Ovary-tumor
Last revised 6 February 2010
Last major update January 2009
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Neoplasms: ovarian tumors-general, childhood, classification
Surface epithelial tumors: general
Serous tumors: general, cystadenoma, borderline, microinvasive, carcinoma, micropapillary, psammomacarcinoma, surface, ovarian implants
Mucinous tumors: general, mural nodules, cystadenoma, adenofibroma, primary retroperitoneal mucinous cystadenoma, borderline, microinvasive, carcinoma, mucinous metastases, pseudomyxoma peritonei, peritoneal mucinous carcinomatosis
Endometrioid tumors: general, cystadenoma, adenofibroma, borderline, carcinoma
Brenner tumors: general, benign, borderline, malignant
Other surface epithelial tumors: clear cell carcinoma, urothelial carcinoma, mixed epithelial-papillary
Germ cell tumors: general, carcinoid tumors, choriocarcinoma, dysgerminoma, embryonal carcinoma, mixed, polyembryoma, struma ovarii, teratoma-mature, teratoma-immature, yolk sac tumor
Sex cord stromal tumors: general, fibroma, gonadoblastoma, granulosa cell-adult, juvenile, gynandroblastoma, Leydig cell, lipid cell, myxoma, sclerosing stromal, Sertoli cell, Sertoli-Leydig, sex cord tumor with annular tubules, steroid cell tumor NOS, thecoma, tumor of adrenogenital syndrome, unclassified
Other ovarian specific tumors: female adnexal tumor of wolffian origin, microcystic stromal tumor, small cell carcinoma-hypercalcemic type, pulmonary type
Other tumors not specific to ovary: adenoid cystic/basaloid carcinoma, angiomyolipoma, angiosarcoma, benign papillary mesothelioma, endometrial stromal sarcoma, fibromatosis, fibrosarcoma, granulocytic sarcoma, hemangioma, infantile hemangioendothelioma, leiomyoma, leiomyosarcoma, lymphoepithelioma-like carcinoma, lymphoma, malignant mixed mullerian tumor (MMMT), mesothelioma, metastases to ovary, mullerian adenosarcoma, myofibroblastoma, nephroblastoma, neuroendocrine carcinoma, osteoclast-like giant cell tumor, osteosarcoma, paraganglioma, PNET, rhabdomyosarcoma, squamous cell carcinoma, undifferentiated carcinoma
Other: staging, features to report
See also Ovary-non tumor chapter
Primary references - Ovary chapter
AJCC Cancer Staging Manual (7th ed)
American Journal of Clinical Pathology [random articles are free full text-no registration], January 1975 to January 2009
American Journal of Surgical Pathology, March 1977 to December 2008
Archives of Pathology and Laboratory Medicine [always free full text and no registration], January 1976 to December 2008
Biomed Central [always free full text and no registration], 27 May 1999 to 17 December 2008
Human Pathology, December 1971 to January 2009
Modern Pathology [free full text and no registration after 1 year], March 1988 to December 2008
Rosai, J: Ackerman’s Surgical Pathology (9th Ed), Mosby, 2004 , not 1656-1671, 1673-1689, 1702-36
Tavassoli: Tumours of the Breast and Female Genital Organs (WHO, 2003), not 114-96
Websites: PathoPic - start page 5 (ovary)
Virtual slides - USCAP, vSlides
Journal search terms: each disease entity listed - last searched January 2009
Please refer to these primary references for more detailed discussions and photographs
Neoplasms
Ovarian Tumors - general- Ovary chapter
#5 cause of cancer death in women; incidence has not changed recently (15,000 estimated US deaths in 2008, American Cancer Society)
80% benign (usually ages 20-45 years)
90% of malignancies are carcinoma, 80% have spread beyond the ovary at diagnosis
Note: in one study, 15% of ovarian specimens required additional clinical information, which caused an altered diagnosis/revised report (Arch Pathol Lab Med 1999;123:615)
Risk factors for carcinoma: nulliparity, family history, older age, childhood gonadal dysgenesis, clomiphene, hereditary nonpolyposis colon cancer, long term estrogen replacement therapy (US National Cancer Institute)
Negative risk factors: history of oral contraceptives, pregnancy before age 25, prophylactic oophorectomy
BRCA1 or BRCA2 mutations: cause 10% of ovarian carcinomas; 16% with these mutations have tumors, usually serous cystadenocarcinomas; occult tumors in 4.5% of prophylactic salpingo-oophorectomies (Cancer 2007;109:1784); may be detectable only by examining entire ovary (Am J Surg Pathol 2001;25:1283, Am J Surg Pathol 2006;30:1222); BRCA1+ tumors are usually not borderline or mucinous (Hum Pathol 2000;31:1420)
Higher risk of BRCA1 or BRCA2 mutation if ovarian carcinoma (any age), breast cancer (any age), early onset breast cancer
BRCA1 prevalence is 1-2% in US Ashkenazi Jews is 1-2%, 0.24% in other US whites (Cancer Epidemiol Biomarkers Prev 2004;13:2078)
Note: 1-2% of patients undergoing prophylactic oophorectomy develop peritoneal adenocarcinoma, which resembles papillary serous carcinoma of ovary clinically and histologically
Origin: (a) surface coelomic epithelium, which gives rise to fallopian tubes, endometrium, endocervix; (b) germ cells which migrate to ovary from yolk sac; (c) stroma of ovary, which includes the sex cords, forerunners of endocrine apparatus
Symptoms: lower abdominal pain, abdominal enlargement, increased pressure on adjacent organs; occasionally causes bilateral diffuse uveal melanocytic proliferation, a paraneoplastic syndrome in which uveal melanocytes proliferate and cause blindness (Am J Surg Pathol 2001;25:212)
CA-125: a high molecular weight glycoprotein discovered in 1981 (J Clin Invest 1981;68:1331); elevated serum levels are somewhat sensitive but not specific for ovarian carcinoma; not recommended as a screening test (American College of Preventive Medicine)
Metastases from primary ovarian tumors - Ovary chapter
Contralateral ovary, peritoneal surfaces (1-5 mm tumor nodules which rarely invade deeply), para-aortic/pelvic nodes, liver, lung, pleura, omentum, diaphragm
Sister Joseph’s nodule: umbilical metastasis, may be first manifestation of disease
Metastases are associated with ascites, intestinal obstruction, ureteral involvement and hydronephrosis
Metastases are often positive for WT1, ER, PR, CA125; negative for GCDFP-15, CEA (except mucinous tumors, Am J Clin Pathol 2002;117:745, Am J Clin Pathol 1997;107:12)
Case reports: metastasis to breast (Am J Surg Pathol 1993;17:193)
Coexistence with uterine carcinoma: uncommon; may reflect metastases from uterus or ovary or two independent tumors; can differentiate with molecular techniques (Am J Clin Pathol 1996;105:350, Clin Cancer Res 2008;14:5840); overall excellent prognosis (Asian Pac J Cancer Prev 2006;7:234), better than metastatic disease
Metastasis from endometrial tumor to ovary is more likely if multinodular, bilateral, small ovarian tumors, tubal lumen involvement is present, deep myometrial invasion or myometrial vascular invasion is present (Hum Pathol 1985;16:28)
Tumors with endometrioid appearance in uterus and ovary are probably independent, have excellent prognosis
Metastases from cervix to ovary likely if bilateral ovary involvement, extensive extracervical disease and microscopic type is unusual for ovary, such as squamous or small cell
Other tumor histology often signifies metastases with poor prognosis
Treatment: must examine peritoneal cavity for proper staging
Benign or borderline tumors: unilateral salpingo-oophorectomy
Malignant tumors: bilateral salpingo-oophorectomy with total abdominal hysterectomy
Cytology: staging incorporates presence of malignant cells in washings or ascites fluid
Serous / endometrioid carcinomas more often have positive cytology than other carcinomas, particiularly if high grade
DD: reactive mesothelial cells
Childhood ovarian tumors - Ovary chapter
Most ovarian tumors are benign; malignant tumors have favorable outcome with chemotherapy, even after recurrence (Am Surg 2008;74:1062)
Usually present as unilateral mass without metastases (Pediatr Blood Cancer 2005;44:167)
Of malignant tumors, germ cell tumors predominate, followed by sex-cord stromal (15%) and epithelial tumors (15%) (Semin Pediatr Surg 2005;14:100)
Mature cystic teratomas are common
Excellent prognosis for germ cell tumors, even if malignant (Pediatr Blood Cancer 2006;46:459)
DD: neuroblastoma, Ewings/PNET, adnexal gland carcinoma, rhabdomyosarcoma, intraabdominal desmoplastic small cell tumor
Classification of tumors of ovary - Ovary chapter
Surface epithelial (65%), germ cell (15%), sex cord-stroma (10%), metastases (5%), miscellaneous
Benign, borderline (atypical proliferation, low malignant potential) or malignant; malignant may be invasive or non-invasive
Most malignant tumors are surface epithelial (90%)
WHO classification to be added
Surface epithelial tumors
Surface epithelial tumors-general - Ovary chapter
Risk of malignancy rises with increase in grossly solid areas
Derived from surface epithelium (also called coelomic or germinal epithelium) that invaginates to form glands or cysts; this epithelium is continuous with mesothelium that lines peritoneal cavity
Ovarian epithelium may undergo metaplasia/neoplasia to resemble tubal, endometrial or endocervical mucosa (mullerian differentiation)
Classify based on cell type, pattern (cystic, solid, surface), amount of fibrous stroma, invasiveness/atypia
Sample solid foci, base of papillary formations, areas adjacent to ovarian surface
Serous tumors
Serous tumors-general - Ovary chapter
25% of all ovarian tumors
60% benign, 15% borderline, 25% malignant
May also occur as primary tumors of peritoneal surface
If cystic, name as serous “cystadeno...”
