JPC SYSTEMIC PATHOLOGY

URINARY SYSTEM

December 2023

U-N02

 

Slide A: Signalment (JPC #1655998): Older, adult German shepherd dog, gender unspecified.

 

HISTORY: A renal mass was taken at necropsy.

 

HISTOPATHOLOGIC DESCRIPTION: Kidney: Expanding the renal cortex, compressing adjacent glomeruli and tubules, and extending to cut borders is a greater than 2 cm, well-demarcated, partially encapsulated, densely cellular neoplasm composed of uniform polygonal cells arranged in tubules, islands, trabeculae, and solidly cellular areas. Neoplastic cells are supported by fine, wispy strands of fibrovascular stroma, which often contains large, ectatic vessels. Neoplastic cells have indistinct cell borders and small amounts of finely granular, eosinophilic cytoplasm with occasional 2-4 µm clear intracytoplasmic vacuoles. The nuclei are irregularly round, with finely stippled chromatin and 1-2 variably distinct nucleoli. The mitotic rate is less than 1 per 2.37mm². Multifocally scattered throughout the neoplasm, there is single cell necrosis and small amounts of hemorrhage. Within the adjacent cortical interstitium, there is mild, multifocal interstitial fibrosis with multifocal aggregates of few lymphocytes, plasma cells and rare macrophages. There is mild atrophy and loss of adjacent tubules, and surrounding tubules are often mildly ectatic, lined by attenuated epithelium, and contain eosinophilic material (atrophic). Multifocally, the parietal epithelium of the glomerulus is mildly hypertrophied; Bowman’s capsule is moderately thickened; and the uriniferous space is dilated and contains small amounts of proteinaceous material. Sclerosis of the glomeruli is multifocally present.

 

MORPHOLOGIC DIAGNOSIS: Kidney: Renal cell carcinoma, mixed, German shepherd dog, canine.

 

Slide B: Signalment (JPC #1804128): A 768-day-old, Fischer 344 rat, gender unspecified

 

HISTORY: A 1 cm diameter, cream-colored mass located on the anterior pole of the left kidney was removed from this rat, which was used as a control animal in a two-year feeding study.

 

HISTOPATHOLOGIC DESCRIPTION: Effacing the cortex and medulla, elevating the renal capsule, and compressing the adjacent parenchyma is an irregular, 1x1cm, well-circumscribed, unencapsulated, multilobulated neoplasm. Neoplastic cells are polygonal and arranged in islands and trabeculae that are separated by thin bands of fibrovascular stroma and anastomosing trabeculae of well-differentiated (metaplastic) bone. Neoplastic cells have distinct cell borders with either abundant, foamy, eosinophilic cytoplasm or cytoplasm containing one or more irregular, discrete, clear vacuoles that marginate the nucleus. Nuclei are round to oval with moderately coarse stippling of chromatin and 1-3 variably distinct nucleoli. There is mild anisokaryosis and moderate anisocytosis. The mitotic rate averages 2 per 2.37mm². There is scattered single cell necrosis, hemorrhage and red crystals (hemoglobin). Adjacent to the neoplasm, there is mild interstitial fibrosis with tubular atrophy and loss. Multifocally, tubules are variably ectatic, lined by attenuated epithelium, and contain homogeneous, brightly eosinophilic, proteinaceous material (proteinosis). The interstitium multifocally contains moderate numbers of lymphocytes mixed with fewer macrophages and plasma cells. 

 

MORPHOLOGIC DIAGNOSIS: Kidney: Renal cell carcinoma, mixed, with stromal osseous metaplasia, F344 rat, rodent.

 

SYNONYMS: Renal adenocarcinoma, malignant nephroma, clear cell carcinoma, hypernephroma, Grawit’s tumor

 

GENERAL DISCUSSION: 

 

PATHOGENESIS:

• Exact histologic origin of canine RCCs is not established, and likely arise from different segments of the kidney than human RCC (well worked out in humans, based on cell of origin) 
• Specific causes include viruses (Ranid herpesvirus-1 in frogs, avian erythroblastosis virus in birds), chemical carcinogens (such as nitrosamines), and genetic causes (Autosomal dominant gene mutations: BHD gene in German shepherd dogs, other genes in Eker rats) 

 

TYPICAL CLINICAL FINDINGS:

• Occur in mature and older animals
  1. Dogs: Average age ~8 years (although reported in dogs <2 years); males affected twice as often as bitches
  2. Cattle: Overwhelming higher occurrence in cows (likely due to higher population of aged females) 
  3. Cats: Rarely diagnosed, but mean age 9 years with no sex or breed predilection and only sporadic metastases
• Common presenting signs include hematuria, palpable abdominal mass, and weight loss
• Renal carcinoma has been associated with paraneoplastic syndromes:
  1. Polycythemia due to neoplastic production of erythropoietin, or erythropoietin-like peptide causing increased bone marrow production of erythrocytes, very rare in animals, more common in humans
  2. DIC, neutrophilic leukocytosis (neoplastic cells secrete GM-CSF), leukemoid blood response, hypoglycemia, hypercalcemia, and bone infarcts also occur rarely
  3. Hypertrophic osteopathy may occur in cases with pulmonary metastasis

