JPC SYSTEMIC PATHOLOGY

REPRODUCTIVE SYSTEM

January 2025

R-N03

 

Signalment (JPC #1357631): A dog 

 

HISTORY: Not provided

 

HISTOPATHOLOGIC DESCRIPTION: Testis: Two neoplasms are present. First, comprising 30% of the section, markedly expanding the testis, and compressing the adjacent seminiferous tubules is an 8 mm diameter, well-circumscribed, encapsulated, multilobulated, densely cellular neoplasm composed of polygonal cells arranged in cords and indistinct nests supported by a fine fibrovascular stroma. Neoplastic cells have distinct cell borders, a moderate amount of eosinophilic granular or occasionally vacuolated cytoplasm with eosinophilic globules, and one round, central nucleus with finely-stippled chromatin and a prominent magenta nucleolus (interstitial cells). There is moderate anisocytosis and anisokaryosis. The mitotic rate is less than 1 per 2.37mm² (10 HPF). There are rare intranuclear cytoplasmic invaginations. The second neoplasm fills the lumens and replaces spermatogenic and Sertoli cells in 30% of surrounding seminiferous tubules. This neoplasm is composed of round cells with distinct cell borders, a scant to moderate amount of eosinophilic, granular cytoplasm, and large, round, vesiculate nuclei with coarse chromatin and 1-2 large, prominent, magenta nucleoli (germ cells). There is moderate anisocytosis and anisokaryosis with rare giant cells and frequent multinucleated cells with up to 7 nuclei. The mitotic count averages 2 per 0.237mm² (1 HPF), and there is scattered single cell necrosis.  Remaining non-neoplastic seminiferous tubules exhibit degeneration, characterized by irregular, undulant basement membranes, decreased to absent spermatogenesis, and occasional multinucleated spermatids within tubular lumina. 

 

MORPHOLOGIC DIAGNOSES: 

1. Testis: Interstitial cell tumor, breed unspecified, canine.

2. Testis: Seminoma, intratubular, multifocal.

3. Testis, seminiferous tubules: Germ cell atrophy, chronic, diffuse, moderate, with tubular degeneration and hypospermatogenesis.

 

GENERAL DISCUSSION:

• Major categories of primary testicular tumors:

• Germ cell: Seminoma, teratoma, embryonal carcinoma, yolk sac carcinoma
• Sex-cord stromal: Sertoli cell/sustentacular cell, Leydig cell/interstitial cell
• Mixed germ cell-sex cord stromal tumor (seminoma/sertoli - rare)
• Lining epithelium of modified mesothelium: Mesothelioma (rare in most species)
• Others (rare): Rete adenoma and adenocarcinoma, mesenchymal tumors

• Interstitial cell tumor: Common testicular neoplasm of the dog, cat, rat, and bull (Guernsey), reported in boar and stallion (cryptorchid)

• Distinction between interstitial cell hyperplasia and neoplasia is arbitrarily based on size (neoplasms >2mm in diameter) and encroachment on adjacent tissue
• Unilateral or bilateral, single or multiple

• Seminoma: Most common testicular neoplasm in the stallion; second most common in the dog; reported in the ram, goat, bull, and cat

• Unilateral or bilateral, single or multiple; more common in right testicle than left
• Initially begins as the intratubular form which is confined to the seminiferous tubules; later develops into the diffuse form with cells forming broad sheets
• Distinction between benign and malignant is difficult; all should be considered potentially malignant; metastasis rare in the dog, more likely in the horse

 

PATHOGENESIS:

• Interstitial cell tumor:

• Often incidental; majority are benign, metastasis is extremely rare
• Cryptorchidism predisposes to genesis of interstitial cell tumors in stallions and possibly cats, but not in dogs
• Most do not produce testosterone

• Seminoma:

• Metastasis rare despite malignant histologic appearance
• Microvessel density and vascular endothelial growth factor (VEGF) may be useful prognostic indicators for intrinsic malignancy and growth potential
• Cryptorchid dogs have a higher risk of developing seminoma (or Sertoli cell tumor) than those with scrotal testes

• Seminoma more common in inguinal cryptorchid testes
• Sertoli cell tumor more common in abdominal cryptorchid testes 
• Contralateral testis (even if scrotal) also at increased risk for neoplasia
• Retained testes, especially if enlarged by neoplasia, are more prone to torsion

 

TYPICAL CLINICAL FINDINGS:

• Scrotal enlargement, inguinal or abdominal mass (if cryptorchid testis)
• Interstitial cell tumor (dogs): Commonly associated with perianal gland neoplasia, tail gland (AKA supracaudal gland) and prostatic hyperplasia; rarely causes signs of hyperestrogenism (e.g. gynecomastia, prostatic squamous metaplasia, bone marrow suppression)
• Seminoma: Pain secondary to hemorrhage and necrosis

 

TYPICAL GROSS FINDINGS:

• Interstitial cell tumor:

• Yellow, soft, often contains areas of hemorrhage
• Small, round, well circumscribed; cause little distortion of the affected testicle
• Bulge on cut section, frequently cystic or hemorrhagic

• Seminoma:

• Bulging; gray, white, or pink, and occasional brown mottling (“fish flesh”)
• Lobulated, irregular, compresses adjacent parenchyma, fine septa, soft

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Interstitial cell tumor: Resemble normal interstitial cells; round to polygonal, abundant eosinophilic finely granular to vacuolated cytoplasm, often containing prominent lipid accumulations or yellow or brown lipochrome pigment; small, round, dark nuclei, rare mitoses; PAS-positive intranuclear cytoplasmic invaginations (in up to 15% of cells in canine interstitial cell tumors) 
• Seminoma: Large, uniform, round cells with discrete cell borders, scant cytoplasm, large round to ovoid nuclei, occasional giant nuclei and multinucleated cells, mitoses common, necrosis and hemorrhage, lymphoid aggregates (CD8⁺); two main patterns:

