Testis and epididymis
Sex cord stromal tumors
Leydig cell tumor

Author: Swapnil U. Rane, M.D. (see Authors page)

Revised: 14 July 2017, last major update July 2013

Copyright: (c) 2002-2017, PathologyOutlines.com, Inc.

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

Cite this page: Leydig cell tumor. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/testisleydig.html. Accessed October 20th, 2018.
Definition / general
  • Most common sex cord stromal tumor; recapitulates normal development and evolution of Leydig cells
  • 1 - 3% of testicular tumors
  • No predilection based on ethnicity or race
  • ~10% are malignant
  • Produce testosterone, dehydroepiandrosterone and androstenedione, which cause symptoms described below
  • 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
  • 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
  • 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
  • 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

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Images hosted on PathOut server:

Case of the Week #122:


Contributed by Dr. Mowafak Hamodat, Eastern Health of Newfoundland and Labrador, St. John's, Canada:






Images hosted on other servers:

Sheets of large polygonal cells

Nodular aggregates of tumor cells

High power

With nodules of vacuolated cells

With marked nuclear atypia



Various images

Metastases to perirenal fat

Contributed by Dr. Kristine Cornejo, University of Massachusetts Medical Center:

4x H&E

10x H&E

20x H&E

40x H&E

40x Reinke crystalloid






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

Images hosted on other servers:

Reinke crystalloid

Reinke crystalloid: alcohol fixed smears

Positive stains
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