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Sex cord stromal tumors

Sex cord stromal tumors-general

Author: Vikas Mehta, M.D.

Last author update: 1 September 2018

Last staff update: 11 July 2022 (update in progress)

Copyright: 2002-2023, PathologyOutlines.com, Inc.

PubMed Search: Testis sex cord stromal tumors [TIAB]

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Table of Contents

Cite this page: Mehta V. Sex cord stromal tumors-general. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/testissexcordgeneral.html. Accessed April 1st, 2023.

Definition / general

Includes neoplasms of pure sex cord and pure stromal type and also those with admixtures of both components in various proportions and degree of differentiation; each strikingly different in clinical features and biology
Leydig cell tumor is the most common pure testicular sex cord stromal neoplasm (91 - 93% of testicular sex cord stromal neoplasms)
Some arise in setting of androgen insensitivity syndrome (AIS) or adrenogenital syndrome (AGS); designate as tumor-like lesion occurring in specific syndrome

Terminology

Terminology analogous to ovarian sex cord stromal tumors but some tumors occur almost exclusively in testis (large cell calcifying Sertoli cell tumor and sclerosing Sertoli cell tumor) while others are extremely uncommon in testis (lipid rich Sertoli cell tumor) (Korean J Pathol 2014;48:50, Mod Pathol 2005;18:S81)
Broadly divided as pure (only 1 type) or mixed (2+ types)
Classification
- Pure tumors
  - Leydig cell tumors
    - Malignant Leydig cell tumor
  - Sertoli cell tumor
    - Malignant Sertoli cell tumor
    - Large cell calcifying Sertoli cell tumor
    - Intratubular large cell hyalinizing Sertoli cell neoplasia
  - Granulosa cell tumor
    - Adult granulosa cell tumor
    - Juvenile granulosa cell tumor
- Tumors of fibroma-thecoma group
- Mixed and unclassified sex cord stromal tumors
  - Mixed sex cord stromal tumor
  - Unclassified sex cord stromal tumor
- Tumors containing both germ cell and sex cord / gonadal stromal tumor
  - Gonadoblastoma

Epidemiology

Uncommon; 2 - 5% of adult testicular tumors but ~25% of testicular tumors in infants and children
Wide age range in general but:
- Juvenile granulosa cell tumor is the most common congenital testicular tumor; more common in neonates and infants, associated with ambiguous genitalia or abnormalities of sex chromosomes
- Sertoli cell tumors are common before age 1; associated with Peutz-Jeghers syndrome and Carney complex

Clinical features

Usually presents as testicular mass
Functional tumors are generally uncommon except for Leydig cell tumors (unlike ovarian sex cord stromal tumors)

Prognostic factors

Indolent behavior; 5% are malignant
Morphologic prognostic factors include size, mitotic rate, necrosis, cellular atypia, infiltrative borders and vascular invasion
Stage is the most important prognostic factor
Stage with TNM or Children's Oncology Group (COG) staging system for germ cell tumors

Case reports

7 year old boy with malignant large cell calcifying Sertoli cell tumor (Urology 2018;117:145)
22 year old man with adult granulosa cell tumor (Am J Case Rep 2014;15:471)
27 year old man with large mixed sex cord stromal tumor (Pan Afr Med J 2017;27:51)
62 year old man with large cell calcifying Sertoli cell tumor (J Clin Diagn Res 2016;10:ED03)
78 year old man with adult granulosa cell tumor with a heterologous sarcomatous component (Diagn Pathol 2014;9:107)

Treatment

High inguinal orchidectomy is treatment of choice
Testicular sparing surgery may be attempted in small tumors
Retroperitoneal lymph node dissection if clinical / radiological evidence of metastatic disease

Gross description

Sertoli cell tumor (SCT)
- Typically unilateral (exceptions: if associated with Peutz-Jeghers syndrome or some large calcifying SCTs) with a mean diameter of 3.5 cm (typically smaller if associated with Peutz-Jeghers syndrome)
- Well circumscribed, frequently with a lobulated, yellow, tan or white cut surface

