Sertoli-Leydig cell tumor

Ovary

Sex cord stromal tumors

Author: Natalia Buza, M.D.

Editorial Board Member: Carlos Parra-Herran, M.D.

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

Topic Completed: 20 December 2018

Minor changes: 19 October 2020

Copyright: 2002-2021, PathologyOutlines.com, Inc.

PubMed Search: Sertoli-Leydig cell tumor[title] ovary

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Table of Contents

Cite this page: Buza N. Sertoli-Leydig cell tumor. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/ovarytumorsertolileydig.html. Accessed January 17th, 2021.

Definition / general

Rare ovarian tumor composed of sex cord (Sertoli cells) and stromal (Leydig cells) elements, accounting for less than 0.5% of all ovarian neoplasms

Essential features

Rare ovarian tumor composed of sex cord (Sertoli cells) and stromal (Leydig cells) elements
May occur sporadically or in patients with DICER1 syndrome
Often harbors DICER1 mutations (germline or sporadic)
Express general sex cord markers (inhibin, calretinin, SF1, FOXL2 and CD56), CK7 and EMA immunostains are negative
Behavior correlates with tumor grade and histologic subtype
- Well differentiated Sertoli-Leydig cell tumors are essentially benign
- Approximately 10% of moderately differentiated and 13 - 59% of poorly differentiated tumors have malignant behavior, heterologous elements, retiform pattern, tumor rupture and spread outside the ovary (stage II or higher tumor stage) are adverse prognostic factors

Terminology

Sertoli-Leydig cell tumor
- Well differentiated
- Moderately differentiated / intermediate grade
- Poorly differentiated
Sertoli-Leydig cell tumor with heterologous elements
Sertoli-Leydig cell tumor, retiform variant
Histologic grade and subtype correlates with clinical behavior (see below)

Epidemiology

Rare, accounting for less than 0.5% of all ovarian neoplasms
Most common in young patients with a mean age of 25 years (Am J Surg Pathol 1985;9:543)
May also present after menopause (Eur J Gynaecol Oncol 2017;38:214)

Etiology

May occur sporadically or in patients with DICER1 syndrome (601200: Pleuropulmonary Blastoma; PPB [Accessed 21 September 2018])
- Rare tumor predisposition syndrome caused by germline mutations in DICER1, a gene encoding the RNase III enzyme in the microRNA maturation pathway (N Engl J Med 2012;366:234, Br J Cancer 2013;109:2744)
- Other tumors and disorders associated with DICER1 syndrome include pleuropulmonary blastoma, cystic nephroma, multinodular goiter and botryoid embryonal rhabdomyosarcoma, among others (Nat Rev Cancer 2014;14:662)
- Germline mutation is generally a truncating mutation; may occur anywhere in the gene
- Second hit somatic mutation is a focused hot spot missense mutation affecting the RNase IIIb domain of DICER1 (Histopathology 2016;69:903)
- Sporadic Sertoli-Leydig cell tumors (moderately and poorly differentiated) harbor somatic mutations at the same hot spot of DICER1 gene (Am J Surg Pathol 2017;41:1178)
- Prevalence of germline DICER1 mutations among unselected Sertoli-Leydig cell tumor patients is currently unknown because not all patients undergo genetic counseling and testing

Clinical features

Clinical presentation may include pelvic pain or a pelvic mass, rarely with ascites and tumor rupture
Androgenic hormonal symptoms (virilization) are common and present in approximately 50% of patients; they include hirsutism, clitoromegaly, breast atrophy and menstrual irregularity or amenorrhea (Am J Surg Pathol 1985;9:543)
Estrogenic hormonal manifestations are rare

Diagnosis

May be suspected clinically in a young patient presenting with a combination of virilization, elevated testosterone levels and ovarian / pelvic mass on imaging studies
Clinical presentation often overlaps with other, more common entities, as nearly half of patients with Sertoli-Leydig cell tumors lack the characteristic androgenic symptoms and may be older (peri or postmenopausal, expanding the clinical differential diagnosis) (Eur J Gynaecol Oncol 2017;38:214)
Intraoperative frozen section evaluation is helpful to confirm the clinical suspicion and guide the surgical management

