Incidence

This is a rare tumor in domestic animals, and when found it is usually an incidental lesion at autopsy or slaughter because these tumors are clinically silent.^3,15,16 Of 894 primary renal cancers in dogs, there were 26 (3%) classified as adenoma and in cats 4/120 (3%) (Tables 15.2 and 15.3). Extrapolating from the incidence of renal carcinomas the actual incidence of renal adenomas in dogs and cats is probably less than 0.1%. Adenomas are reported in all species and they are less common than carcinomas. Progression of hyperplasia to adenoma to carcinoma is not known in domestic animals. However in dogs with hereditary dermatofibrosis there appears to be a progression of renal lesions from cysts to hyperplasia, adenoma, and carcinoma. It is logical this would occur in other renal epithelial tumors.

There are no studies on actual incidence, age, breed, or sex predilection for renal adenomas, although there is some data for renal tumors in food animals. Over an 11‐year period, 20 renal cell tumors were identified in approximately 13,500 cattle processed for slaughter.³ All 20 cows were adults, 2–20 years of age. Nineteen of them had multiple tumors; 11 of these were visualized grossly, 8 others were microscopic, and 19 were classified histologically as carcinomas. Only one tumor was classified as an adenoma (8 × 10 mm single lesion in one kidney), however, only 1 of 19 carcinomas metastasized suggesting, despite the classification as carcinoma, they behave in a benign manner. The authors discussed the difficulties of distinguishing adenoma from carcinoma. They suggested the renal tumors were carcinomas, based on the multiplicity of tumors, and indicated they may develop in multiple sites within the kidneys. The occurrence of metastases in only one cow was clearly a different pattern from the high rate of metastases seen in renal carcinomas in humans, dogs, cats, and horses. A survey of 6706 cattle over a 45‐year period in Brazil yielded 586 tumors, of which 9 were in the kidney and none were adenomas (6 carcinomas, 3 adenocarcinomas).¹⁴

Gross morphology and histological features

Adenomas are discrete, solitary, tan to white tumors located in the renal cortex (Figure 15.1A,B). In dogs and cats they are small (usually <2.5 cm) but size of the tumor is dependent on the biologic behavior of the neoplasm and size of the dog or cat. A 2.5 × 2.5 cm renal tubular tumor in a cat did not metastasize or invade adjacent tissues and had a benign histologic appearance with a low MC. This cat also had hypertrophic osteopathy.¹⁷ In horses and cattle, adenomas can be large (>6 cm) and have central areas of hemorrhage and necrosis. Tumors may only be found if the kidneys are sliced in multiple areas. On cut surface they are well demarcated and bulge, and only larger neoplasms have discolored necrotic centers. Bilateral and/or multiple adenomas occur, especially in dogs¹⁸ and cows.³ An inherited disease in German shepherds is associated with dermatofibrosis and renal adenomas. The adenomas in these dogs are almost always multiple, and there can be concurrent cysts or renal adenocarcinoma, partly dependent on the age of the dog and how long the lesions have had the opportunity to progress.¹⁸

Renal adenomas are non‐encapsulated but sharply demarcated from the adjacent cortex. They are composed of well‐differentiated tubules and acini that may be subclassified as tubular, papillary, or solid, based on the major histological pattern: central or elongated lumina (tubular type), papillary growths of varying sizes that project into lumens (papillary type) (Figure 15.2A), or solid sheets. Mixtures of all three types can occur, and this is also seen with renal carcinomas. Cytological and nuclear features are uniform and benign. A single layer of cuboidal epithelial cells with ample eosinophilic cytoplasm will line tubules or papillary projections. Nuclei are single, placed centrally or basally, and have a single nucleolus; mitotic figures are not observed, or found rarely. There is a paucity of supporting stroma, usually consisting of thin strands at the base of tubules.

Corpora amylacea are common in renal cell tumors of cattle. Renal mucous gland cystadenomas were described in a 35‐year‐old horse. Grossly, the lesions were cystic, 1–4 cm in diameter, and found in the medulla and cortex of one kidney.¹⁹ Histologically, the tumors were well differentiated, compressed adjacent parenchyma, and were lined by tall epithelial cells that contained mucinous material, which was also present in the lumina of the cysts. The origin of the tumor was designated as the mucous glands common in the pelvis and proximal ureter of horses.