Immunohistochemistry & special stains

Vimentin is typically positive but not specific
Keratin is frequently positive in Sertoli cell tumors, while staining is focal / absent in Leydig cell tumors and granulosa cell tumors and typically negative in fibromas
EMA is typically negative
Inhibin positivity has been shown in juvenile granulosa cell tumors and Leydig cell tumors even at metastatic sites but Sertoli cell tumors are not uniformly positive (25 - 90%)
Calretinin in postpuberal testis is expressed in Leydig cells but less commonly in Sertoli cells
SF1 is highly specific (negative in germ cell tumors)
FOXL2 positivity and mutations have been detected in granulosa cell tumors
MelanA is often positive in Leydig cell tumors
CD99 is expressed in normal Sertoli and granulosa cells and testicular sex cord stromal tumors but it is not a reliable marker for sex cord stromal tumors
S100 may stain normal Sertoli and Leydig cells and rete testis as well as Sertoli cell tumors (including large cell variant), Leydig cell tumors and sex cord stromal tumors - unclassified
Fibrothecomas are often positive for inhibin (patchy to diffuse), calretinin and keratin; they can also stain for MelanA, BCL2, CD34, S100, muscle specific actin and desmin
PAX2 and PAX8 are typically negative
SALL4 is negative (positive in germ cell tumors)

Immunohistochemistry of sex cord stromal tumors
	Calretinin	Inhibin	S100	Keratin	Vimentin	Actin SM	MelanA
Sertoli cell tumor, NOS	+ / -	+ / -	+ / -	+	+	- / +	-
Leydig cell tumor	+	+	- / +	- / +	+	-	+
Granulosa cell tumor	+	+	+ / -	- / +	+	- / +	-
Sex cord stromal tumor, NOS	+ / -	+ / -	+	- / +	+	+	+ / -

Molecular / cytogenetics description

No pathognomonic findings established
Lack hotspot mutations in DICER1 (in contrast to ovarian sex cord stromal tumors) (Mod Pathol 2015;28:1603)

Sertoli cell tumor (SCT)

Definition / general

See also Sertoli cell tumors
≤ 1% of all testicular neoplasms and are rare in children
Occasionally, they may develop in patients with androgen insensitivity syndrome or in association with Peutz-Jeghers syndrome

Gross description

Typically unilateral (exceptions: if associated with Peutz-Jeghers syndrome or some large calcifying SCTs) with a mean diameter of 3.5 cm (typically smaller if associated with Peutz-Jeghers syndrome)
Tumors are well circumscribed, frequently with a lobulated, yellow, tan or white cut surface

Microscopic (histologic) description

Nodular or diffuse growths with round or elongated hollow, solid (sometimes irregular in size and shape) or retiform tubules
Cord-like or solid growths may predominate
Tubules are lined by a single layer of cuboidal to columnar cells with moderate to abundant eosinophilic to pale (lipid accumulation, sometimes forming large vacuoles) cytoplasm
Stroma may be scanty or abundant with edema or hyalinization; marked sclerosis can occur

Microscopic (histologic) images

Contributed by Vikas Mehta, M.D.

Diffuse and trabecular growth

Molecular / cytogenetics description

Most common changes include gains of chromosomes X and loss of the entirety or part of chromosomes 2 and 19 (Oncol Rep 2007;17:585)
Both the NOS type as well as sclerosing subtype demonstrate CTNNB1 gene mutations (Am J Surg Pathol 2014;38:1160, Am J Surg Pathol 2014;38:66)

Leydig cell tumor (LCT)

Definition / general

See also Leydig cell tumor
Most common sex cord stromal tumor (2 - 3% of all testicular neoplasms) but only 25% diagnosed beyond age 50
15 - 30% of patients develop gynecomastia and children almost always present with isosexual pseudoprecocity
Approximately 10% of patients have undescended testis or rarely Klinefelter or Turner syndrome
Only about 3% are bilateral and 10% are malignant (the latter only in adults) (Anal Quant Cytol Histol 2007;29:139, Am J Surg Pathol 1985;9:177)

Gross description

Usually well circumscribed ranging from 3 to 5 cm with a uniform solid, yellow to tan cut surface
Lobulation may be grossly seen; areas of hemorrhage or necrosis are seen in approximately 30% of cases

Microscopic (histologic) description

Often diffuse or nodular growths; in the latter, the stroma may be prominent and extensively hyalinized forming broad bands
Cells are typically large and polygonal with abundant, slightly granular, eosinophilic cytoplasm but occasionally it is clear (abundant lipid)
Nuclei are typically round and contain a single prominent nucleolus
Crystals of Reinke and lipochrome pigment identified in one - third and 10 - 15% of cases respectively (Am J Surg Pathol 2002;26:1424)

Microscopic (histologic) images

Contributed by Vikas Mehta, M.D.

