Signalment:  

8-year-old male Rhesus macaque (Macaca mulatta)Clinical History: This monkey developed intermittent antibiotic unresponsive hematuria, and ultrasonography showed a rounded, misshapen right kidney with a loss of architecture in the renal pelvis. A CT scan revealed a mass occupying the caudal 2/3 of the kidney and proximal ureter, consistent with a neoplasm. Unilateral nephrectomy was performed and the specimen was submitted as a biopsy.

Experimental History: This monkey received a single 7.55 Gy dose of whole-body irradiation at 3 years of age.

Gross Description:  

The entire right kidney, with attached capsule and 4.5cm segment of ureter was submitted in 10% neutral buffered formalin. An irregularly-shaped, 3.8x3x2cm firm, tan mass with scattered hemorrhages on cut surface replaced the caudal two-thirds of the kidney. A 5mm diameter x 4mm nodule protruded from the surface, underneath the capsule. The renal capsule was easily removed except for a 3mm diameter area, where it was firmly attached. The ureter measured 5mm in diameter where it exited the renal pelvis and was of normal diameter at the distal end of the specimen.

Histopathologic Description:

An infiltrative neoplasm, irregularly dissected by tracts of mature collagenous connective tissue, distends the proximal ureteral lumen, effaces the adjacent renal parenchyma (more prominent in some sections) and compresses normal renal cortical tissue. The neoplasm is composed of fronds of collagenous connective tissue lined by single to multiple layers of epithelial cells which have oval, 15x10 micron nuclei with finely stippled basophilic chromatin and single nucleoli. The cytoplasm is eosinophilic, sometimes with clear vacuoles, and cell borders are indistinct. Mitotic figures are rare, with up to only 1 per five 40X fields. Small accumulations of granular to clumped deeply basophilic material (mineral) are scattered throughout. Rafts of neoplastic cells are present in blood vessels at the margins in some sections. Lymphoplasmacytic infiltrates are scattered throughout the neoplasm. Immunohistochemical staining for uroplakin III is negative. An internal positive control is provided by normal urothelium of the ureter. The parenchyma adjacent to the renal cortex is atrophied, with loss of tubules and glomeruli, and interstitial lymphoplasmacytic inflammation. Glomeruli are often small, occasionally segmented and some are surrounded by variably thick fibrous connective tissue. Cystic structures, lined by flattened epithelium, are filled with pale pink amorphous material. Occasional renal tubular epithelial cells have undergone karyolysis, and others have abundant eosinophilic cytoplasm containing brown granular pigment. Sporadically, epithelial cells are present in the tubular lumina. Interstitial fibrous connective tissue is prominent in areas where tubules are less numerous.

Morphologic Diagnosis:  

1. Papillary carcinoma, kidney and ureter with vascular invasion
2. Glomerulonephropathy, diffuse, subacute to chronic, mild, with interstitial fibrosis, glomerular atrophy, tubular loss and cyst formation

Lab Results:  

Blood Chemistry:
BUN 13 mg/dL (13-27 mg/dL)
Creatinine 1.5 mg/dL (0.8-1.5 mg/dL)

Urinalysis:
Specific Gravity 1.007
Blood 80 cells/mL
Protein: 2+ (100 mg/dL)
Bacteria: none
WBC: 6-10/HPF
RBC: 30-50/HPF

Condition:  

Papillary renal carcinoma

Contributor Comment:  

This submission provides a good example of what are considered to be radiationinduced lesions in the kidney. The kidney is one of the most radiosensitive organs(16) and is prone to secondary malignancies(2, 3, 5, 13), as well as degenerative changes leading to renal dysfunction(6, 16) following irradiation. Fifty percent of rhesus macaques that received whole body irradiation developed malignant neoplasms, 80% of which were renal carcinomas(2, 5). Humans undergoing radiation treatment for neoplasia have increased risk for developing renal neoplasms(13). Although primary renal tumors are rare, greater than 65% in dogs (11), and more than 85% in humans are carcinomas(1), with the main differential diagnosis being urothelial (transitional cell) carcinomas. Primary tumors of the ureter are rare and often occur concurrently with neoplasms of the renal pelvis or urinary bladder(1, 4, 11).