If prominent fibrous component, name as adenofibroma or adenocarcinofibroma
Micro: tall, columnar, ciliated epithelial cells, resembling fallopian tube, filled with clear serous fluid; carcinomas frequently have psammoma bodies (concentric calcifications); squamous metaplasia unlikely (in contrast to endometrioid tumors)
Positive stains: CK7, CK8/18, CK19, EMA, B72.3, S100, amylase (25%), ER (50%), PR (50%), androgen receptor (50%), N-Cadherin (Hum Pathol 1997;28:734); usually CK7+ and CK20- (Am J Clin Pathol 2002;117:944)
Negative stains: CEA
Serous cystadenoma / cystadenofibroma - Ovary chapter
Benign; 25% bilateral
Case reports: giant serous cystadenoma arising from an accessory ovary in a morbidly obese 11 year old girl (J Med Case Reports 2008;2:7), with mural nodules of genital rhabdomyoma (Hum Pathol 2005;36:433)
Gross: smooth glistening cyst wall; papillary tumors have papillary projections on outer surface or protruding into cystic cavity
Gross images: serous cystadenoma #1; #2; #3; #4; #5
Micro: usually small, multilocular, simple papillary processes; single layer of tall, columnar, ciliated cells resembling normal tubal epithelium; stroma contains spindly fibroblasts; no atypia, no architectural complexity, no invasion
Micro images: benign glands within fibrous stroma; papillary areas; lining of simple cuboidal epithelium
Cytology images: small epithelial cell cluster; epithelium is negative for CD68 but macrophages are CD68+
Videos: #1
Serous cystadenofibroma - ovary chapter
More pronounced proliferation of fibrous stroma
Gross images: multinodular tumor; cystadenofibroma
Micro images: adenofibroma
Virtual slides: with stromal sex cord elements
Serous borderline tumors (serous - low malignant potential) - Ovary chapter
Younger women, often pregnant, rarely has malignant behavior
Bilateral in 1/3 if include microscopic tumors
5 year survival is 100% if confined to ovary; 90% if involves peritoneum
5 year survival is not equal to cure due to delayed recurrence or transformation to invasive carcinoma
Death due to bowel obstruction, ureteral obstruction, invasive carcinoma, sepsis and treatment complications
Define as invasive if cytologic atypia (cells round up and have increased eosinophilic cytoplasm as in squamous cell carcinoma, round nuclei, prominent nucleoli), destructive stromal invasion, stromal reaction, capsular invasion; invasive nests have loss of calretinin+ mesothelial cells and loss of stromal CD34+ fibrocytes around the nests, with presence of alpha-smooth muscle actin+ myofibroblasts present as a stromal response (Mod Pathol 2006;19:364)
Define as borderline if typical histologic features (papillary, stratification, detached papillae), even if metastases exist
Serous borderline and invasive carcinomas have different genetic aberrations, indicating that invasive carcinomas do not arise from preexisting serous borderline tumors (Hum Pathol 2002;33:632)
Rarely has supradiaphragmatic nodal involvement (Am J Surg Pathol 2006;30:739)
Poor prognostic factors: invasive implants, micropapillary or cribriform patterns (associated with invasive implants, Am J Surg Pathol 1999;23:397)
Lymph node involvement: tumors are diploid, no short term adverse prognostic significance (Am J Surg Pathol 1994;18:904)
Mullerian inclusion cysts: small cysts lined by bland, cuboidal-columnar serous-type epithelium with a simple architecture; found in lymph nodes, pelvic peritoneum, omentum, bowel serosa, uterine serosa and parametrial connective tissues; often multiple sites; may be bland-appearing metastases from serous borderline tumors (Am J Surg Pathol 2000;24:710)
Case reports: initial presentation as cervicovaginal psammoma bodies (Arch Pathol Lab Med 1988;112:564)
Gross images: serous borderline tumor; bilateral tumors
Micro: (need more complete description); no stromal invasion; may have stromal microinvasion or patterns that are not destructive stromal invasion, including individual eosinophilic cells and cell clusters, cribriform pattern, simple and noncomplex branching papillae, inverted macropapillae and micropapillae; individual, discrete aggregates of invasive epithelium may be up to 12 mm, and there may be diffusely scattered invasive foci without discrete aggregates; recommended to identify stromal-epithelial alterations featuring micropapillae in pathology reports as a higher risk lesion than serous borderline possibly analogous to low grade serous carcinoma (Am J Surg Pathol 2006;30:1209)
Serous borderline tumors (serous - low malignant potential) - continued
Autoimplants: usually on surface or between exophytic surface tumor papillae; consist of single cells or glands and clusters of cells with abundant eosinophilic cytoplasm and mild-moderate atypia within fibroblastic stroma, stroma dominates over epithelium in autoimplant; associated with noninvasive peritoneal implants; no apparent adverse prognostic value, so must distinguish from true stromal invasion (Am J Surg Pathol 2006;30:457)
Micro images: serous borderline tumor #1; #2; noninvasive implant; noninvasive desmoplastic implants; mixed invasive and noninvasive implants; invasive implants surrounded by myofibroblasts
Virtual slides: with noninvasive implants and pelvic lymph node involvement; with microinvasion
Videos: #1
DD: ovarian clear cell carcinoma with papillary features (unilateral, nonhierarchical branching, monomorphic cells with classic features elsewhere, endometriosis, focal cytologic atypia, Am J Surg Pathol 2008;32:269), low grade serous carcinoma (has destructive stromal invasion)
References: Mod Path 1988;1:407, Am J Surg Pathol 2002;26:1129, Am J Surg Pathol 2002;26:592
Microinvasive serous carcinoma - Ovary chapter
Same prognosis as serous borderline tumors
Small stromal foci (up to 2 mm) of single cells / small clusters of cells, occasionally cribriform or rounded aggregates of papillae
Eosinophilic cytoplasm with minimal/absent stromal reaction (Hum Pathol 1996;27:521, Hum Pathol 1990;21:397)
Serous cystadenocarcinoma / carcinoma - Ovary chapter
5 year survival of 70% if confined to ovary; drops to 25% if involves peritoneum
May present as lymphadenopathy (usually inguinal or supraclavicular, has similar survival by stage as classic presentation, Am J Surg Pathol 2004;28:1217)
Rarely metastasizes to breast or axillary nodes, associated with advanced stage disease; usually have papillary features but only occasionally psammoma bodies, WT1+, GCDFP-15 negative (Am J Surg Pathol 2004;28:1646)
65% bilateral
Rarely produces AFP (Arch Pathol Lab Med 1984;108:710)
May arise from tubal intraepithelial carcinoma (Am J Surg Pathol 2007;31:161)
Treatment: high grade tumors often have extreme drug resistance
Gross: solid, hemorrhagic, necrotic
Gross images: serous carcinoma #1; #2; #3; #4; #5; #6; #7, #8, #9, #10
Micro: branching papillary fronds, glandular complexity, nuclear atypia and stratification, frequent mitoses, stromal invasion (irregular or destructive infiltration by small glands or sheets of cells); psammoma bodies (calcium concretions with concentric laminations, may be intracellular due to autophagocytosis)
Recommended to classify as high grade or low grade (Am J Surg Pathol 2008;32:1667)
Micro images: serous carcinoma #1; #2; psammoma bodies
Virtual slides: #1; #2; low grade tumor
Videos: #1
Positive stains: WT1 (78%), CA125 (78%), mesothelin (also lung, pancreas, endometrial adenocarcinomas); also CK5/6 (55%) and D2-40 (23%) (Mod Pathol 2008;21:1147)
Molecular: frequent loss of heterozygosity of p53 and BRCA1 loci in high grade tumors; disseminated tumors appear to be monoclonal (Mod Path 1996;9:166)
DD: peritoneal mesothelioma (usually h-caldesmon+, calretinin+, ER-, Ber-EP4-, Am J Surg Pathol 2007;31:1139; calretinin+, D2-40+, podoplanin+, BerEP4-, MOC31-, Mod Pathol 2006;19:34); also metastatic invasive micropapillary carcinoma of breast (GCDFP-15+ (38%), WT1-, Hum Pathol 2008;39:666)
Serous micropapillary carcinoma - Ovary chapter
Also called low grade serous carcinoma
Behaves like low-grade adenocarcinoma; appear to be derived from serous borderline tumor or adenofibroma
Recurs as classic serous carcinoma
10 year survival is 70% vs. ~100% for borderline tumors
Invasive if destructive infiltrative growth; most are non-invasive
Survival: dependent on stage and invasiveness of implants; stage I invasive or noninvasive has 100% disease free survival; stage II/III noninvasive or invasive with noninvasive implants has 80% disease free survival, stage II/III noninvasive with invasive implants has 55% 10 year survival; stage II/III invasive with invasive implants has 45% 10 year survival
Micro: filigree pattern of small, uniform, elongated, stroma-poor or stroma-free papillae, at least five times as long as wide, arising directly in a nonhierarchical fashion from large fibrotic, edematous, or myxoid papillary stalks or from cyst walls; or a cribriform pattern of epithelial cells lining the stalks or cyst walls; or both; either or both patterns should be present on a confluent area at least 5 mm in greatest dimension on at least one slide; occasionally also have large macropapillae
Noninvasive: numerous delicate micropapillae (length > 5x width) with no/rare fibrovascular cores; radiates in “medusa” nonhierarchical branching pattern from thick fibrous stalks; may be cribriform due to fusion; micropapillae are covered by cuboidal/columnar cells with minimal cytoplasm, variable psammoma bodies, no cilia, no/rare mitotic figures; more recurrences but similar survival as serous borderline tumors (Am J Surg Pathol 2002;26:1129)
Invasive: by definition, have destructive infiltrative growth; invasive areas may be < 3 cm (microinvasion) or larger; stromal invasion is characterized by micropapillae and solid epithelial nests surrounded by a cleft or space and fibroblastic stroma; may also have noninvasive component; variable psammoma bodies; rarely mitotic figures or atypical mitotic figures; macropapillary component may signify invasive disease (Am J Surg Pathol 2008;32:1800); single cells or small clusters of cells appearing to be in spaces within nonreactive stroma are considered to NOT represent stromal invasion
Micro images: large fibrovascular core entirely surrounded by long, slender micropapillae #1; #2; low grade nuclei #1; #2
Molecular: chromosomal imbalances intermediate between serous borderline tumors and serous carcinomas (Hum Pathol 2002;33:47)
References: Am J Surg Pathol 2003;27:725, Am J Surg Pathol 2002;26:592, Am J Surg Pathol 2001;25:419
Serous psammomacarcinoma - Ovary chapter
Rare variant of serous carcinoma with massive psammoma body formation and low grade cytologic features
Behaves similar to serous borderline tumors
Serous surface tumor - Ovary chapter
Grows exophytically on ovarian surface, with little involvement of underlying organ (surface papilloma, surface borderline papillary tumor, serous surface papillary adenocarcinoma)
Malignant tumors tend to be bilateral, aggressive, have widespread dissemination to peritoneum at presentation
May develop in women with family history of ovarian cancer even after prophylactic oophorectomy
Micro: features of typical serous carcinoma; contiguous with hyperplastic mesothelium of ovarian surface or other locations; confined to ovarian surface or with focal minimal invasion
