JPC SYSTEMIC PATHOLOGY
REPRODUCTIVE SYSTEM
January 2022
R-N02

Signalment (JPC #2329127): 12-year-old Belgian malinois military working dog

HISTORY:  None

HISTOPATHOLOGIC DESCRIPTION: Testis and epididymis: Expanding and replacing normal testicular architecture and compressing surrounding atrophic seminiferous tubules is an unencapsulated, well demarcated, multilobulated, densely cellular neoplasm composed of polygonal cells arranged in tubules, islands, and cords which are separated and surrounded by dense bands of fibrous connective tissue.  Neoplastic cells are triangular to columnar and have indistinct cell borders, a moderate amount of eosinophilic granular cytoplasm with frequent 5 um clear vacuoles (lipid droplets), and a round to oval nucleus with coarse chromatin and up to two distinct nucleoli.  Cells frequently palisade perpendicular to the basement membrane of tubules. Anisocytosis and anisokaryosis are mild. Mitoses average less than 1 per 40x HPF (2.37mm²).  Remaining seminiferous tubules are compressed at the periphery of the testicle and are diffusely atrophied, characterized by irregular, undulant basement membranes and lack of developing sperm stages, with only Sertoli cells remaining.  The epididymis is devoid of spermatids. The pampiniform plexus is essentially normal. 

MORPHOLOGIC DIAGNOSES: 

1. Testis: Sertoli cell tumor, Belgian malinois, canine.
2. Testis, seminiferous tubules; epididymis: Atrophy, diffuse, moderate, chronic with aspermatogenesis.

GENERAL DISCUSSION:

• 3^rd most common testicular neoplasm in dogs; rare in other species
  • Increased occurrence with age and in cryptorchid testicles
  • More than 50% of Sertoli cell tumors located in retained testis
• Some animals develop hyperestrogenism syndrome - amount of estrogen production is proportional to the size of the neoplasm
• Metastasis is rare; but can go to spermatic cord and scrotal lymph node

PATHOGENESIS:

• Estrogen secretion occurs in 20-30% of Sertoli cell tumors and leads to a hyperestrogenism syndrome that may result in feminization; bone marrow suppression with accompanying thrombocytopenia, anemia, immunosuppression due to granulocytopenia; and/or squamous metaplasia of the prostate gland
• Inhibin, which is produced by neoplastic sertoli cells, reduces testosterone production through inhibition of trophic pituitary hormone secretions (GnRH and subsequently, LH/FSH release) and enhances the feminization syndrome via hyperestrogenism

TYPICAL CLINICAL FINDINGS:

• Feminization to include: attraction to other male dogs, reduction of libido, redistribution of adipose tissue, symmetrical alopecia, testicular and penile atrophy, gynecomastia, preputial swelling, perineal hernia
• Some dogs may develop depression of myelopoiesis: thrombocytopenia, hemorrhage, anemia (due to blood loss or decreased erythropoiesis), neutropenia (which may result in infection and fever)

TYPICAL GROSS FINDINGS: 

• Well demarcated, very firm (due to abundance of its fibrous stroma), white, with bulging cut surface; irregularly lobulated by dense bands of connective tissue
• May contain fluid-filled cysts or yellow to tan areas of hemorrhage
• Atrophy of the contralateral testicle common
• Local extension of neoplastic cells into the testicular vein and lymphatics may cause a hydrocele, resulting in massive scrotal swelling

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Neoplastic cells are arranged in well-formed tubules (intratubular pattern) or in a diffuse pattern
• Neoplastic cells are tall and slender (resembling normal Sertoli cells) with indistinct borders; they often contain lipochrome pigment granules; may palisade along stroma
• Nuclei are round to elongate; mitoses are uncommon
• Abundant dense fibrous stroma that may undergo hyalinization
• Fragmentation or loss of basement membranes correlate with proliferative activity and invasiveness and may be a prognostic indicator

ULTRASTRUCTURE:

• Sertoli cell tumor: Characteristic intracellular junctions and crystals of Charcot-Bottcher; if those features are not present, there are also abundant organelles that allow differentiation from seminomas and interstitial cell tumors 

ADDITIONAL DIAGNOSTIC TESTS:

• Immunohistochemistry: Reported IHC labeling varies; however, immunoreactivity to inhibin and anti- mullerian hormone (AMH) are suggestive of the diagnosis; positive for vimentin (same as Leydig [interstitial] cells)

DIFFERENTIAL DIAGNOSIS:

• Interstitial cell tumor (R-N03)
  • Gross: Tan to yellow-orange, discrete, and soft, with areas of hemorrhage
  • Microscopic: Polygonal cells with abundant, finely vacuolated, eosinophilic cytoplasm and small round nuclei; prominent lipid accumulations; rare mitoses
• Seminoma (R-N03)
  • Gross: Pale to gray, soft; compresses adjacent parenchyma; bulging, lobulated, and irregular
  • Microscopic: Large, uniform, fairly discrete round cells with variable amounts of cytoplasm, large round nuclei, prominent nucleoli; arranged in a diffuse or intratubular pattern; multinucleate cells; mitoses common; individual cell necrosis; lymphocytes
• Mixed germ cell-sex cord stromal tumor
  • Gross: Gray, white or tan, firm, hemorrhage and necrosis in larger tumors
  • Microscopic: Admixed neoplastic germ cells and Sertoli cells in tubular structures
  • Immunohistochemistry: Sertoli cells are NSE and vimentin positive; germ cells are negative for NSE
• Mesothelioma (R-N04, P-N06)
• Transmissible venereal tumor (TVT; R-N01)

COMPARATIVE PATHOLOGY:

• Rare in domestic species other than the dog.
• Reported in the bull, stallion, ram, tom cat, and less often in various other species species (cotton top tamarin, rabbit, tree shrew, bottlenose dolphin, short beaked dolphin, budgerigars, Nyasa lovebird, Chinese alligator, carp, medaka, and goldfish); often have more than one testicular neoplasm

REFERENCES:

1. Agnew D, Nofs S, Delaney MA, et al. Xenartha, Erinacoemorpha, Some Afrotheria, and Phloidota. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Academic Press; 2018:527.
2. Conley KJ, Shilton CM. Crocodilia. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Academic Press; 2018:859.
3. Delaney MA, Treuting PM, Rothenburger JL. Lagomorpha. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Academic Press; 2018:486.
4. Foster RA. Male reproductive system. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier Inc; 2017:1204, 1211-1212.
5. Foster RA. Male genital system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed.   Louis, MO: Elsevier Inc; 2016:494-495.
6. Frasca S, Wolf JC, Kinsel MJ, et al. Osteichthyes. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Academic Press; 2018:966.
7. Miller AD. Neoplasia and Proliferative Disorders of Nonhuman Primates. In: Abee CR, Mansfield K, Tardif S, et al, eds. Nonhuman Primates in Biomedical Research, Volume 2: Diseases. San Diego, CA: Elsevier; 2012:338.
8. Reavill DR, Gorrestein G. Psittacines, Coliiformes, Musophagiformes, Cuculiformes. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Academic Press; 2018:784.
9. Leger J, Raverty S, Mena A. Cetacea. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Academic Press; 2018:550.

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