Abnormalities were not detected in the urinary bladder during the CT scan or visible during the nephrectomy surgery in this animal. This combined with negative uroplakin III staining makes an urothelial carcinoma less likely. However, urothelial carcinomas in humans may not stain for uroplakin III, particularly those with invasive or metastatic behaviors(15). In humans, renal carcinomas are further characterized based on morphology(14, 15).

Although mild, the nephropathy is likely secondary to irradiation. Irradiation-induced nephropathy is a significant long-term complication in rhesus macaques and humans6, 16. The changes in rhesus macaques, 6-8 years after a single dose of irradiation (7.2-8.5 Gy) include glomerulopathy, ectatic capillaries, glomerulosclerosis, and periglomerular fibrosis(16). About 25% of human patients receiving comparable doses of radiation (7-7.5 Gy) develop renal dysfunction(6).

JPC Diagnosis:  

1. Kidney: Renal papillary carcinoma.
2. Kidney: Glomerulonephropathy characterized by interstitial fibrosis, tubular degeneration and regeneration, proteinosis, and lymphoplasmacytic interstitial nephritis.

Conference Comment:  

Primary renal neoplasms are relatively uncommon in animals and humans; however, renal adenocarcinoma is the most common primary neoplasm affecting the kidneys of dogs, cats, cattle and horses, and occurrence is sporadic in sheep and pigs. The origin is most likely proximal convoluted tubular epithelial cells. Small, well-circumscribed neoplasms with no evidence of capsular invasion or metastasis are generally considered to be benign. Well-differentiated carcinomas may be very difficult to differentiate from adenomas, with cellular atypia, a high mitotic rate, local or vascular invasion, necrosis, and size (>2 cm) used as criteria for malignancy. Renal adenocarcinomas are reported more often in middle-aged male dogs with no breed predilection. In dogs, 50- 60% of renal epithelial neoplasms metastasize, compared with 5% in the cow and 70% in the horse(9, 10, 12).

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(7). A notable paraneoplastic syndrome and common clinical pathology finding is secondary absolute polycythemia due to secretion of erythropoietin or erythropoietin-like peptide by the tumor(12).

Grossly, renal adenocarcinomas appear as large (>2 cm), spherical to ovoid, well-demarcated masses that are usually unilateral and occupy one pole of the kidney. They usually arise in the cortex and compress adjacent renal parenchyma, and may occupy 80% or more of the kidney. They often present as light yellow to gray lobulated masses with areas of necrosis and hemorrhage. Common sites of metastasis are the lungs, regional lymph nodes, liver, and occasionally the skin. Invasion into the renal vein and posterior vena cava may can occur. Multiple and bilateral renal neoplasms, without evidence of metastasis to other organs, are considered to be of multi centric origin(9, 10, 12).

Histologically, these neoplasms are often described by the predominant histologic type and further sub-classified by the predominant cytologic type, although there is no prognostic significance to histologic or cytologic type. Histologic types include papillary, tubular, and solid, and a mixture of all three patterns may be present in any one tumor. The tubular variant is most common in domestic animals, and often, the solid variant is usually poorly differentiated. There are several cytologic types, such as chromophobic, eosinophilic, and clear cell (with vacuolated cytoplasm) (9, 10, 12). The clear cell variant is more often seen in laboratory animals and they tend to be solid rather than tubular. Electron micrographs, may demonstrate abundant monoparticulate glycogen often within phago-lysosomes and few mitochondria or endoplasmic reticulum(10). Uromodulin (Tamm-Horsfall glycoprotein), a unique protein produced by the kidney, is useful as an immunohistochemical marker(9).

