Testis & epididymis

Sex cord-stromal tumors

Leydig cell tumor


Editorial Board Member: Maria Tretiakova, M.D., Ph.D.
Editor-in-Chief: Debra L. Zynger, M.D.
Zhengshan Chen, M.D., Ph.D.
Manju Aron, M.D.

Topic Completed: 4 March 2021

Minor changes: 12 April 2021

Copyright: 2002-2021, PathologyOutlines.com, Inc.

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

Zhengshan Chen, M.D., Ph.D.
Manju Aron, M.D.
Page views in 2020: 15,723
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Cite this page: Chen Z, Aron M. Leydig cell tumor. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/testisleydig.html. Accessed October 21st, 2021.
Definition / general
Essential features
  • Most common sex cord stromal tumor of the testis
  • Histology: diffuse / nodular growth of polygonal cells with abundant eosinophilic cytoplasm, uniform round nuclei and prominent central nucleoli; Reinke crystals may be present
  • Immunohistochemistry: inhibin A+, calretinin+, MelanA+, SF1+, AR+
  • Features associated with malignant potential include: size > 5 cm, infiltrative borders, cytological atypia, frequent mitoses (> 3/10 high power fields), vascular invasion and necrosis
  • Treatment: surgical resection, curative for nonmetastasizing tumors
  • Prognosis: overall 5 year survival after orchiectomy > 90%
Terminology
  • Interstitial cell tumor - obsolete term
ICD coding
  • ICD-10: D40.10 - Leydig cell tumor of testis
Epidemiology
Sites
Pathophysiology
  • Produces androgen, mainly testosterone, which can cause symptoms described below
  • Can also produce estrogen by either direct production of estradiol or by peripheral aromatization of testosterone (Arch Pathol Lab Med 2007;131:311)
Etiology
  • Little is known
  • Rare association with germline fumarate hydratase mutations in patients with hereditary leiomyomatosis and renal cell carcinoma syndrome and activating mutations of the luteinizing hormone receptor (N Engl J Med 1999;341:1731)
Clinical features
Diagnosis
  • Tumor histology and immunohistochemistry
Laboratory
  • Serum testosterone and estrogen levels may be elevated
  • Lower sperm concentration, lower total sperm count and motility (Hum Reprod 2019;34:1389)
Radiology description
  • Nonspecific
  • On ultrasound, tumors are generally well defined, homogeneous hypoechoic, small solid masses with hypervascularity (Arch Pathol Lab Med 2007;131:311)
  • May show cystic areas
Radiology images

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CT scan: circumscribed mass

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MRI: solid enhancing mass

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Ultrasound: mixed echogenic mass

Prognostic factors
  • Benign Leydig cell tumors: excellent prognosis, curative by surgery
  • Malignant Leydig cell tumors: poor survival, most develop metastatic disease leading to death (J Urol 2020;203:949)
Case reports
Treatment
Gross description
  • Well circumscribed, solid homogeneous mass
  • Usually < 5 cm in size
  • Golden brown or brownish green cut surface
  • Hyalinization and calcification may be present
  • Gross features suggestive of malignancy (Arch Pathol Lab Med 2007;131:311)
    • Large size: > 5 cm
    • Infiltrative margins
    • Hemorrhage and necrosis
    • Extratesticular extension
Gross images

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

Small tumor



Images hosted on other servers:
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Circumscribed brown tumor

Frozen section description
  • Diffuse sheets of uniform polygonal cells with round nuclei, central nucleoli, abundant granular, eosinophilic cytoplasm and rectangular to club shaped Reinke crystals (Hum Pathol 2015;46:600)
  • Touch imprint and scrape smear preparations are better to highlight Reinke crystals (Arch Pathol Lab Med 2005;129:e65)
Frozen section images

Images hosted on other servers:
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Reinke crystals

