Ovary
Sex cord stromal tumors
Granulosa cell tumor-adult

Editorial Board Member: Gulisa Turashvili, M.D., Ph.D.
Editor-in-Chief: Debra Zynger, M.D.
Shabnam Zarei, M.D.

Topic Completed: 7 October 2020

Minor changes: 7 October 2020

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PubMed search: Ovarian granulosa cell tumor [title]

Shabnam Zarei, M.D.
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Cite this page: Zarei S. Granulosa cell tumor-adult. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/ovarytumorgctadult.html. Accessed October 29th, 2020.
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
  • ICD-10: D39.11 - Neoplasm of uncertain behavior of right ovary
  • ICD-10: 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 Large pelvic mass

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
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

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Hirsutism

Hirsutism

Intraoperative mass

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.
Solid, cystic and hemorrhagic mass

Solid, cystic and hemorrhagic mass

Solid and cystic mass

Solid and cystic mass


AFIP images
Solid yellow mass

Solid yellow mass

Predominantly cystic mass

Predominantly cystic mass

Solid and cystic tumor


Images hosted on other servers:
Solid cystic mass

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

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

Classic diffuse pattern

Nuclear grooves

Nuclear grooves

Luteinized

Luteinized

Luteinized with round nuclei

Luteinized with round nuclei

Luteinized

Luteinized

Calretinin

Calretinin


Reticulin

Reticulin

Diffuse pattern

Diffuse pattern

Inhibin

Inhibin

Calretinin

Calretinin

CK7

CK7



AFIP images
Trabecular pattern

Trabecular pattern

Insular pattern

Insular pattern

Microfollicular pattern

Microfollicular pattern

Microfollicular pattern

Macrofollicular pattern

Watered silk (moire silk) pattern

Watered silk (moire silk) pattern

Gyriform pattern

Gyriform pattern


Cystic tumor

Cystic tumor

Enlarged, hyperchromatic, bizarre nuclei

Theca cells

Theca cells

Virtual slides

Images hosted on other servers:
Diffuse pattern

Diffuse pattern

Cytology description
  • Scant cytoplasm, naked nuclei, relatively uniform mildly convoluted nuclei with grooves, vacuolated cytoplasm (Diagn Cytopathol 2008;36:297)
Positive stains
Negative stains
  • EMA (in contrast to juvenile type)
  • CK7
Molecular / cytogenetics description
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
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?

  1. CDH1
  2. FOXL2
  3. P53
  4. STK11
Board review 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?

  1. Cytologic atypia
  2. FOXL2 heterozygous mutation
  3. Tumor necrosis
  4. Tumor rupture
Board review 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
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