Pathology in Practice

Alissa St. Blanc Departments of Pathobiological and Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803.

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Nicholas A. Crossland Departments of Pathobiological and Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803.

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Peter M. DiGeronimo Departments of Pathobiological and Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803.

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Rachel E. Cianciolo International Veterinary Renal Pathology Service, The Ohio State University, Columbus, OH 4310.

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Gordon J. Pirie Jr Baton Rouge Zoo, 3601 Thomas Rd, Baton Rouge, LA 70807.

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Amy E. Thiessen Antech Diagnostics, 2433 Globe Cove, Southaven, MS 38671.

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Nobuko Wakamatsu Departments of Pathobiological and Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803.

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History

A 16-year-old 7.8-kg (17.16-lb) sexually intact female serval (Leptailurus serval) housed at the Baton Rouge Zoo was evaluated at the zoo's veterinary hospital because of recurrent hematuria, pollakiuria, and intermittent anorexia of several weeks' duration.

Clinical, Clinicopathologic, and Gross Findings

Over a 6-month period, the hematuria became refractory to treatment. Urinalysis performed on a free-catch urine sample revealed a urine specific gravity of 1.014, 1+ proteinuria, 3+ blood, 25 to 50 RBCs/low power field (10X), and 1 to 3 WBCs/low power field (10X). Examination of a cytospin preparation of urine sediment revealed 1 to 3 epithelial cells/hpf (40X), some of which had moderate atypia including increased cytoplasmic basophilia, a variable and increased nucleus-to-cytoplasm ratio, marked anisokaryosis, rare multinucleation, and prominent nucleoli (Figure 1). After 1 week, the animal developed persistent hematuria and anorexia despite medical treatment and was euthanized by IV administration of a barbiturate solution overdose because of its poor prognosis and quality of life.

At necropsy, gross findings included transmural thickening of approximately 70% of the urinary bladder body by a pale tan-to-red, multinodular, infiltrative, poorly demarcated neoplasm measuring 3.5 × 3.0 × 0.6 cm (Figure 1). Abdominal adipose tissue was segmentally adhered to the ventral adventitial surface of the urinary bladder; the lumen of the urinary bladder was devoid of urine and scant free fluid was observed in the peritoneal cavity. No evidence to support urinary obstruction (ie, hydroureter and hydronephrosis) was observed. A yellow transparent and fluctuant paraovarian cyst (1.2 cm in diameter) was present along the cranial pole of the right ovary. Kidneys were considered grossly normal.

Figure 1—
Figure 1—

Photographs of a cytospin preparation (A) of a urine sample sediment and a segment of the urogenital tract (including the urinary bladder, uterine horns, and ovaries [B]) from an adult sexually intact female serval (Leptailurus serval) that was evaluated because of recurrent hematuria, pollakiuria, and intermittent anorexia of 6 months' duration. A—Notice the cluster of pleomorphic urothelial cells in the urine sediment. These cells have moderate to marked anisokaryosis and consistently high nuclear-to-cytoplasmic ratio, features that are supportive of malignancy. Wright stain; bar = 50 μm. B—The urinary bladder is opened to illustrate the irregular, raised, poorly delineated, multinodular, tan-to-red urinary bladder mucosa. The cranial pole of the right ovary contains a paraovarian cyst. At the top right, there is a transverse section through the affected urinary bladder wall, with the lumen indicated by an asterisk. The urinary bladder wall, adventitia, and adjacent peritoneal adipose tissues are infiltrated by a poorly demarcated, moderately firm, tan mass containing chalky white granular material (mineralization).

Citation: Journal of the American Veterinary Medical Association 253, 1; 10.2460/javma.253.1.53

Formulate differential diagnoses from the history, clinical findings, and Figure 1—then turn the page→

Histopathologic Findings

At necropsy, tissue samples were collected and fixed in neutral-buffered 10% formalin, routinely processed, paraffin-embedded, sectioned at 4-μm intervals, and stained with H&E stain. The raised multinodular and poorly demarcated urinary bladder mass (Figure 1) was histologically characterized by a raised, infiltrative, unencapsulated, and moderately cellular neoplasm with segmental mucosal ulceration and extension of neoplastic cells across the muscularis into the adventitia and adjacent peritoneal adipose tissues (Figure 2). Neoplastic cells were cuboidal and columnar epithelial cells, which were arranged in acini, tubules, and trabeculae and supported by a moderate to scirrhous fibrovascular stroma (desmoplasia). Neoplastic cells had variably distinct cellular borders, a moderate amount of granular eosinophilic cytoplasm, round to oval nuclei with finely stippled chromatin, with 1 or 2 prominent centrally located magenta nucleoli. Anisocytosis and anisokaryosis were moderate, with 20 mitotic figures/10 hpf (40X). Strong cytoplasmic chromogenic immunoreactivity to cytokeratin AE1/AE3 was observed. Large areas of transmural necrosis were characterized by lakes of hypereosinophilic cellular debris. A large focus of mineralization was observed adjacent to an area of necrosis (dystrophic mineralization). Vascular invasion was not observed in the sections examined; however, multiple microscopic foci of pulmonary metastasis that had expanded alveolar septa were observed. Kidneys had mild interstitial fibrosis with associated mild tubular degeneration and atrophy. Some of these tubules contained large clear spaces within the lumens (lipid casts). Lymphoplasmacytic and histiocytic inflammation surrounded these foci. Some tubules had ruptured and released the intraluminal lipid content into adjacent interstitium, wherein there was also an accumulation of lipid-laden macrophages (lipogranulomatous inflammation). Glomeruli were evaluated with a combination of special stains including periodic acid–Schiff, Masson trichrome, and Jones methenamine silver stains. Periodic acid–Schiff and Jones methenamine silver staining were used to highlight glomerular basement membranes and Bowman's capsule. Masson trichrome staining was used to highlight fibrillar collagen. Mild mesangial expansion of glomerular tufts was observed; glomeruli otherwise appeared to be unremarkable. Gastrointestinal serosa and the splenic capsular serosa were diffusely hypertrophied, moderately indicative of mesothelial reactivity.

