A case of canine urothelial carcinoma of the urinary bladder with skull and skeletal metastases

Abstract

Canine urinary bladder neoplasia is uncommon, representing less than 1% of canine neoplasms. Amongst cases of urinary bladder neoplasia in dogs, primary urothelial carcinoma is the most frequent. Urothelial carcinomas are malignant invasive tumours which tend to be slow growing and metastasise late. However, the metastatic rate is high, with approximately 50% of cases developing metastases typically to the regional lymph nodes and lungs. Skeletal metastases are rare, with the most common reported sites being the femur and the vertebrae. Metastases to the skull are even rarer, with only a few previously documented cases in dogs. This report describes a case of primary urothelial carcinoma in the urinary bladder of a dog, with widespread metastases, including to the skull. The dog presented for chewing difficulties and limping of the left hindlimb, with large firm masses found on the skull and the left tibiotarsal joint. A necropsy revealed the masses on the head and left tibia were metastatic carcinomas, the latter site also having invaded into the tibiotarsal joint. Additional carcinomas of similar cellular morphology were found in the urinary bladder, ribs, skin and lungs. Neoplastic cells contained cytoplasmic Melamed‐Wolinska bodies, a characteristic feature of urothelial carcinomas. Collectively, the findings are suggestive of a primary urinary bladder urothelial carcinoma with widespread metastases, including to rarely documented sites, such as the parietal bone of the skull, left tibia, left tibiotarsal joint and the ribs. This represents the third documented case of skull metastases from a urothelial carcinoma in a dog.

Abbreviations

BID

Bis in die

ALP

alkaline phosphatase

CT

computed tomography

CUP

carcinoma of unknown primary origin

GGT

Gamma‐glutamyl transferase

M‐WB

Melamed‐Wolinska bodies

MMM

masticatory muscle myositis

PU/PD

polyuria/polydipsia

PAS

periodic acid‐Schiff

RI

reference interval

VPDS

veterinary pathology diagnostic services

Urothelial carcinomas, also known as transitional cell carcinomas, are invasive malignant neoplasms that arise from the urothelial cells lining the urinary system, including anywhere from the renal pelvis to the urethra, but most often developing in the urinary bladder. ¹ , ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ Urinary bladder urothelial carcinomas occur most frequently in dogs, cats and cattle, and uncommonly in other species such as horses, sheep, goats and pigs. ¹ , ² , ¹⁴ Urothelial carcinoma is also observed in humans with a relatively high incidence, particularly amongst males. ³ , ¹³ Whilst neoplasia of the urinary bladder is uncommon in dogs, representing less than 1% of canine neoplasms overall, the most frequent primary urinary bladder neoplasm in canines is the urothelial carcinoma. ¹ , ² , ⁴ , ⁵ , ⁶ , ⁷ , ⁹ Most dogs with urothelial carcinoma of the bladder present with signs of lower urinary tract disease including haematuria, stranguria, dysuria and pollakiuria. ¹ , ⁹ , ¹⁰ Scottish terriers are markedly overrepresented amongst reported cases. ¹

Approximately 50% of canine urothelial carcinomas metastasise, typically to the regional lymph nodes and the lungs. ¹ , ² , ⁶ Uncommonly, urothelial carcinomas can metastasise to the skeletal system, with the vertebrae and femur the most common reported sites in dogs. ⁵ , ¹⁰ Metastases to the skull are exceptionally rare, with only two previously documented cases of skull metastases of a urothelial carcinoma in dogs to date. ⁵ , ⁸ Cutaneous metastasis is similarly a rare event, ⁶ which does include needle‐tract implantation of neoplastic cells into the abdominal wall, a rare but recognised complication of needle aspirates taken from bladder urothelial carcinomas. ¹¹ , ¹⁵

The histological diagnosis of urothelial carcinoma is usually straightforward and readily recognised, especially when Melamed‐Wolinska bodies (M‐WB) are seen; these are unique and characteristic cellular features of urothelial carcinomas. ¹ Due to this distinctive feature of urothelial carcinomas, the detection of M‐WB both on histology and cytology greatly enhances the ability to recognise and diagnose this specific neoplasm. ¹ , ¹²

This report describes a case of primary urothelial carcinoma in the urinary bladder of a dog with widespread metastases to the skull, left tibiotarsal joint and left tibia, ribs, skin and lungs.

