing aggregated amounts of immature neuroepithelium in any one slide
- Original grading system (Cancer 1976;37:2359)
  - Grade 1: ≤ 1 low power field (using a 4x power objective, which when using a 10x eyepiece, leads to a 40x magnification) in any slide
  - Grade 2: > 1 but ≤ 3 low power fields in any slide
  - Grade 3: > 3 low power fields in any slide
- Grade 2 and 3 tumors are considered high grade, therefore the updated grading system is 2 tiered, with improved reproducibility (Int J Gynecol Pathol 1994;13:283)
  - Low grade: ≤ 1 low power field (using a 4x power objective, which when using a 10x eyepiece, leads to a 40x magnification) in any slide
  - High grade: > 1 low power field in any slide
Neural tissue can have a prominent associated benign vascular proliferation with Wagner-Meissner-like corpuscles, which should not be interpreted as an immature component (Int J Gynecol Pathol 2002;21:16, Int J Surg Pathol 2008;16:320)
Fetal cartilage can be present and is not considered an immature element
Small foci of yolk sac tumor or embryonal carcinoma (< 3 mm) can be seen in immature teratomas without changing prognosis; however, presence of any yolk sac or embryonal carcinoma component changes the classification to a mixed germ cell tumor (Int J Gynecol Pathol 1994;13:283, Cancer 1976;37:2359)
Peritoneal and nodal gliomatosis nodules consist of mature glial tissue, considered grade 0 for grading purposes; thorough sampling is required to identify immature tissue (metastatic immature teratoma component), which has a worse prognosis

Microscopic (histologic) images

Contributed by Aurelia Busca, M.D., Ph.D.

Mature component

Immature component

Virtual slides

Images hosted on other servers:

Large ovarian mass, ruptured on removal

Cytology description

Immature elements are rarely observed in ascites (Diagn Cytopathol 2005;33:39)

Positive stains

Immunohistochemistry has limited role in diagnosis of immature teratoma
Immature neuroepithelium
- S100, GFAP, NSE (does not differentiate between mature and immature components)
- OCT4 and PAX6 (OCT4 preferentially expressed in immature neural tissue of advanced stage immature teratomas) (Am J Surg Pathol 2010;34:1842)
- SALL4, SOX2, glypican 3 (Hum Pathol 2010;41:716, Histopathology 2011;58:312)
Gliomatosis peritonei: SOX2+ (Mod Pathol 2015;28:1613)

Negative stains

Gliomatosis peritonei: OCT4- / NANOG- (Mod Pathol 2015;28:1613)
Neuroepithelium is negative for CD30, alpha fetoprotein (AFP), keratin, PAX8

Molecular / cytogenetics description

i(12p) and 12p amplification is present in immature teratomatous components of mixed germ cell tumors but not in pure immature teratomas (Mod Pathol 2006;19:766)

Sample pathology report

Left ovary, oophorectomy:
- Immature teratoma (see synoptic report)
  - Tumor grade: 1 (low grade)
  - Tumor size: 16 cm
  - Ovarian surface involvement: present

Differential diagnosis

Mature cystic teratoma with mature neural elements:
- Predominantly cystic appearance grossly
- Neural elements are mature
- Microscopic foci of immature elements do not warrant a diagnosis of immature teratoma (Int J Gynecol Pathol 1987;6:203)
Mature solid teratoma:
- Grossly similar
- Composed exclusively of mature elements
- Very rare, requires very rigorous sampling to rule out an immature component (Gynecol Oncol 1989;33:212)
Carcinosarcoma:
- Usually postmenopausal women
- Mixed malignant epithelial and mesenchymal components, usually high grade
- Mesenchymal component is frequently chondrosarcoma (no fetal cartilage)
- Rare cases of ovarian carcinosarcoma with neuroectodermal differentiation have been reported (teratoid carcinosarcoma) (J Obstet Gynaecol Res 2010;36:907, Case Rep Oncol 2019;12:241)
Mixed germ cell tumor:
- Extensive sampling is required to rule out another germ cell component (usually yolk sac tumor or embryonal carcinoma)

Additional references

WHO Classification of Tumours Editorial Board: Female Genital Tumours, 5th Edition, 2020

Board review style question #1

Which of the following is true about gliomatosis peritonei found in ovarian immature teratoma?

Considered a metaplastic rather than a true metastatic process
Consists of immature glial tissue
Has no impact on prognosis of immature teratoma
Is used for grading of the immature teratoma

Board review style answer #1

A. Considered a metaplastic rather than a true metastatic process. The current understanding of gliomatosis is as a metaplastic rather than a true metastatic process. Answer B is incorrect because gliomatosis consists of mature neural tissue. Answer C is incorrect because presence of gliomatosis has been linked with increased risk of recurrence. Answer D is incorrect because only immature neuroepithelium component is used for grading.

Comment Here

Reference: Teratoma - immature

Board review style question #2

Which of the following is true about grading of immature teratoma of the ovary?

Both grade 1 and grade 2 tumors are considered low grade in the 2 tier classification system
Grade does not impact prognosis
Presence of immature elements in more than 1 low power field is in keeping with high grade
Takes into account all histologic types of immature tissue

Board review style answer #2

C. Presence of immature elements in more than 1 low power field is in keeping with high grade in the 2 tier classification system. Answer B is incorrect because higher grade correlates with worse prognosis. Answer A is incorrect because grade 2 tumors are considered high grade in the 2 tier classification system. Answer D is incorrect because only immature neuroepithelium component is used for grading.

Comment Here

Reference: Teratoma - immature

Teratoma-mature

Table of Contents

Definition / general

Benign tumor of the ovary composed of mature tissue representing at least 2 embryonic layers (ectoderm, mesoderm or endoderm)

Essential features

Mature tissue representing at least 2 embryonic layers
If malignant transformation, prognosis is related to the type of malignancy

Terminology

Mature cystic teratoma
Not recommended: dermoid cyst, mature solid teratoma

ICD coding

ICD-O: 9080/0 - teratoma, benign
ICD-11: 2F32.0 - cystic teratoma

Epidemiology

Most common ovarian tumor (20% of all ovarian tumors, 95% of all ovarian germ cell tumors)
Reproductive age
10% bilateral (Cancer 1971;27:343)

Sites

Ovary

Pathophysiology

Most widely accepted origin is from the primordial germ cell (Mod Pathol 2017;30:1467)

Etiology

No known causative agents

Diagrams / tables

Images hosted on other servers:

Signs of ovarian teratomas in different imaging modalities

Clinical features

Slow growing, often incidental finding
Rarely present with or are associated with:
- Torsion or rupture
- Mucinous tumors of the ovary (e.g., mucinous cystadenoma) (Clin Diagn Res 2016;10:ED11)
- Autoimmune hemolytic anemias (Saudi Med J 2019;40:397)
- Paraneoplastic encephalitis (Ann Neurol 2007;61:25)

Diagnosis

Mainly by ultrasound
Histologic examination

Radiology description

Wide variety of presentations, depending on the tissues present (see Diagrams / tables)

Radiology images

Images hosted on other servers:

Ultrasound characteristics

CT characteristics

MRI characteristics

Prognostic factors

Benign tumor
Malignant transformation occurs rarely
- Usually in older patients
- Most common is squamous cell carcinoma
- Prognosis dependent on stage
Microscopic foci of immature neuroepithelium does not warrant diagnosis of immature teratoma and will not affect prognosis (Int J Gynecol Pathol 1987;6:203)
Gliomatosis peritonei (mature glial tissue implanted on peritoneal surface) does not adversely affect prognosis (J Ovarian Res 2016;9:45)
Anti–n-methyl-D-aspartate receptor (NMDAR) encephalitis will have best outcome with early treatment (immunotherapy and tumor removal) (Lancet Neurol 2013;12:157)

Case reports

15 year old girl with meningioma arising in a mature cystic teratoma (Cancer Imaging 2020;20:15)
20 year old woman with mature teratoma in ectopic ovary (J Minim Invasive Gynecol 2019;26:348)
22 year old woman with secondary retroperitoneal mature teratoma 4 years after resection of mature teratoma of the ovary (Radiol Case Rep 2019;14:692)
59 year old woman with squamous cell carcinoma in a mature teratoma of ovary (BMC Cancer 2019;19:217)
71 year old woman with ovarian clear cell carcinoma arising in a mature cystic teratoma (J Ovarian Res 2018;11:74)

Treatment

Cystectomy in young women to preserve fertility
Salpingo-oophorectomy in older women

Gross description

Smooth cyst that may contain hair, teeth, cartilage, bone or sebaceous material
Generally < 10 cm
Raised protuberance in cyst wall (Rokitansky nodule)
Reference: StatPearls: Cystic Teratoma [Accessed 29 July 2021]

Gross images

Contributed by Shannon Mingo Welter, M.D., AFIP and @Andrew_Fltv on Twitter

Fragmented ovarian mature teratoma

Ovarian mature teratoma

Mature teratoma

Frozen section description

Rarely performed but will show mixture of mature tissues
Solid areas should be sampled to exclude immature teratoma

Microscopic (histologic) description

Mixture of mature, benign tissues
- Ectodermal (most common): squamous epithelium, sebaceous glands, hair follicles, brain tissue
- Mesodermal (second most common): bone, cartilage, smooth muscle, fibroadipose tissue
- Endodermal: intestinal or respiratory epithelium, thyroid, salivary gland
Microscopic foci of immature neuroepithelium (less than or equal to 4 foci or 21 mm²) does not warrant diagnosis of immature teratoma and will not affect prognosis (Int J Gynecol Pathol 1987;6:203)
Fat necrosis and foreign body reaction may be seen
Cases associated with NMDAR encephalitis usually show neuroglial tissue associated with lymphoid aggregates with germinal centers, low number of mature neurons and a hypercellular astrocyte population (Am J Surg Pathol 2019;43:949)
Reference: StatPearls: Cystic Teratoma [Accessed 29 July 2021]

Microscopic (histologic) images

Contributed by Shannon Mingo Welter, M.D. and @Andrew_Fltv on Twitter

Skin with sebaceous glands

Skin with keratin and adnexa

Rokitansky nodule

Mucin producing epithelium

Multiple tissue types

Orderly arrangement of tissues

Cartilage and other mature tissues

Glial tissue

Gliomatosis peritonei

Mature teratoma

Virtual slides

Images hosted on other servers:

Mature teratoma with
well differentiated
neuroendocrine tumor

Molecular / cytogenetics description

Diploid with normal (46XX) karyotype

Sample pathology report

Ovary, right, cystectomy:
- Mature teratoma

Differential diagnosis

Immature teratoma:
- Contains immature tissues (greater than 4 foci or greater than 21 mm²) (Int J Gynecol Pathol 1987;6:203)
- Younger patients
- Larger and fast growing
Monodermal teratoma:
- Contain a single germ layer
  - Neuroectodermal cyst - lined by ependymal cells
  - Epidermoid cyst - lined by squamous epithelium (no sebaceous glands present)
- Struma ovarii - thyroid tissue is the dominant or sole component
- Strumal carcinoid - well differentiated neuroendocrine tumor admixed / juxtaposed with thyroid tissue

Board review style question #1

A 25 year old pregnant woman is seen in the obstetrics clinic for a routine ultrasound. During the exam, a cystic mass is noted near her left ovary. The mass is eventually surgically removed and a pathologic examination shows the features in the picture shown above. What is an essential feature of this tumor?

