Leydig cell tumor

Testis and epididymis
Sex cord stromal tumors
Leydig cell tumor

Author: Swapnil U. Rane, M.D.

Topic Completed: 1 July 2013

Revised: 28 March 2019

Copyright: 2002-2018, PathologyOutlines.com, Inc.

PubMed Search: Testis [title] Leydig cell tumor [title]

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Table of Contents

Cite this page: Rane S. Leydig cell tumor. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/testisleydig.html. Accessed February 21st, 2020.

Definition / general

Most common sex cord stromal tumor; recapitulates normal development and evolution of Leydig cells

Epidemiology

1 - 3% of testicular tumors
No predilection based on ethnicity or race
~10% are malignant

Sites

Origin from testis is demonstrable in most cases
Rarely originates from epididymis (Andrologia 2013;45:430)

Pathophysiology

Produce testosterone, dehydroepiandrosterone and androstenedione, which cause symptoms described below

Etiology

Associated with cryptorchidism, testicular atrophy, infertility; also germline mutations in fumarate hydratase (J Clin Endocrinol Metab 2006;91:3071), hereditary leiomyomatosis and renal cell carcinoma
Rarely due to drugs (finasteride) but drug induced tumors are more well defined in rats than humans (Hum Exp Toxicol 1995;14:562)

Clinical features

Usually unilateral
Wide age range at presentation (20 - 60 yrs) with one peak in childhood and a second peak in adulthood
Children have small functional tumors
- Almost always present with isosexual precocious puberty caused by androgen
- 10% present with gynecomastia due to estrogen production
Adult have nonfunctioning testicular masses
- 30% present with gynecomastia prior to detection of testicular masses
- Rarely present with infertility (Hinyokika Kiyo 2009;55:777) or with impaired sexual function (J Androl 2012;33:578)
Malignant Leydig cell tumors are associated with older (adult) age

Radiology description

Nonspecific findings
On ultrasound, tumors are generally well defined, hypoechoic, small solid masses
May show cystic areas, hemorrhage, necrosis
Radiology cannot distinguish between germ cell tumor and Leydig cell tumor
Radiology cannot distinguish between benign and malignant Leydig cell tumors

Case reports

30 year old man with metastases to perirenal fat 17 years later (Arch Pathol Lab Med 1999;123:1104)
43 year old man with metachronous malignant Leydig cell tumors of bilateral testes (Hum Pathol 1997;28:1318)
43 year old man presented with a painless testicular mass and normal serum AFP and beta hCG (Case of the Week #122)
68 year old man with hypertesteronemia (J Androl 2012;33:578)
Cryptorchid man with an incidental Leydig cell tumor presenting with gynecomastia (Eur Urol 1997;32:368)
Finasteride related Leydig cell tumor (Andrologia 2012;44:836)

Treatment

Benign Leydig cell tumors
- Orchidectomy
- Testis sparing surgery may be performed if tumor is small, benign and frozen section facilities are available to confirm diagnosis
Malignant Leydig cell tumors
- Radical orchidectomy with retroperitoneal lymph node dissection
- Do not respond to radiation or chemotherapy

Prognosis

Benign Leydig cell tumors: excellent prognosis
Malignant Leydig cell tumors: poor survival, most develop metastatic disease resulting in death

Gross description

Well circumscribed, often encapsulated
3 - 5 cm in size
Cut surface is homogenous yellow or mahogany brown
Hyalinization and calcification may be identifiable
Extension into paratesticular in 10 - 15%
Gross features suggestive of malignancy (Arch Pathol Lab Med 2007;131:311) (most malignant tumors will have all the features)
- Large size: > 5 cm
- Infiltrative margins
- Extratesticular extension
- Necrosis

Gross images

Images hosted on other servers:

Leydig cell tumor

Microscopic (histologic) description

Histology recapitulates the evolution of Leydig cells
Growth patterns: usually diffuse
Uncommon patterns: insular, nodular, pseudoglandular, ribbon-like, trabecular, vague follicles (Am J Surg Pathol 1985;9:177), microcystic (Am J Surg Pathol 1999;23:546)
Commonly medium to large polygonal cells with abundant eosinophilic cytoplasm and distinct cell borders, round nuclei and prominent nucleoli
Uncommon cell types: scant cytoplasm, spindle cells (Am J Surg Pathol 2002;26:1424)
Cells may be vacuolated or foamy
Cells can be pigmented (contain lipofuscin: golden yellow on H&E stain, red purple granular appearance on PAS stain)
Binucleated and multinucleated cells may be present
Usually rich vascular network, scant stroma but stroma may become hyalinized and more prominent
Reinke crystals: definitive feature but present in only 30 - 40%; intracytoplasmic, nuclear or extracellular
Mitosis: rare
Mild nuclear atypia permissible
Occasional psammoma bodies
Rarely osseous metaplasia, fatty metaplasia, calcification (Am J Surg Pathol 2002;26:1424)
Microscopic features suggestive of malignancy (most malignant tumors will have all the features)
- Frequent mitoses ( > 3/10 HPF)
- Atypical mitosis
- Vascular space invasion
- Infiltrating edges
- Necrosis
- Invasion of rete testis or beyond
- DNA aneuploidy