Laboratory

May have elevated testosterone (Eur J Gynaecol Oncol 2017;38:214)

Radiology description

Ultrasound, pelvic CT or MRI can show a solid or solid and cystic adnexal mass

Radiology images

Images hosted on other servers:

Large tumor

Prognostic factors

Behavior correlates with tumor grade and histologic subtype
Well differentiated Sertoli-Leydig cell tumors are essentially benign
Approximately 10% of moderately differentiated and 13 - 59% of poorly differentiated tumors have malignant behavior (Gynecol Oncol 2012;125:673, Gynecol Oncol 2012;127:384, J Obstet Gynaecol Res 2013;39:305)
Heterologous elements, retiform pattern, tumor rupture and spread outside the ovary (stage II or higher tumor stage) are adverse prognostic factors (J Obstet Gynaecol Res 2013;39:305, Gynecol Oncol 2012;125:673)

Case reports

9 year old girl with retiform tumor (Int J Clin Oncol 2011;16:705)
17 year old girl with heterologus elements masquerading as mucinous tumor on frozen section (J Clin Diagn Res 2015;9:ED01)
19 year old woman with heterologous element (Int J Clin Exp Pathol 2014;7:1176)
21 year old woman with mucinous adenocarcinoma as heterologous element in moderately differentiated tumor (Pathol Res Pract 2010;206:489)
Familial multinodular goiter and Sertoli-Leydig cell tumors associated with a large intragenic in frame DICER1 deletion (Eur J Endocrinol 2018;178:K11)

Treatment

Conservative fertility sparing surgery (unilateral salpingo-oophorectomy) and staging procedure (with or without lymphadenectomy) is usually performed in young patients with stage I tumors (Gynecol Oncol 2012;125:673, Gynecol Oncol 2012;127:384, J Obstet Gynaecol Res 2013;39:305)
Older patients who do not wish to preserve fertility typically undergo bilateral salpingo-oophorectomy, total hysterectomy and complete surgical staging
Platinum based adjuvant chemotherapy has also been reported in patients with moderately and poorly differentiated tumors, heterologous mesenchymal elements, advanced stage or rupture (J Obstet Gynaecol Res 2013;39:305, Eur J Gynaecol Oncol 2017;38:214)
Genetic counseling and germline DICER1 mutation testing is recommended (Am J Surg Pathol 2017;41:1178)

Gross description

Almost always unilateral (Am J Surg Pathol 1985;9:543)
Tumor size ranges widely from < 1 cm to 35 cm (mean 12 - 14 cm) (Am J Surg Pathol 1985;9:543)
Cut surface is typically solid, tan-yellow
Cystic component may also be seen, especially in tumors with heterologous elements or with a retiform morphologic pattern
Poorly differentiated tumor may show grossly identifiable foci of necrosis

Gross images

Contributed by Natalia Buza, M.D.

Sertoli-Leydig cell tumor, intermediate grade

AFIP images

Solid yellow lobulated mass

Cystic tumor

Retiform pattern

Heterologous elements

Frozen section description

Most critical issue is differenttiation from epithelial ovarian malignancies
- Sertoli-Leydig cell tumor: fertility sparing surgery is typically performed in younger patients
- Epithelial ovarian malignancies: generally requires complete surgical staging and the role of fertility preserving surgery is more controversial (Pei: Atlas of Intraoperative Frozen Section Diagnosis in Gynecologic Pathology, 1at Edition, 2015, Mod Pathol 1999;12:933, J Obstet Gynaecol Res 2013;39:305, Gynecol Oncol 2012;125:673)

Frozen section images

Contributed by Natalia Buza, M.D.