Gliomatosis peritonei
Immature tissue
Mature tissue representing at least 2 embryonic layers
Size greater than 10 cm

Board review style answer #1

C. Mature tissue representing at least 2 embryonic layers. Mature teratoma can contain microscopic foci of immature neuroectodermal tissue in the cyst wall. This finding does not change the prognosis and should not lead to the tumor being classified as immature teratoma. Gliomatosis peritonei is a rare finding associated with teratoma and size of tumor is variable with most less than 10 cm. Mature teratomas must contain at least 2 embryonic layers.

Comment Here

Reference: Teratoma - mature

Board review style question #2

A 19 year old woman presents with a symptom of left adnexal fullness. On physical examination, a 9 cm mass is palpated near the left ovary. The mass is surgically removed and a gross picture is shown above. What is the most likely diagnosis?

Yolk sac tumor
Immature teratoma
Lipoma
Mature teratoma

Board review style answer #2

D. Mature teratoma. The photo shows a mass with yellow sebaceous material and hair. In a 19 year old woman, this most likely represents a mature teratoma. Mature teratomas are the most common ovarian tumor and are especially common in women of reproductive age.

Comment Here

Reference: Teratoma - mature

Thecoma

Table of Contents

Definition / general

Ovarian stromal neoplasm, almost always benign, composed of cells resembling theca cells

Essential features

Almost always benign
Usually occurs in postmenopausal women who present with uterine bleeding
Histology shows a predominant population of cells with ovoid to round nuclei and pale gray cytoplasm
Reticulin stain and molecular testing for FOXL2 mutation help distinguish thecoma from adult granulosa cell tumor

Terminology

Theca cell tumor

ICD coding

ICD-O: 8600/0 - thecoma, NOS
ICD-10: D27 - benign neoplasm of ovary
ICD-11: 2F32.Y & XH34A0 - other specified benign neoplasm of ovary & thecoma, NOS

Epidemiology

Uncommon
Usually postmenopausal women
Mean age = 59 years (Ann Diagn Pathol 2008;12:12)
Age ranges from 16 to 81 (Am J Surg Pathol 2014;38:1023)

Sites

Ovary

Pathophysiology

Molecular alterations, such as trisomy 12 and loss of heterozygosity (LOH) at the PTCH gene (see Molecular / cytogenetics description)

Etiology

Unknown

Clinical features

May be discovered incidentally
Most common symptom is postmenopausal bleeding (Am J Surg Pathol 2014;38:1023)
Symptoms can be related to mass: pelvic pain / pressure
May present with estrogenic or androgenic manifestations
Associated with endometrial hyperplasia and malignancy

Diagnosis

Histologic examination

Laboratory

Occasionally elevated serum inhibin A and inhibin B (Gynecol Oncol Rep 2020;34:100658, Gynecol Endocrinol 2016;32:872)

Radiology description

Sonographic features:
- Adnexal hypoechoic mass with clear border and acoustic attenuation
- Minimal Doppler flow signal (J Ovarian Res 2016;9:81)
Magnetic resonance imaging features:
- Isointense or slightly hyperintense
- Pelvic fluid accumulation (Medicine (Baltimore) 2020;99:e20358)
Computed tomography features:
- Isodense or hypodense (J Comput Assist Tomogr 2012;36:46)
Occasionally thecomas have positive F-FDG uptake on PET scan (J Obstet Gynaecol Res 2017;43:599)

Radiology images

Images hosted on other servers:

Bilateral thecomas on MRI

Prognostic factors

Thecomas are almost always benign but may be associated with endometrial malignancy

Case reports

57 year old woman with postmenopausal bleeding and elevated serum inhibin B level (Gynecol Oncol Rep 2020;34:100658)
58 year old woman with progressive scalp hair loss (Skin Appendage Disord 2019;5:259)
61 year old woman with Meigs syndrome and elevated CA-125 level (J Menopausal Med 2015;21:56)

Treatment

Oophorectomy if fertility sparing is desired
Total hysterectomy with bilateral salpingo-oophorectomy is indicated in postmenopausal patients
References: Gynecol Oncol 1994;55:S62, Acta Radiol Oncol 1980;19:241, Gynecol Oncol 1985;21:135

Clinical images

Images hosted on other servers:

Bitemporal hair loss

Frontal balding and hirsutism

Gross description

Usually unilateral
Most are < 5 cm
Solid, yellow and lobulated or white with focal yellow areas
Occasionally cystic change and hemorrhage are present
Necrosis is rare (Am J Surg Pathol 2014;38:1023)

Gross images

Contributed by Victoria Collins, M.D., Tamara Kalir, M.D., Ph.D. and AFIP

Well circumscribed, yellow-tan mass

Lobulated and yellow

Images hosted on other servers:

Yellow, lobulated mass

Frozen section description

Sheets of oval to round cells with moderate to abundant pale gray cytoplasm
Bilaterality should raise suspicion for metastasis
- Signet ring cells may be missed on frozen section and misinterpreted as fibrothecoma (Yeungnam Univ J Med 2019;36:163)

Frozen section images

Contributed by Victoria Collins, M.D. and Tamara Kalir, M.D., Ph.D.

Spindled to ovoid cells

Moderate cytoplasm

Microscopic (histologic) description

Predominant population of cells showing ovoid to round nuclei and pale gray cytoplasm, which can be abundant
Minor component of the tumor may have spindled nuclei, reflecting overlap between fibroma and thecoma
Indistinct cell membranes impart a syncytial appearance
Diffuse or nodular growth pattern
Absent or minimal nuclear atypia
Mitotic rate usually < 5/10 high power fields
Hyaline plaques
Cytoplasmic lipid vacuoles may be present but are not essential
May show aggregates of cells with brightly eosinophilic cytoplasm (lutein cells)
Calcification is more common in young patients (Int J Gynecol Pathol 1988;7:343)
Uncommon features include keloid-like sclerosis, nuclear grooves, bizarre nuclear atypia (Am J Surg Pathol 2014;38:1023)
Rarely contains a minor component of sex cord elements (Int J Gynecol Pathol 1983;2:227)
Malignant thecoma: very rare, diagnosis requires diffuse moderate to severe nuclear atypia and high mitotic rate (> 4/10 high power fields) (Am J Surg Pathol 2011;35:e15)

Microscopic (histologic) images

Contributed by Victoria Collins, M.D., Tamara Kalir, M.D., Ph.D. and AFIP

Well circumscribed

Ovoid to round cells

Mild nuclear atypia

Thecoma and fibroma areas

Cystic change

Hyaline plaques

Reticulin

Inhibin

Vacuolated tumor cells

Stromal calcification

Oil red O stain

Virtual slides

Images hosted on other servers:

Thecoma, with cystic change

Thecoma, reticulin stain

Positive stains

Inhibin
Calretinin
Reticulin stain shows a pericellular pattern (Int J Gynecol Pathol 2018;37:305)
SF1
FOXL2 (Mod Pathol 2013;26:860)
WT1 (Am J Surg Pathol 2009;33:354)
CD56 (Am J Surg Pathol 2008;32:884)
Vimentin
Oil red O in lipid rich cells
GLUT5 in FDG PET positive tumors (J Obstet Gynaecol Res 2017;43:599)

Negative stains

Electron microscopy description

Cytoplasmic lipid (Ultrastruct Pathol 1992;16:363)
Type I cells: dispersed chromatin, basal lamina investment of each cell, coiled / branching rough endoplasmic reticulum, sparse smooth endoplasmic reticulum, irregular mitochondria
Type II cells: degenerative changes, large round mitochondria with incomplete cristae and centers displaced by microfilaments (Hum Pathol 1984;15:153)

Molecular / cytogenetics description

Trisomy 12 or tetrasomy 12 (Gynecol Oncol 1990;36:413, Cancer Genet Cytogenet 1993;71:180)
Trisomy 4 (Gynecol Oncol 1992;45:66)
Loss of heterozygosity (LOH) at 9q22.3 (PTCH1) and 19p13.3 (Hum Pathol 2005;36:792)
FOXL2 mutation has been reported in a subset of thecomas (3 out of 14 tumors in one series) (N Engl J Med 2009;360:2719)
- However these may represent misdiagnosed granulosa cell tumors (PLoS One 2009;4:e7988)
- Pericellular reticulin staining is 100% specific for absence of FOXL2 mutation (Int J Gynecol Pathol 2018;37:305)

Videos

Thecoma of ovary

Ovarian pathology

Sample pathology report

Right ovary and fallopian tube, salpingo-oophorectomy:
- Ovarian thecoma
- Fallopian tube with no significant pathologic changes

