Testis & epididymis
Sex cord-stromal tumors
Leydig cell

Topic Completed: 1 July 2013

Minor changes: 11 January 2021

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

Swapnil U. Rane, M.D.
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Cite this page: Rane S. Leydig cell. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/testisleydig.html. Accessed January 17th, 2021.
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

Contributed by Debra L. Zynger, M.D.
Small tumor

Small tumor

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

Contributed by Mowafak Hamodat, M.B.Ch.B.

Various images






Contributed by Kristine Cornejo, M.D.

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

Case #122

Various images

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
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