Microscopic (histologic) description
  • Architecture:
    • Diffuse or nodular with fibrous bands
    • Uncommon patterns: insular, trabecular, pseudotubular, ribbon-like, trabecular, spindled and microcystic (Surg Pathol Clin 2018;11:739)
  • Cytologic features:
    • Polygonal cells with abundant eosinophilic granular cytoplasm, uniform round nuclei and prominent central nucleoli; rarely, nuclei may have a ground glass appearance
    • Uncommon cell types: scant cytoplasm, foamy cytoplasm and spindling (Am J Surg Pathol 2002;26:1424)
    • Lipofuscin pigment maybe present: golden yellow on H&E stain, red-purple granular appearance on PAS stain
    • Binucleated and multinucleated cells may be present
    • Reinke crystals: pathognomonic; identified in only up to 30% (degradation / dissolution by formalin fixation); intracytoplasmic, rarely extracellular
    • Mitosis: rare
    • Mild nuclear atypia permissible
    • Occasionally, psammoma bodies, calcification, osseous and adipocytic metaplasia may be identified (Am J Surg Pathol 2002;26:1424)
  • Microscopic features suggestive of malignancy (most malignant tumors will have more than 2 of these features) (Am J Surg Pathol 1985;9:177):
    • > 5 cm
    • Infiltrative borders
    • Cytological atypia
    • Frequent mitoses (> 3/10 high power fields)
    • Vascular invasion
    • Necrosis
Microscopic (histologic) images

Contributed by Manju Aron, M.D. and Kristine Cornejo, M.D.

Polygonal cells

Eosinophilic cells

Reinke crystals

Inhibin positive

SF1 positive

Cytology description
  • Fine needle aspiration is rarely performed unless in a metastatic lymph node
  • Cellular smears with discohesive cells having eccentric round nuclei, evenly distributed chromatin, prominent nucleoli and abundant eosinophilic granular cytoplasm
  • Naked nuclei are common
  • Cytoplasm may be vacuolated due to lipid accumulation
  • Nuclear grooves, binucleation and multinucleation may be identified
  • Nuclear pseudoinclusions and Reinke crystals can be seen
  • No cytological features to differentiate Leydig cell tumors from nodular Leydig cell hyperplasia (J Am Soc Cytopathol 2019;8:220)
Positive stains
Negative stains
Electron microscopy description
  • Reinke crystals are diagnostic
    • Appearance depends on plane of sectioning: prismatics, hexagonal lattices or hexagonal microtubules with parallel lines
    • Located in cytoplasm but can be seen in nucleus or interstitium
  • Abundant smooth endoplasmic reticulum, mitochondria with tubulovesicular cristae, numerous lipid droplets and lipofuscin granules (Case Reports Histol Histopathol 1989;4:247)
Molecular / cytogenetics description
  • DNA aneuploidy is associated with malignant Leydig cell tumors, benign Leydig cell tumors are diploid
  • Gain of chromosome X, 19 or 19p and loss on chromosome 8 and 16 are most frequent findings (Oncol Rep 2007;17:585)
  • Somatic GNAS (guanine nucleotide binding protein, alpha stimulating activity polypeptide 1)
Sample pathology report
  • Right testicle, radical orchiectomy:
    • Leydig cell tumor, 2 cm in greatest dimension (see synoptic report)
    • Tumor limited to testis
    • Resection margins uninvolved by tumor
  • Note that benign tumors are not staged
Differential diagnosis
Board review style question #1

A 21 year old man had a 2 cm painless mass in the left testicle. Histological features are shown in the image above. Which marker will be positive in this tumor?

  1. SALL4
  2. PLAP
  3. OCT4
  4. Inhibin A
  5. Cytokeratin
Board review style answer #1
D. Inhibin A. The diagnosis is Leydig cell tumor.

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Reference: Leydig cell tumor
Board review style question #2
Malignant potential in Leydig cell tumor is associated with which of the following factors?

  1. Younger patient age
  2. Diffuse growth pattern
  3. Large tumor size (> 5 cm)
  4. Calcification
  5. Reinke crystals
Board review style answer #2
C. Large tumor size (> 5 cm)

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Reference: Leydig cell tumor
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