Metastatic transitional cell carcinoma in proximal humerus of a dog

Case description

Upon presentation to OVC, the dog had a moderate to severe lameness on the right forelimb and was intermittently weight bearing on this limb. Orthopedic examination revealed pain on palpation of the caudoproximal aspect of the shoulder joint, the proximal humerus, and upon extension of the shoulder joint. The remainder of the complete physical examination including a digital rectal examination revealed a body condition score of 4/5 with no other abnormalities. Serum chemistry panel revealed moderate elevation in creatinine kinase of 1959 U/L [reference range (RR): 40 to 225 U/L]. The complete blood (cell) count (CBC) revealed mild neutrophilia of 15.47 × 10⁹/L (RR: 2.9 to 10.6 × 10⁹/L) consistent with a stress leukogram.

Orthogonal radiographs of the right shoulder revealed a poorly marginated area of decreased opacity and a small amount of cortical lysis in the caudal aspect of the humeral head (Figure 1). At the proximo-medial aspect of the humerus there was evidence of moth-eaten lysis and the trabecular bone was coarse. Adjacent to this lesion there was an area of mineralization in the soft tissues that had irregular margins. The conclusion was that there was a possible aggressive bone lesion of the proximal right humerus. Based on the soft tissue involvement in the proximal shoulder, an ultrasound examination of the right shoulder and axillary regions was performed and no abnormalities were noted.

Due to suspected neoplastic process in the bone and a history of a thoracic mass, three-view thoracic radiographs were taken. The radiographs revealed presence of a 4-cm spherical right cranial lung lobe mass. The differentials for this mass included neoplasia (primary or metastatic), granuloma and, less likely, an abscess.

Magnetic resonance imaging (MRI) of the caudal cervical and shoulder regions was performed (Figure 2). Caudal to the humeral head there was a poorly defined lesion in the origin of the triceps muscle and the surrounding fascia. This lesion was hyperintense to muscle on the T2 weighted images, isointense to muscle on the T1 weighted sequences and had strong contrast enhancement. The caudoproximal cortex of the humerus, immediately adjacent to this lesion, was thin. There was also a focal lesion in the marrow of the caudal humeral condyle. This lesion had high signal intensity on the STIR sequence, was hypointense to marrow on the T1 weighted sequence, and had mild contrast enhancement. A focal nodule in the right cranial lung lobe was also noted. The differential diagnoses based on these findings included inflammation or infection of the accessory head of the triceps, enthesopathy of the humerus, and neoplasia.

Bone marrow aspirates and core samples were obtained from the right proximal humeral head using a Jamshidi needle (bone marrow aspiration biopsy needle, 11G × 4 inches, Monoject; Tyco Healthcare, Pointe Claire, Quebec). Histologic and cytological evaluation of the bone marrow did not reveal any abnormalities other than a mild decrease in cellularity in some regions.

The patient showed no clinical improvement on fentanyl patch (Janssen-Ortho, Toronto, Ontario) and codeine phosphate (Radiopharm, Mississauga, Ontario) with restricted activity. He became non-weight-bearing lame on the right forelimb after a week of medical management. A surgical exploration and re-biopsy of the right shoulder were recommended in search of a definitive diagnosis.

The patient was routinely anesthetized and a caudolateral approach to the right shoulder revealed grey, firm abnormal tissue between muscle bundles at the proximo-caudal aspect of the humerus and inside the joint near the caudal attachment of the joint capsule. A 2- × 2-cm region of lysis of the humeral head was also detected and biopsies of both sites were obtained and submitted for histopathological examination.

Histologic examination of the biopsies revealed neoplastic epithelial cells characterized by pleomorphism, hyperchromasia, and abundant cytoplasm. Osteolysis and reactive fibroplasia were also noted. The histopathologic findings were indicative of carcinoma, and morphology suggested metastatic transitional cell carcinoma (TCC).

Based on the poor prognosis associated with metastatic TCC the owners opted for humane euthanasia. On necropsy, the prostate gland was markedly asymmetrical, with an enlarged right side 20 mm in diameter, soft, with a round smooth surface and cavitated center containing 1.5 mL of turbid fluid. The smaller left side was 8 mm in diameter with 2 raised firm 4-mm nodules protruding from the surface. Three 4-mm-diameter raised plaques were noted in the prostatic urethral mucosa. The cranial aspect of the proximal humerus, the site of the previous surgical biopsy, was noted to contain an irregularly demarcated 8- × 4-mm lytic area filled with hemorrhage immediately beneath the articular cartilage. Additionally, the right cranial lung lobe contained a well-demarcated 40-mm diameter raised, mottled white and tan nodular mass, with a friable necrotic center, and an incidental subpleural bulla was present in the right middle lung lobe.

