Testis & epididymis
Sex cord-stromal tumors
Leydig cell
Author: Swapnil U. Rane, M.D.
Topic Completed: 1 July 2013
Minor changes: 10 September 2020
Copyright: 2002-2020, PathologyOutlines.com, Inc.
PubMed Search: Testis [title] Leydig cell tumor [title]
Table of Contents
Definition / general | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Radiology description | Case reports | Treatment | Prognosis | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Electron microscopy description | Molecular / cytogenetics description | Differential diagnosisCite this page: Rane S. Leydig cell. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/testisleydig.html. Accessed September 19th, 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
Contributed by Mowafak Hamodat, M.B.Ch.B.
Various images
Pankeratin
Calretinin
Inhibin
Synaptophysin
Vimentin
Contributed by Kristine Cornejo, M.D.
20x H&E
40x H&E
40x Reinke crystalloid
Inhibin
MART1
MelanA
Pankeratin
PLAP
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
- 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%)
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