Positive stains: neutral or acidic mucins (Hum Pathol 1990;21:99), keratin, EMA, B72.3 (85%), LeuM1 (45%), vimentin (35%), CEA (25%)
Molecular: 65% have loss of heterozygosity of p53 and BRCA1 loci (Hum Pathol 1999;30:203)
EM: epithelial differentiation
DD: ovarian implants (in patients with primary ovarian tumors)
References: Hum Pathol 1989;20:426
Ovarian implants - Ovary chapter
In patients with primary ovarian tumors, implants are deposits of ovarian tumor on peritoneal surfaces, lateral pelvic gutters, right side of diaphragm or omentum, usually close to primary
Entire peritoneum may contain tumor nodules < 1 cm, resembling miliary tuberculosis
Implants are seen in 1/3 of patients with serous borderline tumors, mortality is 25%; some may arise from peritoneal mesothelium; destructive invasion and cytologic atypia are associated with disease progression
May regress spontaneously leaving psammoma bodies behind
Criteria: ovarian carcinoma if multiple peritoneal nodules with features of ovarian serous borderline tumor or carcinoma and some minimal ovarian involvement; extraovarian serous carcinoma or papillary tumor of peritoneum if no ovarian involvement
Criteria for implants associated with primary benign or borderline tumor - invasive: either invasion of underlying normal tissue, micropapillary architecture or solid epithelial nests surrounded by clefts; noninvasive: none of these features
Invasion by these criteria is associated with adverse outcome (Am J Surg Pathol 2001;25:419); features that do not correlate with invasion are nuclear atypia, mitoses, calcification, necrosis, and individual cell infiltration of the stroma
Micro: tufting, stratification, atypia, psammoma bodies; invasive cases usually had micropapillary pattern and solid epithelial nests surrounded by clefts
Positive stains: LeuM1, B72.3, CEA
DD: desmoplastic response in noninvasive tumors
Mucinous tumors
Mucinous tumors-general - Ovary chapter
15% of ovarian neoplasms, rare before puberty or after menopause
80% are benign, 10% are borderline and 10% are carcinoma
Compared to serous neoplasms, have more cysts, larger size (up to 25kg), more often unilateral
Filled with sticky, gelatinous fluid rich in glycoproteins
Fibromas rare
Based on genetic analysis, some ovarian and appendiceal lesions are independent, others are related
Features favoring appendiceal (non-ovarian) origin: ovarian surface involvement only; signet ring cell differentiation with appendiceal tumor identified (current or prior) of similar morphology, bilateral tumor consistent with appendiceal or colonic primary, unilateral tumor consistent with appendiceal or colonic primary with a history of appendiceal or colonic adenocarcinoma; also normal/slightly enlarged ovaries, bilateral ovarian involvement, simple or focally proliferative mucinous epithelium with abundant extracellular mucin in cases with predominantly surface involvement of the ovaries; multifocal or extensive abdominal cavity mucin in cases with stromal involvement, ruptured appendiceal adenoma and unruptured ovarian tumor of similar histology; presence of an associated mucinous intestinal tumor (Hum Pathol 1995;26:509)
May be associated with mature cystic teratoma (Am J Surg Pathol 2007;31:854)
Positive stains: CEA (particularly malignant tumor of intestinal type), keratin, EMA, amylase (present in 75% of malignant tumors, 20% of benign tumors); usually CK7+/CK20+ (similar to upper GI and endocervical tumors, Am J Surg Pathol 2006;30:1130); or CK7+/CK20- (Am J Clin Pathol 2002;117:944, Hum Pathol 1997;28:1039)
Negative stains: N-Cadherin (Hum Pathol 1997;28:734)
Mural nodules in mucinous cystic neoplasms - Ovary chapter
Associated with benign, borderline or malignant mucinous cystic tumors (Am J Surg Pathol 2002;26:1467)
Sarcoma-like mural nodules - Ovary chapter
Usually young women (mean 39-47 years old)
Considered benign or reactive
Excellent prognosis; presence does not affect the outcome of the tumor
Gross: typically multiple, small (0.6 to 6 cm), discrete, sharply demarcated, red-brown
Micro: well circumscribed with hemorrhage and necrosis but no vascular invasion; either (1) pleomorphic and epulis-like, composed of heterogeneous cell population including numerous multinucleated giant cells of the epulis type, atypical spindle cells with prominent mitotic activity and inflammatory cells, (2) pleomorphic and spindle cell, consisting predominantly of atypical spindle cells with large, hyperchromatic nuclei, prominent nucleoli, frequent atypical mitotic figures, mixed with histiocytes and inflammatory cells or (3) giant cell-histiocytic, composed of regular, round, well differentiated mononucleated giant cells
Positive stains: vimentin, CD68
Negative stains: keratin (may be a few scattered keratin+ cells)
Sarcomatous nodules - Ovary chapter
Older population
Poor prognosis
Gross: large, poorly circumscribed
Micro: monotonous spindle cell population, vascular invasion
Negative stains: cytokeratin, EMA
Positive stains: variable desmin and actin
Anaplastic carcinoma foci - Ovary chapter
May not affect prognosis in stage I tumors if unruptured (Am J Surg Pathol 2008;32:383)
Case reports: with multicystic mass and anaplastic carcinoma in mural nodule (Arch Pathol Lab Med 2002;126:871)
Gross: large, poorly circumscribed
Micro: rhabdoid, sarcomatoid or pleomorphic features; no prominent inflammatory reaction, no multinucleated giant cells
Micro images: H&E, keratin (fig 2C), EMA (fig 2D)
Positive stains: keratin, EMA
Mucinous cystadenoma - Ovary chapter
5% bilateral
Associated with carcinoid tumors in same ovary and endocervical adenocarcinoma; rarely with Zollinger-Ellison syndrome
Case reports: with cholesterol granuloma in draining lymph nodes (Arch Pathol Lab Med 1985;109:1124)
Gross images: mucinous cystadenoma #1; #2; #3; #4
Micro: tall, columnar, nonciliated cells, basal nuclei, abundant intracellular mucin; usually endocervical type; also intestinal type (picket fence architecture with Paneth cells) or mixed; stroma may be hypercellular or luteinized
Positive stains: CEA, keratin, EMA, amylase (20%); usually CK7+/CK20- (Am J Clin Pathol 2002;117:944)
Mucinous adenofibroma - Ovary chapter
Rare; mean 51 years old (24-76 years)
Benign
Gross: unilateral, 1-25 cm
Micro: glands lined by single layer of mucin-containing columnar cells; may have crowded glands with atypia
DD: metastatic adenocarcinoma
References: Am J Surg Pathol 1991;15:227
Primary retroperitoneal mucinous cystadenoma - Ovary chapter
Uncommon, found only in women
Resembles ovarian mucinous cystadenoma but is not attached to ovary
Appears to arise from mesothelial cell inclusions and subsequent mucinous metaplasia to form a cystadenoma
Case reports: 30 cm retroperitoneal cystic mass in 25 year old woman (Arch Pathol Lab Med 2001;125:691)
Gross: thin walled (1 mm) multilocular cyst containing clear serous fluid; smooth inner lining
Micro: lining composed of tall columnar cells with clear cytoplasm and basal nuclei and low cuboidal cell resembling mesothelial cells, in densely cellular collagenous stroma composed of closely packed spindle cells
Gross/micro images: H&E, PAS, ER, calretinin
Positive stains: PAS/diastase and Alcian blue (pH 2.5) in tall columnar cells; ER in stroma and low cuboidal cells; calretinin in low cuboidal cells; both cell types positive for CAM 5.2, CK7, CK20
Negative stains: PAS/diastase and Alcian blue (pH 2.5) in low cuboidal cells; ER and calretinin negative in tall columnar cells; all cells negative for B72.3, PR, CEA
Mucinous borderline tumors - Ovary chapter
Also called atypical proliferative mucinous tumor of ovary or mucinous ovarian tumor of low malignant potential
10% bilateral
Pure borderline tumors and borderline tumors with intraepithelial carcinoma are almost always Stage 1 and clinically benign, but must sample tumor extensively to rule out invasion
High stage borderline tumors with abdominal cavity mucin may represent ovarian metastases rather than primary borderline tumors - must examine appendix to correctly interpret (Am J Surg Pathol 2000;24:1447)
Micro: resemble villous or tubular adenomas of intestines; endocrine cells common; are noninvasive with intraglandular or intracystic epithelial proliferations; either endocervical (mullerian) or intestinal types
Classification: borderline may have slight atypia (grade 1 nuclei); borderline with intraepithelial carcinoma have grade 2/3 nuclei, 4+ layers or cribriform or stroma-free papillary growth pattern
Molecular: 40% have K-ras mutations (vs. 11% of mucinous carcinomas, Am J Surg Pathol 1999;23:323)
References: Am J Surg Pathol 2002;26:139
Endocervical type - Ovary chapter
Tumors usually mixed, but clinically resemble serous tumors due to papillary architecture, serous-type differentiation, frequent bilaterality, smaller size, indolent clinical behavior (only rare deaths, Am J Surg Pathol 2002;26:1529)
Mean 39 years (younger patients), range 25-64 years
Associated with endometriosis in 41% of cases, endosalpingiosis in 32%
Malignancy is based on cytology, not number of cell layers
Almost always stage I, excellent prognosis with no evidence of disease at followup, even with intraepithelial carcinoma or microinvasion (Am J Surg Pathol 2004;28:1311)
Micro: proliferation of branching papillary structures resembling borderline serous tumors; papillae composed of fibrovascular cores of variable size covered by variable epithelium; mucinous cells have basal nuclei; some papillary tips lack fibrovascular cores; small detached clusters of cells may be observed over the papillary tufts; hobnail cells also present; occassionally intraepithelial carcinoma or stromal microinvasion, but no stromal invasion; associated with noninvasive desmoplastic implants
Micro images: H&E, ER, PR
References: Am J Surg Pathol 2002;26:139, Am J Surg Pathol 2000;24:1447
Intestinal type - Ovary chapter
Comprises most borderline mucinous cases
Occurs in older patients, not associated with endometriosis
Excellent prognosis
Must count cell layers (1-3 layers is borderline tumor, 4 or more layers is malignant)
Gross images: seromucinous borderline tumor
Micro images: H&E, ER negative
Microinvasive mucinous adenocarcinoma - Ovary chapter
Same prognosis as mucinous borderline tumor
Small stromal foci (up to 2 mm) of single cells / small clusters of cells, occasionally cribriform
Eosinophilic cytoplasm with minimal/absent stromal reaction (Hum Pathol 1996;27:521)
Pale nuclear staining, fibrous reaction or edema in stroma, particularly in intestinal subtype
References: Am J Surg Pathol 2002;26:139
Mucinous cystadenocarcinoma / carcinoma - Ovary chapter
77% are ovarian metastases (see below), 23% are ovarian primaries (Am J Surg Pathol 2003;27:985)
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)
Definition: stromal invasion distinguishes these tumors from borderline tumors
Survival: 95% for stage 1 vs. 32% for stages 2+
10 year survival: borderline stage 1 - 95% (better than previously thought; prior series may have included metastases from intestine and pancreas); noninvasive malignant - 90%, invasive malignant - 66%
Distant metastases are rare
Expansile tumors are usually stage 1 and behave “benign”; infiltrative tumors may demonstrate malignant behavior and cause death even if stage 1 (Am J Surg Pathol 2002;26:139)