The histological distinction of renal adenoma from carcinoma is subjective for tumors in the 2 cm range, and because carcinomas may be well differentiated, they each have similar histologic types and neither has a capsule. As pathologists, it seems likely we favor a diagnosis of well‐differentiated carcinoma over adenoma for tumors in the “gray zone” and especially if multiple tumors are present. The easiest solution is to count mitotic figures.¹ Regardless of the designation, if the MC is <10/10 HPF the biologic behavior of the tumor is likely to be benign and survival time long (years), at least in dogs. Adenomas are small, sharply demarcated, noninvasive, and composed of well‐differentiated epithelium with no or few mitoses. Carcinomas that are large and infiltrative and have cellular and nuclear pleomorphism are easy to classify. Gradations of the two will make distinction difficult in some cases but MC has been shown to correlate with survival in dogs.¹

An arbitrary cut‐off of 2 cm as a criterion of malignancy has been used: less than 2 cm adenoma, greater than 2 cm carcinoma. The use of size is based on older information from renal tumors in humans and is not a sound generalization for tumors in animals.²⁰ Certainly small tumors, less than 1 cm, are likely to be benign in any species, but neoplasms larger than 2 cm may also have a benign course.¹⁷ In dogs and cats this generality is a guide and in cattle most renal tumors are greater than 2 cm in diameter but they rarely metastasize. The best criteria to distinguish benign versus malignant are metastases, increased MC, invasion, anaplastic cellular and nuclear features, as well as historical data for each species. Neither adenomas nor carcinomas have a capsule. Multiplicity of gross tumors suggests a malignant classification or metastases from a nonrenal organ (lung, prostate, or mammary). However, multiplicity of renal tumors is also associated with benign biologic behavior in several species.

General considerations

These are malignant epithelial tumors without features of embryonal differentiation. They have also been classified as RCC, malignant nephroma, clear cell carcinoma, hypernephroma, and Grawit’s tumor.⁶ Many tumors will have well‐differentiated tubules or papillary structures that make their epithelial identification easy. Solid variants and sarcomatous regions also occur and one of the most common histologic characteristics is a mixture of various cell types.

Incidence

Renal carcinoma is an uncommon tumor in domestic animals; however, it is the most common primary renal tumor in dogs, cats, and horses. The reported incidence for dogs is 1.5 in 100,000 and for cats 0.7 in 100,000.²¹ Other reported incidences include 0.3–1.5% for dogs⁸ and 0.2–0.5% for cats.¹² A retrospective study found 4 (0.05%) in 8149 canine tumors and 3 (0.23%) in 1299 feline neoplasms, suggesting that in this limited number of cases renal carcinoma was 4.5 times more frequent in cats than in dogs.¹³ Table 15.2 summarizes five studies, and of 894 canine neoplasms, 510 were classified as RCC (57%), 48 (5%) as transitional (urothelial) cell carcinoma, 11 (1.2%) as squamous cell carcinoma (SCC) and only 2 as undifferentiated carcinoma. There were 601 epithelial tumors and 569 (94%) were classified as malignant. Overall 86% of the epithelial and mesenchymal tumors were classified malignant. One study reported pulmonary metastases were detected in 10/61 (16%) at the time of diagnosis and at the time of death 37/49 (76%) had metastases.² Metastases were found in 70% of the dogs with carcinoma, 88% with sarcomas, and 75% with nephroblastomas.²

Table 15.3 summarizes three studies in cats, and of 120 neoplasms 55, 46% were classified as RCC, 11 (9%) as urothelial cell carcinoma (UC), and there were no undifferentiated carcinomas. A search from databases of four veterinary colleges and one private referral practice during a 6‐year interval identified 19 primary renal neoplasms in cats.⁵ There were 13 renal carcinomas (11 tubular; 2 tubulopapillary), 3 UC, and 1 each nephroblastoma, hemangiosarcoma, and adenoma.⁵

Abattoir surveys report rates of 8.5, 4.3, and 0.9 renal tumors per million animals in cattle, pigs, and sheep, respectively.²² During an 11‐year period, 20 renal cell tumors were identified in 13,500 cattle processed for slaughter. Nineteen were classified as carcinoma even though only 1 tumor metastasized; 1 tumor was classified as an adenoma, a single 8 × 10 mm mass.³ The diagnosis of carcinoma was based on multiplicity of tumors. A survey of 6706 cattle in Brazil over a 45‐year period reported 586 tumors, 9 of which (6 carcinomas and 3 adenocarcinomas) were in the kidney; all 3 adenocarcinomas metastasized to lung and renal lymph node and no information was provided on the other 6.¹⁴ There were 35 tumors in the urinary bladder.¹⁴

Tumors in the kidneys of horses are rare; if primary or secondary tumors occurred frequently they would be found on routine autopsies. Only 4 cases were found in 3633 equine autopsies (0.11%) at Cornell over a 23‐year period: 2 RCCs, 1 renal adenoma, and 1 mesenchymal tumor.¹⁵ The reported incidence of 0.11% for renal tumors and 0.055% for RCC is similar to citations in the older literature of 62 in 40,000 necropsies.¹⁵ A 2009 report summarized clinical characteristics in horses with primary renal tumors. Twenty‐three cases were from reports in the literature and 4 were new cases.⁴ The diagnoses were renal carcinoma 18, renal adenocarcinoma 6, and 1 each tubular adenocarcinoma, papillary adenocarcinoma, and transitional cell carcinoma (TCC) in the renal pelvis. Metastases were identified in 19 of the horses.

