Ovary

Sex cord stromal tumors

Sertoli-Leydig cell tumor


Editorial Board Member: Gulisa Turashvili, M.D., Ph.D.
Deputy Editor-in-Chief: Jennifer A. Bennett, M.D.
Natalia Buza, M.D.

Topic Completed: 26 August 2021

Minor changes: 26 August 2021

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

Natalia Buza, M.D.
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Cite this page: Buza N. Sertoli-Leydig cell tumor. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/ovarytumorsertolileydig.html. Accessed October 18th, 2021.
Definition / general
  • Rare ovarian tumor composed of sex cord (Sertoli cells) and stromal (Leydig cells) elements, accounting for < 0.5% of all ovarian neoplasms
Essential features
  • Rare ovarian tumor composed of sex cord (Sertoli cells) and stromal (Leydig cells) elements
  • May occur sporadically or in patients with DICER1 syndrome
  • 3 molecular subtypes (Am J Surg Pathol 2019;43:628):
    • DICER1 mutant: younger age, moderately / poorly differentiated, retiform or heterologous elements
    • FOXL2 c.402C>G (p.Cys134Trp) mutant: postmenopausal patients, moderately / poorly differentiated, no retiform or heterologous elements
    • DICER1 / FOXL2 wildtype: intermediate age, no retiform or heterologous elements, including all well differentiated tumors
  • Express general sex cord markers (inhibin, calretinin, SF1, FOXL2 and CD56); CK7 and EMA immunostains are negative
  • Behavior correlates with tumor grade and histologic subtype
Terminology
  • Sertoli-Leydig cell tumor
    • Well differentiated
    • Moderately differentiated / intermediate grade
    • Poorly differentiated
  • Sertoli-Leydig cell tumor with heterologous elements
  • Sertoli-Leydig cell tumor, retiform variant
  • Histologic grade and subtype correlates with clinical behavior (see Prognostic factors)
ICD coding
  • ICD-O:
    • 8631/1 - Sertoli-Leydig cell tumor, NOS
  • ICD-11:
    • XH0UP7 - Sertoli-Leydig cell tumor of intermediate differentiation
    • XH6FQ9 - Sertoli-Leydig cell tumor, NOS
    • XH8U56 - Sertoli-Leydig cell tumor, intermediate differentiation, with heterologous elements
    • XH6XB6 - Sertoli-Leydig cell tumor, retiform
    • XH3PN1 - Sertoli-Leydig cell tumor, retiform, with heterologous elements
Epidemiology
  • Rare, accounting for < 0.5% of all ovarian neoplasms and 1 - 2% of pediatric ovarian cancers
  • Most common in young patients with a mean age of 25 years (Am J Surg Pathol 1985;9:543)
  • May also present after menopause (Eur J Gynaecol Oncol 2017;38:214)
  • Tumors with a retiform pattern or germline DICER1 mutation occur at a younger age (Gynecol Oncol 2017;147:521)
  • Nearly all pediatric Sertoli-Leydig cell tumors are moderately or poorly differentiated, are DICER1 syndrome associated and often show a retiform pattern or heterologous elements
Sites
  • Ovary
Pathophysiology
Etiology
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
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
Case reports
Treatment
Gross description
  • Almost always unilateral (Am J Surg Pathol 1985;9:543)
  • Tumor size ranges widely from < 1 cm to 35 cm (mean 12 - 14 cm) (Am J Surg Pathol 1985;9:543)
  • Cut surface is typically solid, tan-yellow
  • Cystic component may also be seen, especially in tumors with heterologous elements or with a retiform morphologic pattern
  • Poorly differentiated tumor may show grossly identifiable foci of necrosis
Gross images

Contributed by Natalia Buza, M.D.

Intermediate grade tumor

Frozen section description
  • Most critical issue is differentiation from epithelial ovarian malignancies
    • Unlike epithelial malignancies, Sertoli-Leydig cell tumor is almost always unilateral and typically occurs in younger patients
    • Clinical history of hormonal (androgenic) symptoms is helpful and should be actively sought from the surgical team
    • Key microscopic features on frozen section include admixture of Sertoli cell tubules or compressed cords with variable amount of Leydig cell clusters
    • Intracytoplasmic Reinke crystals may be better preserved compared to formalin fixed paraffin embedded permanent sections
    • Sertoli-Leydig cell tumor: fertility sparing surgery is typically performed in younger patients
    • Epithelial ovarian malignancies: generally requires complete surgical staging and the role of fertility preserving surgery is more controversial (Hui: Atlas of Intraoperative Frozen Section Diagnosis in Gynecologic Pathology, 1st Edition, 2015, Mod Pathol 1999;12:933, J Obstet Gynaecol Res 2013;39:305, Gynecol Oncol 2012;125:673)
Frozen section images

Contributed by Natalia Buza, M.D.

