Pathology in Practice

Leah R. Stein Veterinary Diagnostic Laboratory, Veterinary Medical Center, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.
Department of Pathobiology and Diagnostic Investigation, Veterinary Medical Center, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.

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Jason Couto Department of Small Animal Clinical Sciences, Veterinary Medical Center, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.

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Dodd G. Sledge Veterinary Diagnostic Laboratory, Veterinary Medical Center, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.

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Matti Kiupel Department of Pathobiology and Diagnostic Investigation, Veterinary Medical Center, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.

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History

An 18-month-old 24.25-kg (53.35-lb) sexually intact female Rottweiler was evaluated because of bloody vulvar discharge and a suspected urinary bladder mass. The dog had persistent hematuria of at least 6 months’ duration despite multiple treatments with antimicrobials and NSAIDs. The dog had progressive weight loss and lethargy and developed a cough with wheezing during that period.

Clinical and Gross Findings

On physical examination, the dog's respiratory rate and effort were increased, and auscultation of the lungs revealed decreased lung sounds and rare wheezes during exhalation. Pulse oximetry indicated the dog had 87% to 89% oxygen saturation of hemoglobin without oxygen supplementation. Abdominal palpation elicited signs of mild pain; there was a large, firm mass in the caudal portion of the abdomen. There was bloody, purulent discharge dripping from the dog's vulva. The dog was able to void its urinary bladder with mild stranguria.

Abdominal ultrasonography revealed a large (approx 11 × 4.8-cm) heterogeneous mass in the caudal portion of the abdomen; it was not possible to definitively determine whether the mass was associated with the urinary bladder wall, uterus, or left medial iliac lymph node. The right medial iliac lymph node was enlarged. The right kidney contained a slightly ovoid, isoechoic nodule in the cortex that measured 2.5 × 2.2 cm. Ultrasonography of the thorax revealed multiple hypoechoic masses. Additionally, the thoracic and abdominal cavities contained scant free fluid.

Owing to the dog's deteriorating condition and grave prognosis, euthanasia by IV administration of euthanasia solution was elected. On gross postmortem examination, the urinary bladder contained a single, large, irregularly shaped mural mass that extended from the trigone region along the ventral aspect of the bladder wall approximately halfway to the apex (Figure 1). The mass was mottled white, tan, and red; it varied from firm to soft regionally, and it invaded through the bladder wall at the level of the trigone. The lumen of the urinary bladder contained small amounts of red-tinged, mucinous fluid. Caudal abdominal lymph nodes were enlarged and firm and ranged from 1 to 5 cm in diameter. The cortex of the cranial pole of the right kidney contained a well-circumscribed, expansile, 3-cm-diameter, soft, white nodule that appeared similar to the bladder mass on cut section.

Figure 1
Figure 1

Photographs of the urinary bladder (A) and thoracic cavity (B) of an 18-month-old Rottweiler that was evaluated because of bloody vulvar discharge and a suspected urinary bladder mass. A—In the urinary bladder, there is a large multinodular mass that originates from the trigone region and fills most of the lumen. B—There are hundreds of variably sized, irregularly shaped masses covering the pulmonary, costal, and pericardial pleura and largely replacing the mediastinum and caudal lung lobes.

Citation: Journal of the American Veterinary Medical Association 258, 11; 10.2460/javma.258.11.1197

The pleural cavity contained approximately 800 mL of red-tinged, slightly opaque, watery fluid containing few scattered strands of red, lacy fibrin. The mediastinum, costal pleura, pulmonary pleura, and pericardial sac were covered by hundreds of 1-mm- to 8-cm-diameter, often coalescing, irregularly shaped nodules that were variably soft to firm, mottled white to tan to red, and often centrally umbilicated (Figure 1). Hundreds of similar nodules were scattered throughout the parenchyma of all lung lobes, largely replacing the caudal lung fields.

