JPC SYSTEMIC PATHOLOGY
REPRODUCTIVE SYSTEM
January 2022
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 fairly 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 rate 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 spermatid multinuclear giant cells within lumina.

MORPHOLOGIC DIAGNOSES: 

1. Testis:  Interstitial cell tumor, breed unspecified, canine.
2. Testis: Seminoma, intratubular, multifocal.
3. Testis, seminiferous tubules: Germ cell atrophy, diffuse, moderate, chronic, 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  
  • Positive for PLAP and PAS in rabbits (Banco, J Comp Pathol, 2017)

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
• Rabbit: Interstitial cell tumor is most common in older literature; recent report that testicular granular cell tumor is most common (Reineking, J Comp Pathol, 2019)
• 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; case report of a mixed teratoma and seminoma in a rooster (Tavella, J Vet Diag Invest, 2019); testicular neoplasms are associated with formation of medullary bone in male budgerigars (Hoggard, Vet Pathol, 2022)
• Human: Interstitial cell tumors are rare and contain Reinke crystals (cytoplasmic inclusions) that are considered diagnostic; seminomas are common, often malignant
• Dog:
  • Malignant Leydig cell tumors with cutaneous metastasis have been reported in dogs (Kudo et al., J Vet Diagn Invest, 2019)
  • No evidence of increased cells exhibiting the senescence-associated secretory phenotype (SASP) P21 and gH2AX IHC markers (nuclear) in testicular neoplasms (despite increased p21 with age), (Merz, Vet Pathol, 2019)

REFERENCES:

1. Agnew DW, MacLachlan NJ. Tumors of the genital systems. In: Meuten DJ, ed. Tumors in Domestic Animals, 5th ed. Ames, IA: John Wiley & Sons, Inc.; 2017:706-711.
2. Banco B, Ferreira da Silva J, Cotti Cometti S, et al. Immunohistochemical expression of placental alkaline phosphatase in five cases of seminoma in rabbits. J Comp Pathol. 2017; 156:366-370.
3. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits, 4th ed. Ames, IA: John Wiley & Sons, Inc.; 2016: 169-170.
4. Foster RA. Male genital system. In: Maxie MG ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. St. Louis, MO: Elsevier; 2016:492-497.
5. Foster RA. Male reproductive system. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6^th St. Louis, MO: Elsevier; 2017:1210-1212.
6. Hoggard NK, Craig LE. Medullary bone in male budgerigars (Melopsittacus undulates) with testicular neoplasms [published online ahead of print January 08 2022]. Vet Pathol. 2022. https://journals.sagepub.com/doi/pdf/10.1177/03009858211069126. Accessed January 12, 2022.
7. Kudo T, Kamiie J, Aihara N, et al. Malignant Leydig cell tumor in dogs: two cases and a review of the literature. J Vet Diagn Invest. 2019;31(4):557-561.
8. Merz SE, Klopfleisch R, Breithaupt A, Gruber AD. Aging and senescence in canine testes. Vet Pathol. 2019;56(5):715-724.
9. Reineking W, Seehusen F, Lehmbecker A, et al. Predominance of granular cell tumours among testicular tumours of rabbits (Oryctolagus cuniculi dom.). J Comp Pathol. 2019; 173:24-29.
10. Tavella VJ, Walters JN, Crofton LM, et al. Mixed germ cell tumor composed of a tridermic testicular teratoma and seminoma in a rooster. J Vet Diagn Invest. 2019; 31(3): 395-398.

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