Differential diagnosis

Adult granulosa cell tumor:
- Reticulin stain shows nested pattern (Int J Gynecol Pathol 2019;38:143)
- Harbors FOXL2 mutation (Mod Pathol 2013;26:860, Int J Gynecol Pathol 2018;37:305)
Fibroma:
- Intersecting bundles of spindle cells producing collagen
- A morphologic spectrum between fibroma and thecoma exists
- Indeterminate tumors have been called fibrothecoma
Luteinized thecoma associated with sclerosing peritonitis:
- Younger age at presentation (median age: 28)
- Symptoms include abdominal pain, ascites and bowel obstruction
- Cutaneous involvement has been reported (Ann N Y Acad Sci 1985;448:231)
- Bland spindle cell proliferation circumferentially involving the ovarian cortex with sparing of the medulla
- Almost always bilateral (Am J Surg Pathol 2008;32:1273)
Sclerosing stromal tumor:
- Pseudolobular growth pattern with cellular nodules separated by dense collagenous or edematous connective tissue (Cancer 1973;31:664)
- Staghorn vessels
Microcystic stromal tumor:
- Small, anastomosing cysts
- Inhibin-, calretinin-
- Nuclear beta catenin+
- Cyclin D1+
- CD10+ (Am J Surg Pathol 2015;39:1420)
Steroid cell tumor, NOS:
- FOXL2- (Am J Surg Pathol 2011;35:484)
- Polygonal cells with abundant eosinophilic cytoplasm
- Typically has a component of lipid rich cells (pale and vacuolated) (Arch Pathol Lab Med 2018;142:1459)
Leydig cell tumor:
- Tumor centered in ovarian hilus
- Cytoplasmic Reinke crystals
- Nuclei tend to cluster, forming eosinophilic nuclei free zones (Int J Gynecol Pathol 1989;8:299)
- Fibrinoid necrosis of blood vessel walls

Additional references

Surg Pathol Clin 2019;12:587, Pathology 2018;50:5

Board review style question #1

A 59 year old woman presents with bitemporal hair loss and hirsutism. Exploratory laparotomy reveals a 6 cm right ovarian mass, which is resected. Which of the following is true of this tumor?

30 - 40% are malignant
CD10 positive
Harbors a FOXL2 mutation
Reticulin stain shows a pericellular pattern

Board review style answer #1

D. Reticulin stain shows a pericellular pattern

Comment Here

Reference: Thecoma

Board review style question #2

A 62 year old woman presents with postmenopausal bleeding and on workup is found to have a 5 cm left ovarian mass. Which of the following immunostains is typically positive in this tumor?

AE1 / AE3
CD99
Cyclin D1
DOG1
Inhibin

Board review style answer #2

E. Inhibin

Comment Here

Reference: Thecoma

Torsion

Table of Contents

Definition / general

Ovary:

Rare; partial or complete rotation of ovarian vascular pedicle, causing obstruction to venous outflow and arterial inflow
In children, ovary is often normal (Arch Pediatr Adolesc Med 2005;159:532)

Fallopian tube:

"Twisting" of fallopian tube that blocks blood flow, causing ischemia and associated edema and pain
Often accompanies torsion of adjacent ovary (often with a cyst) but may be isolated to tube

Epidemiology

Fallopian tube:

Occurs in women of all ages
2/3 involve right tube

Etiology

Fallopian tube:

Usually associated with a mass / cyst causing rotation / obstruction
Also PID, hydrosalpinx, tubal ligation or adhesions
Occasionally no identifiable cause

Clinical features

Ovary:

Presents with abdominal pain, patients need emergency ultrasound and laparoscopy (J Pediatr Adolesc Gynecol 2008;21:201)
Predisposing factors: large cyst, neoplasms (benign or malignant), pelvic inflammatory disease; also associated with in vitro fertilization

Fallopian tube:

sharp lower abdominal pain, fever, tachycardia, leukocytosis (Acta Obstet Gynecol Scand 2010;89:1354)

Radiology description

Fallopian tube: ultrasound usually shows adnexal mass with heterogeneous echogenicity and cystic component with fluid levels

Case reports

25 year old woman with isolated fallopian tube torsion (AJR Am J Roentgenol 2005;185:1590)
32 year old woman at 32 weeks gestation with nausea, pain and vomiting (J Med Case Reports 2008;2:378)

Treatment

Ovary:

Cases during pregnancy (J Obstet Gynaecol Res 2008;34:683)
Recommended to attempt to preserve ovary, since most are viable (Clin Obstet Gynecol 2006;49:459)

Fallopian tube:

May resolve or tube may become necrotic and calcified with autoamputation of tube and ovary
Often requires surgical excision

Clinical images

Images hosted on other servers:

Fallopian tube

Gross description

Fallopian tube: swollen, dusky fallopian tube, with or without associated mass / cyst

Gross images

AFIP images

Hemorrhagic infarction of tube

Microscopic (histologic) description

Fallopian tube: ischemic necrosis of mucosa and wall

Tubo-ovarian abscess

Table of Contents

Abscess | Pelvic inflammatory disease (PID)

Abscess

Definition / general

Nonspecific abscess localized to the ovary
Primary ovarian abscess is defined as inflammation arising in the ovarian tissue
Secondary ovarian abscess originates in extraovarian sites

Epidemiology

Primary ovarian abscesses are quite rare; most cases of ovarian abscess are secondary

Etiology

Primary abscesses may arise due to disruption of ovarian capsule, as in ovulation or surgical intervention (vaginal hysterectomy, ovarian cystectomy, caesarean section, pregnancy, use of intrauterine device, transvaginal or percutaneous needle aspiration of endometrioma or follicle aspiration as part of in vitro fertilization), which gives bacteria access to the ovarian stroma (Tunis Med 2010;88:285)
Also occurs due to hematogenous and lymphatic spread
Secondary ovarian abscess may be associated with tubo-ovarian abscess, salpingitis, ascending infection of lower genital tract (pelvic inflammatory disease) or complication of GI infections (diverticulitis, appendicitis)

Clinical features

Nonspecific symptoms, making diagnosis difficult
Time between capsule disruption and clinical presentation depends on bacterial inoculum dose, type and virulence and if infection occurred secondary to direct contamination at surgery or via devitalized tissue

Laboratory

Most common infectious organisms are Streptococcus type B; other bacteria

Case reports

2 cases of Brucella ovarian abscess (J Clin Ultrasound 2007;35:395)
Enterobius vermicularis infection with tubo-ovarian abscess and peritonitis occurring during pregnancy (Surg Infect (Larchmt) 2009;10:545)
Tubo-ovarian abscess with Morganella morganii bacteremia (J Microbiol Immunol Infect 2009;42:357)
Abdominal abscesses with Streptococcus milleri group after laparoscopic chromopertubation (Acta Obstet Gynecol Scand 2010;89:982)

Treatment

Initial treatment is intravenous antibiotics
If no response within 72 hours, if abscess ruptures or if surrounding organs are affected, immediate laparoscopy or laparotomy with removal of the ovary is the main treatment

Gross description

Large, loculated cyst with pus or secretion

Gross images

AFIP images

Tubo-ovarian abscess
complicating colonic
diverticulitis

Ovarian abscess
associated with
Crohn's disease

Microscopic (histologic) description

Cyst wall often contains ovarian stroma

Microscopic (histologic) images

Contributed by Eman Abdelzaher, M.D., Ph.D. and AFIP

Tubo-ovarian actinomycosis

Ovarian stroma
is replaced by
collagenous tissue

Pelvic inflammatory disease (PID)

Definition / general

Polymicrobial infection in women characterized by inflammation of the upper genital tract, including endometritis, salpingitis, pelvic peritonitis and occasionally leading to tubo-ovarian abscess

Epidemiology

Primarily affects young, sexually active and reproductive aged women
Inversely proportional to age with the highest rates in the 15 to 19 year old group
Incidence steadily increased in 1970s due to rising rates of STDs and peaked in early 1980s
Although current incidence is lower, estimates of prevalence are not exact and likely underrepresent the true prevalence of disease due to subclinical PID, increasing rates of outpatient diagnosis and inaccuracies in diagnosis

Sites

Usually begins in endometrium and is associated with tubal involvement and tubo-ovarian abscess or cyst

Etiology

Most commonly due to gonorrhea, chlamydia, enteric bacteria or puerperal infections (from end of third stage of labor until uterus completely involutes at 3 - 6 weeks)
Acute, symptomatic forms, previously primarily due to Neisseria gonorrhoeae, have been replaced by mild to moderate cases due to Chlamydia trachomatis or mycoplasmas
Usually polymicrobial

Clinical features

No single, subjective complaint, physical examination finding or laboratory finding is highly sensitive or specific for the diagnosis
Pelvic pain, adnexal tenderness, fever and vaginal discharge are common
Classified as acute, subacute or subclinical

Laboratory

Peripheral white blood cell count is nonspecific and elevated in only 44% of cases
Elevations in C reactive protein or erythrocyte sedimentation rate show good sensitivity and specificity
Vaginal wet smear with 3+ white blood cells per high power field has a high sensitivity for upper genital tract infection and the absence of WBCs has a high negative predictive value
Transvaginal ultrasound may demonstrate a swollen, tortuous fallopian tube
Laparoscopic evaluation of the pelvic organs is considered the gold standard for diagnosing PID

Prognostic factors

Short and long term sequelae include tubal factor infertility, ectopic pregnancy, chronic pelvic pain, peritonitis, bacteremia or intestinal obstruction due to adhesions

Treatment

Outpatient treatments, mostly by the oral route, have replaced inpatient, intravenous treatments for uncomplicated PID (Curr Opin Infect Dis 2010;23:83)

Gross images

Images hosted on other servers:

Abscess

Additional references

eMedicine: Imaging in Pelvic Inflammatory Disease and Tubo-Ovarian Abscess [Accessed 17 January 2024], Wikipedia: Pelvic Inflammatory Disease [Accessed 17 January 2024], Infect Dis Clin North Am 2008;22:693

Undifferentiated / dedifferentiated carcinoma (endometrium / ovary)