Clinical features

History and clinical findings

An 11‐year‐old female spayed Cavoodle dog presented for difficulties with chewing her food and polyuria, polydipsia (PU/PD) and stranguria. On physical examination, most of her teeth were coated with moderate amounts of calculus with associated gingivitis. Serum biochemistry revealed mild hyperglobulinaemia (46 g/L; reference interval [RI] 25–45). Initially, periodontal disease was suspected as the cause of the chewing difficulties and the dog was scheduled for a dental scale and polish procedure under general anaesthesia. Further diagnostic investigation into the PU/PD and stranguria was declined by the owner at this time. The patient's jaw was difficult to open under anaesthesia during the dental procedure, and after recovery from the procedure, attempts to open the dog's jaw resulted in a pain response. Two muscle biopsies were taken from the left and right temporalis muscles and submitted for histological evaluation. Microscopically, there was polyphasic mononuclear myositis and attempts at muscle regeneration. Collectively, this appeared to be suggestive of masticatory muscle myositis (MMM), although this clinical diagnosis was not confirmed serologically by measuring type 2 M antibody titres due to financial constraints. The dog was treated with prednisolone (1 mg/kg bis in die (BID), tapered to 0.72 mg/kg BID after 1 month) and azathioprine (1.8 mg/kg every other day) for a presumptive diagnosis of masticatory myopathy, with improvement in chewing reported by the owner. The PU/PD reportedly became more frequent, which was suspected to be a side effect of the prednisolone. An ultrasound‐guided cystocentesis over the ventral abdomen was performed; no significant abnormalities were detected on wet‐mount sediment examination, and no growth was observed on routine aerobic bacterial culture at a commercial laboratory. No obvious masses in the urinary bladder were observed during the urinary bladder ultrasound. Whilst the lower urinary tract signs persisted, referral for further abdominal imaging was declined.

Two months later, the dog presented for a left hindlimb lameness and reportedly, the lower urinary tract signs were still present as well. Haematology and biochemistry revealed a non‐regenerative normocytic normochromic anaemia (0.34 L/L; RI 0.373–0.617), lymphopaenia (0.56 × 10⁹/L; RI 1.05–5.10), low creatinine (39 μmol/L; RI 44–159), hypochloraemia (106 mmol/L; RI 109–122) and increased alkaline phosphatase (ALP) (690 U/L; RI 23–212) and gamma‐glutamyl transferase (GGT) (37 U/L; RI 0–11). Marked firm swellings were found over the cranium, in the area where the original muscle biopsies were taken and the left hind tibiotarsal joint. Radiographs of the head and hock showed large proliferative osseous lesions at both sites with associated degenerative changes and osteolysis (Figure 1A,B). A biopsy was taken from the left hindlimb swelling and a metastatic carcinoma of unknown primary origin (CUP) was diagnosed. The left hindlimb lameness progressed to the point where the dog almost became nonweight bearing on the limb resulting in marked ambulatory impairment. Due to the continued clinical deterioration of the dog, she was eventually euthanised with intravenous pentobarbitone sodium and submitted for a postmortem examination.

Figure 1.

Lateral radiographs of the head and left hindlimb of a dog with metastatic urothelial carcinoma. (A) Left lateral view of the head; white arrow shows a large proliferative lesion on the dorsal cranium with associated degenerative and osteolytic changes. (B) Lateral radiograph of the left hindlimb; the white arrow shows a large proliferative lesion at level of the distal tibia with associated new bone formation and osteolysis.

The consent process included both a signed consent form for the postmortem at The University of Sydney and verbal consent for the case findings to be shared with the scientific community to benefit other beloved pets.

Gross findings

A necropsy was performed at the Veterinary Pathology Diagnostic Services (VPDS), Sydney School of Veterinary Science, The University of Sydney. The most significant gross findings were masses and nodules identified in the urinary bladder mucosa, bones of the calvarium and ribs, the left hindlimb and tibiotarsal joint space and on the ventrolateral abdominal skin (Figure 2).

Figure 2.

Gross necropsy findings from a dog with metastatic urothelial carcinoma. (A) Urinary bladder mucosa with multifocal to coalescing, yellow, firm nodules at the apex and trigone regions (black arrows). (B) Calvarium with large bilateral multilobulated firm masses involving the left and right parietal bones. Black arrows point to the masses. (C) Left tibiotarsal joint with a firm prominent irregular swelling (black arrow). (D) Opened left tibiotarsal joint with neoplastic invasion into the joint space. Black arrows show the inner surface of the joint capsule lined by an irregular poorly demarcated mass. (E) Left 3rd rib with an irregular hard mass. Black arrow points to the mass. (F) Ventrolateral abdominal skin with a firm subcutaneous mass (black arrow).