Differential diagnoses include oncocytoma, nephroblastoma and transitional cell carcinoma(9, 10, 12).

References:

1. Alpers, CE. The Kidney. In: Robbins and Cotran Pathologic Basis of Diseases. 8th ed. Philadelphia, PA: Saunders Elsevier; 2010: 905-967.
2. Broerse JJ, Bartstra RW, van Bekkum DW, van der Hage MH, Zurcher C, van Zwieten MJ, Hollander CF. The carcinogenic risk of high dose total body irradiation in non-human primates. Radiotherapy and Oncology 2000; 54:247-253.
3. Broerse JJ, van Bekkum DW, Zurcher C. Radiation carcinogenesis in experimental animals. Experientia 1989; 45: 60-69.
4. Epstein, JI. The Lower Urinary Tract and Male Genital System. In: Robbins and Cotran Pathologic Basis of Diseases. 8th ed. Philadelphia, PA: Saunders Elsevier; 2010: 971-1004.
5. Hollander CF, Zurcher C, Broerse JJ. Tumorigenesis in High-Dose Total Body Irradiated Rhesus Monkeys A Life Span Study. Toxicologic Pathol 2003; 31(2): 209-213.
6. Kal HB, van Kempen-Harteveld ML. Renal Dysfunction after Total Body Irradiation: Dose-effect Relationship. Int J Radiation Oncology Biol Phys 2006; 64(4): 1228-1232.
7. Khan KNM, Stanfield KM, Trajkovic D, Knapp DW: Expression of cyclooxygenase-2 in canine renal cell carcinomas. Vet Pathol 38:116-119, 2001
8. Lingaas F, et al. A mutation in the canine BHD gene is associated with hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis in the German shepherd dog. Hum Mol Genet. 2003; 12(23):3043-53.
9. Maxie MG, Newman SJ: Urinary system. In: Jubb, Kennedy, and Palmers Pathology of Domestic Animals, ed., Maxie MG, 5th ed., Vol 2 pp. 498-501. Elsevier Limited, New York, NY, 2007
10. Meuten D: Tumors of the urinary system. In: Tumors in Domestic Animals, ed. Meuten D, 4th ed., pp. 509-518. Iowa State Press, Ames, IA, 2002
11. Meuton, DJ. Tumors of the urinary system. In: Meuten DJ, ed. Tumors of Domestic Animals 4th ed. Ames, IA: Iowa State Press; 2002:380-392.
12. Newman SJ, Confer AW, Panciera RJ: Urinary system. In: Pathologic Basis of Veterinary Disease, ed., McGavin MD, Zachary JF, 4th ed., pp. 640-1. Mosby, St. Louis, MO, 2007
13. Suit H, Goldberg S, Niemierko A, Ancukiewicz M, Hall E, Goitein M, Wong W, Paganetti H. Secondary Carcinogenesis in Patients Treated with Radiation: A Review of Data on Radiation-Induced Cancers in Human, Non-human Primate, Canine and Rodent Subjects. Radiat Res 2007; 167: 12-42.
14.Tickoo SK, Reuter VE. Differential Diagnosis of Renal Tumors With Papillary Architecture. Adv Anat Pathol 2011; 18:120-132.
15.Truong LD, Shen SS. Immunohistochemical diagnosis of renal neoplasms. Arch Pathol Lab Med2011; 135:92-109.
16. van Kleff EM, Zurcher C, Oussoren YG, Te Poele JAM, van der Valk MA, Niemer-Tucker MMB, van der Hage MH, Broerse JJ, Robbins MEC, Johnston DA, Stewart FA. Long-term effects of total-body irradiation on the kidney of Rhesus monkeys. Int J Radiat Biol 2000; 76(5): 641-648.

A virtual slide is not available for this case.

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4-1. Renal papillary carcinoma

4-2. Renal papillary carcinoma

4-3. . Renal papillary carcinoma

4-4. Renal papillary carcinoma

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