Well differentiated tumor

Moderately differentiated tumor

Poorly differentiated tumor

Heterologous elements

Microscopic (histologic) description

Difficulty of histologic diagnosis increases with tumor grade
While Sertoli and Leydig components can be readily identified in well differentiated tumors, less differentiated tumors lack well formed Sertoli cell tubules and have fewer Leydig cells
Well differentiated
- Open or compressed Sertoli cell tubules, admixed with clusters of Leydig cells in the intervening stroma
- Sertoli cells are low columnar to cuboidal with oval to round nuclei, which often show nuclear grooves and small nucleoli
- Leydig cells can be recognized by their round nuclei and abundant eosinophilic cytoplasm with characteristic Reinke crystals and lipofuscin pigment
- No significant atypia or mitotic activity
Moderately differentiated
- Typically has a diffuse or lobulated architectural pattern and may show alternating hypo and hypercellularity on low magnification
- Sertoli cells form compressed tubules, cords or diffuse sheets and have hyperchromatic, oval or spindled nuclei with mild to moderate atypia and occasional mitotic figures (average 5 per 10 high powered fields)
- Rare small clusters of Leydig cells are admixed with the Sertoli cell component
Poorly differentiated
- Diffuse sheets of immature, sarcomatoid Sertoli cells with moderate to marked nuclear atypia and only rare foci of vague cord formation
- Increased mitotic activity, up to 20 mitoses per 10 high powered fields
- Leydig cells are difficult to find; a few small clusters are typically located at the periphery of tumor nodules
Sertoli-Leydig cell tumor with heterologous elements
- Heterologous (epithelial or mesenchymal) elements may be seen in approximately 20% of moderately or poorly differentiated tumors and in retiform Sertoli-Leydig cell tumor (Am J Surg Pathol 1985;9:543)
- Most common heterologous element is mucinous (intestinal or gastric type) epithelium, which may be benign, borderline or malignant (Cancer 1982;50:2448)
- Carcinoid tumor (trabecular or goblet cell) has also been described arising from heterologous mucinous epithelial elements (Cancer 1982;50:2448)
- Heterologous mesenchymal (cartilage or skeletal muscle) elements are less common (Cancer 1982;50:2465)
- Rare focal hepatocyte differentiation has also been reported and may be associated with increased serum AFP (Hum Pathol 1999;30:611)
Sertoli-Leydig cell tumor, retiform variant
- Approximately 15% of Sertoli-Leydig cell tumors demonstrate focal or diffuse retiform pattern, forming anastomosing, slit-like, irregular spaces or multicystic, sieve-like or papillary architecture (Am J Surg Pathol 1985;9:543, Am J Surg Pathol 1983;7:755)

Microscopic (histologic) images

Contributed by Natalia Buza, M.D.

Well differentiated tumor

Moderately differentiated tumor

Poorly differentiated tumor

Retiform pattern

Heterologous elements

AFIP images

Heterologous elements

Positive stains

Express general sex cord proteins, such as inhibin, calretinin, SF1, FOXL2, CD56, WT1 and CD99 (Am J Surg Pathol. 1997;21:583, Arch Pathol Lab Med 2017;141:1052)
Vimentin and pancytokeratin cocktails are also positive (Am J Surg Pathol. 2007;31:592)
Leydig cell component may be negative with FOXL2, WT1 and CD99 but stains with melanA / MART1 (Am J Surg Pathol 2011;35:484)
Heterologous intestinal type mucinous epithelium stains with CK20 and CDX2, hepatoid elements may stain with AFP
Reticulin histochemical staining may be helpful in differentiating Sertoli-Leydig cell tumor from fibromas and thecomas
- Recent study showed loss of pericellular Reticulin staining in 4/4 Sertoli-Leydig cell tumors, which showed completely absent or nested pattern; this contrasts with the individual pericellular reticulin network seen in ovarian fibromas / thecomas
- However, the absence of reticulin staining is not specific for Sertoli-Leydig cell tumors, as adult granulosa cell tumors and epithelial ovarian tumors also show the same staining pattern (Int J Gynecol Pathol 2018;37:305)