Poor prognostic factors for stage 1 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: primary tumors are usually unilateral, > 10 cm, smooth capsule, cystic and solid areas of tumor evenly distributed throughout ovary without discrete nodularity
Gross images: 33 cm tumor
Mucinous cystadenocarcinoma / carcinoma - Ovary chapter (continued)
Micro: 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 (disorderly penetration of stroma by neoplastic glands, single cells or cell clusters, may have desmoplastic response) or expansile (complex arrangement of glands, cysts or papillae lined by malignant epithelium with minimal or no intervening stroma)
Glands are almost always intestinal type and not endocervical type
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: grade 1-no solid areas, grade 2-up to 50% solid foci; grade 3-more than 50% solid foci; severe nuclear atypia can raise grade 1 or 2 carcinomas by one grade
Micro images: destructive invasion (fig c/d); CEA (fig A/B)
Virtual slides: 38 cm tumor
Positive stains: CEA, CK7, CK20, CA125 (weak)
Molecular: K-ras mutations are common
DD: 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)
References: Am J Surg Pathol 2000;24:1447, Am J Surg Pathol 2002;26:1529
Metastatic mucinous carcinoma to ovary - Ovary chapter
Primary sites: 45% GI, 20% pancreas, 18% gynecologic, 8% breast, 10% unknown
Features favoring metastasis and not primary ovarian tumor are history of extra-ovarian primary mucinous adenocarcinoma, bilaterality, surface implants (gross or microscopic), infiltrative pattern of stromal invasion; also nodular invasive pattern, ovarian hilar involvement (due to tumor emboli), single cell invasion, signet ring cells, vascular invasion, surface mucin (Am J Surg Pathol 2003;27:281); CDX2+ tumor cells suggests GI primary (Mod Path 2003;16:913)
Surface implant: nodular protrusion above adjacent cortical surface, composed of neoplastic glands and single cells
Gross: usually bilateral tumors or unilateral tumors < 10 cm, involves surface / superficial cortex, typically with nodular pattern; also surface implants
Micro: nodular pattern of invasion characterized by circumscribed aggregates of glands surrounded by zones of normal ovarian stroma, particularly in superficial ovary; may be mixed with haphazard infiltrative mucinous glands irregularly distributed throughout the ovarian stroma; borderline-like areas usually display much greater cytologic atypia than borderline / benign mucinous tumors; metastatic pancreatic carcinoma may contain bland mucinous epithelium simulating mucinous cystadenoma
References: Am J Surg Pathol 2003;27:985
Pseudomyxoma peritonei - Ovary chapter
Clinically represents mucinous ascites accompanied by peritoneal lesions with bland to low-grade adenomatous mucinous epithelium intimately associated with pools of extracellular mucin and fibrosis, diagnosed pathologically as disseminated peritoneal adenomucinosis
Peritoneal mucinous tumor/ascites almost always has mucinous epithelium present, if adequately sampled
Virtually all cases have appendiceal, not ovarian origin
Rare cases lacking mucinous epithelium usually do not recur
Three types of pseudomyxoma peritonei: (1) superficial; mucin contains hyperemic organizing vessels and fibroblasts; (2) dissecting with fibrosis; (3) metastatic mucinous carcinoma
Mucin is associated with cystic epithelial implants on peritoneal surfaces, adhesions to bowel, abdominal wall and bladder; intestinal obstruction and peritonitis
Due to production of MUC2, a gel-forming mucin that forms strong bonds with stroma
Treatment: excise as much tumor as possible, plus chemotherapy
References: Am J Surg Pathol 2000;24:1447
Peritoneal mucinous carcinomatosis - Ovary chapter
Rarely ovarian in origin
Micro: histologic features of carcinoma, usually signet-ring morphology
Endometrioid tumors
Endometrioid tumors-general - Ovary chapter
20% of surface ovarian tumors, usually carcinomas
15-40% are accompanied by endometrial carcinoma, but are considered independent primaries; often have a good prognosis;
may represent (a) single clonal tumor with concordant genetic alterations (based on identical loss of homozygosity, identical PTEN mutation or sporadic microsatellite instability patterns) or (b) single clonal tumor with genetic progression or (c) double/triple clonal tumors (Hum Pathol 2002;33:421)
Presence of
endometriosis in ovary usually means ovarian tumor is primary
Mixed tumors with endometrioid and serous / mucinous patterns also exist
Benign tumors are often cystadenofibromas
Gross: 40% bilateral, usually associated with extension beyond genital tract
Micro: tubular glands resembling endometrium; usually foci of squamous differentiation; often arises in background of fibroma / adenofibroma
Endometrioid cystadenoma - Ovary chapter
Micro: cystic tumor with endometroid features; no cytologic atypia, no architectural complexity; benign lesions may be adenofibroma, adenoma or cystadenoma
Endometrioid adenofibroma - Ovary chapter
No recurrence or deaths in patients with atypia
Micro: endometroid and fibroma-like features; may have mild to severe cytologic and architectural atypia
References: Am J Surg Pathol 1985;9:205
Endometrioid borderline tumor - Ovary chapter
Rare (<200 cases reported)
Mean age 55 years, range 28-86 years
97% present with stage I disease
Typically no recurrent disease or metastasis on follow-up, even if intraepithelial carcinoma or microinvasion (Am J Surg Pathol 2003;27:1253)
Micro: composed of aggregates, glands or cysts of endometrioid-type epithelium that is atypical or cytologically malignant 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%)
References: Am J Surg Pathol 2000;24:1465
Endometrioid carcinoma - Ovary chapter
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10-25% of primary ovarian carcinomas
15% coexist with endometriosis; tumors may arise from endometriotic cysts
15-30% of patients have endometrial hyperplasia or carcinoma; these tumors are often well differentiated with squamous metaplasia
Associated with keratin granulomas of peritoneum (Am J Surg Pathol 1990;14:925)
Mean age 51 years, range 26-87 years
Prognosis: better than serous/mucinous tumors because usually stage 1 and well differentiated; not as good as borderline tumors; may have malignant behavior if limited destructive stromal invasion (Mod Pathol 2005;18:903)
Sample thoroughly, as serous or undifferentiated carcinoma component lowers 5 year survival from 63% (pure) to 8% (Am J Surg Pathol 1994;18:687)
Tumors with yolk sac component are unusually aggressive (Am J Surg Pathol 1996;20:1056)
Cytologic atypia and microinvasion do not appear to affect prognosis (Am J Surg Pathol 2000;24:1465)
Gross: cystic, solid, hemorrhagic; papillary formations are absent or inconspicuous; 5% bilateral; mean 11 cm, range 3-22 cm
Gross images: focal necrosis; solid tumor
Micro: either non-cystic villoglandular pattern, glandular confluence or stromal disappearance; resembles endometrioid adenocarcinoma of uterus, usually well differentiated; 50% have squamous metaplasia (morules or keratin pearls, formerly called adenoacanthomas), 40% of well differentiated tumors have adenofibromatous component; 10% are associated with luteinized stroma cells; may contain luminal but not cytoplasmic mucin, may have clear cells (but lacks the architecture of clear cell carcinoma, Am J Surg Pathol 2007;31:1203); vascular invasion rare
Stromal invasion is defined as confluent glandular growth, stromal disappearance or obvious stromal invasion
Micro images: destructive invasion (fig a/b); low and high power
Virtual slides: resembling sex cord stromal tumor
Positive stains: keratin, CEA (some), HPL (some), N-Cadherin (Hum Pathol 1997;28:734)
EM: paranuclear microfilaments, “mesh basket” nucleoli
Molecular: PTEN mutations in 21%
DD: Sertoli-Leydig tumors (usually younger patients with endocrine symptoms, no squamous metaplasia, no typical endometrioid features elsewhere, no mucin, no adenofibroma component, keratin negative), metastatic colonic carcinoma, metastatic endometrial carcinoma (bilateral, multinodular, surface implants, prominent angiolymphatic invasion within ovarian stroma)
References: Am J Surg Pathol 1982;6:513, Am J Surg Pathol 2003;27:1253
Granulosa cell tumor like variant of endometrioid carcinoma of ovary - Ovary chapter
Micro: resembles granulosa cell tumor but has nonmorular nests with nuclear clearing and biotin activity; may have classic endometrioid features
Micro images: variant (fig 1A, C, E, G) versus granulosa cell tumor (fig 1B, D, F, H); variant (fig 2A-2E) versus granulosa cell tumor (fig 2F-2H)
Positive stains: PR
DD: granulosa cell tumor
Sertoliform variant of endometrioid carcinoma of ovary - Ovary chapter
Uncommon; resembles Sertoli and Sertoli-Leydig cell tumors
Usually age 60-70 years, older than Sertoli tumors (mean 25 years)
Good prognosis if limited to ovary (Arch Pathol Lab Med 2007;131:979)
Micro: compact anastomosing cords and small tubules within fibrous stroma without desmoplasia; usually low grade nuclear features, mucin at apical border of tumor cells; associated with classic endometrioid carcinoma in all cases, often with squamous metaplasia; usually focal adenofibroma component
Micro images: various images
Positive stains: keratin (CK7), EMA, ER, PR
Negative stains: inhibin (except for luteinized stromal cells, Mod Path 1999; 12:933), calretinin
Spindle cell variant of endometrioid carcinoma of ovary - Ovary chapter
Classify as endometrioid based on typical endometrioid glands, foci of squamous differentiation or adenofibromatous component
Similar behavior as typical endometrioid carcinoma
Micro: predominance of spindle-shaped epithelial cells
Positive stains (spindle cells): EMA, keratin
DD: sex cord stromal tumor, female adnexal tumor of wolffian origin, mixed mullerian tumor
References: Am J Surg Pathol 1995;19:1343
Brenner tumors-general- Ovary chapter
One of two types of transitional cell tumors - also transitional cell carcinoma
1-2% of ovarian neoplasms
Usually age 40+; median age 50 years
Slow growth, rarely ascites
Adenofibromas in which epithelial component consists of sharply demarcated nests of urothelial-like cells
Associated with hyperestrinism (endometrial hyperplasia and uterine bleeding), mucinous cystadenoma, struma ovarii, urothelial carcinoma of bladder
Has true urothelial differentiation based on immunostains (Am J Surg Pathol 2003;27:1434)
Epidermoid cysts may originate from epithelial cell nests of Brenner tumor (Am J Clin Pathol 1980;73:272)
Case reports: cervical carcinoma metastatic to Brenner tumor (Mod Path 1995;8:307)
Gross: unilateral, firm, white/yellow; resembles fibroma/thecoma except for cystic areas with yellow-brown fluid
Gross images: infarcted tumor
Micro: solid and cystic nests of urothelium-like cells surrounded by abundant dense, fibrous stroma; epithelial cells have sharp outlines; clear to pale cytoplasm, small but distinct nucleoli and nuclear grooves, similar to granulosa cell tumors
Positive stains: keratin, EMA, CEA, glycogen, chromogranin (focal), NSE; also EGFR (Am J Surg Pathol 2008 Nov 19 [Epub ahead of print])
Negative stains: p16, p53
References: Hum Pathol 1989;20:787
Benign Brenner tumor- Ovary chapter
Derived from ovarian surface epithelium and metaplasia; similar to Walthard nests
6% bilateral
Gross images: solid and cystic