Table of Contents

Definition / general

This topic covers tumors of the endometrium and ovary
Undifferentiated carcinomas are characterized by a patternless, sheet-like growth of discohesive cells with an aggressive clinical course (Am J Surg Pathol 2005;29:1316, Mod Pathol 2010;23:781, J Pathol Clin Res 2021;7:144)
Tumors are often associated with mismatch repair and SWI / SNF protein deficiency (Mod Pathol 2016;29:302, Histopathology 2016;69:560, Mod Pathol 2016;29:1586)
If areas of a differentiated carcinoma are found, the tumor is called dedifferentiated carcinoma (Int J Gynecol Pathol 2006;25:52)

Essential features

At least focal sheet-like growth pattern with lack of glandular or papillary differentiation
High mitotic and proliferation indices
Absence or significantly diminished expression of markers of differentiation (e.g. CK7, PAX8, ER and claudin4)
Presence of a differentiated component (usually low grade endometrioid adenocarcinoma) is necessary for the diagnosis of dedifferentiated carcinoma
Loss of a core SWI / SNF protein is helpful in confirming the diagnosis but not essential to make the diagnosis

ICD coding

ICD-O:
- 8020/3 - carcinoma, undifferentiated, NOS
- 8020/3 - dedifferentiated carcinoma
ICD-11:
- 2C73.Y & XH1YY4 - other specified malignant neoplasms of the ovary & carcinoma, undifferentiated, NOS
- 2C73.Y & XH5R16 - other specified malignant neoplasms of the ovary & dedifferentiated carcinoma
- 2C76.Y & XH1YY4 - other specified malignant neoplasms of the corpus uteri & carcinoma, undifferentiated, NOS
- 2C76.Y & XH5R16 - other specified malignant neoplasms of the corpus uteri & dedifferentiated carcinoma

Epidemiology

Median age is 55 years; range 21 - 76 years (Mod Pathol 2010;23:781)
2% of endometrial carcinomas (Mod Pathol 2010;23:781)
0.5% of ovarian carcinomas (Int J Gynecol Pathol 2010;29:203)

Sites

Endometrium
Ovary

Pathophysiology

Likely evolves from a differentiated endometrial or ovarian carcinoma secondary to disrupted epigenetic modulation
Inactivation of the SWI / SNF chromatin remodeling complex is common
Often associated with mismatch repair deficiency

Etiology

No associated environmental risk factors

Clinical features

Usually presents at advanced stage
Abdominal pain and swelling

Diagnosis

There are no established tests to screen for endometrial and ovarian malignancies where the vast majority of undifferentiated and dedifferentiated carcinomas occur
When clinical suspicion arises, abdominal ultrasound and computed tomography scans are useful adjunct
Definitive diagnosis requires biopsy tissue

Radiology description

Large, solid adnexal mass with variable hemorrhage and necrosis

Prognostic factors

Undifferentiated and dedifferentiated tumors have a poor prognosis (Int J Gynecol Pathol 2006;25:52, Mod Pathol 2010;23:781, J Pathol Clin Res 2021;7:144)
Presence of undifferentiated component in a differentiated tumor carries similar prognosis as pure undifferentiated carcinoma

Case reports

54 year old woman with dedifferentiated carcinoma of the ovary (Cesk Patol Spring 2018;54:33)
55 year old woman with BRG1 deficient dedifferentiated endometrioid adenocarcinoma of the ovary (Pathology 2016;48:82)
63 year old postmenopausal woman with an abdominal mass (Int J Clin Exp Pathol 2014;7:4422)
73 year old woman with ovarian undifferentiated carcinoma with voluminous mesenteric presentation (Int J Surg Case Rep 2012;3:551)

Treatment

Primary ovarian tumor treated primarily with chemotherapy followed by surgery
Total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH BSO) with or without lymphadenectomy
Emerging evidence supports that SWI / SNF deficient undifferentiated and dedifferentiated carcinoma does not respond to the conventional platinum based regimens (J Pathol Clin Res 2021;7:144)

Gross description

Large, solid mass with extensive tumor necrosis

Gross images

Images hosted on other servers:

Surgical specimen

Microscopic (histologic) description

Undifferentiated component:
- Diffuse, sheet-like growth pattern with lack of glandular or papillary architecture (occasionally glandular or papillary structures from the differentiated component may be entrapped)
- Comprised of a proliferation of monomorphic, medium sized cells
- Abrupt keratinization may be seen
- Cells frequently show discohesion (at least focally)
- Variable amount of cytoplasm, sometimes with rhabdoid features
- Brisk mitoses
- Necrosis frequently present
- Some cases may show focal spindling and myxoid changes
Differentiated component:
- Typically low grade endometrioid adenocarcinoma
- Rarely high grade endometrioid adenocarcinoma, high grade serous carcinoma or clear cell carcinoma

Microscopic (histologic) images

Contributed by Basile Tessier-Cloutier, M.D.

Undifferentiated and differentiated components

Solid architecture

Discohesive rhabdoid cells

ARID1B

Positive stains

In the differentiated component (if present): CK7, PAX8, ER / PR, E-cadherin
In the undifferentiated component:
- Elevated Ki67 index
- EMA, keratins, CK18 or PAX8, ER / PR may be focally expressed but can be completely absent (Mod Pathol 2010;23:781)
- Neuroendocrine markers (chromogranin, INSM1, synaptophysin and CD56) are frequently expressed; most cases show only focal expression in 1 or 2 neuroendocrine markers

Negative stains

In the differentiated component (if present):
- p53 wild type pattern (patchy negative to intermediate nuclear staining)
  - Uncommonly the differentiated component may be high grade, which can be associated with a mutant p53 IHC pattern
- p16 (patchy negative to weak nuclear and cytoplasmic staining)
  - Uncommonly the differentiated component may be high grade, which can be associated with a diffuse p16 IHC pattern
- Mismatch repair deficiency (MLH1, PMS2, MSH2, MSH6) is common (~50%)
In the undifferentiated component:
- CK7, PAX8, ER, WT1, claudin4 (may have weak or focal expression)
- SWI / SNF complex loss of protein expression (BRG1, INI1 or co-loss of ARID1A and ARID1B)
- Usually p53 wild type (negative to patchy intermediate nuclear staining)
- p16 (negative to patchy weak nuclear and cytoplasmic staining)
- Mismatch repair deficiency (MLH1, PMS2, MSH2, MSH6) is common (~50%)

Molecular / cytogenetics description

Commonly shows an inactivating mutation in one of the core SWI / SNF complex genes, resulting in the loss of expression of BRG1 (SMARCA4 gene), INI1 (SMARCB1 gene) or co-loss of ARID1A and ARID1B
Most cases are associated with mismatch repair deficiency and of those with MLH1 deficiency, almost all show MLH1 promoter hypermethylation
Mutations in other genes associated with endometrioid carcinoma, such as PTEN, PIK3CA, KRAS and CTNNB1, are often reported

Sample pathology report

Uterus, fallopian tubes and ovaries, hysterectomy and bilateral salpingo-oophorectomy:
- Endometrial dedifferentiated carcinoma (see synoptic report)
- Associated with an endometrioid adenocarcinoma FIGO grade 1
- Mismatch repair status: abnormal (MLH1 lost)
Uterus, fallopian tubes and ovaries, hysterectomy and bilateral salpingo-oophorectomy:
- Undifferentiated carcinoma of the ovary (see synoptic report)
- Mismatch repair status: abnormal (MLH1 lost)

Differential diagnosis

Endometrial undifferentiated and dedifferentiated carcinoma:
- Endometrial serous carcinoma, solid variant:
  - Tumor cells have a cohesive growth pattern
  - Mutated p53 IHC pattern
  - Intact SWI / SNF immunohistochemistry
- High grade endometrial endometrioid adenocarcinoma:
  - Tumor cells have a cohesive growth pattern
  - Intact SWI / SNF immunohistochemistry
  - May show isolated ARID1A loss of expression
- Carcinosarcoma of the endometrium (malignant mixed Müllerian tumor):
  - Homologous or heterologous sarcoma
  - Frequently mutated p53 IHC pattern
- SMARCA4 deficient uterine sarcoma:
  - Intact mismatch repair (MMR) status
  - Lacks differentiated component
  - Complete absence of differentiation markers of endometrial carcinomas (PAX8, CK7, claudin4)
  - Younger patient demographic
  - Low mutational burden
- Endometrial small cell neuroendocrine carcinoma:
  - Neuroendocrine nuclear features (fine chromatin, nuclear molding)
  - Diffuse expression of 2 or more neuroendocrine markers (chromogranin, synaptophysin, INSM1, CD56)
  - Intact SWI / SNF immunohistochemistry
- Lymphoma:
  - CD45 positive
  - Intact SWI / SNF immunohistochemistry
Ovarian undifferentiated and dedifferentiated carcinoma:
- High grade serous carcinoma of the ovary, solid variant:
  - Tumor cells have a cohesive growth pattern
  - Mutated p53 IHC pattern
  - Intact SWI / SNF immunohistochemistry
- High grade endometrioid adenocarcinoma of the ovary:
  - Tumor cells have a cohesive growth pattern
  - Intact SWI / SNF immunohistochemistry
    - May show isolated ARID1A loss of expression
- Carcinosarcoma of the ovary (malignant mixed Müllerian tumor):
  - Homologous or heterologous sarcoma
  - Frequently mutated p53 IHC pattern
- Small cell carcinoma of the ovary hypercalcemic type:
  - Intact mismatch repair (MMR) status
  - WT1 is usually positive unlike most undifferentiated or dedifferentiated carcinomas
  - Shows loss of expression of BRG1 (SMARCA4 gene) and BRM (SMARCA2 gene)
  - Younger patient demographic
  - Low mutational burden
  - Clinical finding of hypercalcemia
- Small cell neuroendocrine carcinoma (small cell carcinoma of the ovary, pulmonary type):
  - Neuroendocrine nuclear features (fine chromatin, nuclear molding)
  - Diffuse expression of 2 or more neuroendocrine markers (chromogranin, synaptophysin, INSM1, CD56)
  - Intact SWI / SNF immunohistochemistry
- Lymphoma:
  - CD45 positive
  - Intact SWI / SNF immunohistochemistry

Additional references

Semin Diagn Pathol 2021;38:137

Board review style question #1

This is a representative image from a solitary ovarian tumor in a 75 year old woman. The tumor shows absent INI1 immunohistochemistry expression. What is the most likely diagnosis?