On histopathologic examination, prostatic tissue was effaced by dense fibrous tissue containing neoplastic cells arranged in nests and tubules (Figure 3). The neoplastic cells were polygonal, 20 to 30 μm in diameter, with abundant eosinophilic cytoplasm. Some cells contained 1 to 2 μm diameter clear cytoplasmic vacuoles or more rarely larger vacuoles up to 15 μm diameter that gave a signet-ring appearance to the cells. The central round nuclei had finely stippled chromatin, 1 to 3 nucleoli, 4-fold anisokaryosis, and 3 mitoses per ten 400× fields. Plasma cells and small lymphocytes infiltrated the neoplasm. This morphology was consistent with a transitional cell carcinoma, which was confirmed by cytoplasmic immunolabeling for uroplakin in about 10% of the neoplastic cells (data not shown).

The humeral lesion contained a morphologically similar population of neoplastic cells that formed clusters or nests in marrow spaces adjacent to bone trabeculae that demonstrated weak uroplakin labelling, consistent with a metastatic lesion (Figure 3). The pulmonary mass had undergone extensive necrosis complicating interpretation; however, the arrangement of neoplastic cells was consistent with a low-grade papillary adenocarcinoma. This lesion was considered distinct from the prostatic and humoral tumors because of the morphologic differences, low grade of the pulmonary lesion and its prolonged clinical course (approximately 1 year) which is inconsistent with the aggressive clinical course of transitional cell carcinomas. A unilateral parathyroid adenoma was also present.

Discussion

The TCC in this case likely originated from the adjacent prostatic urethra, invading the prostate gland and metastasizing to the humerus. TCC is a highly metastatic and malignant tumor that often metastasizes to the local lymph nodes as well as distant sites (1). This case was unique in that the presenting clinical sign was of right forelimb lameness, and there were no other systemic indications for TCC. Therefore, the diagnostic work-up was focused on determining the etiology of the humeral lesion. The commonly utilized diagnostic modalities for bony and soft tissue abnormalities of the shoulder joint and its surrounding structures include plain radiography, arthrography, ultrasonography, magnetic resonance imaging (MRI), computed tomographic scan (CT-scan), and bone scan (2–8). The radiographic appearance of an aggressive bony lesion can be osteoblastic or osteolytic which can occur with variable frequencies in osteomyelitis, primary or metastatic tumors. This renders radiography an unreliable modality in making a diagnosis of the type of tumor based on the radiographic appearance alone (9). Plain radiography and arthrographs may also provide only limited information (6). Ultrasound examination of the shoulder has proved to be a very useful diagnostic tool, but it may be limited in examining deeper structures due to bone interference (3–5). Computed tomography is very useful in evaluating bone (10), but the differentiation of surrounding soft tissue structures with similar densities remains challenging (8). Magnetic resonance imaging provides a high contrast, multiplanar depiction of anatomy and can be useful in the diagnosis of canine shoulder lameness (11,12). In this case due to the radiographic evidence of soft tissue abnormalities adjacent to the proximal humerus lesion and inconclusive results of ultrasound examination of the region, an MRI study of the shoulder was performed that further delineated the soft tissue abnormalities. Magnetic resonance imaging provides excellent contrast resolution for musculoskeletal lesions that cannot be detected with other imaging modalities. In particular MRI is being used with increasing frequency to evaluate shoulder lamenesses (13).

An aggressive bony lesion similar to the one observed in this case, presenting as a source of lameness, can be due to a neoplastic or an infectious process. The neoplastic lesions can be divided into primary or metastatic tumors. Primary bone tumors are the most common neoplastic lesions in dogs (9) and the most common malignant primary bone tumors in dogs are osteosarcoma (85%), chondrosarcoma (55% to 10%), fibrosarcoma (< 5%), and hemangiosarcoma (< 5%) (14). Cytologic or histopathologic evaluation of biopsies from bony lesions is the definitive method of diagnosing the tumor type (15). In this case, the definitive diagnosis of transitional cell carcinoma was based on histological examination of surgically obtained biopsies. The anatomic site of the bony lesion can not be used to differentiate osteomyelitis from metastatic bone lesion. Osteomyelitis is associated with extensive soft tissue swelling and can involve multiple bones; however, the involved bones are usually adjacent to one another (15). This case had an isolated bony lesion and there was no palpable soft tissue swelling surrounding the shoulder area.

Metastatic bone tumors can be unique in their presentation and can be the primary or secondary clinical sign of the disease. Pain or lameness related to bone lesions may be the presenting clinical signs in up to 79% of dogs with metastatic skeletal tumors (16). Previous studies have shown some differences in signalment and anatomic distribution of the skeletal lesions in dogs with metastatic skeletal carcinomas compared to those with primary bone sarcomas (9,16). Small breed dogs appear to have a higher risk of presenting with metastatic skeletal carcinomas compared to primary bone tumors (16). The metastatic bone lesions are most frequently observed in the ribs, vertebrae, humerus, and femur (9,16). The metastatic skeletal lesions in areas distal to the elbow and the stifle joints appear to be less frequent (11%, and 16% in previous reports) compared with primary bone tumors (9,16,17). Primary bone tumors usually involve a single bone, while metastatic bone tumors can involve multiple bones (9,16).