Micro: sharply demarcated solid epithelial nests in dense fibrous stroma; cells are uniform, polygonal with pale cytoplasm and often grooved nuclei; frequent microcysts within epithelial nests
Metaplastic - with prominent cystic formation, accompanied by florid mucinous changes similar to cystitis glandularis
Proliferating - with papillary pattern and low grade nuclear atypia (resembles low grade urothelial carcinoma of bladder)
Micro images: #1
Virtual slides: Brenner tumor
Videos: #1
Positive stains: CK7, thrombomodulin, uroplakin III (focal)
Negative stains: CK20
References: Am J Surg Pathol 2003;27:1434
Borderline Brenner tumor- Ovary chapter
Mean age 60 years, older than for benign Brenner tumor
Larger tumor with mass related symptoms
May be associated with bladder urothelial carcinoma
Rare local recurrence, otherwise benign behavior
Gross: unilateral, multilocular cysts, 10-25 cm with papillary or polypoid projection into lumen
Micro: solid and papillary epithelial proliferation with high grade nuclear atypia; papillary areas lined by multilayer epithelium (looks like high grade urothelial carcinoma), cells have prominent nucleoli, nuclear grooves, no stromal invasion
Positive stains: CK7
Negative stains: CK20
References: Am J Surg Pathol 2003;27:1434
Malignant Brenner tumor- Ovary chapter
Atypical cytology and stromal invasion
May be bilateral
Better prognosis than urothelial (transitional cell) carcinoma
Micro: resembles urothelial, squamous or undifferentiated carcinoma, but associated with benign or borderline Brenner component; stromal invasion is present
Micro images: #1
Other surface epithelial tumors
Clear cell adenocarcinoma - Ovary chapter
Also called mesonephroid adenocarcinoma
Associated with endometriosis or endometrioid carcinoma of the ovary
Usually ages 40-59 years
Stage for stage, similar prognosis to other ovarian carcinomas
Gross: spongy, cystic
Gross images: multiloculated
Micro: tubular-cystic, papillary or solid; papillary cores have prominent hyalinization; large tumor cells, some with nuclei that protrude into lumina (hobnail), clear cytoplasm (glycogen, mucin, fat); resembles mucinous tumor on frozen section
Micro images: #1
Positive stains: keratin, Leu-M1 (90%), hyaline globules are PAS+ diastase resistant but AFP negative; VHL gene product (90%, Am J Clin Pathol 2008;129:592), hepatocyte nuclear factor 1 beta (Mod Pathol 2006;19:83)
Negative stains: AFP, WT1, ER, usually GPC3
Micro images: H&E and HNF-1beta expression (fig a)
DD: high grade serous carcinoma (usually WT1+, hepatocyte nuclear factor 1 beta negative, often ER+, Am J Surg Pathol 2009;33:14), yolk sac tumor (AFP+, GPC3+ , Am J Surg Pathol 2008;32:600), dysgerminoma (Oct3/4+)
References: Am J Clin Pathol 1989;91:511
Oxyphilic variant of clear cell adenocarcinoma - Ovary chapter
Abundant eosinophilic cytoplasm, but also typical clear cell areas (Am J Surg Pathol 1987;11:661)
Urothelial carcinoma (transitional cell carcinoma) - Ovary chapter
1-2% of surface epithelial tumors of ovary
Mean age 56 years, range 33-94 years
Resembles urothelial carcinoma of bladder but no coexisting Brenner component
Poorer prognosis than malignant Brenner tumor
Median survival for stage 3/4 disease is 28 months, similar to serous carcinoma (Hum Pathol 1996;27:1267)
Gross: mean 10 cm, range 3-30 cm, 60% solid and cystic, 41% bilateral
Micro: undulating, diffuse, insular or trabecular patterns; papillary structures lined by urothelium-like cells and nests of epithelial cells with high grade features, pale granular cytoplasm, large nucleoli or longitudinal grooves, separated by fibrous stroma; usually necrosis; may have other ovarian epithelial components (usually serous)
Micro images: fig 5: H&E, fig 6: ER+
Positive stains: CK7, WT1, p53, p16, ER (Arch Pathol Lab Med 2005;129:194)
Negative stains: uroplakin III, CK20, EGFR (Am J Surg Pathol 2008 Nov 19 [Epub ahead of print])
References: Am J Surg Pathol 2003;27:1434, Am J Surg Pathol 2004;28:453
Mixed epithelial-papillary cystadenoma of borderline malignancy of mullerian type - Ovary chapter
Associated with endometriosis, favorable prognosis
Mean age 35 years
Micro: mucinous, serous, endometrioid and squamous epithelium; may have squamous overgrowth, prominent neutrophilic infiltration of epithelium (Am J Surg Pathol 2003;27:242)
DD: borderline Brenner tumor
Germ cell tumors
Germ cell tumors - general- Ovary chapter
20% of ovarian tumors; resemble germ cell tumors in testis
Usually children and young adults
Usually benign cystic teratomas
8% are mixed
Survival: 95% disease free survival due to chemotherapy with bleomycin, etoposide and cisplatin
Case reports: systemic mast cell disease 3 months after chemotherapy for mixed malignant germ cell tumor (Hum Pathol 1998;29:1546)
Carcinoid tumors - Ovary chapter
May be a form of monodermal teratoma; 15% have cystic teratoma or mucinous neoplasm in contralateral ovary
Good prognosis if ovarian primary
1/3 are associated with carcinoid syndrome; may cause constipation due to secretion of peptide YY
Case reports: primary ovarian carcinoid with metastases and simultaneous borderline mucinous tumor and colonic adenocarcinoma (Arch Pathol Lab Med 1996;120:393)
Treatment: excision, although mucinous types are more aggressive
Gross: mean 10 cm, yellow, solid cut surface; usually unilateral
Micro: resembles carcinoid tumors elsewhere; patterns are insular (resembles appendix or small bowel tumors), trabecular (resembles stomach or rectal tumors); strumal (below), mucinous; may have abundant fibrous stroma; rarely has prominent pleomorphism, mucinous features (below) or signet ring pattern
Positive stains: chromogranin, synaptophysin, neuron specific enolase (NSE)
Negative stains: inhibin
EM: neurosecretory granules
DD: fibroma-thecoma, Brenner tumor; GI metastasis (bilateral, associated with peritoneal implants, no other teratomatous elements)
References: Arch Pathol Lab Med 1987;111:440
Mucinous (goblet cell) carcinoid - Ovary chapter
Rare; usually stage 1
Presence of frank carcinoma may be poor prognostic factor
Gross: solid nodules/areas of thickening in wall of mature cystic teratoma or solid tumors associated with other cystic tumors
Micro: often well-differentiated with small glands, many floating in mucin pools; glands lined by goblet cells and columnar cells, some neuroendocrine
References: Am J Surg Pathol 2001;25:557
Atypical mucinous carcinoid - Ovary chapter
Micro: crowded glands, some confluent with cribriform pattern and scattered microcystic glands; glands are lined by cuboidal and columnar cells, some neuroendocrine and goblet cells
Carcinoma arising in mucinous carcinoid - Ovary chapter
Micro: islands, larger nodules, closely packed glands or single cells of mainly signet ring cell type; most cells lack mucin and are severely atypical, with marked mitotic activity and necrosis
DD: metastatic mucinous carcinoid from appendix or elsewhere (ovarian origin suggested if ovarian teratoma or surface epithelial tumor present, no angiolymphatic invasion, involves only one ovary), strumal carcinoid, insular carcinoid
References: Am J Surg Pathol 2001;25:557
Strumal carcinoid - Ovary chapter
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)
Micro: often other teratomatous elements
Positive stains: neuron specific enolase, chromogranin, synaptophysin, thyroglobulin, PAP (similar to rectal carcinoids)
Negative stains: calcitonin
EM: numerous electron-dense neurosecretory granules, Am J Clin Pathol 1978;69:356
Choriocarcinoma - Ovary chapter
Most ovarian choriocarcinomas are metastases from uterine tumors
Pure ovarian choriocarcinomas are rare, develop from ovarian pregnancy or as a germ cell tumor (pure or mixed)
Rarely arise from surface ovarian carcinomas with choriocarcinomatous differentiation
After puberty, origin from an ovarian ectopic pregnancy cannot be excluded
Have high levels of serum hCG; monitoring serum levels is helpful in predicting recurrence
In contrast to placental tumors, nongestational tumors are usually fatal and unresponsive to chemotherapy; metastases to lungs, liver, bone and viscera are common at diagnosis
Micro: mixture of syncytial and cytotrophoblastic elements in a hemorrhagic and necrotic background
Positive stains: hCG, CD10
Less than 1% of ovarian malignancies
Counterpart of testicular seminoma
Usually young patients (81% under age 30)
5% associated with gonadal dysgenesis/Swyer syndrome (World J Surg Oncol 2007 Jun 23;5:71), androgen insensitivity or pseudohermaphroditism; rarely associated with hypercalcemia
Metastasize to opposite ovary, retroperitoneal nodes, peritoneal cavity
Rarely transforms to yolk sac tumor (Mod Path 1995;8:881)
Survival: 95%
Mixture with choriocarcinoma, yolk sac or embryonal carcinoma worsens prognosis
Treatment: surgery and chemotherapy (NOT radiotherapy, although it is effective for seminoma)
Gross: 15% bilateral; solid, nodular, small to huge, gray-pink (resembles cerebral cortex); hemorrhage and necrosis common but less prominent than other malignant tumors
Gross images: dysgerminoma #1; #2; #3 (25 cm); #4; #5; #6; #7 with focal necrosis
Micro: nests of tumor cells separated by fibrous stroma with T lymphocytes; large vesicular cells with well defined cell borders, cleared cytoplasm containing glycogen, central nuclei; 1+ prominent nucleoli; occasional granulomas; may have hCG+ syncytiotrophoblastic cells close to blood vessels or hemorrhagic foci with increased serum hCG; may have abortive yolk sac elements with increased serum AFP; may be present in wall of mature teratoma; may have pseudotubular or cord-like architecture
Early carcinomatous differentiation: 30+ mitoses per 10 high power fields, may worsen prognosis
Micro images: H&E and FISH; H&E and c-kit
Virtual slides: dysgerminoma
Videos: #1
Positive stains: OCT4 (strong nuclear staining in 90%+ cells, Am J Surg Pathol 2004;28:1341), c-kit (87%, Mod Pathol 2005;18:1411), CAM5.2 (20%), AE1-AE3 (8%, Hum Pathol 2006;37:1015)
Negative stains: CK7, CK20, EMA, HMW keratin, CD30, vimentin
Molecular: 12p abnormalities in 81% (Mod Pathol 2006;19:611)
Embryonal carcinoma - Ovary chapter
Similar to testicular embryonal carcinoma
Median age 15 years, patients often present with precocious puberty, also vaginal bleeding, amenorrhea, hirsutism
Serum hCG always high (positive pregnancy test), AFP sometimes high
Gross: median 17 cm, smooth and glistening, variegated cut surface with extensive hemorrhage and necrosis
Micro: sheets and nests of large primitive cells, occasional papillae and abortive glands; syncytiotrophoblast-like tumor cells seen (hCG+)
Mixed Germ Cell tumor of Ovary - Ovary chapter
Micro images: teratomatous component of respiratory epithelium (left) with yolk sac tumor
Molecular: often isochromosome 12p in teratomatous and non-teratomatous components (Mod Pathol 2006;19:766)
Embryonal carcinoma composed primarily of embryoid bodies
Embryoid body has amniotic cavity-like structure and is continuous with intestinal duct, and rarely has squamous cell nests, while "yolk sac" is continuous with hepatic tissue
Embryoid body is not considered to be a real or teratomatous embryo, but a product of divergent differentiation into intestine and liver from the plastic epithelium, which seems to be derived from embryonic gut (Hum Pathol 1988;19:1144)
Rare monodermal teratoma composed predominantly of mature thyroid tissue