Figure 2—
Figure 2—

Photomicrographs of sections of the affected urinary bladder from the serval in Figure 1. A—The urinary bladder wall is transmurally expanded and disrupted by a raised, infiltrative, poorly demarcated neoplasm originating from the uroepithelium, with extension into the underlying muscularis, adventitia, and adjacent peritoneal adipose tissue (arrowheads). The mucosa is partially ulcerated (star) with large areas of intratumoral necrosis and mineralization (asterisk). H&E stain; bar = 6 mm. B—Neoplastic cells are composed of cuboidal to columnar epithelial cells arranged in a combination of acini, tubules, and trabeculae. H&E stain; bar = 120 μm. Inset—Neoplastic cells have diffuse strong cytoplasmic brown chromogenic immunoreactivity to cytokeratin AE1/AE3. Monoclonal cytokeratin AE1/AE3 immunohistochemical reaction; bar = 300 μm.

Citation: Journal of the American Veterinary Medical Association 253, 1; 10.2460/javma.253.1.53

Morphologic Diagnosis and Case Summary

Morphologic diagnosis: nonpapillary, infiltrative, urothelial carcinoma with pulmonary micrometastasis and mild, chronic, tubulointerstitial, lipogranulomatous, nephritis with interstitial fibrosis, lipid casts, tubular degeneration, and atrophy.

Case summary: urothelial carcinoma of the urinary bladder and interstitial lipogranulomatous nephritis resulting in renal and postrenal disease in a female serval.

Comments

Results of cytologic evaluation of urine sediment that include clusters of large anaplastic epithelial cells with prominent nucleoli, a high nuclear-to-cytoplasmic ratio, and anisokaryosis are often suggestive of a diagnosis of urothelial carcinoma.1,2 However, neoplastic cells cannot always be distinguished from reactive epithelial cells associated with severe cystitis, and determination of a definitive diagnosis requires histologic examination of the urinary bladder. Urothelial carcinomas of the urinary bladder are classified as papillary or nonpapillary and as infiltrating or noninfiltrating.1,2 Papillary tumors project into the lumen of the urinary bladder, whereas nonpapillary tumors often are either flat or fail to form a discrete exophytic mass. Infiltrating tumors are characterized by extension into the underlying substantia propria and muscularis, with occasional transmural involvement; on the other hand, noninfiltrating tumors do not invade the substantia propria. The likelihood of metastasis is greatest for nonpapillary infiltrative tumors, followed by papillary infiltrative tumors. Metastasis is not likely with papillary noninfiltrative tumors. Nonpapillary noninfiltrative tumors are synonymous with carcinomas in situ and are confined to the surface epithelium. Histologic features that may suggest an increased likelihood of metastasis include marked cellular atypia, prominent muscular invasion or desmoplastic response, and the presence of vascular invasion.1 Metastases to regional lymph nodes, lungs, and bones are most commonly reported, but peritoneal and cutaneous implantation has been documented.3