The most frequent primary tumor sites in dogs with skeletal metastasis are mammary gland, liver, prostate, and lung (9,15,17–19). In 1 case series, the primary tumor could not be identified in 58% of cases (16). In humans, carcinomas of unknown primary site are well-documented and account for about 3% to 5% of metastatic carcinomas (20,21).

Canine TCC is the most common form of urinary tract neoplasia in the dog and comprises 1.5% to 2% of all canine cancers. The trigone of the bladder appears to be affected in the majority of canine TCC cases (1,22,23). The etiology of TCC in dogs is considered multifactorial and the known risk factors include sex (increased risk for females and neutered dogs of both sexes), age (increased risk for older patients), exposure to topical and field insecticides, obesity, cyclophosphamide, and breed predisposition (for example, Scottish terrier) (24–27).

Common presenting clinical signs in TCC patients include hematuria, stranguria, and other forms of dysuria, lethargy, weight loss, and less commonly, lameness caused by bone metastasis or hypertrophic osteopathy (1,28,29). Physical examination findings usually include urethral masses palpable by rectal or vaginal examination, palpable abdominal masses, prostatomegaly, distended bladders, or evidence of abdominal pain. The rectal examination that was performed initially in our patient had revealed no pain or palpable mass or asymmetry. This may have been due to the localization of the tumor within the prostatic tissue making it unreachable by rectal palpation. In a study of 115 dogs with bladder and lower urinary tract tumors, 30% of dogs had no physical examination abnormalities at the time of presentation (30).

Diagnostic techniques for urinary tract TCC include urinalysis which can be suggestive in up to 30% of TCC cases. However, reactive non-neoplastic transitional cells due to inflammation can be a confounding factor in making the definitive diagnosis; therefore, urine cytology needs to be supported by other diagnostic techniques (30). Percutaneous ultrasound-guided biopsies are not recommended due to potential for needle tract implantation of neoplastic cells (31). Traumatic urethral catheterization is another recommended technique for yielding a cell-rich sample (31). Ultrasound-guided catheter biopsy of urethral lesions has also shown promise in assisting with diagnosis of lower urinary tract lesions (32). A commercial canine urine antigen screening test (V-BTA test, Alidex, Redmond, Washington, USA) has 90% sensitivity and 78% specificity (33). Additional tests include double-contrast cystography, ultrasonography, and endoscopy. Nevertheless, definitive diagnosis of TCC requires histopathologic examination of tissues obtained by acceptable biopsy techniques (1). When TCC is suspected, a CBC, serum biochemistry profile, and urine culture should also be part of the minimum data base (23).

Clinical staging of the disease would be the next step to determine prognosis and treatment options. The staging process involves thoracic and abdominal radiographs, and abdominal ultrasonography (29). A study of 102 dogs with TCC revealed regional lymph node and distant metastasis of 16% and 14%, respectively, and 10% of the dogs had both nodal and distant metastasis (25). Of the 102 dogs, 57 (56%) had urethral involvement and 29% of the 38 male dogs had prostate involvement (25). Skeletal metastasis of TCC is not common (23). Reported skeletal metastatic sites in the dog include rib, vertebrae, femur, skull, and humerus (1). The humerus has been reported as a metastatic site for TCC in only 1 other published report (34). Where metastatic skeletal lesions are suspected, a whole body nuclear bone scan compared to radiographic findings can be utilized to investigate bone metastasis (23).

Treatment options available for canine TCC include surgical intervention, radiation therapy, chemotherapy, and non-steroidal anti-inflammatory drug therapy (for example, piroxicam or meloxicam) (1,29). Approximately 10% of dogs with TCC develop complete urinary tract obstruction secondary to tumor progression, and the cause of death is related to the local effects of the primary tumor in as many as 60% of cases (25). Attempts at surgical resection vary based on the location and extent of the disease. Palliative measures are available to temporarily relieve urethral obstruction and include urethral stenting, placement of cystostomy tubes (35,36), and LASER ablation (37,38). Although most dogs with TCC die of their disease, many can survive for several months or longer with a good quality of life. The median survival times in several studies have been reported to exceed 6 mo (29).

In conclusion, this case was unusual because of the clinical presentation of forelimb lameness, without other clinical features typically associated with TCC. Although uncommon, metastatic neoplasia should always be part of the differential diagnosis of a radiographically aggressive bone lesion. The contribution of MRI in this case to further delineate the lesions also highlights the merit in using this diagnostic modality in cases presenting with such musculoskeletal lesions. Canine TCC is a disease that can manifest with a wide array of clinical signs, therefore, meticulous physical examination including rectal examination, as well as complete diagnostic work-up to facilitate diagnosis, staging and appropriate treatments are warranted.