Age, breed, and sex

Renal carcinomas are reported to occur in middle‐aged male dogs (mean age 8–9 years),^2,8,9 but can be seen in dogs less than 6 years of age and tumors in younger dogs may behave more aggressively.¹ The only breed predilection is German shepherds, with hereditary dermatofibrosis and renal tumors. Most reports suggest a male predominance in dogs, approximately 2:1. In humans, the incidence of renal tumors is 2–5 times greater in males.⁶ In cats, renal tumors (all types) tend to occur in the 8‐ to 11‐year‐old age group (range 2–13 years). Some studies report tumors in cats are more common in males¹⁰ and others report equal numbers in male and female cats.⁵ Horses with renal tumors range in age from 4 to 25 years old (mean 13 years); no breed or sex predilections are reported.^4,23,49 Twenty cows with renal cell tumors ranged in age from 2 to 20 years.³

Clinical signs are vague and by the time dogs present, between 20 and 50% will have a palpable abdominal mass and about the same will have evidence of pulmonary metastases via imaging.^1,2 Some dogs will have cachexia, which is associated with a negative outcome.

Clinical and clinical pathology characteristics

In all species the chief complaints and clinical signs associated with primary or secondary renal tumors are nonspecific. In dogs and cats, reported clinical problems are an abdominal mass (20–50%), weight loss, pollakiuria, and nonspecific problems such as lethargy, vomiting, and anorexia.^2,5,8–11 By the time these tumors produce clinically detectable problems in dogs, cats, and horses the tumor is advanced. Metastatic disease can be detected with thoracic radiographs in approximately 15–50% of dogs with renal carcinoma at initial presentation.^2,24 Abdominal radiographs will detect a mass in 80% of the cases, and in 50% of these the mass can be identified in a kidney.^9,10 Ultrasound or intravenous pyelograms are reported to correctly detect a mass in 80–100% of the cases, depending on the host and location of the tumor.^2,9

There are no specific clinical pathology abnormalities that suggest a renal tumor is present. Several paraneoplastic syndromes have been reported with renal tumors: polycythemia vera, paraneoplastic leukocytosis, hypertrophic osteopathy, hypoglycemia, and hypercalcemia. The most common abnormalities are hematuria (50–100%) and pyuria (50%).² Proteinuria is reported in a high percentage of cases, but the majority or all of these patients have concurrent hematuria and/or pyuria. Hemorrhage with or without inflammation is the most likely explanation for proteinuria in these cases. Distinction between glomerular and hemorrhage‐induced proteinuria for patients with renal tumors is not reported. Azotemia is present in approximately 25% but probably involves superimposed prerenal (dehydration) or concurrent renal disease, as the majority of the total renal mass is unaffected if the only lesion is renal neoplasia.^2,9 Lymphoma would be one of the few tumors that could destroy enough functioning renal mass to cause renal azotemia.

One report provides information on clinical characteristics, laboratory data, and diagnostic evaluation by histologic groups.⁹ Most results are similar across histologic groups; notable differences were that hematuria was more common with TCC than with renal tubular cell tumors, and none of the eight dogs with TCC had detectable metastases at the time of initial diagnosis. Searching for tumor cells in urine is generally futile but occasional successes are possible.

Anemia is reported in approximately one‐third to half of the animals with renal tumors. Mechanisms are not identified but several factors are probably superimposed, including anemia of chronic inflammatory disease, hemorrhage, and hematuria; however, decreased erythropoietin seems very unlikely as there is so much remaining renal mass. Secondary absolute polycythemia has been reported infrequently with renal tumors in dogs and cats.^5,25,26 The increased red blood cell mass is likely due to the production and secretion of erythropoietin or erythropoietin‐like peptide from the tumor. Packed cell volume will be increased in the range of 60–70% in dogs and will return to reference range after tumor removal. This syndrome has been seen with renal adenoma, carcinoma, nephroblastoma, TCC, fibrosarcoma, and lymphoma as well as non‐neoplastic lesions such as cysts and hydronephrosis.^5,25,26 Paraneoplastic leukocytosis of >100,000 WBC/μL has been reported in a few dogs with renal tumors.^2,27 In one case production of granulocyte–macrophage colony‐stimulating factor by the tumor cells was documented and the marked leukocytosis resolved after nephrectomy.²⁷ This dog also had concurrent hypertrophic osteopathy, which has been reported in a few other dogs with primary renal tumors. This unusual bone lesion is seen more frequently with tumors in the urinary bladder. Hypercalcemia was attributed to the production of parathyroid‐related protein (PTHrP) by a renal angiomyxoma²⁸ and hypercalcemia has been associated with a chromophobe carcinoma in a dog.²⁹