Well differentiated tumor

Moderately differentiated tumor

Poorly differentiated tumor

Heterologous elements

Microscopic (histologic) description
  • Difficulty of histologic diagnosis increases with tumor grade
  • While Sertoli and Leydig components can be readily identified in well differentiated tumors, less differentiated tumors lack well formed Sertoli cell tubules and have fewer Leydig cells
  • Well differentiated
    • Open or compressed Sertoli cell tubules, admixed with clusters of Leydig cells in the intervening stroma
    • Sertoli cells are low columnar to cuboidal with oval to round nuclei, which often show nuclear grooves and small nucleoli
    • Leydig cells can be recognized by their round nuclei and abundant eosinophilic cytoplasm with characteristic Reinke crystals and lipofuscin pigment
    • No significant atypia or mitotic activity
  • Moderately differentiated
    • Typically has a diffuse or lobulated architectural pattern and may show alternating hypo and hypercellularity on low magnification
    • Sertoli cells form compressed tubules, cords or diffuse sheets and have hyperchromatic, oval or spindled nuclei with mild to moderate atypia and occasional mitotic figures (average 5 per 10 high power fields)
    • Rare small clusters of Leydig cells are admixed with the Sertoli cell component
    • Follicular differentiation may be seen in moderately and poorly differentiated tumors and may resemble juvenile granulosa cell tumor (Am J Surg Pathol 2021;45:59)
  • Poorly differentiated
    • Diffuse sheets of immature, sarcomatoid Sertoli cells with moderate to marked nuclear atypia and only rare foci of vague cord formation
    • Increased mitotic activity, up to 20 mitoses per 10 high power fields
    • Leydig cells are difficult to find; a few small clusters are typically located at the periphery of tumor nodules
  • Sertoli-Leydig cell tumor with heterologous elements
    • Heterologous (epithelial or mesenchymal) elements may be seen in approximately 20% of moderately or poorly differentiated tumors and in retiform Sertoli-Leydig cell tumor (Am J Surg Pathol 1985;9:543)
    • Most common heterologous element is mucinous (intestinal or gastric type) epithelium, which may be benign, borderline or malignant (Cancer 1982;50:2448)
    • Carcinoid tumor (trabecular or goblet cell) has also been described arising from heterologous mucinous epithelial elements (Cancer 1982;50:2448)
    • Heterologous mesenchymal (cartilage or skeletal muscle) elements are less common (Cancer 1982;50:2465)
    • Rare focal hepatocyte differentiation has also been reported and may be associated with increased serum AFP (Hum Pathol 1999;30:611)
  • Sertoli-Leydig cell tumor, retiform variant
Microscopic (histologic) images

Contributed by Natalia Buza, M.D.

Well differentiated tumor

Moderately differentiated tumor


Poorly differentiated tumor

Retiform pattern

Heterologous elements

Positive stains
Negative stains
Molecular / cytogenetics description
  • 3 molecular subtypes (Am J Surg Pathol 2019;43:628):
    • DICER1 mutant: younger age, moderately / poorly differentiated, retiform or heterologous elements
    • FOXL2 c.402C>G (p.Cys134Trp) mutant: postmenopausal patients, moderately / poorly differentiated, no retiform or heterologous elements
    • DICER1 / FOXL2 wildtype: intermediate age, no retiform or heterologous elements, including all well differentiated tumors
  • Somatic hotspot DICER1 mutations are present in approximately half of all cases (range: 15 - 97%), 61 - 69% of which also have germline DICER1 mutations (Gynecol Oncol 2017;147:521, Am J Surg Pathol 2017;41:1178, Histopathology 2016;68:279, Mod Pathol 2015;28:1603)
  • More recent study identified DICER1 mutations in all of their moderately and poorly differentiated tumors, whereas none of the well differentiated tumors had DICER1 mutations, raising the possibility that well differentiated Sertoli-Leydig cell tumors may represent a different pathogenetic entity (Am J Surg Pathol 2017;41:1178)
  • FOXL2 mutation has been reported in up to 22% of ovarian Sertoli-Leydig cell tumors and is mutually exclusive with DICER1 mutations (Histopathology 2016;68:279, J Pathol 2010;221:147, Int J Gynecol Pathol 2018;37:305)
Sample pathology report
  • Ovary and fallopian tube, right, salpingo-oophorectomy:
    • Sertoli-Leydig cell tumor of the ovary, poorly differentiated, with heterologous elements (embryonal rhabdomyosarcoma) (see comment)
    • Tumor size: 28 cm
    • Tumor ruptured intraoperatively (see surgeon's operative report)
    • Ovarian surface involvement: not definitely identified
    • Fallopian tube: negative for tumor
    • TNM stage (AJCC 8th edition): pT1c1 Nx, at least stage IC1
    • Comment: Pelvic wash cytology is negative. Referral for genetic counseling is recommended.
Differential diagnosis
Board review style question #1

The ovarian tumor in this image most commonly harbors mutations in which gene?

  1. ARID1A
  2. DICER1
  3. FOXL2
  4. SMARCA4
  5. STK11
Board review style answer #1
B. DICER1. Somatic hotspot missense mutation affecting the RNase IIIb domain of DICER1 gene are common in Sertoli-Leydig cell tumors. In a recent large case series, all moderately and poorly differentiated Sertoli-Leydig cell tumors harbored DICER1 mutations.

Comment Here

Reference: Sertoli-Leydig cell tumor
Board review style question #2
Sertoli-Leydig cell tumors of the ovary typically show which of the following immunoprofiles?

  1. CK7+ / EMA+ / inhibin- / calretinin+
  2. CK7- / EMA+ / inhibin+ / calretinin-
  3. CK7- / EMA- / inhibin+ / calretinin+
  4. CK7- / EMA- / inhibin+ / calretinin-
Board review style answer #2
C. CK7- / EMA- / inhibin+ / calretinin+. Sertoli-Leydig cell tumors express general sex cord immunohistochemical markers, such as inhibin and calretinin. CK7 and EMA immunostains are negative and can help differentiate Sertoli-Leydig cell tumors from sertoliform endometrioid adenocarcinoma of the ovary, which is typically positive for both CK7 and EMA.

Comment Here

Reference: Sertoli-Leydig cell tumor
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