• Intratubular: Cells are restricted to the tubules, multifocal
• Diffuse: With progression, intratubular seminomas invade the interstitium and form broad sheets (or less often, cords or lobules); individual cell necrosis and vacuolated histiocytes impart a “starry-sky” appearance

 

ULTRASTRUCTURAL FINDINGS:

• Interstitial cell tumor: Abundant mitochondria with tubular cristae, smooth endoplasmic reticulum; intranuclear cytoplasmic invaginations are composed of smooth and rough endoplasmic reticulum, vesicles, and lipid vacuoles, myelin figures, and disrupted membranous profiles
• Seminoma: Straight cell borders not limited by a basement membrane; intercellular bridges; oval nucleus; distinct Golgi complex

 

ADDITIONAL DIAGNOSTIC TESTS: 

• Interstitial cell tumor: Positive for GATA-4 and cytoplasmic invaginations PAS positive; also KIT (CD117), LH, and 3ß hydroxysteroid dehydrogenase (3ßHSD)
• Seminoma: Positive for calretinin, KIT (CD117), PGP 9.5, E-cadherin, inhibin, and NSE; negative for GATA-4 

 

DIFFERENTIAL DIAGNOSIS: 

• Sertoli cell tumor (R-N02): Common in the older dog; usually unilateral and associated with cryptorchid testes; often hormonally active; may exhibit hyperestrogenism (feminization, gynecomastia, atrophy of contralateral testicle, squamous metaplasia of prostate gland, alopecia, bone marrow atrophy); very firm, multinodular, white to grey; consist of variably sized aggregates of Sertoli cells separated by abundant fibrous tissue stroma
• Teratoma (R-N08): Uncommon but occur in young horses; tumor consisting of tissues from more than one germ layer; rare in the dog; unilateral or bilateral, single or multiple; may have both solid and cystic areas and may contain foci of cartilage, bone, fat, or haired skin; histologic appearance is highly variable and depends on the type of tissues produced
• Mixed germ cell-sex-cord stromal tumor: tubules and cords of admixed sertoli/interstitial cells and germ cells in varying proportions, different than a collision tumor when a seminoma collides with a Sertoli cell tumor 
• Embryonal carcinoma: Rare, derived from poorly differentiated embryonal epithelium; trophoblastic differentiation and α-fetoprotein supportive 

 

COMPARATIVE PATHOLOGY:

• Rat: 

• Interstitial cell tumor (R-N04):

• Most common testicular tumor in rats; seen mostly in older F344 rats
• Associated with concurrent hypercalcemia
• Two cell types: polyhedral to elongate cells with granular to vacuolated cytoplasm, and smaller cells with hyperchromatic nuclei and scant cytoplasm

• Other important testicular lesions in rats: mesothelioma (F344; R-N04), scrotal hemorrhage and peritesticular/testicular necrosis and fibrinous exudate associated with Kilham’s rat virus (parvovirus); associated with rat parvovirus; polyarteritis nodosa in pampiniform plexus

• Stallion: 

• Seminoma is most common testicular neoplasm
• Interstitial cell tumor:

• Occurs almost exclusively in cryptorchid testes
• Associated with vicious behavior and hormone production
• Two cell types: hypertrophic interstitial cell and pleomorphic fusiform cell

• Bull: Guernsey bulls overrepresented and those with interstitial cell tumors have high incidence of hepatic telangiectasis, thyroid C cell tumors, and infertility; neoplastic interstitial cells are not vacuolated and contain little lipid
• Camels: Unilateral seminoma reported in dromedary camels; ovarian interstitial cell tumor reported in alpaca 
• Rabbit: Interstitial cell tumor is most common in older literature; recent report that testicular granular cell tumor is most common 
• Cat: Testicular tumors are rare; interstitial cell tumors can be extratesticular in the scrotal skin and spermatic cord of neutered males, some of these cats develop male behaviors such as urine marking and male odors
• Avian: Testicular tumors are rarely reported in chickens; rare seminoma in roosters reported to be caused by leukosis/sarcoma group viruses.); testicular neoplasms are associated with formation of medullary bone in male budgerigars (Hoggard, Vet Pathol, 2022); seminomas usually unilateral, are rarely bilateral; malignant seminomas in birds often metastasize to the kidneys
• Human: Interstitial cell tumors are rare and contain Reinke crystals (cytoplasmic inclusions) that are considered diagnostic; seminomas are common, often malignant
• Seminomas reported in dolphins and multiple fish species 
• Non-human primates: Both Leydig cell tumors and seminomas have been reported in NHPs; spread more slowly than in humans
• Boars: Testicular tumors are rare in boars, seminomas are the predominant testicular neoplasm in commercial boars with infertility; may only be detectable microscopically; can boars demonstrate three different growth patterns (intratubular, diffuse, and intratubular/diffuse); intratubular seminomas negative for c-kit, cytokeratin, and vimentin, while diffuse seminomas were c-kit and cytokeratin negative but vimentin showed multifocal granular or perinuclear cytoplasmic labeling

 

REFERENCES:

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16. Reineking W, Seehusen F, Lehmbecker A, et al. Predominance of granular cell tumours among testicular tumours of rabbits (Oryctolagus cuniculi f. dom.). J Comp Pathol. 2019; 173:24-29.

 

 

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