Increased serum gamma glutamyltransferase (GGT) was present in a dog with renal adenocarcinoma and it decreased gradually following nephrectomy and then increased associated with growth of pulmonary metastases.³⁰ Bilirubin and other hepatic enzymes were not increased and albumin and urea nitrogen were not decreased. This observation is interesting and the patterns of a substance increasing, decreasing, and increasing with presence, removal, and recurrence of a tumor type is how hypercalcemia of malignancy was first discovered. GGT is located in the brush border of proximal convoluted tubules and has been measured in the urine of dogs to indicate nephrosis. The authors cited two similar cases in dogs that had increased serum GGT and renal tumors. Increased serum GGT and isoenzymes of GGT are seen in some cases of renal adenocarcinomas in people. In a fairly large series of renal tumors in dogs GGT was increased in 6 of 64, but alkaline phosphatase (ALP) was increased in 21 of 65.² Hepatic enzymes in different combinations (ALP, alanine transaminase (ALT), aspartate transaminase (AST), GGT) may be increased in 10–25% of dogs due to secondary liver diseases or stress. It will be interesting to see if others can identify cases of a unique increase in GGT with primary canine renal tumors.

A report of 27 horses indicated that ages of affected horses was 4–25 years old (mean 13 years); weight loss, anorexia, hematuria, and colic were the most common clinical problems. Clinical histories were varied and not specific. Routine laboratory data was not specific. The tumors were epithelial, malignant, and metastases were present in the majority of horses.⁴ Hematuria was present in 94% of horses with a urinalysis and hypoglycemia was present in 19%. Paraneoplastic hypoglycemia is reported in a horse with RCC.³¹ Rectal palpation and/or imaging studies revealed a mass or an enlarged kidney in the majority of these horses. Four of five horses had pulmonary nodules seen in radiographs of the thorax. Nineteen had metastases at autopsy; the most common sites were lungs (16) and liver (14) and several cases had metastases to bone and/or muscle.⁴ In ruminants, the tumors are usually asymptomatic or at least they are undetected ante mortem.

Gross morphology

Most carcinomas are unilateral, but they can be bilateral and multiple; neither kidney is more predisposed.^3,4,18,32,33 They are well‐demarcated masses, located in the cortex, yellow, tan‐brown to cream colored, often located at one pole, and they vary considerably in size, from 2 cm in diameter to occupying greater than 80% of one kidney (Figure 15.1C). Large neoplasms that invade the renal capsule and enter the retroperitoneal space and encompass and/or invade the adjacent adrenal gland are easy to classify as carcinoma. The smaller the primary tumor the more difficult it is to differentiate carcinoma and adenoma. Large masses have expected areas of necrosis and hemorrhage and are friable due to little supporting stroma. They may also invade the renal pelvis or enter blood vessels (Figure 15.1C,D). Rarely, they infiltrate through the retroperitoneal space and spread by implantation metastasis through the abdomen but can occur in all species.

Multiplicity of renal tumors occurs dogs, cattle, and humans and smaller tumors may only be found during microscopic examination of random sections. Nineteen of 20 cows with renal cell neoplasia had multiple tumors; 11 of these were visualized grossly, and 8 others were microscopic. Canine tumors can be cystic, and the cysts contain variable amounts of clear or red‐brown fluid. The report of 27 horses indicated that the tumors were unilateral: 15 left kidney, 8 right kidney (4 not specified). Four of these horses had tumor in the contralateral kidney, but these were interpreted as metastases. Bilateral renal tumors occur in other species and there is no clear means to distinguish multicentric origin from metastases. None of the retrospective reports indicated the primary tumor in horses invaded other parts of the urinary tract.

Histological features

Renal carcinomas can be subdivided into histological and cytological types. However, to predict biologic behavior and estimate survival times for dogs with RCC use MC.¹ Histologic types of RCC seen in animals are solid, tubular, papillary, or cystic (multilocular cystic). A study of 70 dogs indicated 34% were solid, 21% papillary, 24% tubular, 4% multilocular cystic, 9% clear cell, and 9% chromophobe. Forty percent of the total had mixed patterns and 7% had sarcomatoid features. Tubular is the most common type in other animals, and clear cell type accounts for 75% of RCC in humans. Each histological type can be classified cytologically as chromophobic, eosinophilic, or clear cell, and mixtures of all three are typical.