Solid sheets of tumor cells

Significant cytologic atypia

Molecular / cytogenetics description

Most common changes include gains of chromosomes X, 19 and 19p and losses of chromosomes 8 and 16 (Oncol Rep 2007;17:585)
Some childhood LCTs have acquired missense mutations in codon 578 of the gene for the luteininzing hormone / choriogonadotropin receptor (LHCGR)
Rarely LCTs are found to have mutations in the FH gene, either sporadically or as part of the hereditary leiomyomatosis and renal cell carcinoma syndrome (J Clin Endocrinol Metab 2006;91:3071)

Sertoli-Leydig cell tumor (SLCT)

Definition / general

These tumors are rare and their histologic appearance is similar to that seen in their ovarian counterpart

Gross description

They typically have a solid, yellow and often lobulated cut surface

Microscopic (histologic) description

Most tumors have tubules, cords and trabeculae in a haphazard arrangement embedded in a stroma that frequently contains Leydig cells
Most tumors are of intermediate differentiation
Cellular, neoplastic stroma, sometimes with a Leydig cell component, is diagnostic of SLCT

Adult granulosa cell tumor (AGCT)

Definition / general

See also Adult granulosa cell tumor
This rare tumor occurs in adult males with an average age of 42
Patients may have a testicular mass for several years or gynecomastia (Clinics (Sao Paulo) 2006;61:77, Hum Pathol 1993;24:1120, Arch Pathol Lab Med 2000;124:1525)

Gross description

Tumors may be as large as 13 cm and typically they have a homogeneous, yellow-gray or white, firm and lobulated cut surface and cysts may be present

Microscopic (histologic) description

Appearance is similar to ovarian adult granulosa cell tumors; more common patterns include diffuse or microfollicular with Call-Exner bodies
Cells typically have scant cytoplasm and elongated nuclei with frequent grooves; mitotic rate is generally low
Tumors may have a prominent fibromatous or fibrothecomatous background as seen in the ovary (Clinics (Sao Paulo) 2006;61:77, Hum Pathol 1993;24:1120, Arch Pathol Lab Med 2000;124:1525)
Gross or microscopic features associated with aggressive behavior include size > 7 cm, vascular or lymphatic invasion and hemorrhage or necrosis (Hum Pathol 2008;39:701)

Microscopic (histologic) images

Contributed by Vikas Mehta, M.D.

Diffuse growth pattern

Molecular / cytogenetics description

Acquired FOXL2 mutations have been identified in a smaller proportion of these tumors than in their ovarian counterpart (Arch Pathol Lab Med 2012;136:825)

Juvenile granulosa cell tumor (JGCT)

Definition / general

See also Juvenile granulosa cell tumor
Most common neoplasm of the testis during the first 6 months; almost all tumors are diagnosed during the first year of life and only occasionally seen in older children or adults
Approximately 20% of tumors occur in neonates with sex chromosome abnormalities affecting the Y chromosome and ambiguous genitalia (Drash syndrome) and nearly 40% occur in cryptorchid testes; no malignant cases reported (Am J Surg Pathol 1985;9:87, Am J Surg Pathol 1996;20:72, Am J Surg Pathol 1986;10:577, Am J Surg Pathol 1985;9:737)

Gross description

Tumors measure up to 6.5 cm in largest dimension
May be solid (yellow-orange or tan-white), cystic or both

Microscopic (histologic) description

Solid, nodular or follicular patterns are the most common and sometimes alternate
Follicles vary from large and round / oval to small and irregular containing basophilic or eosinophilic secretion (mucicarmine+)
In solid or nodular areas, the cells grow in sheets or irregular clusters
Cells have moderate to large amounts of pale to eosinophilic cytoplasm, round to oval hyperchromatic nuclei, some of which contain nucleoli
Mitoses are common in contrast to AGCT
Extensive hyalinization (forming nodules) and prominent myxoid background may be seen (Am J Surg Pathol 1985;9:87, Am J Surg Pathol 1996;20:72, Am J Surg Pathol 1986;10:577, Am J Surg Pathol 1985;9:737)

Fibroma-thecoma

Definition / general

See also Fibromas
Uncommon tumors in contrast to their ovarian counterpart
Thecomas are truly exceptional
Patients present with symptoms and signs related to a testicular mass (Am J Surg Pathol 2013;37:1208)

Gross description

Variable sized, typically well circumscribed but not encapsulated with a firm, white-tan to yellow cut surface

Microscopic (histologic) description

Spindle shaped fibroblasts growing in a storiform pattern with variable amounts of collagen or edema but they can also grow in short fascicles
They may be cellular and also have ≤ 2 mitoses/10 HPFs
They may entrap seminiferous tubules (Am J Surg Pathol 2013;37:1208)

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