Testis & paratestis

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.

Last author update: 4 March 2021
Last staff update: 11 April 2023

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PubMed Search: Testis Leydig cell tumor

Zhengshan Chen, M.D., Ph.D.
Manju Aron, M.D.
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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 May 30th, 2023.
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%
  • Interstitial cell tumor - obsolete term
ICD coding
  • ICD-10: D40.10 - Leydig cell tumor of testis
  • 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)
  • 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
  • Tumor histology and immunohistochemistry
  • 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
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

Nodular tumor

Nodular 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
Board review style question #3

A 41 year old man was hit in the groin area by a baseball. An ultrasound showed a 3 cm tumor of the testis. On histology, the tumor showed diffuse sheet-like growth of cells with minimal stroma, shown above. The tumor cells were large and polygonal with abundant, slightly granular, eosinophilic cytoplasm. The tumor cell nuclei were round and contained a single prominent nucleolus. Rare intracytoplasmic eosinophilic crystals were identified. The most likely diagnosis of this tumor is which of the following?

  1. Adult granulosa cell tumor
  2. Juvenile granulosa cell tumor
  3. Leydig cell tumor
  4. Sertoli cell tumor
Board review style answer #3
C. Leydig cell tumor

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Reference: Leydig cell tumor
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