The predominant histologic and/or cell type should be used to classify the tumor and areas of sarcomatoid change and cysts can be described. The classification used in human tumors is based on numerous cases that have long‐term follow‐up and molecular profiles correlated with morphology. We can characterize the morphology of tumors in animals but in veterinary pathology it is very difficult to gather large case series that have enough overall tumors and examples of each variant, to avoid sample bias. The largest study of RCC in dogs used case materials gathered from the United States and Canada to find approximately 200 cases of renal tumors over a 16‐year period, from which 70 cases had adequate tissues, clinical data and follow‐up information that was archived or could be determined. The number of cases per group was small, but the types of RCC that appeared to have prognostic value in dogs were: clear cell carcinoma (6 cases), which had decreased median survival time (MST) of 87 days, increased risk of death and 3 of 6 had metastases; multilocular cystic tumors (3 cases) which appeared to have longer survival time and a more benign course.¹

Clear cell type RCC is seen more frequently in laboratory animals and human beings, whereas in dogs only 6/70 (9%) were clear cell carcinoma in the same study,¹ and they are observed rarely in cattle. They are easy to recognize with H&E by their “clear” cytoplasm, which is due to high glycogen and lipid content (Figures 15.3 and 15.4). They are usually in solid rather than tubular RCCs. Cell borders are distinct, cytoplasm is abundant, and nuclei are round and dense, providing the appearance of a well‐differentiated tumor. The clear cytoplasm and solid growth that resembles adrenal cortical tissue led to the name hypernephroma. Foci of clear cells can be found in many renal cell tumors if they are searched for and will help suggest renal origin if the location of the primary tumor is uncertain. In dogs they are reported to have cytoplasmic staining for vimentin and are negative for CD117 (KIT).¹ They are derived from the proximal convoluted tubules, hereditary, and associated with mutations in the VHL gene.³⁴ Approximately 75% of renal carcinomas in humans are clear cell type, making them the most common renal tumor in humans by a wide margin, and as in dogs they shorten lives and metastasize.

Chromophobic cell variants have cuboidal cells with granular, lightly to intensely eosinophilic, abundant cytoplasm and distinct cell membranes. They stain positively for colloidal iron^1,29 and are immunoreactive to CD117 (KIT), encoded by the c‐KIT proto‐oncogene.¹ They may be in found in any histologic type of RCC. They often form trabeculae of varying sizes, with or without lumina. They should be distinguished from oncocytomas, which are solid tumors filled with cells of similar appearance. Chromophobe RCC was documented in a 12‐year‐old female husky that had hypercalcemia.²⁹ The tumor was 8 cm in diameter and it contained a mixture of epithelial and mesenchymal cells. The epithelial cells had abundant, cloudy eosinophilic cytoplasm that resembled cells seen in chromophobe RCCs of humans and in oncocytomas of humans and dogs.

Differentiation between oncocytomas and chromophobe RCCs may require histochemistry, IHC, and electron microscopy. Oncocytoma and chromophobe RCC may be the same tumor. Chromophobe RCCs stain positively for colloidal iron and KIT, negatively for periodic acid Schiff (PAS) and should not be packed with mitochondria. Oncocytomas should be negative for colloidal iron but positive for PAS and should contain numerous mitochondria. In the aforementioned chromophobe RCC in a husky, the epithelial component was negative for vimentin and PAS and positive for colloidal iron and KIT. A subpopulation was positive for CD10 and results for cytokeratin were not reported.²⁹ The only cells positive for vimentin were the sarcomatoid elements. Because chromophobe RCC resembles oncocytoma the authors encouraged separation of these differentials. Chromophobe RCCs and oncocytomas are negative for vimentin. Chromophobe RCCs, collecting duct carcinomas, and oncocytomas are derived from collecting ducts and may look similar histologically.

The eosinophilic cell type is a variant of chromophobe tumors in which the cytoplasm is intensely eosinophilic. Cells are cuboidal shaped, cell borders are distinct, and they form trabeculae of various widths, usually without lumina. This is the most common variant in cattle (19/20 cattle tumors are eosinophilic, 1/20 are clear cell). The eosinophilic variant and oncocytomas look similar with H&E. Oncocytomas have more numerous mitochondria, an absence of cytoplasmic vesicles, and they are positive to cytokeratin but negative to vimentin.³² The majority of RCCs in humans and dogs are cytokeratin and vimentin positive, which is a unique characteristic.^6,32 Chromophobic and eosinophilic tumors stain light blue with histochemical stains for colloidal iron.⁶

Tubular RCCs have numerous tubules and acini of various sizes that are the predominant histologic features. Epithelial cells lining tubules range from well differentiated to anaplastic (Figure 15.2E). Lining cells are usually singular. More anaplastic tumors have cells piling together irrespective of adjacent cells and may invade adjacent tissues. Some lumina will contain homogeneous secretory material and/or sloughed cells. There may be regions with papillary formation or solid proliferations devoid of lumina. Stroma is minimal and desmoplasia absent. These are common in cattle and although designated carcinoma they do not metastasize.

Papillary tumors have distinct branching papillae projecting into clear spaces of varying sizes. They look well differentiated at first observations with low and medium magnifications. Papillae may be small and singular within a space or have multiple branches (Figure 15.2A–D). In cross‐section they appear as a circle with cells lining the outside and a central core of stroma and a blood vessel.

Solid tumors contain epithelial cells apposed closely together. They do not form tubules, acini, or papillae, although foci with these structures may be seen in regions of the tumor. Cell borders are usually distinct and cytoplasm stains lightly. There is considerable variation in cell sizes between different tumors but within one tumor, cells and nuclei tend to be fairly uniform. This is a common pattern in dogs (Figures 15.3 and 15.4).