The urinary bladder mucosa was regionally thickened at the apex (25 × 15 × 5 mm) and circumferentially in the trigone area (25 × 20 × 5 mm) by multifocal to coalescing, yellow, slightly firm nodules (Figure 2A). Protruding from the exterior surface of the calvarium was a multilobulated, irregular, firm mass (80 × 65 × 30 mm) involving the left and right parietal bones of the skull (Figure 2B). Over the cranial aspect of the left hindlimb tibiotarsal joint, there was a firm, pale irregular swelling (40 × 35 × 35 mm; Figure 2C). The mass protruded cranially from the joint capsule and lined most of the inner surfaces of the joint capsule (Figure 2D). The internal surface of the left 3rd rib had an irregular hard nodule (15 × 13 × 6 mm; Figure 2E). Similar smaller nodules, approximately 10 mm in diameter, were also present on the internal surfaces of the ventral right 3rd and 4th ribs. The ventrolateral abdominal skin had a 10 mm diameter, slightly raised, off‐white, well circumscribed, firm nodule that was not associated with the mammary glands (Figure 2F).

A representative set of tissues was collected and fixed in 10% neutral buffered formalin for histopathology and processed routinely.

Microscopic findings

Histological examination of the urinary bladder revealed a poorly demarcated, unencapsulated, infiltrative, multinodular carcinoma that replaced the normal urothelium and invaded into the deeper propria‐submucosa (Figure 3A). Neoplastic cells in the carcinoma were arranged in nests. Lymphovascular invasion was observed. The other masses on the parietal bones of the skull, left tibiotarsal joint and distal tibia, the left 3rd rib and the ventral abdominal skin were consistent with carcinomas of similar cellular morphology (Figure 3B,C). Multifocal nodules consisting of similar neoplastic cells were also observed in the lungs. Neoplastic cells in all the aforementioned sites contained varying numbers of large intracytoplasmic vacuoles occasionally with eosinophilic globular material (Figure 3D–F). These cytoplasmic bodies stained positive with a periodic acid‐Schiff (PAS) stain, consistent with M‐WB, a characteristic cellular feature of urothelial carcinomas (Figure 4A,B). Coagulative myonecrosis was observed in representative histological sections of the masseter and temporalis muscles.

Figure 3.

Photomicrographs of the masses from the urinary bladder (A, D), skull (B, E) and the left 3rd rib (C, F). (A) Low‐power photomicrograph of the urinary bladder mass which is poorly demarcated and unencapsulated, replacing the normal urothelial lining and invading into the underlying propria‐submucosa. The black vertical bar indicates the region of the urothelial carcinoma and the black arrows show nests of neoplastic cells invading into the underlying propria‐submucosa. (B) Low‐power photomicrograph of the skull mass showing nests of similar neoplastic epithelial cells invading into the bone, accompanied by a dense fibrous stroma (desmoplasia). The black arrow shows the nests of neoplastic epithelial cells. (C) Low‐power photomicrograph of the rib mass showing nests of similar neoplastic epithelial cells invading into the bone. (D) High‐power photomicrograph of the urinary bladder mass showing the neoplastic epithelial cells containing clear cytoplasmic vacuoles with pink globules (Melamed‐Wolinska bodies [M‐WB]) (black arrows). (E) High‐power photomicrograph of the skull mass with nests of invasive neoplastic epithelial cells. Black arrows show the M‐WB. (F) High‐power photomicrograph of the rib mass with nests of neoplastic epithelial cells. Black arrows show the M‐WB.

Figure 4.

Photomicrographs of the urinary bladder mass (A) and the skull mass (B) stained with periodic acid‐Schiff (PAS) stain to highlight the cytoplasmic Melamed‐Wolinska bodies (M‐WB) in a dog with metastatic urothelial carcinoma. Black arrows point towards the cytoplasmic globular M‐WB, stained dark purple‐pink.

Collectively, the histological findings indicated that the primary tumour was a urothelial carcinoma of the bladder that had metastasised to the bones, skin and other sites including the lungs.

