JPC SYSTEMIC PATHOLOGY
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 um clear intracytoplasmic vacuoles. The nuclei are irregularly round, with finely stippled chromatin and 1-2 variably distinct nucleoli. The mitotic rate is less than 1/10 HPF. 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 10 HPF. 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
- Primary renal neoplasms are uncommon in animals, but the most common primary renal neoplasm in dogs, cats, cattle and horses is renal cell carcinoma
- Sporadic occurrence in pigs and sheep.
- Histological differentiation between adenoma and adenocarcinoma may be impossible; small, well-circumscribed neoplasms with no evidence of capsular invasion or metastasis are considered adenomas by most authors
- Renal adenocarcinomas are reported most frequently in middle-aged to older (8 years) male dogs (2/3rds male); no breed predilection (except nodular dermatofibrosis – see below)
- In dogs < 6 years old, tumors may behave more aggressively
- Cats 8-11 years old, no breed predilection
- Horses 4-25 years old
- A recent retrospective study found that mitotic index (MI) is the best overall predictor of survival in canine RCC
- Median survival for dogs with a MI of >30 was 187 days
- MI between 10 and 30 had a median survival of 452 days
- MI < 10 had median survival of 1184 days
- German shepherd dogs: Nodular dermatofibrosis (characterized by subcutaneous fibrous nodules) is associated with concurrent renal cystadenocarcinomas/cystadenomas (usually bilateral), as well as multiple uterine leiomyomas (in affected females)
- Inherited autosomal dominant; renal-tumor derived growth factors may stimulate fibrous tissue proliferation at various sites
- Missense mutation in the Birt-Hogg-Dubé (BHD) gene, a tumor suppressor gene located on chromosome 5; gene product is folliculin
- Tend to arise from the cortex (medullary masses are more likely to be metastatic)
- Histologic features not always well correlated with metastatic potential (sometimes small, well-differentiated tumors metastasize)
- Exact histologic origin of canine RCCs is not established, and likely arise from different segments of the kidney than human RCC
- A recent study indicates that mitotic index is the sole independent prognostic variable for survival time.
- Some renal adenocarcinomas in dogs have elevated expression of COX-2, suggesting COX-2 mediated prostaglandins may play a role in the modulation of neoplastic cell growth in some cases of canine renal adenocarcinoma
- Certain carcinogens, such as nitrosamines, predispose to RCC development.
TYPICAL CLINICAL FINDINGS:
- Usually asymptomatic; often well advanced at the time of clinical detection
- 20-50% of dogs will have pulmonary metastasis at the time of detection
- Nonspecific findings include: Lethargy, anorexia, vomiting, and weight loss
- Palpable abdominal mass – dogs and cats
- Clin Path: hematuria, pyuria, proteinuria, pollakiuria, azotemia, GGT elevation (from brush border of proximal convoluted tubules)
- Hematuria and cachexia are negative prognostic factors for survival
- Abdominal ultrasound or intravenous pyelogram are most effective diagnostics for detection
- Paraneoplastic syndromes:
- Secondary absolute polycythemia: due to neoplastic production of erythropoietin, or erythropoietin-like peptide. Very rare in dogs, more common in humans
- DIC, neutrophilic leukocytosis (neoplastic cells secrete GM-CSF), leukemoid blood response, hypoglycemia, hypercalcemia, and bone infarcts also occur rarely.
- Hypertrophic osteopathy may occur in cases with pulmonary metastasis
TYPICAL GROSS FINDINGS:
- Large (>2 cm), spherical to ovoid, well-demarcated; usually unilateral and occupies one pole of the kidney; appears to arise in the cortex; compresses adjacent renal parenchyma, can occupy 80% or more of the kidney
- Light yellow to tan to gray; lobulated; areas of necrosis and hemorrhage
- Invasion into the renal vein, posterior vena cava, renal pelvis, ureter, retroperitoneal space
- Sites of metastasis: Lung, liver, regional lymph nodes, adrenal gland, intrarenal, peritoneal brain, heart and occasionally skin. Metastatic rate is 50-70% in most species.
- Multiple and bilateral renal neoplasms without evidence of metastasis are considered to be of multicentric origin
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Neoplasms are often described by the predominant histologic type and further sub-classified by the predominant cytologic type (multiple histologic/cytologic types are often present in one tumor – mixed types occur in 40% of canine cases)
- Patterns/architectural types: Papillary, tubular, solid and cystic; ‘
- Many canine RCC have a mix of papillary, tubular and solid subtypes
- Papillary RCC is most common in dogs: branching fibrovascular stroma lined by cuboidal epithelium
- Canine multilocular cystic tumors: composed entirely of variably-sized cysts separated by densely collagenous fibrous septa lined by cuboidal epithelial cells.
- Appear to have a favorable clinical course, with no detection of metastasis and long survival times
- Solid: closely spaced cells form small nests, clusters, or sheets with minimal stromal elements.
- Tubular: neoplastic cells form tubules and are separated by small amounts of fibrovascular stroma. Lumina contain cellular debris and basophilic material.