Cystic and multilocular cystic are likely variants in which cysts are the predominant feature. Cysts are of various sizes and may be empty or contain a lightly stained homogeneous product (Figure 15.2G). They are lined by benign‐appearing epithelial cells. Counting mitotic figures, or at least producing reliable counts, is problematic in these tumors, as a majority of the tumor may be acellular or paucicellular, clear or fluid‐filled spaces. MC should be started in regions that have mitotic figures or if none are found then start in a solid region. Crossing regions with cystic spaces is inevitable. Multilocular cystic is a variant used in human RCC and has been used in dogs. The canine tumors were described as “multiple, variably sized cystic spaces separated by fibrous septa lined by cuboidal epithelium” and 3 of 70 cases were so designated.¹ Although results are not statistically significant, multilocular cystic type may be associated with longer survival times.¹ Sarcomatoid features can be found in some renal tumors (10%) and when seen there is an obvious transition from one of the epithelial patterns into a spindle cell tumor with high cellular and nuclear density.

A collecting duct carcinoma in a dog has been described histologically, histochemically, and via IHC and compared to the same diagnosis in humans.³⁵ The tumor contained papillary and tubular structures and others may have considered this a tubular RCC. Without histochemistry or IHC, the derivation from collecting ducts would not be appreciated. The neoplasm had cellular and nuclear pleomorphism, a high mitotic count, and it invaded regionally and metastasized widely.³⁵ Collecting duct carcinomas are highly malignant in humans.

Interstitial stroma ranges from mild, with just enough stroma for tubules to rest on, to marked desmoplastic reactions. Occasional RCCs will have marked desmoplasia encasing tumor cells. If there is retraction of the connective tissue from the tumor cells it gives the false impression on intralymphatic emboli. Capsules are absent or incomplete. Tumors tend to grow by pushing at the edges more than by infiltrating. When tumors infiltrate and extend beyond the kidney, the diagnosis of carcinoma is straightforward. Hemosiderin, proteinaceous secretions, and corpora amylacea are features of renal cell tumors in cattle.

Histologic diagnoses in 27 horses with primary renal tumors were 18 carcinomas, 6 adenocarcinomas, and 1 each of tubular adenocarcinoma, papillary adenocarcinoma, and TCC in the renal pelvis.⁴

Growth, metastases, and survival

In dogs, 50–70% metastasize,^2,8,9 whereas 70% metastasize in horses,⁴ 50% in cats,^5,10 and only 5% in cattle.³ The most likely sites are lung, liver, and regional lymph node. Other sites reported are serosal surfaces and ipsilateral adrenal gland.^8,9 Metastases to the skin is an unusual site for any tumor. However, this site has been reported with renal tumors and urothelial carcinomas in dogs. Metastases are common in horses and are widely disseminated.^4,23,36 Four of five horses had pulmonary nodules seen in radiographs of the thorax. Nineteen had metastases at autopsy; the most common sites were lung (16) and liver (14) and several cases had metastases to bone and/or muscle. The high rates of metastases in most species is attributable to the biology of the tumor and the finding that RCCs are clinically silent, so by the time they are detected the tumor has months or years to develop its full malignant potential. In humans, bone is a common site for metastases of RCC and RCC is one of the most common tumors in humans to metastasize to bone.³⁷

One of the earliest reports indicated that 37 of 54 dogs with renal tumors survived less than 21 days; however, it is often not clear how decisions from owners influence survival data.⁹ Some dogs in that study survived 8–24 months,⁹ while a median survival of 16 months with a range of 0–59 months is reported in another.² Another study in dogs indicated 20 of 29 carcinomas, 14 of 16 sarcomas, and 3 of 4 nephroblastomas had metastases at death.² All groups of renal neoplasms in this study exhibited malignant behavior and no difference in survival could be detected between groups of tumors or within histologic subtypes.² The survival ranges for carcinoma was 0–59 months (median 16 months) and for sarcoma 0–70 months (median 9 months). Metastases may be as fully differentiated as the primary tumor. Less‐differentiated varieties have the expected features of reduced cytoplasmic area, indistinct cell borders, nuclear crowding, multiple cells piled together, various sizes and shapes of nuclei, mitoses, and vesicular chromatin (Figure 15.3D). Some tumors will have very high MC (up to 60 mitoses/10 400× fields, 2.37 mm²). The more differentiated varieties resemble adenoma and have one or two layers of well‐differentiated eosinophilic cells lining tubules (Figure 15.2E).