May show pathologic changes of thyroid gland including hyperfunctioning; malignancies are usually papillary thyroid carcinoma
Associated with mucinous cystadenoma, Brenner tumor, carcinoid tumor, dermoid cyst
Case reports: struma salpingis (Am J Surg Pathol 1993;17:1187), follicular variant of papillary carcinoma with intraluminal crystalloids (Arch Pathol Lab Med 1991;115:145)
Gross: resembles red-brown thyroid tissue but usually multilocular cystic; usually unilateral
Gross images: partially cystic tumor resembling thyroid #1; #2
Micro: thyroid follicles with colloid; other teratomatous elements may be present; rarely has solid or pseudotubular patterns, microfollicles, abundant eosinophilic cytoplasm, abundant clear cytoplasm or minimal thyroid follicles
Micro images: thyroid-like follicles
Virtual slides: clear cell struma ovarii
Positive stains: thyroglobulin
Molecular: BRAF mutations frequent in malignant but not benign tumors (Am J Surg Pathol 2007;31:1337)
DD: metastatic thyroid carcinoma to ovary
References: Am J Surg Pathol 1995;19:21, Am J Surg Pathol 1994;18:785, Arch Pathol Lab Med 1978;102:180
Teratoma-mature - Ovary chapter
Mature if only contains adult tissues
Usually teenage women (solid) or children (cystic)
Excellent prognosis, even if peritoneal implants are present
Rarely associated with hemolytic anemia
May rupture into peritoneal cavity causing foreign body reaction that simulates metastatic carcinoma or miliary tuberculosis
Tumors arise from a single germ cell after first meiotic division
Cystic tumors may contain squamous cell carcinoma, carcinoid tumor or adenocarcinoma
Dermoid cyst: usually means teratoma resembles skin; some use dermoid cyst and mature teratoma interchangeably
Gliomatosis peritonei: peritoneal implants exclusively composed of mature glial tissue; benign if all tissue is mature and other teratomatous elements are absent
Case reports: corticotroph pituitary adenoma (Am J Surg Pathol 1987;11:218), glomus tumor (Arch Pathol Lab Med 2000;124:1373), homunculus (fetiform) coexisting with intrauterine pregnancy (Arch Pathol Lab Med 1986;110:1192), mature teratoma with anti-Ri antibodies and memory impairment (Int Semin Surg Oncol 2004 Nov 10;1(1):11), mucinous tumor (Am J Surg Pathol 2003;27:650), nodal gliomatosis (Arch Pathol Lab Med 1986;110:975), peptic ulcer with spindle cell nodule, (Arch Pathol Lab Med 1990;114:529), pituitary tissue (Arch Pathol Lab Med 1978;102:122), prostate tissue (Am J Surg Pathol 1992;16:780, Arch Pathol Lab Med 1985;109:675), skin adnexal tumor (Arch Pathol Lab Med 1993;117:846)
Gross: solid or cystic; cystic content may contain greasy material composed of keratin, hair, teeth; rarely is “fetiform” (partial human body-like structure) or contains partial mandible; teeth may be found in Rokitansky’s protuberance-a well defined nipple-like structure covered with hair
Gross images: dermoid cyst-like #1; #2; #3; with sebum, hair and teeth #1; #2; #3; #4; with hair, fat and teeth
Micro: ectodermal structures in 100%, mesodermal in 93%, endodermal in 71%; skin and glial tissue common; prostate tissue in 10%; still considered mature if microscopic foci of immature tissue
Micro images: mature teratoma with sebaceous glands and cartilage; thyroid, cartilage, fat & GI; glomus tumor; carcinosarcoma arising from dermoid cyst
Virtual slides: dermoid cyst; mature teratoma #1; #2
Videos: dermoid cyst; benign teratoma
DD: immature teratoma grade 1 (sample extensively to distinguish); epidermoid cyst (no skin adnexae or other tissues)
References: Am J Surg Pathol 2003;27:650
Malignant change in cystic teratoma - Ovary chapter
Tumor is apparently derived from germ cell elements of teratoma, but behavior is based on phenotype
Squamous cell carcinoma: most common malignant change in cystic teratoma; 5 year survival is 52%, dependant on histologic grade and vascular invasion; appears to arise from columnar epithelium (Am J Surg Pathol 1989;13:397)
Case reports: apocrine adenocarcinoma, (Arch Pathol Lab Med 1993;117:647), carcinosarcoma arising from dermoid cyst (BMC Cancer 2006 Mar 1;6:47), Paget’s disease in squamous epithelium (Am J Surg Pathol 1991;15:1002), small cell epidermoid carcinoma (Arch Pathol Lab Med 1995;119:551), squamous cell carcinoma in situ (Arch Pathol Lab Med 1991;115:172)
Teratoma-immature - Ovary chapter
Malignant tumor, whose tissue resembles embryonal or fetal tissue
Usually prepubertal or young women (mean 18 years)
Most recurrences within 2 years; presence of yolk sac component is best predictor of recurrence in pediatric tumors (Am J Surg Pathol 1998;22:1115)
Common errors are classifying differentiating tissue as immature and not recognizing hepatoid and well-differentiated glandular patterns of yolk sac tumor
Case reports: 17 year old woman with predominant malignant retinal anlage component, tumor parthenogenically derived, GFAP+, neuroglia by EM (Am J Surg Pathol 1985;9:221)
Treatment: surgery, multiagent chemotherapy; better prognosis if only mature teratoma found after chemotherapy, although abnormal karyotype is maintained in mature teratoma
Gross: bulky, solid or cystic with necrosis, hemorrhage
Gross images: hepatic teratoma with yolk sac component #1; #2; #3
Micro: usually neurogenic elements (GFAP+); mesodermal elements common; some tumors derived primarily of esophageal, liver and intestinal structures (endodermal)
Grading: histologic grade is based on proportion of tissue containing immature neuroepithelium
Norris grading system (correlates best with extraovarian spread, survival)
1 - abundant mature tissue, loose mesenchymal tissue with occasional mitoses, immature cartilage, tooth anlage
2 - less mature tissue than grade 1, rare foci of neuroepithelium with mitoses, < 4 low power fields in any one slide
3 - little/no mature tissue; numerous neuroepithelial elements merging with cellular stroma occupying 4+ low power fields
Micro images: immature elements #1; #2; bone; neural tissue
yolk sac tumors - #1; #2; Schiller Duval bodies #1; #2; AFP stain
Immature teratoma variants
Endodermal teratoma - Ovary chapter
High serum AFP, low serum hCG, no neuroectodermal component
Micro: early endoderm - liver, esophagus, intestine
Positive stains: AFP, alpha-1-antitrypsin
References: Hum Pathol 1993;24:364
Ependymoma - Ovary chapter
May derive from teratoma
Neuroectodermal component composed entirely of primitive ependymal structures
Appears to derive from distinct precursors or to differentiate along distinct pathways from CNS ependymoma based on different immunostaining patterns (Am J Surg Pathol 2008;32:710)
Case reports: PR+ bilateral tumors in pregnant woman (Hum Pathol 1992;23:962), 68 year old woman (Am J Surg Pathol 1993;17:623), tumor of broad ligament (Am J Surg Pathol 1984;8:203)
Micro: resembles CNS ependymoma; cells have fibrillary cytoplasmic processes, often arranged around blood vessels forming perivascular pseudorosettes
Virtual slides: ependymoma
Positive stains: CK18 (100%), ER (100%), CK7 (80%), PR (80%), 34betaE12 (60%), CAM5.2 (60%); GFAP, vimentin, neuron-specific enolase, S100, EMA
EM: cilia on surface of cysts and within intracellular lumina, abundant intermediate filaments in cytoplasmic processes, intercellular junctions
References: Hum Pathol 1984;15:632
Growing teratoma syndrome - Ovary chapter
Treatment: long term follow up since recurrent masses can appear many years after primary tumor, although most nodules appear within 2 years of initial primary
Case reports: carcinoid teratoma arising in mature teratoma of liver (Am J Surg Pathol 2007;31:1913)
Yolk sac tumor - Ovary chapter
Also called endodermal sinus tumor
May be derived from embryonal carcinoma
Usually children or young adults (median age 19 years) with abdominal pain and rapidly growing mass, increasing alpha fetoprotein (AFP) and alpha-1-antitrypsin serum levels; negative hCG
Fatal without chemotherapy since most have subclinical metastases at presentation
Case reports: with associated virilization (Am J Surg Pathol 1981;5:385)
Gross: mean 15 cm, smooth and glistening external surface, cystic cut surface with hemorrhage and necrosis; often has benign teratoma component; rarely is found in pelvis unattached to ovary
Micro: numerous patterns; Schiller-Duval body is pathognomonic - central blood vessel enveloped by germ cells within a space similarly lined by germ cells, resembles glomerulus; hyaline droplets present in all tumors (positive for AFP, PAS and alpha-1-antitrypsin)
Patterns: reticular or microcystic patterns formed by a loose network of flat/cuboidal cells;
polyvesicular vitelline pattern: in 25%; vesicular structures with eccentric constrictions surrounded by a dense spindle cell stroma; may have better prognosis in pure form
Other patterns - hepatoid (large polyhedral cells with hyaline bodies but no bile, resembles metastatic hepatocellular carcinoma), intestinal differentiation, glandular (may be cribriform or resemble endometrioid carcinoma), solid, parietal yolk sac (thick layers of basement membrane) and undifferentiated
Micro images: contributed by Dr. Debra Zynger, Northwestern University, Chicago, IL:
#1; #3; #5; #7; #8; #9; #10; #11; #12; #13; #14; #15; #17; #18; #19; #20; #21; #22; #23; #25; #26; #27; #28; #29
Micro images from liver yolk sac tumor (similar histology): yolk sac #1; #2; Schiller Duval #1; #2; AFP stain
Virtual slides: retiform tumor
Positive stains: keratin, AFP (yolk sac elements, hepatic or intestinal epithelium in teratomas), CD10
Molecular: usually aneuploid or tetraploid
References: Am J Surg Pathol 1987;11:767 (endometrioid pattern)
Sex cord-stromal tumors
Sex cord-stromal tumors-general - Ovary chapter
5% of ovarian neoplasms, 7% of malignant ovarian neoplasms
Derived from ovarian stroma, itself derived from sex cords of embryonic gonad (predecessor of Sertoli, Leydig, granulosa and theca cells)
Theca cells produce estrogens; Leydig cells produce androgens
Morphology and clinically evident hormonal activity may go together, but classify based on morphology
Positive stains: alpha-inhibin, mullerian inhibiting substance, alpha-inhibin (>95%), calretinin (more sensitive, less specific than inhibin (Am J Surg Pathol 2002;26:1477), CD99 (Arch Pathol Lab Med 2000;124:563), MART1/MelanA, WT-1
Negative stains: EMA, PLAP, CEA
Notes: anti-Mullerian hormone staining is present in only a small percentage of granulosa or Sertoli tumor cells, but is specific for these tumors (Hum Pathol 2000;31:1202), particularly compared to endometrioid tumors (Hum Pathol 1998;29:840)
Strong alpha-inhibin staining is relatively specific for ovarian sex-cord stromal proliferations, although luteinized cells from other tumors are also immunoreactiveb (Hum Pathol 1997;28:1387, Am J Surg Pathol 1997;21:583)
Common; benign; arise after puberty
40% of tumors > 6 cm are associated with ascites
Also associated with right sided hydrothorax, Meigs syndrome, basal cell nevus syndrome
Meigs syndrome: ovarian fibromas, right sided hydrothorax, ascites; after tumor excision, hydrothorax and ascites disappear
Basal cell nevus syndrome (Gorlin syndrome): autosomal dominant disease of multiple basal cell carcinomas, odontogenic keratocysts, palmoplantar pits, congenital skeletal abnormalities and ectopic calcifications, caused by mutational inactivation of the PTCH gene; also have calcified, bilateral, often multinodular ovarian fibromas