Carcinosarcoma
High grade serous carcinoma of the ovary
Primary diffuse large B cell lymphoma of the ovary
Small cell carcinoma of the ovary hypercalcemic type
Undifferentiated carcinoma of the ovary

Board review style answer #1

E. Undifferentiated carcinoma of the ovary

Comment Here

Reference: Undifferentiated / dedifferentiated carcinoma (endometrium / ovary)

Board review style question #2

This is a representative image from an endometrial tumor in a 75 year old woman. What is the most likely diagnosis?

Carcinosarcoma of the ovary
Collision tumor
Endometrial dedifferentiated carcinoma
High grade endometrioid adenocarcinoma of the ovary
High grade serous carcinoma of the ovary

Board review style answer #2

C. Endometrial dedifferentiated carcinoma

Comment Here

Reference: Undifferentiated / dedifferentiated carcinoma (endometrium / ovary)

Upper gastrointestinal tract

Table of Contents

Definition / general

Secondary ovarian involvement by an adenocarcinoma of gastric, pancreatic or biliary tract origin is, by definition, evidence of advanced tumor stage (pM1), and carries a poor prognosis
Significant overlap of clinical, radiologic and pathologic features between primary and metastatic ovarian adenocarcinoma
In the work up of a mucinous ovarian neoplasm, a secondary malignancy should always be excluded pathologically or clinically

Terminology

Although commonly used to refer to all metastatic carcinoma involving the ovary, the term Krukenberg tumor strictly refers to adenocarcinoma with signet-ring cell differentiation; most (76%) arise from the stomach (J Clin Pathol 2012;65:585)

Epidemiology

The rate of secondary (metastatic) ovarian malignancies varies from 6 - 22% (Pathol Int 2005;55:231)
The rate of metastatic tumors from non-gynecologic organs is 9 - 14% (World J Gastrointest Surg 2010;2:109)
Gastric carcinoma
- Average age of diagnosis is 45 years
- An ovarian mass is usually the presenting sign, and 70 - 75% of patients have no primary identified at time of diagnosis
- Rates of ovarian involvement by gastric carcinoma depends on:
  - Prevalence - more frequent in regions with high prevalence such as Japan and Colombia
  - Type of cancer – diffuse (signet ring cell) type is more likely to metastasize
  - Young patients (< 36 years) have higher rates of diffuse-type cancer, with reported ovarian involvement in 55% of cases (Adv Anat Pathol 2006;13:205)
Pancreatic and biliary tree carcinoma
- A primary lesion is commonly unsuspected at oophorectomy and only discovered intra- or post-operatively (Am J Surg Pathol 1989;13:748, Int J Gynecol Pathol 2008;27:366)

Pathophysiology

Poorly differentiated tumors (most with signet-ring cell morphology) are more likely to metastasize to the ovary

Clinical features

Symptoms related to a pelvic mass include abdominal pain or discomfort, bowel obstruction, abnormal vaginal bleeding

Laboratory

Elevated CA-125 levels (> 100 U/mL) are common; suggested as a useful feature to distinguish from primary ovarian mucinous carcinoma (Gynecol Obstet Invest 2011;72:196), which have elevated CEA levels (> 5 ng/mL) and CA19-9 levels (> 37 U/mL) in a minority of cases

Radiology description

Bilaterality is a strong indicator of secondary origin, and occurs more frequently in gastric cancer (~ 80%) than in colon and pancreatobiliary tumors (Ultrasound Obstet Gynecol 2012;39:581)
Krukenberg tumor: bilateral complex masses with hypodense solid components (due to prominent stromal reaction) and internal hyperdensity (mucin) on T1 and T2 weighted MRI images
Other types: cystic and solid masses with multinodular and necrotic solid components

Treatment

Gastric adenocarcinoma is amenable to HER2 targeted therapy (Lancet 2010;376:687)

Gross description

Mass is frequently complex (solid and cystic) or purely solid
Purely cystic unilocular lesions are rare
Solid tumors have a multinodular appearance and extend to the ovarian / tumor surface
Some authors have reported a predominant small size (< 10 cm) and bilateral ovarian involvement; algorithms based solely on laterality and size have been proposed to separate primary from secondary neoplasms with high accuracy (Am J Surg Pathol 2003;27:985, Am J Surg Pathol 2008;32:128)
There is, however, reported evidence of significant overlap of such features: in a recent series, all metastatic carcinoma of upper GI origin were unilateral (2 / 6) or > 10 cm (4 / 6) (Int J Gynecol Pathol 2016;35:191)

Microscopic (histologic) description

Metastases frequently mimic the appearance of an ovarian mucinous neoplasm
May have areas mimicking a borderline or even benign primary mucinous tumor
Several clinical and pathologic features have been described as indicative of secondary (metastatic) origin, including:
- Bilaterality
- Size less than 10 cm
- Surface involvement
- Infiltrative pattern of invasion
- Presence of signet ring cells
- Extensive lymphovascular space invasion
- Mucin extravasation
If any of the above is present, the possibility of a metastasis should be considered and prompt ancillary testing and clinical investigation should be conducted
The term Krukenberg tumor should be reserved for adenocarcinoma involving the ovary with a signet ring cell component > 10% of tumor volume
Krukenberg tumors are usually solid and show a prominent fibromatous background
- Stroma is variably cellular and edematous
- Tumor cell infiltration is subtle, but diffuse
- Carcinoma cells have a dense eosinophilic cytoplasm and hyperchromatic irregular nuclei
- Signet-ring cells are usually dispersed between stromal fibers, but can also aggregate in clusters
Upper GI adenocarcinoma without a significant (> 10%) signet-ring cell component tends to be moderately to poorly differentiated
- The amount of intracellular mucin varies according to the degree of mucinous differentiation
Adenocarcinoma with mucin depletion mimics the architecture and cytoplasmic appearance of primary endometrioid tumors; however, nuclear pleomorphism and hyperchromasia tends to be prominent, and exceed what is expected for a primary ovarian tumor

Microscopic (histologic) images

Contributed by Carlos Parra-Herran, M.D.

Gastric

Pancreatic

Positive stains

Immunohistochemistry is useful to distinguish primary ovarian tumors from lower GI tract metastases (colon, rectum, appendix), but its role in identifying upper GI primaries (gastric, pancreatic, biliary tract) is limited given the significant overlap with primary ovarian tumors
- CK7: 88% (vs 95% of primary ovarian tumors)
- CK20: 43% (vs 45% of primary ovarian tumors)
- CDX2: 65% (vs 50% of primary ovarian tumors)
- SATB2: 11.5% (vs 5% of primary ovarian tumors)
Mucins MUC1, MUC4 and MUC5AC may be useful markers of GI adenocarcinoma:
MUC1 and MUC5AC may discriminate among different origins (Int J Gynecol Pathol 2014;33:166, Int J Clin Exp Pathol 2013;6:613)
- Pancreatic: MUC1+, MUC5AC+
- Biliary: MUC1+, MUC5AC-
- Ovary: MUC1-, MUC5AC+
- Gastric and colorectal: MUC1-, MUC5AC-
Keratin 17 (CK17) is expressed in 90% of pancreatic and 50% of pancreatobiliary adenocarcinoma, whereas esophageal and gastric cancers tend to be negative (Am J Surg Pathol 2005 Mar;29:359)

Negative stains

Rates of expression in upper GI tract tumors are as follows:
- PAX8: 2.8% (vs 30 - 65% of primary ovarian mucinous tumors and 80% of primary ovarian endometrioid tumors)
- Among upper GI tumors, PAX8 expression has only been documented in pancreatic and esophageal adenocarcinoma (Am J Surg Pathol 2011;35:816)
- ER: 0% (vs 30% of primary ovarian tumors)
Inactivation of DPC4 / SMAD4 tumor suppressor gene is seen in approximately 55% of pancreatic ductal adenocarcinoma (Am J Clin Pathol 2001;116:831)

Contributed by Carlos Parra-Herran, M.D.

An algorithm to determine origin using currently available markers

Differential diagnosis

Primary ovarian neoplasm (benign, borderline or malignant): no suspicious features described above (bilaterality, surface involvement, signet-ring cell morphology, etc), PAX8+
Metastases from lower GI tract: positive for SATB2 / CK20 / CDX2 / MUC2, CK7-
Metastases from cervix: p16+ (strong, diffuse)
Sertoli-Leydig cell tumors: main differential with Krukenberg tumors given the solid appearance, the fibromatous background and the presence of cells with dense eosinophilic cytoplasm seen in both entities
- The former lacks signet-ring cells and cytokeratin expression (pan-cytokeratin, CK7, CK20), and will conversely express inhibin and calretinin

Additional references

Am J Surg Pathol 2003;27:281, J Clin Pathol 2012;65:591

WHO classification

Table of Contents

Definition / general

This topic covers tumors of ovarian origin (primary) only, with most tumors falling under the categories of epithelial, mesenchymal, sex cord stromal and germ cell
The remaining (exceptionally rare) tumors are in the miscellaneous category

Major updates

WHO first classified low and high grade serous carcinoma as different subtypes of the same tumor; now it is evident that these are 2 different types of carcinoma with different molecular characteristics, immunohistochemical profile, morphology, pathogenesis and tumor progression
Most high grade serous carcinomas of the ovary arise from the distal fimbria of the fallopian tube from a precursor lesion known as serous tubal intraepithelial carcinoma (STIC) (Pathology 2015;47:423, Mod Pathol 2015;28:1101)
Low grade serous carcinomas of the ovary arise from benign or borderline serous neoplasms
SET (solid, endometrial-like, transitional) patterns harbor p53 mutations and are now under the category of high grade serous carcinoma
Many mutations have been found in sex cord stromal tumors and can differentiate subtypes, such as adult granulosa cell tumor (FOXL2) from poorly differentiated Sertoli-Leydig cell tumors (DICER1) and microcystic stromal tumor (CTNNB1 or APC mutation) (N Engl J Med 2009;360:2719, Am J Surg Pathol 2017;41:1178, Genes Chromosomes Cancer 2015;54:353)
Small cell carcinoma of hypercalcemic type is associated with SMARCA4 mutations (Histopathology 2016;69:727)
Seromucinous carcinoma has been removed and is now a subtype of endometrioid carcinoma (Am J Surg Pathol 2015;39:983)
Gynandroblastoma has been reintroduced after being removed from the previous WHO edition