- This is the most common type in most other species
- Cellular types: Chromophobic, eosinophilic, and clear cell (vacuolated cytoplasm). Can also have a mixture of types.
- Clear cell is most common type in laboratory animals and humans (75%)
- “Clear”, vacuolated cytoplasm due to high glycogen and lipid content.
- Derived from the proximal convoluted tubule.
- Tend to be solid rather than tubular
- In dogs, clear cell RCCs are associated with decreased survival
- Chromophobe RCC has moderate amounts of granular, lightly eosinophilic cytoplasm that stains positively with colloidal iron stain for acid mucopolysaccharides. Form trabeculae.
- Eosinophilic type is a variant of chromophobe, but the cytoplasm is intensely eosinophilic. Common in cattle.
- Neoplastic cells are cuboidal to polygonal and are arranged in tubules, acini, or sheets; scant, well-vascularized stroma; occasionally, RCC may have a marked desmoplastic reaction
- Sarcomatoid change (likely due to epithelial-to-mesenchymal transition) can occur with any histologic subtype; positive for vimentin; does not affect survival
- Well-differentiated carcinomas are very difficult to differentiate from adenomas
- Cellular atypia, high mitotic rate, invasion, necrosis, and size (>2 cm) are used as criteria for malignancy
- Clear cells: Abundant monoparticulate glycogen, often within phagolysosomes; few mitochondria or endoplasmic reticulum
- Eosinophilic cells: Either organelle poor or contain abundant mitochondria
- Uromodulin: Tamm-Horsfall glycoprotein labelled all canine RCC in one study
- Pax8: the most sensitive marker for labelling canine RCC in another study, and was also useful in distinguishing renal metastases and feline RCC
- Napsin A: a human marker for RCC, is variably expressed in canine RCC (58-62%)
- CD10: labels proximal tubules; sporadic expression (33-62%) in canine RCC
- Vimentin: often labels canine RCC, except those with papillary or cystic architecture
- Cytokeratin: tends to be expressed in tubular, papillary, cystic architecture types, but not solid.
- C-KIT: negative in clear cell canine RCC, positive in chromophobe types (including papillary architecture type)
- c-KIT may be involved in the pathogenesis of canine RCC – it is a transmembrane tyrosine kinase growth factor receptor for the ligand stem cell factor; binding triggers signaling pathways that lead to cell proliferation and resistance to apoptosis
- 14-3-3σ: a protein expressed in 38% of canine RCC, 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.
- PAS: Clear cell renal cell carcinoma is PAS positive; chromophobe variant is PAS negative; Oncocytoma is PAS positive
- Renal adenoma:
- Grossly: Discrete, small (<2 cm in dogs and cats), tan or white, can be bilateral or multiple
- Much more common in horses and cattle
- Microscopically: 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:
- Polygonal cells arranged in nests, cords, and tubules
- Abundant, intensely eosinophilic, granular, PAS positive cytoplasm
- Numerous mitochondria on EM
- Difficult to differentiate from chromophobe RCC on light microscopy.
- Immature glomeruli, abortive tubules, myxomatous mesenchyme; triphasic
- Transitional cell carcinoma
- Arise from pelvic urothelium
- Squamous and glandular metaplasia
- Long-Evans (Eker) rats have an autosomal dominant mutation that predisposes to bilateral renal cell carcinoma and a variety of other secondary cancers, resembling the human von Hippel-Lindau (VHL) disease
- VHL protein normally inhibits hypoxia-inducible gene and functions as a tumor suppressor > inactivation of VHL gene> renal clear cell carcinoma (in people)
- Renal neoplasms can also be induced by numerous chemical agents (eg. nitrosomorpholine) and hormones (eg. estrogen)
- Sprague-Dawley and Fischer 344: Spontaneous renal adenomas and adenocarcinomas arising in young rats (12-18 weeks); thought to be familial – phenotype is amphophilic and/or vacuolar
- Mice (Tg.rasH2) – similar phenotype to Sprague-Dawley and Fischer 344 rats, but not familial.
- Bovine: Renal adenocarcinomas often have corpora amylacea; low rate of metastasis (5%) but bilateral involvement is common. Usually tubular pattern, eosinophilic cell type.
- Horses – renal adenocarcinoma are highly invasive and have high metastatic potential.
- Pig: Nephroblastomas are the most common primary renal neoplasm.
- Chickens: Adenocarcinomas and nephroblastomas may occur spontaneously or be induced by avian leukosis virus (alpharetrovirus)
- Other avian: Budgerigars may develop renal adenocarcinoma
- Frogs: Lucke’s adenocarcinoma; caused by a gammaherpes virus
- Ferret: Single reported case of adenocarcinoma
- Cat: Rare, usually unilateral. Mostly tubular pattern, most express Pax-8 and vimentin.
- Snakes: colubrids are prone to renal adenocarcinomas and resultant disruption of renal function causes urate tophi deposition in remaining parenchyma.
- “Hobnailing” pattern similar to human collecting duct carcinomas
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