Microscopic (histologic) images

Images hosted on PathOut server:

Contributed by Dr. Mowafak Hamodat

Various images

Pankeratin

Calretinin

Inhibin

Synaptophysin

Vimentin

Contributed by Kristine Cornejo, M.D., University of Massachusetts Medical Center

20x H&E

40x H&E

40x Reinke crystalloid

Inhibin

MART1

MelanA

Pankeratin

PLAP

Images hosted on other servers:

Sheets of large polygonal cells

Nodular aggregates of tumor cells

High power

Cytology description

Cytology is rarely performed; smears are highly cellular with singly scattered cells having eccentric round nuclei, 1 - 3 nucleoli, eosinophillic granular cytoplasm
Naked nuclei are common
Cytoplasm may be vacuolated due to lipid accumulation
A spindle cell pattern may be observed
Nuclear pseudoinclusions and Reinke crystals can be seen
There are no cytological features to differentiate Leydig cell tumors from nodular Leydig cell hyperplasia or benign from malignant tumors (Cytopathology 1999;10:217)

Cytology images

Images hosted on PathOut server:

Case of the Week #122

Various images

Images hosted on other servers:

Reinke crystalloid

Reinke crystalloid: alcohol fixed smears

Positive stains

Inhibin (Am J Surg Pathol 1998;22:615), calretinin (Appl Immunohistochem Mol Morphol 2002;10:159), MelanA (granular, cytoplasmic, Am J Surg Pathol 1998;22:57), vimentin, WT1
Androgen and other steroid hormones, steroidogenic factor I (nuclear)
Chromogranin ( > 90%), synaptophysin (70%), CD99 (MIC2) membranous staining (67%) (Mod Pathol 1998;11:774)
Cytokeratin cocktail (~40%), S100 (8 - 60%)

Negative stains

Electron microscopy description

Reinke crystals are diagnostic
- Appearance depends on plane of sectioning: polygonal, dot patterns, parallel lines, prismatic or hexagonal lattice
- Located in cytoplasm but can be seen in nucleus or interstitium
Abundant smooth endoplasmic reticulum, mitochondria with tubulovesicular cristae (Hum Pathol 1977;8:621)

Molecular / cytogenetics description

DNA aneuploidy is associated with malignant Leydig cell tumors, benign Leydig cell tumors are diploid
Somatic GNAS (guanine nucleotide binding protein, alpha stimulting activity polypeptide 1) - activating mutation (R201S) is seen occasionally (J Androl 2012;33:578)
- This somatic activating gsp mutation in Leydig cells may result in tumor development, leading to overexpression of inhibin alpha subunit and hyperactivity of the testosterone biosynthetic pathway
Another case report documents presence of germline fumarate hydratase mutation (N64T) and absence of GNAS mutation (J Clin Endocrinol Metab 2006;91:3071)

Differential diagnosis

Adrenogenital syndrome: usually bilateral, dark brown nodules with cellular pleomorphism, pigmentation, broad bands of hyalinized collagenous stroma; variable lipofuscin but no Reinke crystals; due to 21-hydroxylase deficiency (Am J Surg Pathol 1988;12:503)
Leydig cell hyperplasia: interstitial growth pattern with nodules < 0.5 cm; usually bilateral, multifocal; corticosteroid therapy restores symptoms and laboratory findings to normal
Large cell calcifying Sertoli cell tumor: associated with Carney syndrome; extensive calcification, variable tubular growth or intratubular growth, stroma more myxoid and contains neutrophils, no Reinke crystals; patchy staining for MelanA and CD10, more diffuse S100 beta; unlike Leydig cell tumor (Pathol Int 2005;55:366)
Malakoplakia: Michaelis Guttman bodies, prominent intratubular involvement
Nelson syndrome (Urol Int 1996;56:200)
Seminoma: confused when Leydig cell tumor has clear cells; clear cells in seminoma are due to glycogen unlike the lipid containing clear cells of Leydig cell tumor; seminoma has intratubular germ cell neoplasia, lymphocytic infiltrate, granulomas, fibrous septae and different immunostaining properties