Long survival times of 4–5 years in some dogs with a diagnosis of RCC suggest a propensity to diagnose primary renal epithelial tumors as malignant, but their clinical behavior may be benign. Using MC will help identify RCCs with different biologic behaviors.¹ In a study of 70 dogs the authors used MC cut‐offs of <10, 10–30, and >30 in 10 400× fields using oculars with FN22 and therefore a field‐of‐view area of 2.37 mm². Dogs with an MC of <10 (n = 36) had a significantly increased median survival time (MST) of 1184 days, dogs with intermediate MC (n = 14) had an MST of 452 days, and dogs (n = 20) with tumors >30 had an MST of 147 days and an increased hazard ratio for experiencing death or euthanasia, regardless of histologic or cytologic classification or nuclear grade. MC was the only independent prognostic variable found using multivariate analysis. MC should be used when evaluating a biopsy or nephrectomy specimen to help predict biologic behavior, at least survival times in dogs.

Some of the low‐grade RCCs with 0–3 MC may have been considered adenoma, Regardless of adenoma versus low‐grade carcinoma, MC provides a useful prognostic parameter that is easy to determine. The nuclear grading system is one designed for RCC in humans that uses defined, subjective nuclear and nucleolar characteristics that are not as easy to determine as MC.³⁸ When applied to the dogs of this study it revealed different patterns of outcome: grade 1 – 6 dogs, MST not reached; grade 2 – 28 dogs, MST 1065 days; grade 3 – 31 dogs, MST 379 days; and grade 4 – 5 dogs, MST 87 days.¹ The trend is clear that as nuclear and nucleoli variabilities increase survival times decrease. The 6 dogs with grade 1 RCC had survival times of 136, 362, 451, 718, and 955 days, and 1 dog was alive at 3703 days. All material was selected from biopsy or nephrectomy specimens. Metastasis and recurrence data could not be determined for all cases. Metastasis detected by imaging at the time of initial diagnosis was noted in 5/44 (11%), and an additional 10 developed radiographically detectable pulmonary nodules in 2–23 months (15/44 (34%)).

Fuhrman et al. defined four nuclear grades (1–4) in order of increasing nuclear size, irregularity, and nucleolar prominence. The study found that nuclear grade was more effective than other parameters examined in predicting development of distant metastasis following nephrectomy of humans with various RCC.³⁸ Future studies should employ this grading scheme on animal tumors to confirm its utility and determine if it and MC are needed to predict behavior of RCC in animals. Presently, determining the MC and type of RCC should suffice for biopsy or nephrectomy specimens.

Short survival times are reported in horses (0–1 year),⁴ but for all species an obvious reason for short MSTs is euthanasia at the time of diagnosis, which can be for a variety of reasons. Overall, the prognosis for renal carcinomas in dogs, cats, and horses is poor, as the majority of cases has or will develop metastases. However, long‐term survival is possible with nephrectomy when tumors are unilateral, not large, and have not metastasized.^1,2

It can be difficult to decide if a small tumor is benign or malignant. Large tumors are often easy to classify because the tumor has already metastasized or invaded the renal pelvis, capsule, or vessels. Although tumor size has been stated to be a criterion (<2 cm adenoma, >2 cm favors carcinoma), this is an oversimplification from the older literature.²⁰ A single tumor less than 2 cm in diameter is likely to be benign in all species, but renal tumors in cattle³ behave in a benign fashion even though tumors can be as large as 60 cm. Only 1 of 20 renal cell tumors studied in cattle metastasized; most had minimal cellular atypia yet were classified as carcinoma based on their multiplicity. Two of the 20 had marked cellular pleomorphism; one of these metastasized and one did not. The one tumor classified as an adenoma was 8 × 10 mm and was confined to one kidney. Characteristics that favor carcinoma are large size, large areas of necrosis, infiltration, invasion of parenchyma or vessels, increased MC, and nuclear atypia. Only MC and nuclear grade are correlated with long‐term follow‐up studies.¹ Classification by histological or cytological subtype is not predictive of biological behavior in domestic animals. Multiplicity of primary renal cell tumors is not a reliable criterion as this occurs in 33% of canine and in 95% of bovine cases. If a renal tumor metastasizes to the opposite kidney, there are invariably metastases in other organs.

Diagnostic considerations and immunohistochemistry

Most tumors located in the kidney are easy to diagnose via H&E sections and gross patterns. Diagnostic challenges can be to determine the biologic behavior of a primary renal tumor or to find the primary if there are multiple epithelial tumors. Adenoma and tubular RCCs resemble similar tumors that originate in lung, mammary, and prostate glands. If lesions are confined to the kidney, especially the cortex, and/or regional lymph nodes, a diagnosis of primary RCC is straightforward. Renal tumors that are multiple and bilateral yet do not metastasize to other locations are primary renal cell tumors, probably of multicentric origin. If a renal tumor metastasizes to the opposite kidney, there are metastases in other organs. When metastases are widespread, the distinction is less easy and the criterion more subjective: location of the largest tumor suggests that organ as the primary site, and metastases to the kidney will be multiple, not singular. Renal carcinomas invariably arise in the cortex, and lesions in the medulla favor a metastatic tumor. If the primary source is unknown and IHC is desired, it is worth noting that, while not specific, dual positivity for cytokeratin and vimentin is suggestive of renal origin. Finding an IHC pattern of positivity for uromodulin, PAX8, napsin A, and neprilysin confirms renal origin. Foci of clear cells are also consistent with renal origin. Corpora amylacea are features of renal cell tumors in cattle.