 

TYPICAL GROSS FINDINGS:

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Nests of well-differentiated to pleomorphic, cuboidal to polygonal cells sometimes arranged in irregular tubules with scant, highly vascularized stroma
• Usually, there are a variety of cell types and architectures, including clear cells (glycogen/lipid), poorly stained chromophobe cells, and eosinophilic cells 
• Histologic types of renal carcinomas include papillary, tubular, multilocular cystic, and solid
  1. All of these patterns may occur in a single tumor (mixed-type); different patterns have not been associated with specific prognoses in veterinary medicine
  2. Solid variants can be poorly differentiated and sometimes can be subclassified as clear cell or chromophobe variants
  3. Clear cell carcinomas result in a significantly decreased median survival time for the animal
• Canine grading (Avallone, Vet Pathol. 2021)
  1. Fuhrman grading system based solely on nuclear and nucleolar morphology
     • Grade I (low-grade): Small, round, uniform nuclei (10 μm) with inconspicuous nucleoli (looks like lymphocytes)
     • Grade II (medium-grade): Slightly irregular nuclei; diameter 15 um; nucleoli visible only at 40x; open chromatin
     • Grade III (high-grade): Nuclei very irregular; diameter 15 um; nucleoli visible at 10x; open chromatin
     • Grade IV (high-grade): Mitoses; bizarre, multilobated, pleomorphic cells plus grade 3 features; macronucleoli
  2. Mitotic count: >30 had lower survival time (120 days) compared to cases with MC <10 or 10 to 30 (545 and 532 days, respectively) 
• There is also a sarcomatoid variant with the tumor composed of spindle-shaped cells 
  1. Most recently reported in binturongs and a cat with peritoneal effusion and carcinomatosis (Wu, J Vet Diagn Invest. 2022)
• NOTE: In human medicine, types often reflect origin from different segments of the kidney; in veterinary medicine (particularly in canine RCCs), IHC has helped elucidate the segment of origin (see Additional Diagnostics)

 

ADDITIONAL DIAGNOSTICS

• Immunohistochemistry (IHC):
  1. Uromodulin: All canine and bovine RCCs reported positive for uromodulin, indicating they are derived from distal segments of the nephron
  2. C-KIT: Commonly expressed in most cases 
  3. Some RCCs can be both vimentin and cytokeratin positive
     • Vimentin: Often labels canine RCC, except those with papillary or cystic architecture
       • Suggests that these vimentin-positive tumors are derived from the metanephric mesenchyme
     • Cytokeratin: More often expressed in tubular, papillary, cystic architecture types, but not solid
  4. 14-3-3σ: A protein expressed in 38% of canine RCC that is a downstream product of activation of the p53 pathway, is not expressed in normal kidney, regulates several oncogenes and tumor suppressor genes, and is associated with significantly shorter survival times than canine RCC cases where it is not expressed (Suárez-Bonnet, Vet Pathol. 2018) 
  5. Normal canine nephron labeling:
     • Proximal tubules normally stain CD10 positive
     • Distal tubules and collecting ducts stain with Dichloros biflorus, agglutinin, peanut agglutinin, and Ulex europaeus agglutinin I
• Cytology: Malignant renal epithelial neoplasms often exfoliate well for cytologic evaluation with cells having variable N:C ratios with a moderate amount of often deep blue cytoplasm and round to polygonal nuclei

 

DIFFERENTIAL DIAGNOSIS:

• Renal adenoma
  1. Much more common in horses and cattle; originate in the cortex
  2. Gross: Discrete, small (<2 cm in dogs and cats), tan or white, can be bilateral or multiple
  3. Histo: Well differentiated tubules and acini, nonencapsulated but well-circumscribed, little atypia, few mitoses; may be subclassified as tubular, papillary, or solid based on the major histological pattern
• Renal oncocytoma
  1. Clinically asymptomatic
  2. Histo: large eosinophilic, granular, round cells arranged in nests, cords, and tubules; abundant, intensely eosinophilic, granular, PAS positive cytoplasm
  3. Ultrastructure: Numerous mitochondria on EM
• Nephroblastoma (U-N01)
  1. Immature glomeruli, abortive tubules, myxomatous mesenchyme; triphasic
• Transitional cell carcinoma (U-N04)
  1. Arise from pelvic urothelium
  2. Histo: Squamous and glandular metaplasia 
• Renal sarcoma: Arise from vessels or smooth muscle within the kidney, exfoliate poorly on cytology
• Renal interstitial cell tumor (RICT): Rare renal sarcoma of dogs arising from renal interstitial cells; grossly appears as white nodules in cortex and/or corticomedullary junction; histologically composed of interlacing bundles of stellate-to-spindle cells; IHC positive for vimentin and vimentin and cyclooxygenase 2 (Rissi, J Vet Diagn Invest. 2020) 