WHO (2020)

Epithelial tumors

Serous tumors
- Serous cystadenoma, adenofibroma and surface papilloma
- Serous borderline tumor
  - Serous borderline tumor, micropapillary variant
- Low grade serous carcinoma
- High grade serous carcinoma
Mucinous tumors
Endometrioid tumors
Clear cell tumors
- Clear cell cystadenoma and adenofibroma
- Clear cell borderline tumor
- Clear cell carcinoma
Seromucinous tumors
- Seromucinous cystadenoma and adenofibroma
- Seromucinous borderline tumor
Brenner tumors
Other carcinomas
- Mesonephric-like adenocarcinoma
- Undifferentiated and dedifferentiated carcinoma
- Carcinosarcoma
- Mixed carcinoma

Mesenchymal tumors

Endometrioid stromal sarcoma
- Low grade
- High grade
Smooth muscle tumors
- Leiomyoma
- Smooth muscle tumor of uncertain malignant potential
- Leiomyosarcoma
Ovarian myxoma

Mixed epithelial and mesenchymal tumors

Adenosarcoma

Sex cord stromal tumors

Pure stromal tumors
- Fibroma, NOS
  - Cellular fibroma
- Thecoma
  - Luteinized thecoma associated with sclerosing peritonitis
- Sclerosing stromal tumor
- Microcystic stromal tumor
- Signet ring stromal tumor
- Leydig cell tumor
- Steroid cell tumor, NOS
  - Malignant steroid cell tumor
- Fibrosarcoma
Pure sex cord tumors
Mixed sex cord stromal tumors
- Sertoli-Leydig cell tumor
- Sex cord stromal tumor, NOS
- Gynandroblastoma

Germ cell tumors

Teratoma, benign
Immature teratoma, NOS
Dysgerminoma
Yolk sac tumor
Embryonal carcinoma
Choriocarcinoma, NOS
Mixed germ cell tumor
Monodermal teratomas and somatic type tumors arising from a dermoid cyst
- Struma ovarii, NOS
- Struma ovarii, malignant
- Strumal carcinoid
- Teratoma with malignant transformation
- Cystic teratoma, NOS
Germ cell sex cord stromal tumors
- Gonadoblastoma
  - Dissecting gonadoblastoma
  - Undifferentiated gonadal tissue
- Mixed germ cell - sex cord stromal tumor, unclassified

Miscellaneous tumors

Rete cystadenoma, adenoma and adenocarcinoma
Wolffian tumor
Solid pseudopapillary tumor
Small cell carcinoma of the ovary, hypercalcemic type
Wilms tumor

Tumor-like lesions

Microscopic (histologic) images

Contributed by Lewis A. Hassell, M.D.

Serous borderline tumor

Serous
borderline tumor,
micropapillary
type

High grade serous carcinoma

Clear cell carcinoma, ovary

Clear cell adenofibroma, borderline

Seromucinous borderline tumor

Dedifferentiated carcinoma in ovary

Sclerosing stromal tumor

Steroid cell tumor, ovary

Granulosa cell tumor, adult type

Sex cord tumor with annular tubules

Retiform Sertoli-Leydig tumor

Sertoli-Leydig tumor, intermediate

Mixed germ cell tumor

Immature teratoma

Additional references

WHO Classification of Tumours Editorial Board: Female Genital Tumours, 5th Edition, 2020

Board review style question #1

The WHO 2020 classification of ovarian tumors defines benign, borderline and malignant versions of which of the following tumor types?

Brenner tumors
Endometrial stromal tumors
Granulosa cell tumors
Mesonephric tumors
Seromucinous tumors

Board review style answer #1

A. Brenner tumors are classified into 3 groups: benign, borderline and malignant. Malignant seromucinous tumors were removed from WHO 2019. The other tumors do not include these separations.

Comment Here

Reference: Ovary - WHO classification

Board review style question #2

This histologic pattern would be most commonly expected in which of the following ovarian tumors listed in WHO 2020?

Clear cell carcinoma
Granulosa cell tumor
Sertoli-Leydig tumor
Sex cord tumor with annular tubules
Steroid cell tumor

Board review style answer #2

D. Sex cord tumor with annular tubules is characterized by cells with clear cytoplasm, basal nuclei and eosinophilic tubular material resembling basement membrane. The cells sometimes resemble Sertoli cells and the eosinophilic tubular material can mimic Call-Exner bodies of granulosa cell tumors.

Comment Here

Reference: Ovary - WHO classification

Wilms tumor (nephroblastoma)

Table of Contents

Definition / general

See also topics in Kidney tumor chapter: Childhood Wilms, Adult Wilms
Extrarenal Wilms tumor are very rare, mostly seen in children
Occur mostly in reteroperitoneum and very rarely in ovary
Hypothesis for origin of these tumors is still debated

Epidemiology

To date, limited case reports:
- 14 months (Journal of Gynecologic Surgery 2012;28:306)
- 3.5 years (J Pediatr Surg 2002;37:127)
- 21 years (Hum Pathol 2000;31:761)
- 56 years (Cancer 1988;61:1460)

Sites

Usually retroperitoneal and inguinal regions (J Pediatr Surg 2002;37:127)

Pathophysiology

Hypotheses regarding the origin: see J Indian Assoc Pediatr Surg 2007;12:145
- From ectopic metanephric blastema
- From primitive mesodermal tissue
- Connheim's cell rest theory

Clinical features

Palpable mass

Diagnosis

The diagnostic criteria necessary to establish the diagnosis include absence of primary kidney tumor and supernumerary kidney (radiologically and surgically)

Radiology description

USG and CT: solid mass with cystic components (J Pediatr Surg 2002;37:127)

Prognostic factors

When matched with the appropriate stage, prognosis is similar to its renal counterpart (J Indian Assoc Pediatr Surg 2007;12:145)

Treatment

Excision and chemotherapy
Similar staging and treatment protocol to renal Wilms tumor (J Clin Oncol 1991;9:167)

Gross description

Solid large mass with cystic cavities

Gross images

Images hosted on other servers:

Wilms tumor involving both kidneys

Microscopic (histologic) description

Sheets of undifferentiated blastemal component with or without epithelial, mesenchymal differentiation and anaplastic features

Microscopic (histologic) images

Images hosted on other servers:

Adult tumor (kidney)

Various images (kidney)

Negative stains

CK1, CK7, myoglobin, Myf-4, MyoD1, HMB45, chromogranin A
Synaptophysin, MelanA, beta-HCG, alpha-HCG, alpha-Inhibin, renal cell carcinoma antigen
Glycophorin A, PSA, estrogen and progesterone receptors (Appl Immunohistochem Mol Morphol 2008;16:128)

Differential diagnosis

Xanthogranulomatous oophoritis

Table of Contents

Definition / general

Xanthogranulomatous oophoritis is an uncommon, nonneoplastic, chronic process (Iran J Pathol 2018;13:372)
Destruction by massive cellular infiltration of foamy histiocytes admixed with multinucleated giant cells, plasma cells, fibroblasts, neutrophils and foci of necrosis (Iran J Pathol 2018;13:372)

Essential features

Xanthogranulomatous oophoritis is a rare form of chronic oophoritis (J Indian Med Assoc 2012;110:653)
Affects fallopian tubes or ovaries focally or entirely, forming a mass-like lesion in the pelvic cavity that invades the surrounding tissues (J Cancer 2012;3:100)

Terminology

Xanthogranulomatous oophoritis
Xanthogranulomatous inflammation of the ovary
Xanthogranulomatous inflammation of the female genital tract
Ovarian fibroxanthoma

ICD coding

ICD-10: N70.92 - oophoritis, unspecified

Epidemiology

Most frequent in females of reproductive age (range: 23 - 72 years)
Average age of patients with affected ovaries is 31 years (AJR Am J Roentgenol 2002;178:749)
Only 13 related cases of xanthogranulomatous inflammation involving fallopian tube or ovary have been described through 2012 (J Cancer 2012;3:100)

Sites

Xanthogranulomatous inflammation of the female genital tract is not common and usually involves the endometrium; however, xanthogranulomatous inflammation of the ovaries is a rare entity (J Ayub Med Coll Abbottabad 2017;29:162)

Pathophysiology

Exact pathophysiology is unknown
Associated with infection, ineffective antibiotic therapy
Ineffective clearance of bacteria by phagocytes, endometriosis, intrauterine contraceptive device, pelvic inflammatory disease and drugs (antibiotics) is suggested (Iran J Pathol 2018;13:372)

Etiology

Development can be of multiple predisposing factors, for example, pelvic inflammatory diseases, intrauterine device use, uterine leiomyoma, endometriosis and inappropriate antibiotic intake (BMJ Case Rep 2015 Jun 25;2015)

Clinical features

Longstanding history of pelvic inflammatory disease
Symptoms such as anorexia, fever, suprapubic pain, menorrhagia or vaginal bleeding, adnexal tenderness and a pelvic mass are the usual chief complaints (Iran J Pathol 2018;13:372)

Diagnosis

Careful histopathology by experienced pathologists aided by immunohistochemistry can lead to a definitive diagnosis (J Ayub Med Coll Abbottabad 2017;29:162)

Radiology description

Ultrasound of the abdomen reveals a thick walled, cystic hyperechoic ovarian mass (Iran J Pathol 2018;13:372)
Pelvic CT scan shows a peripherally enhancing ovarian cystic lesion, which represents either an inflammatory process or ovarian neoplasm (Iran J Pathol 2018;13:372)
Presence of nonenhancing intramural nodules in the thickened wall of an ovarian cystic mass may be a unique MRI indicator of xanthogranulomatous oophoritis (AJR Am J Roentgenol 2002;178:749)