Histopathologic Findings

Representative regions of major organs and tissues as well as samples of the masses in the urinary bladder, lungs, and right kidney were fixed for 24 hours in neutral-buffered 10% formalin and routinely processed for histologic examination. The urinary bladder mass consisted of a poorly demarcated proliferation of highly anaplastic neoplastic cells arranged in streams and sheets supported by fine fibrovascular stroma that expanded the suburothelial stroma and infiltrated into the muscularis (Figure 2). Neoplastic cells extended up to but did not invade the overlying intact nonneoplastic urothelium. Neoplastic cells were polygonal to spindle shaped to round, had variably distinct cell borders, and contained moderate amounts of eosinophilic cytoplasm. Nuclei were pleomorphic with finely stippled to vesiculate chromatin and 1 to 2 nucleoli. Anisokaryosis was marked, and there were 22 mitotic figures/10 hpf (400×). Multifocally throughout the mass, there were large areas of necrosis surrounded by granulation tissue and fibrosis. Scattered throughout the lungs, right kidney, adrenal gland, and mediastinum were multiple, well-demarcated, expansile nodules composed of a similar neoplastic cell population associated with variable degrees of necrosis and fibrosis.

Figure 2
Figure 2

Photomicrographs of sections of the urinary bladder mass (A) and a metastatic pulmonary mass (B) from the dog in Figure 1. A—The suburothelial stroma is expanded by a proliferation of highly anaplastic, plump polygonal to spindle-shaped cells arranged in sheets that are distinct from the overlying nonneoplastic urothelium. H&E stain; bar = 50 μm. B—Anaplastic neoplastic cells have strong cytoplasmic immunoreactivity for desmin, as indicated by the brown labeling, which confirms muscle origin of the cells. Desmin-specific immunohistochemical reaction with hematoxylin counterstain; bar = 50 μm.

Citation: Journal of the American Veterinary Medical Association 258, 11; 10.2460/javma.258.11.1197

Sections of the masses in the lungs were immunohistochemically assessed for cytokeratin-7 (CK7 epithelial marker), CD18 (round cell marker), and desmin (muscle marker). The neoplastic cell population was not immunoreactive for CD18 or CK7 but had strong cytoplasmic labeling for desmin (Figure 2).

Morphologic Diagnosis and Case Summary

Morphologic diagnosis and case summary: botryoid rhabdomyosarcoma of the urinary bladder with extensive metastasis in a dog.

Comments

The combined clinical, gross, histopathologic, and immunohistochemical findings of the case described in the present report were consistent with a primary botryoid rhabdomyosarcoma of the urinary bladder with extensive metastasis in a dog. This case represented a unique challenge to clinicians because neoplasia in young animals is uncommon, more so with such substantial metastatic disease.

Although very rare, botryoid rhabdomyosarcomas develop most often in young, female, large-breed dogs that are < 2 years of age.1,2,3 These neoplasms most frequently develop at the trigone of the urinary bladder and project into the lumen as a polypoid, grape-like (ie, botryoid) mass, which can fill the bladder lumen and obstruct the urethra or ureters.3 Clinical signs stem from such obstructions and irritation to the bladder mucosa; affected dogs have dysuria, stranguria, and hematuria and occasionally hydroureter or hydronephrosis.3,4 Such signs can be evident for weeks, and affected dogs are often initially treated for cystitis before the tumor is identified.3,5 Concurrent hypertrophic osteopathy, which was not observed in the dog of the present report, has been described for dogs with urinary bladder rhabdomyosarcomas5 but has also been identified in dogs with renal urothelial carcinomas.6