An unusual feature of most renal cell tumors is that they dual mark with cytokeratin and vimentin. This is also seen in tumors that originate in prostate, ovary, or mesothelium.³⁹ In RCCs this may be due to their origin from primitive renal blastema or an epithelial–mesenchymal transition. An epithelial–mesenchymal transition may assist tumor cells to dissociate enabling invasion and/or metastasis and may have prognostic significance.⁴⁰ Kidneys originate from mesenchymal blastema, which reacts positively to vimentin but not cytokeratins. The blastema differentiates into epithelium and loses some vimentin reactivity as tubules and parietal epithelium develop positive staining to cytokeratins. The coexpression of vimentin and cytokeratins may represent the embryonic mesenchymal blastema, or an epithelial–mesenchymal transition in neoplastic cells, or an origin from renal stem cells. Only the parietal epithelium of Bowman’s capsule and distal tubules of adult mammalian kidney express CK19.

Uromodulin, a unique protein synthesized by the kidney⁴¹ has been a useful IHC marker for identifying and studying renal cell tumors in humans, cattle, and dogs. Two studies found positive uromodulin immunoreactivity in all renal cell tumors in cattle (20) and dogs (13).^3,42 The canine tumors were unilateral and single masses, 9 were clearly epithelial and 4 were solid tumors, 1 of which was classified as sarcomatoid. All 13 were positive for uromodulin, 11 were also positive for vimentin, 12 positive for KIT, 9 positive for wide‐spectrum screening cytokeratins, and 7 were positive for carcinoembryonic antigen.⁴² Only distal convoluted tubules in the non‐neoplastic tissue adjacent to tumors were positive for uromodulin. Normal stromal cells were positive to vimentin and the cytoplasm of tubules, ductules, and urothelium were positive for cytokeratins. One tumor, a tubulopapillary carcinoma did not stain positively with any of the four epithelial antibodies used, but it was positive for vimentin and uromodulin. All three solid tumors were negative for cytokeratins but the sarcomatoid tumor was positive. The two papillary–cystic carcinomas were the only two tumors that were negative for vimentin. Two tumors, both classified as papillary–cystic had low MC of 5/10 HPF, whereas the average MC of the other 11 was 36/10 HPF. Clinical assessment at the time of nephrectomy did not reveal metastases but there were no follow‐up data, clinical data, or autopsies to correlate IHC or histologic results with clinical outcomes. The presence of KIT in 12 of 13 tumors suggests that mutations of the c‐KIT proto‐oncogene may have a role in renal oncogenesis. KIT expression is found in chromophobe renal tumors in humans and was present in the canine renal tumors regardless of histologic type. Only 3 of 13 tumors had CD10 (neprilysin) reactivity, which is in the brush border of renal tubules and can be found in types of renal carcinomas in humans, in 90% of clear cell types, and approximately two‐thirds of papillary tumors.⁴² The IHC pattern for a collection duct carcinoma in a dog has been reported and compared to the human counterpart.³⁵

Although the numbers are small, uromodulin is a useful “IHC marker” to identify a renal cell tumor in dogs and cattle. It will be necessary to know if any other epithelial tumors stain positively or if uromodulin is specific for renal epithelium. Napsin A is proteinase expressed in the lung and renal proximal convoluted tubules and has been used in human RCCs to help identify renal origin.⁴³ Neprilysin (CD10) is expressed in lymphoblastic tumors, germinal cells, and proximal convoluted tubular epithelium. In humans, CD10 is present in 90% of clear cell renal carcinomas and approximately two‐thirds of papillary tumors, but in the canine study it was only present in approximately 20% of the tumors.⁴² Sensitivity and specificity will need to be determined for the different antibodies in different species to help determine their diagnostic utility. Renal tumors are so uncommon in animals it will be difficult to accumulate enough cases with follow‐up data to determine if IHC helps determine prognosis or select treatments as it does in humans.

Differentiation of RCC from UC can be done by anatomical location and histology. RCCs are in the cortex versus pelvis for UCs. Melamed–Wolinska bodies are characteristic of UC, widespread metastases favor UC, tubules and acini favor RCC, but there will always be some gray zone cases in which the distinction is difficult. IHC with uroplakin III (UP III) and p63 should identify UC, whereas uromodulin, neprilysin, napsin A, and PAX8⁴⁴ are all useful to identify renal origin (Figure 15.4). These antibodies and their application to tumors in domestic animals need to be thoroughly evaluated. In human tumors wide panels of antibodies are often needed to differentiate tumors that look similar.^44,45