Radiology images

Images hosted on other servers:

Pelvic sonography
shows a mixed
echogenicity mass

T2 MRI shows multiseptated cystic mass

Axial T2 weighted turbo spin echo MRI (TR / TE, 3900 / 99)

Axial T1 weighted spin echo MRI (800 / 12)

Prognostic factors

Since xanthogranulomatous oophoritis is usually associated with pelvic inflammatory disease, endometriosis, intrauterine death, etc., these patients should be followed up closely (Indian J Pathol Microbiol 2010;53:197)

Case reports

20 year old woman presenting with a tubo-ovarian mass (Iran J Pathol 2018;13:372)
24 year old woman who was misdiagnosed with an ovarian neoplasm (J Midlife Health 2018;9:41)
25 year old woman presented with intermittent fever and lower abdominal pain (Indian J Pathol Microbiol 1999;42:89)
26 year old woman with a 10 year history of pelvic inflammatory disease (Int J Gynecol Pathol 1984;3:398)
31 year old Lebanese woman, 8 years following an open appendectomy as a reaction to talcum powder present on surgical gloves (J Med Liban 2012;60:169)
45 year old woman with heavy vaginal bleeding for 20 days (BMJ Case Rep 2015 Jun 25;2015)
47 year old woman with a several month history of intermittent abdominal pain localized to the left suprapubic region (Arch Pathol Lab Med 2001;125:260)
48 year old woman with a 3 day history of lower abdominal pain and fever (AJR Am J Roentgenol 2002;178:749)

Treatment

Treatment of choice is oophorectomy (J Midlife Health 2018;9:41)

Gross description

Ovarian lesion usually has a solid mass with rugged outer surface
Serial sectioning mostly reveals tan, grayish white and necrotic cut surfaces (J Cancer 2012;3:100)

Gross images

Contributed by Jian-Hua Qiao, M.D.

Yellow nodules

Microscopic (histologic) description

Usually shows characteristic dense fibrosis with infiltration of the ovarian stroma by sheets and nodules of foamy macrophages, many histiocytes, lymphocytes and neutrophils (Iran J Pathol 2018;13:372)

Microscopic (histologic) images

Contributed by Jian-Hua Qiao, M.D.

Foamy histiocytes in cystic wall

Foamy histiocytes mixed with inflammatory cells

Foamy histiocytes

Positive stains

CD68 in foamy histiocytes
CD3 in T cells
CD20 in B cells (J Cancer 2012;3:100)

Negative stains

Pankeratin (AE1 / AE3), PAS

Sample pathology report

Left ovary and fallopian tube, left salpingo-oophorectomy:
- Cystic ovary with endometriosis
- Extensive xanthogranulomatous oophoritis
- Fallopian tube with no significant pathologic change

Differential diagnosis

Ovarian carcinoma:
- May be difficult to differentiate with imaging
- Gross and microscopic pathologic findings will easily differentiate malignant tumors from inflammatory lesions
Endometrioma:
- Usually filled with chocolate colored fluid
- Histologic sections of cystic wall show hemosiderin laden macrophages without abundant foamy histiocytes
Tubo-ovarian mass:
- Benign tumors can occur in the tubo-ovarian area, i.e. leiomyoma
- Gross and histologic examinations reveal smooth muscle neoplasm rather than inflammatory process / lesion

Additional references

Histopathology 1988;13:541, JKIMSU 2013;2:111

Board review style question #1

This gross photo of an ovary is most consistent with:

Endometriotic cyst / endometrioma
Leiomyoma
Ovarian malignancy / carcinoma
Ovarian simple cyst
Xanthogranulomatous oophoritis

Board review style answer #1

E. Xanthogranulomatous oophoritis (the gross photo shows variably sized yellow nodules, which are consistent with changes of xanthogranulomatous nodules of ovary).

Comment Here

Reference: Xanthogranulomatous oophoritis

Board review style question #2

This microscopic photo of an ovary includes changes of:

Endometriosis and xanthogranulomatous oophoritis
Hemorrhagic corpus luteum cyst
Ovarian malignancy / carcinoma
Ovarian simple cyst

Board review style answer #2

A. Endometriosis and xanthogranulomatous oophoritis. The microscopic photo shows endometriosis with increased foamy histiocytes in stroma and adjacent soft tissue, consistent with xanthomatous change.

Comment Here

Reference: Xanthogranulomatous oophoritis

Yolk sac tumor

Table of Contents

Definition / general

Primitive germ cell tumor with a variety of morphologic patterns, ranging from endodermal extraembryonic structures (secondary yolk sac, allantois) to, less commonly, endodermal somatic tissues (intestine, liver, mesenchyme)

Essential features

Most common before the age of 30
Usually occurs as a pure form or rarely as a component of a mixed germ cell tumor
Numerous morphologic patterns, with the hallmark Schiller-Duval bodies in some cases and immunohistochemical expression of SALL4, glypican 3 and AFP
Often associated with elevated serum alpha fetoprotein (AFP)
Usually favorable clinical outcomes due to chemosensitivity

Terminology

Primitive endodermal tumor (not recommended)
Endodermal sinus tumor (not recommended)

ICD coding

ICD-O: 9071/3 - yolk sac tumor
ICD-10: C56 - malignant neoplasm of ovary
ICD-11:
- 2C73.5 - endodermal sinus tumor, unspecified site, female
- 2C73.Y & XH09W7 - other specified malignant neoplasms of the ovary, yolk sac tumor

Epidemiology

~20% of malignant germ cell tumors of the ovary (Obstet Gynecol 2006;107:1075)
Second most common malignant ovarian germ cell tumor after dysgerminoma
Mean age is 19 years; most common in the second and third decades of life (Int J Surg Pathol 2014;22:677)

Sites

Usually ovary
Less common in uterus, vagina, vulva and peritoneum (Am J Surg Pathol 2017;41:1)

Pathophysiology

Chromosome 12 abnormalities, usually isochromosome 12p, in ~75% of patients (Cancer Res 1998;58:3105)

Clinical features

Abdominal enlargement or pain
Lower abdominal or pelvic mass (Int J Surg Pathol 2014;22:677)
Rarely hormonal manifestations

Diagnosis

Microscopic examination

Laboratory

Elevated serum levels of AFP (may be used diagnostically and in monitoring therapy)

Radiology description

Ultrasonography:
- Both echogenic and hypoechoic components (AJR Am J Roentgenol 1996;167:791)
Computed tomography:
- Usually appears as a unilateral large complex mass with solid and cystic components, heterogeneous enhancement and enlarged intratumoral vessels with hemorrhage and capsular tear (Acta Radiol 2016;57:197)
- Helpful features for differentiating yolk sac tumor from other ovarian tumors include a mixed solid / cystic nature, intratumoral hemorrhage, marked enhancement and dilated intratumoral vessels (Sci Rep 2015;5:11000)
- Intratumoral calcification and fatty tissue if associated with teratoma
Magnetic resonance imaging:
- Prominent signal voids (J Comput Assist Tomogr 2000;24:605)
- Often with areas of hemorrhage

Radiology images

Images hosted on other servers:

Large mass with ascites

Bilateral ovarian mass

Prognostic factors

Usually favorable prognosis due to chemosensitivity, with complete cure in > 80% of cases
Stage dependent, with 5 year survival rates of > 95% for stage I - II, 70% for stage III and 50% for stage IV (Gynecol Oncol 2017;147:296, Int J Gynecol Cancer 2018;28:77)
Prominent polyvesicular vitelline pattern associated with more indolent behavior (Am J Surg Pathol 2013;37:393)
Pure hepatoid and glandular intestinal type yolk sac tumors associated with poorer prognosis

Case reports

12 year old girl with ovarian yolk sac tumor presenting with acute abdominal pain and elevated serum AFP (Acta Biomed 2019;90:599)
17 year old girl with bilateral metachronous ovarian yolk sac tumors (J Pediatr Adolesc Gynecol 2017;30:259)
19 year old woman with mixed germ cell tumor (yolk sac tumor and choriocarcinoma) arising in gonadoblastoma (Int J Surg Pathol 2018;26:287)
20 year old woman with fertility sparing surgery for ovarian yolk sac tumor (J Clin Diagn Res 2017;11:QD12)
21 year old woman with ovarian yolk sac tumor associated with granulomatous reaction resembling tuberculosis (Turk Patoloji Derg 2016;32:126)

Treatment

Unilateral salpingo-oophorectomy (Eur J Surg Oncol 2006;32:1063)
Adjuvant multiagent combination chemotherapy

Clinical images

Images hosted on other servers:

Large ovarian tumor

Gross description

Usually unilateral ovarian mass with predilection for right ovary
Encapsulated with smooth and glistening surface, round, oval or globular, may be firm or somewhat lobulated
Rupture in 25% of cases (Int J Surg Pathol 2014;22:677)
Mean size 15 cm (range 3 - 30)
Fleshy, gray-yellow to gray-tan, solid and cystic friable cut surface, often with gelatinous changes and areas of hemorrhage and necrosis (Cancer 1976;38:2404)
May form adhesions to surrounding structures
When part of a mixed germ cell tumor, other components, such as a mature cystic teratoma or dysgerminoma, may be grossly recognizable
Honeycomb appearance (multiple small cysts) on cut surface if polyvesicular vitelline component is present (Am J Surg Pathol 2013;37:393)

Gross images

Contributed by Debra L. Zynger, M.D. and AFIP images

Smooth, nodular exterior

Gelatinous cut surface

Gelatinous cystic surface

Honeycomb surface (polyvesicular vitelline pattern)

Frozen section description

Admixure of characteristic growth patterns and tumor cells with clear to eosinophilic cytoplasm, variable cytologic atypia and mitotic activity, with or without Schiller-Duval bodies

Frozen section images

Contributed by Gulisa Turashvili, M.D., Ph.D.

