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

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

Sites
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• Origin from testis is demonstrable in most cases
• Rarely originates from epididymis (Andrologia 2012 Nov 2 [Epub ahead of print])

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

Etiology
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• 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
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• 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 non functioning 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
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• Non-specific 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
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• 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
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• 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
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• Benign Leydig cell tumors: excellent prognosis
• Malignant Leydig cell tumors: poor survival, most develop metastatic disease resulting in death

Gross description
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• Well circumscribed, often encapsulated
• 3-5cm 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: >5cm
  • Infiltrative margins
  • Extratesticular extension
  • Necrosis

Gross images
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Leydig cell tumor

Micro description
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• 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 (>3/10HPF)
  • Atypical mitosis
  • Vascular space invasion
  • Infiltrating edges
  • Necrosis
  • Invasion of rete testis or beyond
  • DNA aneuploidy

Micro images
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Sheets of large polygonal cells

Nodular aggregates of tumor cells

High power

With nodules of vacuolated cells

With marked nuclear atypia

Inhibin+

Cytokeratin+

Various images

Metastases to perirenal fat

Inhibin

 

Pan-keratin

 

Calretinin

Inhibin

Synaptophysin

Vimentin

4x H&E

10x H&E

20x H&E

40x H&E

40x Reinke crystalloid

Inhibin

Mart1

Melan-A

Pan-keratin

PLAP

Cytology description
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• 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's 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
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Reinke's crystalloid

Reinke's crystalloid: alcohol fixed smears

   

Case of the Week #122

Positive stains
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• 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
• 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
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• EMA

Electron microscopy description
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• 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
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• 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
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• 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 <0.5cm; 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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