Discussion

This report describes an exceptionally rare case of skull and skeletal metastases from a primary urothelial carcinoma of the urinary bladder in a dog. This represents the third documented case of skull metastases from a urothelial carcinoma in dogs. ⁵ , ⁸ Other rare metastatic sites in this case included the left hock, the ribs and skin. ⁵ , ⁶ , ¹⁰ The discussion which follows will focus on multiple key questions from this case: (1) What is the typical clinical presentation of urothelial carcinoma? (2) Were there any potential links between the original temporalis myositis diagnosis and the skull metastases? (3) With the benefit of hindsight, what clinical decisions may have improved the diagnostic accuracy for this case? (4) Are there potential underlying risk factors that may have predisposed this dog to the development of urothelial carcinoma?

Urothelial carcinomas are the most common neoplasia of the bladder of domestic animals, generally carrying a poor prognosis, as most are high grade at the time of diagnosis. ¹ , ² , ⁹ High‐grade invasive urothelial carcinomas are amongst the most aggressive malignant neoplasms in domestic animals, and death typically occurs from the effects of metastases and cancer cachexia. ¹ , ⁹ Reasons for euthanasia of dogs with urothelial carcinomas are most commonly related to local progression usually due to partial or complete urinary obstruction and/or the effects of metastases. ⁹ The majority of urothelial carcinomas in dogs result in concurrent signs of lower urinary tract disease including haematuria, stranguria, dysuria and pollakiuria. ¹ , ⁹ , ¹⁰ This dog did exhibit signs of PU/PD and stranguria throughout the clinical course, and following administration of prednisolone, the PU/PD reportedly became more frequent. However, at the time, urinalysis including ultrasound imaging of the urinary bladder, urine culture and sediment examination did not reveal overt abnormalities nor obvious masses in the urinary bladder. Therefore, the increased frequency of PU/PD was considered to be a side effect of the prednisolone and referral for advanced abdominal imaging was declined. Ultimately in hindsight, and with the assumption of no constraints to diagnostics, further imaging of the urinary tract at both the time of the initial presentation and following the administration of prednisolone, including pursuing specialist level or advanced imaging and cystourethroscopy, may have been helpful for the detection of the urothelial carcinoma earlier in the clinical course.

The typical sites of metastases are the lungs and regional lymph nodes, whereas bones, joints and skin are rarely involved. ¹ , ² , ⁵ , ⁶ , ⁸ , ¹⁰ The usual routes of metastasis include lymphovascular and peritoneal implantation. Pulmonary metastases were observed in this case. There is also a known but uncommon phenomenon of needle‐tract implantation of urothelial carcinoma into the abdominal wall as a complication of fine needle aspiration of the neoplasm. ¹¹ , ¹⁵ Whilst a cystocentesis was performed in this case and there was a cutaneous metastatic nodule over the ventrolateral abdomen, needle‐tract implantation was considered unlikely and true cutaneous metastasis was favoured due to two reasons. Firstly, the original cystocentesis was performed directly over the ventral abdomen, whereas the cutaneous metastatic nodule was found on the ventrolateral side. Secondly, the neoplastic urothelial carcinoma cells in the cutaneous nodule were localised to the dermal layer without overt involvement of the underlying abdominal wall musculature, the latter being a feature of needle‐tract implantation. ⁶