Fibrothecoma: combined fibroma and thecoma; also a generalized term for these two closely related tumors
Case reports: fibrothecoma with ascites and elevated CA125 (Arch Pathol Lab Med 2005;129:701), 69 year old woman with fibrothecoma containing minor sex cord elements and fibrosarcoma (Arch Pathol Lab Med 2003;127:81)
Treatment: excision, does not recur
Gross: mean 6 cm, usually unilateral, solid, lobulated, firm, white, may have myxoid change; not associated with adhesions
Gross images: fibroma #1; #2; fibrothecoma #1; #2
Micro: closely packed spindle cells in “feather-stitched” or storiform pattern; may have hyaline bands and edema; no atypia
Micro images: fibroma; fibrothecoma with focal fibrosarcomatous area; fig 1: bright yellow, firm, glistening soft tissue, fig 2: moderate cellularity with calcification, fig 3: cells have moderate pale vacuolated cytoplasm and oval nuclei, fig 4: focal hypercellular foci with spindle cells in fascicles, but no mitotic figures
Positive stains: CD56 (not specific), WT1, ER-beta, PR, variable smooth muscle actin, occasional S100 and CD34 (Am J Surg Pathol 2008;32:884)
Molecular: trisomy 12
DD: cellular fibroma (up to 3 mitoses/10 high power fields), fibrosarcoma (4+ mitoses/10 HPF), massive edema, fibromatosis, thecoma, Brenner tumor, Krukenberg tumor
References: Am J Surg Pathol 2002;26:1477
Cellular fibroma of ovary - Ovary chapter
Recommended to call mitotically active cellular fibroma (Am J Surg Pathol 2006;30:929)
Treatment: excision and long term follow up; occasionally recurs locally, particularly with rupture or adherence
Gross: mean 9 cm, usually solid, may have cystic component, occasionally ovarian surface adhesions or extraovarian involvement
Gross images: cellular fibroma with hemorrhagic necrosis
Micro: cellular intersecting fundles of spindle cells with bland nuclei, 4+ MF/10 HPF
DD: fibrosarcoma (severe nuclear atypia, 4+ MF/10 HPF, aggressive clinical course)
Fibroma with minor sex cord elements - Ovary chapter
Case reports: 45 year old woman (Diagn Pathol 2007 Dec 4;2:46)
Micro images: various images
Gonadoblastoma - Ovary chapter
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)
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
Gross: 36% bilateral, tumors usually small, may be microscopic
Micro: 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)
Positive staining: anti-Mullerian hormone focally (Hum Pathol 2000;31:1202)
DD: incidental finding in ovaries of normal infants/children (associated with follicular cysts, microscopic foci resembling gonadoblastoma or sex cord tumor with annular tubules)
Granulosa cell tumor-adult - Ovary chapter
Differentiation towards follicular granulosa cells
Usually women age 15+ years; 75% associated with hyperestrogenism, causes precocious puberty in children, metrorrhagia (bleeding between periods), endometrial hyperplasia / carcinoma (usually well differentiated and superficial), breast fibrocystic changes in adults
Endometrial hyperplasia regresses after tumor excision
10 year survival >90%; tends to recur locally, up to 20 years later
5-25% risk of malignancy, cannot predict from histology
Prognostic factors: stage, size, tumor rupture, nuclear atypia
Case reports: Case of the Week #96, tumor to tumor metastasis from breast cancer (Hum Pathol 2002;33:445), collision tumor with colonic adenocarcinoma (World J Surg Oncol 2007 Oct 20;5:118), recurrence after 30 years (Int Semin Surg Oncol 2004 May 11;1(1):4), associated with unusual germline p53 mutation (Mod Pathol 2004;17:868)
Gross: >95% unilateral and confined to ovary; encapsulated with smooth lobulated surface, gray or yellow, solid or cystic with straw colored or mucoid fluid; may resemble cystadenoma; androgenic tumors tend to be large
Gross images: granulosa cell tumor #1; #2; solid and cystic tumor
Micro: small, bland, cuboidal to polygonal cells in various patterns, including Call-Exner bodies (small follicle-like structures filled with acidophilic material), macrofollicular, trabecular, solid, insular patterns; cells may be luteinized (plump with ample cytoplasm), particularly during pregnancy; may have theca cell component
Cells have coffee bean nuclei with folds/grooves; may see floret giant cells, indicative of degeneration
Rarely focal hepatic cell differentiation (large cells with abundant eosinophilic, slightly granular cytoplasm; central round nuclei with single prominent nucleoli; often bile pigment in canaliculi between large cells (Am J Surg Pathol 1999;23:1089, Am J Surg Pathol 1993;17:85), pseudopapillary pattern (Am J Surg Pathol 2008;32:581)
Micro images: low/medium power - image #1; #2; #3; #4; #5
inhibin #1; #2-inhibin alpha (fig 1), CD99 (fig 4)
contributed by Dr. Sharon Bihlmeyer - low power; high power; inhibin; calretinin; CK7
Granulosa cell tumor-adult - Ovary chapter (continued)
Virtual slides: granulosa cell tumor #1; #2
Videos: #1
Positive stains: inhibin alpha, vimentin, calretinin (Am J Surg Pathol 2002;26:1477), CD99 (Mod Path 1998; 11:769), smooth muscle actin, desmoplakin, S100 (50%), keratin (dot like in 30-50%, primarily low molecular weight, Am J Surg Pathol 1992;16:962), anti-Mullerian hormone focally (Hum Pathol 2000;31:1202), desmin (35%), silver stains demonstrate reticulin surrounding cluster of cells
Negative stains: EMA
Cytology: little cytoplasm, intense indentation of nuclear membrane; resembles mesothelial cells (Am J Clin Pathol 1986;85:402)
Molecular: monosomy 22 (~40%), trisomy 12 (~30%), +14 (~30%), monosomy X (~10%), monosomy 17 (5%), although most tumors (80%) are diploid or near-diploid (Mod Path 2002;15:951)
Molecular images: FISH-trisomy 12, monosomy 17
EM: abundant intermediate filaments, desmosomes
DD: poorly differentiated ovarian surface epithelial carcinoma (diffuse cytoplasmic keratin staining, Virchows Arch A Pathol Anat Histopathol 1989;414:439), carcinoid tumor, endometrial stromal sarcoma, endometrioid carcinoma, small cell carcinoma of hypercalcemic type, pregnancy related granulosa cell proliferation (microscopic, multiple, associated with atretic follicles, Hum Pathol 1988;19:657)
Granulosa cell tumor-juvenile - Ovary chapter
5% of ovarian tumors in children
Mean age 13 years, range 0-67 years, 80% occur before age 20, 97% before age 30
Most prepubertal patients present with sexual precocity due to excessive estrogen production; rarely produce androgens (J Endocrinol Invest 2006;29:653); older patients have nonspecific abdominal swelling and pain
Rarely associated with enchondromatosis (Ollier’s disease), Mafucci syndrome, abnormal karyotype / ambiguous genitalia (Am J Surg Pathol 1985;9:737)
Case reports: Case of the Week #59, cystic tumor in 43 year old woman (Arch Pathol Lab Med 2002;126:1123), bilateral tumor in newborn with dysmorphic features (Am J Surg Pathol 1981;5:789)
Treatment: excision is usually adequate for limited disease, although late recurrence may occur (Am J Obstet Gynecol 2004;191:366)
Gross: usually unilateral, up to 12 cm; multiloculated, cystic and solid tumor with yellow-white solid areas; may have hemorrhage and necrosis
Gross images contributed by Dr. Hanni Gulwani, New Delhi (India): 3 year old girl with breast enlargement - mostly solid tumor with focal cystic change
Micro: diffuse or macrofollicular patterns with microcysts containing eosinophilic secretions, tumor cells either have scant cytoplasm or are luteinized; round/oval hyperchromatic nuclei with small nucleoli, irregular nuclear contours; no/rare nuclear grooves; high mitotic rate (mean 7/10 HPF); may have hobnail-type cells, pseudopapillary pattern (Am J Surg Pathol 2008;32:581)
Granulosa cell tumor-juvenile - Ovary chapter (continued)
Micro images: gross, H&E and inhibin; image #1; #2; #3
Micro images contributed by Dr. Hanni Gulwani, New Delhi (India): 3 year old girl with breast enlargement - well demarcated tumor with pseudolobular pattern and compressed normal ovary at periphery; primordial follicles in normal ovary; poorly formed follicles with mucoid secretions; compact spindle cell areas with hemangiopericytoma like pattern #1; #2; loose edematous areas with abortive follicles #1; #2; spindle cells are SMA+; vimentin+; high MIB-1 expression; ER+ and PR+
Virtual slides: 39 cm tumor
Positive stains: inhibin, calretinin
Negative stains: HER2
Molecular: consistent trisomy 12 (as with adult granulosa cell tumors); more aneuploidy in juvenile than adult granulosa cell tumors
DD: adult granulosa cell tumors (more regularly shaped follicles with basement membrane material, prominent nuclear grooves, no hyperchromasia), thecoma (older patients, no follicles, no atypia, no mitotic figures), clear cell carcinoma (older patients, diffuse hobnail cells, no follicles, no juvenile granulosa type cells)
References: Am J Surg Pathol 1984;8:575, Arch Pathol Lab Med 1989;113:40
Gynandroblastoma - Ovary chapter
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)
Leydig cell tumor (hilus cell tumor) - Ovary chapter
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, unresponsive to cortisol suppression
Treatment: excision
Gross: unilateral
Micro: large lipid laden cells with distinct borders; Reinke crystals common
Lipid (steroid, lipoid) cell tumor - Ovary chapter
Any age, usually associated with virilizing syndrome (defeminization and amenorrhea)
Cells either lutein (theca/stroma), hilar (Leydig, with Reinke crystals) or adrenal cortical type
If Cushing syndrome present, tumor often called “adrenal cortical type”
Exact origin of tumor is unknown
May be biologically active or inactive
Malignant: 25%, usually large (7 cm or more), necrosis, hemorrhage, nuclear atypia, mitoses, may have peritoneal implants
Gross: usually unilateral, yellow/brown nodules separated by fibrous trabeculae
Micro: large rounded or polyhedral cells with abundant eosinophilic or vacuolated cytoplasm
Positive stains: fat stains on fresh/frozen tissue, vimentin (75%), keratin (50%), actin (30%)
EM: increased smooth endoplasmic reticulum, mitochondria have tubulovesicular cristae
DD: tumors with secondary proliferation of steroid hormone-producing cells (stromal luteoma, luteinized granulosa cell tumor [usually juvenile], fibroma-thecoma, stromal Leydig cell tumor, proliferations at periphery of other tumors)
Some consider it a variant of fibroma-thecoma (Arch Pathol Lab Med 1993;117:802)
Gross: solid and cystic, with blood filled cysts
Micro: scattered fibroblastic cells in well-vascularized myxoid background
Sclerosing stromal tumor - Ovary chapter
Rare, benign, resembles fibroma-thecoma but in younger patients
Prominent vasculature is associated with vascular endothelial growth factor expression (Am J Surg Pathol 1998;22:83)
Micro: lobular growth pattern of cellular and hypocellular areas composed of dual cell population (collagen producing spindle cells and lipid-containing round/oval cells); interlobular fibrosis, marked vascularity
Positive stains: desmin, smooth muscle actin
Molecular: trisomy 12 by FISH
EM: luteinized theca like cells, spindle-shaped fibroblastic cells, primitive mesenchymal cells
DD: Krukenberg tumor
References: Arch Pathol Lab Med 1989;113:372
Sertoli cell tumor - Ovary chapter
Rare; excellent prognosis
Mean 30 years old, range 2-76 years