 

COMPARATIVE PATHOLOGY:

• Bovine: Low rate of metastasis (5%) but bilateral involvement is common; Renal adenocarcinomas often have corpora amylacea; usually tubular pattern, eosinophilic cell type
• Equine: Rare, but considered locally invasive with potential for metastasis
• Rats: Long-Evans (Eker) rats have an autosomal dominant mutation that predisposes to bilateral renal cell carcinoma and a variety of other secondary cancers; resembles the human von Hippel-Lindau (VHL) disease in humans
• NHP: 
  1. Renal neoplasia rarely reported in NHPs (Kirejczyk, Vet Pathol. 2021)
  2. The aglycone of cycasin, methylazoxymethanol acetate, reported to be capable of inducing renal cell carcinoma 
  3. Primary renal neoplasms are more common in older animals (>15 years) and may be unilateral or bilateral 
• ZEW
  1. Northern leopard frogs: Lucke’s adenocarcinoma, caused by ranid herpesvirus-1 (gammaherpes); virus replicates in cool water (<7˚C) (the algid phase) and in warmer water, there is neoplastic cell proliferation (the calid phase); Gross: White to yellow kidney masses may fill the coelomic cavity and displace viscera; Histo: variably-sized tubules and papillary projections present in the algid phase
  2. Binturongs (viverrids): Several case reports; all have had metastatic disease; tumor morphology similar to other species 
  3. Snakes: Colubrids are prone to renal adenocarcinomas and resultant disruption of renal function causes urate tophi deposition in remaining parenchyma
  4. Psittacines: Young to middle aged (4yr old), male budgies; unilateral paresis or lameness due to ischiatic nerve compression
  5. Dromedary camel: Reported in a Dromedary camel 

 

REFERENCES:

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2. Avallone G, Rasotto R, Chambers JK, et al. Review of Histological Grading Systems in Veterinary Medicine. Vet Pathol. 2021;58(5):809-828.
3. Church ME, Terio KA, Keel MK. Procyonidae, Viverridae, Hyenidae, Herpestidae, and Prionodontidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London: Elsevier/Academic Press; 2018: 309.
4. Cianciolo RE and Mohr FC. Urinary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. 6th ed.Vol 2. Philadelphia, PA: Elsevier Ltd; 2016: 444-446.
5. Cline JM, Brignolo L, and Ford EW. Urogenital System. In: Abee CR, Mansfield K, Tardif S, Morris T. Nonhuman Primates in Biomedical Research: Volume 2: Diseases. 2^nd ed. San Diego, CA: Elsevier; 2012: 4997-498.
6. Ewing PJ, Meinkoth JH, Cowell RL, Tyler RD. The Kidneys. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier Mosby; 2014:368-369. 
7. Kirejczyk S, Pinelli C, Gonzalez O, et al. Urogenital Lesions in Nonhuman Primates at 2 National Primate Research Centers. Vet Pathol. 2021;58(1):147-160.
8. Miller AD. Neoplasia and Proliferative Disorders of Nonhuman Primates. In: Abee CR, Mansfield K, Tardif S, Morris T. Nonhuman Primates in Biomedical Research: Volume 2: Diseases. 2^nd ed. San Diego, CA: Elsevier; 2012: 303.
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11. Reavill DR, Dorrestein G.  Psittacines, Coliiformes, Musophagiformes, Cuculiformes. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London: Elsevier/Academic Press; 2018: 784.
12. Rissi DR, Dill-Okubo JA. Metastatic renal interstitial cell tumor in a dog. J Vet Diagn Invest. 2020;32(6):957-960.
13. Snyder L and Seelig D. Urinary System. In: Raskin RE, Meyer DJ, and Bowes KM. Canine and Feline Cytology: A Color Atlas and Interpretation Guide. 4th ed. St. Louis, MO: Elsevier; 2023:403-405,409. 
14. Suárez-Bonnet A, Lara-García A, Stoll AL, Carvalho S, Priestnall SL. 14-3-3σ Protein Expression in Canine Renal Cell Carcinomas. Vet Pathol. 2018;55(2):233-240. 
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17. Wu B, Kastl B, Cino-Ozuna AG, et al. Feline sarcomatoid renal cell carcinoma with peritoneal carcinomatosis and effusion. J Vet Diagn Invest. 2022;34(1):153-159.

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