High grade neoplasm

Cytologic atypia

Microscopic (histologic) description

Multiple histologic patterns with predominance of 1 or 2 patterns
Reticular / microcystic pattern:
- Most common pattern
- Loose meshwork of anastomosing channels and variably sized cysts (macro or microcysts) lined by primitive tumor cells with varying amounts of clear to eosinophilic cytoplasm (Cancer 1976;38:2404, Histopathology 2012;60:1023, Int J Surg Pathol 2014;22:677)
- Lining cells may be flattened and deceptively bland
- Tumor cells occasionally contain lipid and have a signet ring-like morphology
- Cysts may contain eosinophilic hyaline globules and amorphous, eosinophilic acellular basement membrane-like material
- Loose, hypocellular or myxoid stroma
Endodermal sinus pattern:
- Anastomosing network of labyrinthine-like spaces lined by tumor cells
- Formation of vaguely glomeruloid perivascular structures (Schiller-Duval bodies)
  - Hallmark of yolk sac tumor but their absence does not rule out the diagnosis
  - Variably present, ranging from 20 - 75% of cases (Surg Pathol Clin 2019;12:621)
  - Rounded to elongated papillary structures containing a central fibrovascular core with a single central vessel, surrounded by tumor cells projecting into a cystic / sinusoidal space (resembling immature glomeruli) (Histopathology 2012;60:1023)
Papillary pattern:
- Papillae containing fibrovascular cores lined by pleomorphic tumor cells with brisk mitoses
- Fibrovascular cores may be hyalinized
- May contain tumor giant cells (mono or multinucleated)
Solid pattern:
- Sheets of polygonal tumor cells with large vesicular or pyknotic nuclei with prominent nucleoli, brisk mitoses, clear to eosinophilic cytoplasm and well defined borders, sometimes with prominent hyaline globules
- Cells may be smaller and more blastema-like with scant cytoplasm
- May contain tumor giant cells (mono or multinucleated)
Festoon pattern:
- Complex ribbons and undulating cords
- Occasionally with a drape-like arrangement
Glandular pattern (forming endodermal somatic derivatives):
- Endometrioid type areas with glandular or villoglandular structures lined by single or multiple layers of tall columnar cells containing subnuclear or supranuclear vacuoles resembling secretory endometrium
- Intestinal type areas with glandular structures lined by mucinous columnar or low columnar glands, ranging from primitive cribriform structures to well differentiated glands with goblet cells and rarely Paneth cells
- Both types may occur in pure form and may contain tumor giant cells (mono or multinucleated)
Polyvesicular vitelline pattern (Am J Surg Pathol 2013;37:393):
- May occur in pure form
- Variably sized cysts or vesicles lined by flat to cuboidal to columnar cells, sometimes with basal or paraluminal vacuolation
- Variably cellular stroma, occasionally with eccentric constriction (resembling subdivision of primary yolk sac vesicle)
Parietal pattern:
- Tumor cells embedded in extracellular linear bands of PAS positive basement membrane-like material
Hepatoid pattern:
- Tends to occur in pure form
- Aggregates, clusters or cords of large polygonal cells with abundant uniform or granular eosinophilic cytoplasm, round nuclei and prominent nucleoli, separated by thin fibrous bands (Cancer 1982;50:2355)
Mesenchyme-like pattern:
- Cords, tubules and gland-like structures of tumor cells scattered in edematous to myxoid stroma
- May be markedly myxoid (magma reticulare)
General features:
- Variable cytologic atypia and mitotic activity
- Pale eosinophilic to clear cytoplasm
- Prominent nucleoli
- Intracellular hyaline globules
- Tumor cells lining cystic structures can be deceptively bland
- Rarely stromal luteinization
- May show areas of extramedullary hematopoiesis
- May be admixed with other malignant germ cell tumor, usually with dysgerminoma or gonadoblastoma in patients with gonadal dysgenesis
- May be associated with synchronous or metachronous ipsilateral or contralateral mature cystic teratoma

Microscopic (histologic) images

Contributed by Gulisa Turashvili, M.D., Ph.D., Sharon Song, M.D. and AFIP images

Reticular / microcystic pattern

Glandular pattern

Endometrioid-like glandular variant

Solid pattern

Papillary pattern

Polyvesicular vitelline pattern

Schiller-Duval body

Hepatoid variant

AFP

SALL4

GATA3

Pancytokeratin

CK7

Virtual slides

Images hosted on other servers:

Yolk sac tumor

AFP

Glypican 3

Positive stains

SALL4: marker of primitive germ cell differentiation (Arch Pathol Lab Med 2014;138:351, Am J Surg Pathol 2009;33:894)
AFP: highly specific but 60% sensitive, often patchy / focal and weak (Histopathology 2013;62:71)
Glypican 3: less specific but stronger expression (Am J Surg Pathol 2008;32:600)
PLAP
HNF1β
Pancytokeratin
GATA3: positive in reticular / microcystic, papillary and polyvesicular vitelline patterns but not in the glandular pattern (Histopathology 2016;68:613)
HepPar1: positive in glandular and hepatoid patterns
CEA, albumin: positive in hepatoid pattern (Int J Gynecol Pathol 2014;33:365)
TTF1: positive in foregut / respiratory pattern (Histopathology 2014;65:51)
CDX2: positive in glandular intestinal type pattern
Villin: positive in reticular / microcystic and glandular intestinal type patterns

Negative stains

PAX8: may be positive in ~25% (Appl Immunohistochem Mol Morphol 2012;20:451)
CK7: may be focally positive
EMA: may be focally positive
CD117: may be rarely positive
Napsin A
ER
PR
OCT 3/4
D2-40
NANOG
SOX2
CD30
βHCG

Electron microscopy description

Glandular intestinal type yolk sac tumor shows large nuclei with prominent nucleolonema, numerous intracytoplasmic ribosomes, rough endoplasmic reticulum, mitochondria and dense amorphous intracellular material (Pathol Res Pract 1987;182:609)

Molecular / cytogenetics description

Usually isochromosome 12p (Mod Pathol 2006;19:766)

Sample pathology report

Right fallopian tube and ovary, salpingo-oophorectomy:
- Ovary: yolk sac tumor (see synoptic report)
- Fallopian tube: benign

Differential diagnosis

Clear cell carcinoma:
- Typical architectural patterns (tubulocystic, papillary, solid) with or without hobnail cells
- Lack of microcysts and Schiller-Duval bodies
- Discordance between mitotic activity and cytologic atypia
- Stromal hyalinization
- Background adenofibroma or endometriosis
- Positive for napsin A, HNF1β, PAX8, CK7, EMA
- Negative for SALL4 and AFP
- Glypican 3 is not helpful in this differential diagnosis
Endometrioid carcinoma:
- Usually older patients
- Typical cytology (columnar cells with moderately atypical pseudostratified nuclei)
- Lack of histologic patterns of yolk sac tumor, Schiller-Duval bodies and primitive appearing nuclei (Int J Surg Pathol 2014;22:677)
- Squamous differentiation
- May be associated with endometriosis
- Positive for PAX8, ER, PR, CK7, EMA
- Negative for SALL4 and AFP
- Glypican 3 is not helpful in this differential diagnosis
Dysgerminoma:
- Monomorphic architecture composed of cells with ample pale cytoplasm and large round nuclei
- Lack of histologic patterns of yolk sac tumor, Schiller-Duval bodies and hyaline bodies
- Associated with lymphocytic and granulomatous reactions
- Positive for OCT 3/4 and D2-40
- Negative for AFP and glypican 3
Embryonal carcinoma:
- Very rare in pure form in the ovary
- Lack of histologic patterns of yolk sac tumor and Schiller-Duval bodies
- Aggregated of primitive cells with more marked nuclear atypia and more granular cytoplasm
- Positive for OCT 3/4, CD30 and SOX2
- Negative for AFP and glypican 3
Sertoli-Leydig cell tumor:
- Androgenic manifestations
- Morphologic patterns of Sertoli cell tumor or Leydig cells
- Positive for inhibin, calretinin, FOXL2 and SF1
- Negative for SALL4, AFP and glypican 3
Juvenile granulosa cell tumor:
- Solid or follicular growth composed of polygonal cells with eosinophilic to clear cytoplasm and hyperchromatic nuclei without grooves
- Lack of histologic patterns of yolk sac tumor and Schiller-Duval bodies
- Positive for inhibin, calretinin, FOXL2 and SF1
- Negative for SALL4, AFP and glypican 3
Metastatic hepatocellular carcinoma:
- Clinical history
- Diffuse, corded or trabecular patterns
- With or without bile within canaliculi
- Positive for arginase1, HepPar1, albumin in situ hybridization
- Negative for SALL4
Immature teratoma:
- Admixture of endodermal, mesodermal and ectodermal elements
Somatic yolk sac tumor:
- Yolk sac tumor associated with a somatic epithelial neoplasm, usually high grade (Histopathology 2016;69:739)
- Thought to be due to transdifferentiation of high grade carcinoma to yolk sac tumor, rather than a true mixed or collision tumor (i.e. somatic rather than germ cell origin) (Histopathology 2016;69:739, Int J Gynecol Pathol 2011;30:442)
- Typically displays a reticular pattern (Histopathology 2017;71:562)
- Occurs in postmenopausal women and exhibits poor prognosis (Int J Gynecol Pathol 2011;30:442)

Additional references

Mod Pathol 2016;29:1278, Histopathology 2018;72:634, Am J Surg Pathol 1987;11:767, Am J Surg Pathol 1996;20:1056

Board review style question #1

Which immunohistochemical markers are useful for differentiating this ovarian tumor from a dysgerminoma?

CD10, FOXL2, glypican 3 and SALL4
FOXL2, CD30, SALL4 and OCT 3/4
OCT 3/4, glypican 3, inhibin and SF1
OCT 3/4, glypican 3 and AFP
SALL4, CD10, glypican 3 and CD30

Board review style answer #1

D. OCT 3/4, glypican 3 and AFP

Comment Here

Reference: Yolk sac tumor

Board review style question #2

Which of the following is true about yolk sac tumors?

Call-Exner bodies
Expression of SALL4, AFP and glypican 3 by immunohistochemistry
Homer Wright rosettes
Low serum AFP levels
Most common in postmenopausal women

Board review style answer #2

B. Expression of SALL4, AFP and glypican 3 by immunohistochemistry

Comment Here

Reference: Yolk sac tumor

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