Dogs with botryoid rhabdomyosarcomas have a poor prognosis. Many dogs are euthanized at or soon after the time of the initial diagnosis because of tumor-related complications.7,8 The infiltrative nature of the tumor makes complete resection difficult, and in the few reported cases of surgical intervention, dogs were euthanized soon after the procedure because of either local recurrence or postoperative metastasis.4,7,9 There is a single case report10 of remission in a 10-month-old sexually intact male Labrador Retriever with botryoid rhabdomyosarcoma that was treated aggressively with chemotherapy following early surgical intervention. Metastasis of botryoid rhabdomyosarcoma is considered exceedingly rare, which may be due in part to owners electing euthanasia of affected dogs in early stages of the disease prior to the development of metastases.1 There are few case reports4,8 that document metastasis of botryoid rhabdomyosarcomas to locations outside of the urinary bladder. One botryoid rhabdomyosarcoma in a 2-year-old sexually intact female Golden Retriever was associated with widespread metastasis to the retroperitoneum, reproductive tract, kidneys, liver, lungs, and abdominal and thoracic lymph nodes.8 Another tumor in an 8-month-old, male crossbred Labrador Retriever metastasized to the prostate, kidneys, inguinal lymph nodes, mesentery, liver, lungs, mediastinum, heart, and abdominal, intercostal, cervical, and quadriceps femoris muscles.4 The pattern of metastasis and the gross appearance of these previously reported metastatic lesions parallel those observed in the dog of the present report. Treatment options were limited for the dog of the present report because of its severe metastatic spread and poor clinical status. In veterinary medicine, treatment of soft tissue sarcomas with doxorubicin and other agents, such as ifosfamide, is associated with a 10% to 30% overall response rate (in terms of the extent of gross disease), but such treatment does not increase survival time in human or animal patients without control of the primary tumor (locoregional control), especially in the presence of metastatic disease.11 For the dog of the present report, chemotherapy was discussed with the owners but was not attempted.

On the basis of the unusual signalment of the case described in the present report, several differential diagnoses were considered during the clinical, postmortem, and histologic examinations. Results of routine clinicopathologic analyses, urinalysis and urine culture, and abdominal radiography were used to exclude common causes of lower urinary tract disease, such as urolithiasis and urinary tract infection. Abdominal ultrasonographic findings excluded the less common causes of persistent urinary tract signs in young animals, including congenital abnormalities such as a hypoplastic vulva or ectopic ureters, but was highly suggestive of metastatic disease.12 Although neoplasia is generally a disease of older patients, urogenital neoplasia, including urothelial (transitional cell) carcinoma and botryoid rhabdomyosarcoma, should always be a differential diagnosis for any dog with chronic urinary tract signs, even at a young age. On postmortem examination of the dog of the present report, the size and location of the primary mass in the urinary bladder was suggestive of urothelial carcinoma. Urothelial carcinomas commonly develop at the trigone of the bladder and have a high rate of metastasis, which occurs most frequently in regional lymph nodes and the lungs. The distribution of the masses within the thoracic cavity as well as the degree of fibrosis and frequent central umbilication of the masses were most suggestive of carcinomatosis and further supported the presence of a primary urothelial carcinoma. Interestingly, on histologic examination, there were no dysplastic or neoplastic changes within the intact urothelium and the neoplastic proliferation did not involve the urothelium, making the gross presumption of urothelial origin of the mass less likely. The arrangement of neoplastic cells in sheets and the location of the primary mass were instead indicative of a sarcoma but, in many areas, the neoplastic cells appeared individualized, raising some concerns for a round cell neoplasm.

Immunohistochemical analyses were essential in reaching an accurate diagnosis for the case described in the present report. Often in a diagnostic setting, rhabdomyosarcomas in general are diagnosed as anaplastic sarcomas or undifferentiated sarcomas or are categorized as high-grade soft tissue sarcomas without further differentiation owing, in part, to the marked variation in their gross and histopathologic morphologies.9 Botryoid rhabdomyosarcomas are known for their poor cellular differentiation, making histologic diagnosis especially challenging. They are composed of undifferentiated myotube cells that proliferate in the submucosa and are separated from the urothelium by a distinct layer of connective tissue.1,2,3,9 Neoplastic myotube cells can be spindle shaped to stellate to fusiform or pleomorphic and often lack the cross striations classically seen in other types of rhabdomyosarcoma. Although the age of the dog of the present report and some of the histopathologic features suggested a botryoid rhabdomyosarcoma, the marked anaplasia of the neoplastic cells precluded a final diagnosis on the basis of histopathologic findings alone. Immunohistochemical analyses allowed for the exclusion of an epithelial or round cell origin of the mass; importantly, immunoreactivity of the neoplastic cells for the muscle-specific marker desmin confirmed a diagnosis of botryoid rhabdomyosarcoma.

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