The association between the earlier diagnosis of temporal muscle myositis and the skull metastases detected later warrants discussion and speculation. As mentioned previously, MMM was originally suspected based on the histological results correlated with the patient's difficulty chewing and opening the jaw. However, this clinical diagnosis was not confirmed by demonstrating elevated type 2 M antibody titres, thus precluding a definitive diagnosis of this condition. Furthermore, MMM typically affects young dogs between 1 and 3 years of age, whereas in this case, this dog was 11 years old making this patient signalment atypical for this condition. ¹⁶ We posit that the originally diagnosed inflammatory temporal myositis may be either (1) an unconfirmed atypical masticatory myositis; (2) localised inflammation and muscle injury due to the effects of early but undetected urothelial carcinoma metastasis; and/or (3) a paraneoplastic effect. Inflammatory myositis has been described as a paraneoplastic syndrome observed with canine lymphomas and thymomas. ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ It is thought that in some cancers, neoplastic cells may exhibit common autoantigen expression with muscle tissue, resulting in immune targeting of both neoplastic cells and host myocytes. ²⁰ Interestingly, a preneoplastic inflammatory myositis was previously described in Boxer and Newfoundland dogs. ¹⁷ , ²⁰ These dogs were initially diagnosed with generalised inflammatory myositis and then after several months later, were diagnosed with lymphoma and other round cell tumours including a plasmacytoma and anaplastic round cell tumour. ¹⁸ , ²⁰ This preneoplastic phenomenon was not considered a likely cause of the temporal myositis in this case, as the phenomenon describes neoplasia arising from an immune‐mediated myositis, whereas in the current case described, it is obvious that the skull neoplasia was metastatic urothelial carcinoma from a primary tumour in the urinary bladder. The second theory regarding localised inflammation and muscle injury due to the effects of an early but undetected metastasis may be supported by the observation of coagulative myonecrosis in representative histological sections of the temporal and masseter muscles postmortem. Speculatively, a tumour embolus may have occluded blood flow to the muscles, resulting in ischaemia and coagulative myonecrosis, given the muscles' proximity to the parietal bone metastasis. With the benefit of hindsight and assumption of no constraints to further diagnostics, measurements of type 2 M antibody titres would have been helpful to support the previously discussed theories with regard to the myositis. In addition, antemortem ultrasound or contrast‐enhanced computed tomography (CT) of the temporalis and masseter muscles may have been helpful adjunct diagnostic tests, potentially permitting identification of intramuscular metastatic foci, if they were present. ²¹ , ²²

Urothelial carcinomas in domestic animals can be associated with carcinogens. ¹ , ² , ¹⁴ One of the most well‐established carcinogens in veterinary medicine that exerts tumorigenic effects in the urinary bladder is bracken fern (Pteridium aquilinium). ¹⁴ , ²³ , ²⁴ , ²⁵ The chronic ingestion of bracken fern in cattle is associated with the condition enzootic haematuria, and the development of multiple urinary bladder neoplasms including urothelial carcinomas, squamous cell carcinomas, adenomas, papillomas, haemangiomas, haemangiosarcomas, fibromas, fibrosarcomas and leiomyosarcomas. ¹ , ² , ¹⁴ , ²³ , ²⁴ , ²⁵ In canines, certain risk factors and carcinogens have been identified experimentally or epidemiologically as being associated with the development of urothelial carcinoma. ¹ , ² , ¹⁴ , ²⁶ , ²⁷ These include topical insecticides, exposure to marshes contaminated by antimosquito sprays, industrial chemicals (such as 2‐naphthylamine and benzidine), tryptophan metabolites (ortho‐aminophenol), cyclophosphamide, aromatic hydrocarbons, intermediate components of aniline dyes, tobacco smoke, chronic irritation, foreign bodies, female sex, obesity and breed predispositions (such as Scottish terriers). ¹ , ² , ¹⁴ , ²⁶ , ²⁷ It is theorised that female dogs have reduced frequency of urination compared to male dogs leading to increased contact time of potential urinary carcinogens with the bladder epithelium. ¹ In addition, urine tends to have a longer contact time with the bladder epithelium at the trigone area, potentially explaining why most urothelial carcinomas in the urinary bladder develop in the trigone. ¹ , ¹⁴ Interestingly, a recent study found that dogs with urothelial carcinoma were more likely to swim in a household chlorinated swimming pool compared to control dogs. ²⁶ The same study also found that dogs with urothelial carcinomas had more than fourfold higher municipal water concentrations of chlorination byproducts such as trihalomethanes. ²⁶ Overall however, without further toxicologic examination and thorough evaluation of the dog's home to identify possible environmental and/or chemical carcinogenic risk factors, it is difficult to draw strong conclusions in the case described with regard to possible predisposing risk factors. Nevertheless, it appears that there is a known risk association between numerous industrial and environmental chemicals, and the development of canine urothelial carcinomas, particularly in female dogs and certain breeds such as Scottish terriers.

Conclusion

In summary, this report describes a case of metastatic urothelial carcinoma in a canine with rare skeletal and cutaneous metastases. This case represents the third documented case of skull metastases from a urothelial carcinoma in a dog globally, in addition to other rarely documented metastatic sites including the left tibia, left tibiotarsal joint, the ribs and skin. ⁵ , ⁶ , ⁸ , ¹⁰ Therefore, whilst a rare phenomenon, a metastatic urothelial carcinoma should be a consideration for patients with urinary bladder masses and concurrent skeletal masses with or without associated lameness.

Conflicts of interest and sources of funding

The authors declare no conflicts of interest or sources of funding for the work presented here.

Data availability statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.