Taking into consideration all neoplastic processes, urothelial carcinoma represents the most common urinary bladder neoplasm of both cats and dogs with similar reported frequencies of 0.38% and 0.36%, respectively.4 Among affected dogs, females are overrepresented with a female-to-male ratio of 2:1 reported in some studies.5,6 Additionally, neutered dogs, independent of sex, are more commonly affected than are sexually intact dogs.4,5 Among cats, this predilection of urothelial carcinoma among neutered animals has not been consistent. For dogs, several breed predispositions, including Scottish Terriers, Airedales, Shetland Sheepdogs, Beagles, Collies, Wire Fox Terriers, and West Highland White Terriers have been indicated1,3,5; however, no breed predilection among domestic cats has been identified. Risk factors for development of urinary bladder urothelial carcinoma in dogs include exposure to topical insecticides and obesity; passive inhalation of smoke (so-called secondhand smoke) has not been proven to represent a risk factor as it does for humans.7 An association has been made between the administration of cyclophosphamide and development of urothelial carcinoma in the urinary bladder of dogs.1,2,7 In cattle, spontaneous tumor development in the urinary bladder is uncommon; however, supplementation of feed with bracken fern was previously shown to induce urinary bladder tumors in 20 of 30 cows within 5.3 years.8 Bracken fern contains the carcinogenic ptaquiloside, which is believed to act synergistically with bovine papillomavirus type 2 to cause neoplastic transformation. This is supported by the identification of bovine papillomavirus type-2 antigen within neoplastic lesions.9 Urothelial carcinoma has previously been identified in exotic felids, including 4 related fishing cats (Prionailurus viverrinus).10 Among those fishing cats, the major clinical sign was persistent hematuria, which was temporarily responsive to piroxicam and carboplatin treatment in 1 of the animals. Pulmonary metastasis was detected in 1 fishing cat, as was observed in the serval of the present report.10 To the authors' knowledge, urothelial carcinoma of the urinary bladder in a serval has not been previously described.

In cats, urothelial carcinoma typically affects geriatric animals; these individuals have hematuria with or without stranguria and pollakiuria, although animals may have no clinical signs at all.11 Affected cats may be evaluated because of urinary obstruction, depending on the location of the tumor and the extent of involvement of the trigone and proximal urethra.3 Abnormalities of CBCs and serum biochemical analyses, if present, are often attributable to concomitant disease or are secondary to urinary obstruction.11 Treatment options include both surgery and chemotherapeutic approaches. Partial cystectomy may be curative; however, incomplete margins, tumor recurrence, dehiscence, urinary incontinence, and urinary obstruction are common sequelae.11 In dogs with urothelial carcinoma, administration of piroxicam (a nonsteroidal COX inhibitor) resulted in a median survival time of 181 days (data from 34 dogs)12; when combined with mitoxantrone (an anthracenedione chemotherapeutic agent), median survival time was 291 days (data from 48 dogs).13 For affected animals, supportive care, pain management, and treatment of concomitant disease, such as urinary tract infection, should be addressed. Diagnostic and treatment options for the serval of the present report were limited owing to the requirement for chemical immobilization and the stress associated with such a procedure.

Clinically, the serval of the present report was initially presumed to be have chronic recurrent bacterial cystitis, a presumption supported by resolution of hematuria following multiple courses of antimicrobial treatment. Eventually the animal became refractory to antimicrobials; urinary bladder neoplasia then became the top differential diagnosis as supported by the presence of atypical epithelial cells observed on examination of the urine sediment. Serum biochemical analysis revealed azotemia (high creatinine and BUN concentrations), hyperphosphatemia, hyperkalemia hyponatremia, and hypochloremia. These findings were in part initially attributed to the serval's clinically evident dehydration and resulting prerenal disease (ie, azotemia and hyperphosphatemia). Panhypoproteinemia with a normal albumin-to-globulin concentration ratio was supportive of the clinical concern of dehydration. The immediate cause of the hyperkalemia, hyponatremia, and hypochloremia was unknown, given that the animal had no history of vomiting or diarrhea in the face of dehydration. Postmortem examination revealed extensive transmural compromise of the urinary bladder with segmental plugging of the ventral adventitial surface of the urinary bladder by peritoneal adipose tissues. Although no appreciable free abdominal fluid was identified in the abdomen at the time of necropsy, collective electrolyte abnormalities (hyperkalemia, hyponatremia, and hypochloremia) were highly suggestive of uroperitoneum. Histologically, this was further supported by the finding of generalized mesothelial reactivity of abdominal serosal surfaces, which at the very least was supportive of recent exposure of serosal surfaces to free abdominal fluid. Taken together, these findings were indicative of persistent and slow leakage of urine through the compromised urinary bladder wall.

Histologic evaluation of the kidneys revealed mild tubulointerstitial nephritis; however, inadequate urine-concentrating capability in the face of dehydration (urine specific gravity of 1.014, when one would expect a value of ≥ 1.035 in a dehydrated felid) supported concomitant renal disease, which may have played a contributory role in the electrolyte disturbances and azotemia. Lipogranulomatous inflammation has been identified in domestic cats after various types of renal insults, such as experimentally induced ischemia reperfusion injury and naturally occurring chronic kidney disease. Tubular injury and tubulorrhexis can lead to release of intraepithelial lipid into the interstitium, which incites a granulomatous inflammatory response. This inflammation can then promote further renal injury by expansion of the interstitium and compression of the peritubular capillaries.14

Acknowledgments

Dr. St. Blanc was a fourth-year veterinary student at the time of manuscript submission.

The authors received no financial support for the research, authorship, or publication of this article. The authors declare no potential conflicts of interest with respect to the research, authorship, or publication of this article.

The authors thank Dr. Shannon Dehghanpir for providing the cytologic image.

References

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