Negative stains

CK7 and EMA immunostains are negative; helpful in distinguishing Sertoli-Leydig cell tumors from ovarian epithelial tumors (Arch Pathol Lab Med 2017;141:1052)
Reticulin is absent (highlights the individual pericellular reticulin network in ovarian fibromas / thecomas; also absent in adult granulosa cell tumors and epithelial ovarian tumors) (Int J Gynecol Pathol 2018;37:305)

Molecular / cytogenetics description

Up to 60% harbor hot spot missense mutation affecting the RNase IIIb domain of DICER1 (Mod Pathol 2015;28:1603)
More recent study identified DICER1 mutations in all of their moderately and poorly differentiated tumors, whereas none of the well differentiated tumors had DICER1 mutations, raising the possibility that well differentiated Sertoli-Leydig cell tumors may represent a different pathogenetic entity (Am J Surg Pathol 2017;41:1178)
FOXL2 mutation, a common molecular event in adult granulosa cell tumors of the ovary, is typically absent in Sertoli-Leydig cell tumors and has only been reported in a small number of cases (Histopathology 2016;68:279, J Pathol 2010;221:147, Int J Gynecol Pathol 2018;37:305)

Differential diagnosis

Sertoli-Leydig cell tumor:
- Endometrioid adenocarcinoma, especially sertoliform variant (Mod Pathol 1999;12:933)
  - Positive for CK7 and EMA and negative for sex cord markers (Arch Pathol Lab Med 2017;141:1052)
  - Presence of squamous differentiation is helpful
- Adult granulosa cell tumor
  - Lacks Leydig cell component
  - Majority of tumors have FOXL2 mutations (Histopathology 2016;68:279, J Pathol 2010;221:147, Int J Gynecol Pathol 2018;37:305)
- Fibroma
  - Lacks Leydig cell component
  - Reticulin stain shows individual pericellular network (Int J Gynecol Pathol 2018;37:305)
- Tubular Krukenberg tumor (i.e. tubular variant of metastatic signet ring cell carcinoma)
  - Bilaterality, presence of signet ring cells and positive EMA favor metastasis
  - Depending on the primary site, the tumor is also positive for CK7 or CK20
  - May be positive for CDX2
Retiform Sertoli-Leydig cell tumors:
- Yolk sac tumor
  - Lacks Leydig cell component
  - Positive for AFP and SALL4 (Histopathology 2014;65:51)
- Low grade serous tumors (borderline tumor and low grade serous carcinoma)
  - Positive for CK7
  - Lacks Leydig cell component
  - Often bilateral
Sertoli-Leydig cell tumors with heterologous elements:
- Carcinosarcoma
  - Marked nuclear atypicality in both components
  - Positive for epithelial markers (EMA, CK7), at least in the carcinoma component
- Mucinous tumors (primary ovarian and metastatic)
  - Lack of the surrounding atypical sex cord (Sertoli cell) and Leydig cell component
- Teratoma
  - Lack of atypical sex cord (Sertoli cell) and Leydig cell component
  - Usually predominant ectodermal component

Board review style question #1

Sertoli-Leydig cell tumors of the ovary commonly harbor mutations in which gene?

ARID1A
DICER1
FOXL2
SMARCA4
STK11

Board review style answer #1

B. Somatic hot spot missense mutation affecting the RNase IIIb domain of DICER 1 gene are common in Sertoli-Leydig cell tumors. In a recent large case series all moderately and poorly differentiated Sertoli-Leydig cell tumors harbored DICER 1 mutations.

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Board review style question #2

Sertoli-Leydig cell tumors of the ovary typically show which of the following immunoprofiles?

CK7+ / EMA+ / inhibin- / calretinin+
CK7- / EMA+ / inhibin+ / calretinin-
CK7- / EMA- / inhibin+ / calretinin+
CK7- / EMA- / inhibin+ / calretinin-

Board review style answer #2

C. Sertoli-Leydig cell tumors express general sex cord immunohistochemical markers, such as inhibin and calretinin. CK7 and EMA immunostains are negative and can help differentiating Sertoli-Leydig cell tumors from sertoliform endometrioid adenocarcinoma of the ovary, which is typically positive for both CK7 and EMA.

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