Tends to secrete estrogen/progesterone, but diagnose based on morphology, not hormones
Similar to a well differentiated Sertoli-Leydig tumor without a Leydig component; may have abundant cytoplasmic lipid
Associated with Peutz-Jeghers syndrome
Usually stage I and clinically benign (Am J Surg Pathol 2005;29:143)
Case reports: 67 year old whose tumor has various histologic patterns (Arch Pathol Lab Med 2006;130:e70)
Gross: lobulated, solid, yellow-brown, unilateral, mean 9 cm, up to 30 cm
Micro: closely packed solid or hollow tubules lined by well differentiated cuboidal to columnar epithelial cells; few or no Leydig cells, often fibromatous or sclerotic; may have amyloid-like material; other patterns include cord-like and diffuse; variable stroma; occasional cells with bizarre nuclei; minimal mitoses, minimal atypia
malignant: moderate to severe cytologic atypia and 5+ MF/10 HPF
Positive
stains:
inhibin, vimentin, CD99, CD10, AE1-3 or CAM5.2 (usually), calretinin (50%),
variable smooth muscle actin and S100
Negative stains: EMA, chromogranin
EM: tight junctions, desmosomes, abundant rough endoplasmic reticulum and lipid
DD: endometrioid carcinoma (EMA+, inhibin-), carcinoid (chromogranin+, EMA+, inhibin-)
Lipid rich variant of Sertoli cell tumor - Ovary chapter
Large Sertoli cells with abundant cytoplasmic lipid
May be associated with isosexual pseudoprecocity, Peutz-Jeghers syndrome
“Adenomas” are common in testes of those with testicular feminization (most common tumor after seminomas), but are actually hamartomas, usually bilateral
Sertoli-Leydig tumor - Ovary chapter
Also called Sertoli-stromal cell tumor; formerly called androblastoma, arrhenoblastoma
Rare, < 0.1% of ovarian neoplasms
Morphologically resembles cells of testis at various stages of development, but ultrastructurally resembles ovarian granulosa cell tumors and contains female sex chromatin
Usually young women (mean age 25 years, 75%<age 30), but 10%>age 50; some with edema are diagnosed during pregnancy
Virilization in 30-50% with oligo/amenorrhea, loss of secondary sex characteristics, breast atrophy, masculinization [clitoral hypertrophy, hirsutism, deepening of voice]; also increased RBC count, increased serum testosterone and androstenedione, variable increases in serum alpha-fetoprotein, usually normal serum 17-ketosteroids
Feminine characteristics return after surgery, but manifestations of masculinization disappear more slowly
50% have no endocrine abnormalities
2% bilateral, 97% stage I, 2% spread beyond ovary
5% recur/metastasize
Well differentiated: older age, usually not associated with masculinization; usually clinically benign
Intermediate differentiated: associated with virilization; 11% clinically malignant
Poorly differentiated: 59% clinically malignant; case report of AFP production (Arch Pathol Lab Med 1986;110:65)
Tumors with heterologous elements: 19% clinically malignant
Retiform pattern: often young girls; tumors are stage I
Some cells show differentiation into both Sertoli cells and cells of rete testis, but lack presence of sex-determining region Y (Hum Pathol 2001;32:796, Hum Pathol 1997;28:1206)
Treatment: conservative surgery if tumor confined to ovary
Case reports: 4 year old girl with retiform pattern (Arch Pathol Lab Med 2002;126:377), 13 year old girl with elevated serum AFP, heterologous elements (hepatocytes) and retiform pattern (Am J Surg Pathol 1984;8:709), 17 year old girl with elevated AFP and clusters of hepatocytes (Arch Pathol Lab Med 1995;119:1075), 22 year old woman with retiform pattern and mucinous component (Arch Pathol Lab Med 2004;128:e93)
Gross: similar to granulosa cell tumors - golden-yellow but fewer blood filled cysts, almost never have unilocular cyst
Gross images: tan multinodular tumor; solid yellow-poorly differentiated tumor
Sertoli-Leydig tumor - Ovary chapter (continued)
Micro: hemorrhage/necrosis suggests poorly differentiated tumors or heterologous elements; edematous papillae suggests retiform subtype
Degenerative changes (bizarre and multiple nuclei) have no prognostic significance
Multiple subtypes may exist in same tumor (so % add up to > 100%)
Well differentiated (Meyer type I): 11%, may be nodular; tubular (hollow > solid), easily identifiable Leydig cells and Sertoli cells in a tubular pattern; may resemble endometrioid carcinoma or atrophic seminiferous tubules; crystals of Reinke in 20%
Intermediate differentiated (Meyer type II): 54%, outlines of immature tubules with immature Sertoli cells and large Leydig cells; may have mucus filled epithelial cells, cartilage, skeletal muscle
Poorly differentiated (Meyer type III): 13%, resemble indifferent gonad; may have sarcomatous appearance, Leydig cells in 2/3; may have mucus filled epithelial cells, cartilage, skeletal muscle
Pure Sertoli cell tumors (tubular androblastoma): similar to well differentiated Sertoli-Leydig cells but no Leydig cells and no primitive stromal elements; cytoplasm may have abundant lipid; tubular or follicle-like patterns; variable amyloid
With heterologous elements (teratoid androblastoma): 22%, associated with mucinous epithelium of GI type, liver, skeletal muscle, cartilage
Retiform (“netlike”): 15%, irregular branching, elongated and narrow tubules and cysts, which often have papillary structures; also ribbons of immature Sertoli cells; degenerative cells (large, bizarre cells without mitotic activity); usually associated with intermediate or poorly differentiated tumors; often have homologous or heterologous tissues including hepatocyte differentiation (positive for AE1-AE3, CAM5.2, AFP, ferritin, Hum Pathol 1999;30:611); resemble yolk sac tumors (Schiller-Duval bodies, AFP+), serous borderline tumors (older patients, no ribbons of immature cells)
Micro images: retiform pattern; inhibin alpha (fig 2); fig 1: CT scan; fig 2A/C: network of irregularly branching, elongated and narrow tubules, fig 2B: papillary area, fig 3A: moderate to well differentiated intestinal type mucinous epithelium with goblet cells, fig 3B: focal stratification and nuclear atypia, fig 4A/B: inhibin+
Positive stains: testosterone, estradiol, cytokeratin, AFP (in hepatoid areas), CD99 (Mod Path 1998; 11:769), inhibin alpha, low molecular weight cytokeratin, anti-Mullerian hormone focally (Hum Pathol 2000;31:1202), progesterone receptor, androgen receptor, vimentin (Hum Pathol 1997;28:1206)
Negative stains: EMA, PLAP, CEA, CA19-9, CA125, S100 (use to distinguish from carcinosarcoma)
Molecular: Trisomy 8 in case report (Hum Pathol 2001;32:559)
EM: elongated nuclei with deep indentations and annulate lamellae (resemble Sertoli cells), apical microvilli and frequent desmosomes (resemble rete testis)
DD: endometrioid carcinoma with sex cord-like elements, carcinoid tumor
References: Am J Surg Pathol 1985;9:543, Am J Surg Pathol 1984;8:405, Am J Surg Pathol 1983;7:755 (retiform pattern)
Sex cord tumor with annular tubules - Ovary chapter
Distinctive ovarian tumor associated with hyperestrinism (50%)
1/3 with tumor have Peutz-Jegher’s syndrome
Peutz-Jegher’s syndrome: autosomal dominant with variable penetrance; patients have ovarian sex cord stromal tumors or tumorlets with annular tubules (almost all patients, usually bilateral, often with calcifications, tumorlets are benign); mucocutaneous melanin pigmentation (lips, oral mucosa, digits, palms, soles, genitalia); GI hamartomatous polyposis (florid epithelium supported by broad bands of smooth muscle in stalk, causes intussusception and GI bleeding); occasional adenocarcinomas of GI tract, pancreas, breast, lung; occasional cervical adenoma malignum, ovarian mucinous carcinomas; Peutz was Dutch physician 1886-1957; Jeghers was American physician born 1904
Patients without Peutz-Jegher’s syndrome have large, unilateral tumors, with transitions to granulosa cell tumors, 40% secrete estrogen, 20% are malignant
Arise in ovarian cortex from follicular granulosa cells
Micro: mixture of simple and complex annular tubules with eosinophilic hyaline bodies, often calcified; resembles granulosa cell tumor with Sertoli growth pattern; simple annular tubules are ring shaped, with peripheral oriented nuclei around a central hyalinized body composed of basement membrane material; most of ring is anuclear cytoplasmic zone
Complex annular tubules are made of intercommunicating rings revolving around multiple hyaline bodies, often calcified
Contributed images: by anonymous - 10 year old girl with precocious puberty: image#1; #2; #3; alpha-inhibin
EM: granulosa cell and Sertoli cell features (granulosa cell-deeply indented nuclei, interdigitating plasma membranes joined by abundant desmosomes; Sertoli cell-variable Charcot-Bottcher filaments as cytoplasmic inclusions), Am J Clin Pathol 1981;75:11
DD: Sertoli cell tumors, granulosa cell tumors, gonadoblastoma (different clinical background, has germ cell component)
Steroid cell tumor, NOS - Ovary chapter
< 0.1% of all ovarian tumors
Mean age 42 years, range 2 to 80 years
Usually associated with androgenic changes (56-77%); estrogen secretion in 6-23%, Cushing syndrome in 6-10%
Usually benign in prepubertal children
Clinically malignant in 25-43%, associated with 2+ mitosis per high-power field (92% malignant); necrosis (86% malignant); 7 cm or larger (78% malignant); hemorrhage (77% malignant); and grade 2 or 3 nuclear atypia (64% malignant); some clinically malignant cases are histologically benign
Case reports: 8 year old girl with virilization (Arch Pathol Lab Med 1991;115:150), 22 year old woman with virilization (J Med Case Reports 2007 Dec 18;1:182), 24 year old woman with hirsutism and multiple sclerosis (Arch Pathol Lab Med 2003;127:890), 29 year old woman with virilization and tumor in accessory ovary in broad ligament (Arch Pathol Lab Med 1996;120:405), 35 year old woman with virilization (Arch Pathol Lab Med 2006;130:113)
Gross: up to 45 cm, solid, well-circumscribed, yellow-orange to red-brown to brown-black cut surface (depending on amount of lipid and lipochrome pigment); 6% bilateral; occasional hemorrhage and cystic degeneration
Gross images: tan brown, well circumscribed tumor with hemorrhage
Micro: usually diffusely arranged cells, also nests, clusters, cords, columns; scant stroma may be fibromatous, edematous or myxoid; tumor cells are round/polygonal with spongy to granular, eosinophilic cytoplasm with clear intracytoplasmic vacuoles; distinct cell borders; central nuclei, prominent nucleoli; no Reinke crystals, no significant nuclear atypia or mitotic activity
Gross/micro images: H&E, Oil Red O (figure 4); diffuse sheets of large polygonal cells with vacuolated cytoplasm, vesicular nuclei and nuclear pleomorphism; fig 1: bright yellow lobulated mass, fig 2: medium-large polygonal cells with eosinophilic granular cytoplasm in delicate vascularized connective tissue network, fig 3: vimentin+, fig 4: inhibin+
Positive stains: inhibin, fat stains (75%), vimentin (75%), CAM 5.2 (46%), AE1/AE3 (37%), EMA (8%), S100 (7%)
Negative stains: chromogranin A, CD15 (Leu-M1), myoglobin, neurofilament, AFP, CEA, HMB-45
DD: stromal luteoma, clear cell carcinoma, metastatic renal cell carcinoma, luteoma of pregnancy
References: Am J Surg Pathol 1987;11:835
Usually > 40 years old, 65% after menopause
May be hormonally active, associated with estrogenic and occasionally (if steroid cells present) androgenic symptoms
Usually benign