Introduction

Urinary bladder neoplasia accounts for approximately 2% of all canine neoplasms, with transitional cell carcinoma being the most common form of neoplasia at this location.^1–3 In contrast, canine bladder hemangiosarcoma (HSA) is rare, with only four previous case reports identified in the literature.^4–7

Canine HSA is a highly malignant, mesenchymal tumor arising from endothelial cells, resulting in the formation of irregular vascular spaces filled with blood. It is typically seen in middle-aged to older dogs.^8–10 German shepherd dogs appear to be overrepresented,^6,8,10 and there may be a slight male predisposition.^4,8,9 In dogs, the most common primary site is the spleen^4,6,8; the right atrium and cutaneous and subcutaneous tissue are other common sites.^4,8,11 Metastatic rate is high for visceral HSA, and dogs have a poor prognosis, with median survival time for splenic HSA treated with splenectomy alone of 19–86 days, and a 10% or less survival to 12 mo with additional chemotherapy.^4,12–14

In this report, we present the first successful surgical management of canine bladder HSA and a successful medium-term outcome.

Case Report

A 6 yr old 46 kg (101 lb) neutered male German shepherd dog was evaluated for spontaneous uroabdomen. The patient acutely collapsed and was initially presented to his primary veterinarian. Weakness was identified in the pelvic limbs and a myelopathy was suspected. He was discharged with carprofen (2.2 mg/kg [1 mg/lb] IV q 12 hr) and tramadol (4 mg/kg [1.8 mg/lb] per os [PO] q 8 hr). The dog's condition deteriorated over the next 48 hr; he developed vomiting, diarrhea, and pollakiuria, voiding minimal urine. No stranguria was documented. A biochemical analysis was performed; this identified a severe azotemia (blood urea nitrogen 175 mg/dL; referenced interval, 7–27 mg/dL, creatinine 5.1 mg/dL; referenced interval, 0.5–1.8 mg/dL) and a hyperphosphatemia (11.0 mg/dL; referenced interval, 2.5–6.8 mg/dL). A complete blood count (CBC) identified a mild leukocytosis (17.96 K/μL; referenced interval, 5.50–16.90 K/μL) with a neutrophilia (13.68 K/μL; referenced interval, 2.00–12.00 K/μL) and hemoconcentration (hematocrit 66.1%; referenced interval, 37–55%). An abdominal focused assessment with sonography for trauma (A-FAST) identified peritoneal effusion. Abdominocentesis was performed, and evaluation of the peritoneal fluid identified a potassium of 14.2 mEq/L and a creatinine of 13.3 mg/dL, consistent with uroabdomen.¹⁵ IV isotonic fluids (lactated Ringer’s solution; 300 mL/hr), ampicillin sodium/sulbactam sodium^a (30 mg/kg [13.6 mg/lb] IV q 8 hr), and buprenorphine (0.02 mg/kg [0.01 mg/lb] IV q 8 hr) were administered. An indwelling urinary catheter (8-French red rubber) was placed with a 1 L empty saline bag attached for collection. The dog was transferred to our tertiary referral hospital.

Upon presentation, the dog appeared quiet, alert, and responsive. Cardiovascular and respiratory parameters were within normal limits. An A-FAST revealed moderate abdominal effusion. A venous blood gas analysis demonstrated an improvement in the azotemia (blood urea nitrogen 45 mg/dL; referenced interval, 10–30 mg/dL, creatinine 3.0 mg/dL; referenced interval, 0.8–1.5 mg/dL) and resolution of the hemoconcentration (hematocrit 47%; referenced interval, 40–52%). A mild hyperlactatemia was appreciated (1.6 mmol/L; referenced interval, 0.4–1.5 mmol/L). The urinary catheter was replaced with a 12-French Foley catheter and connected to a sterile collection system. Supportive care was continued: lactated Ringer’s solution (250 mL/hr), ampicillin sodium/sulbactam sodium^a (30 mg/kg [13.6 mg/lb] IV q 8 hr), and hydromorphone (0.05 mg/kg [0.02 mg/lb] IV q 6 hr). A urine culture was obtained from the Foley catheter.

A positive-contrast retrograde cystogram was performed using 200 mL of nonionic iodinated contrast medium (iohexol 300 mgI/mL; Figure 1A). The patient was positioned in left lateral recumbency, and video fluoroscopic images were obtained before and after contrast administration. Dorsal and dorsal oblique images were also acquired. The urinary bladder mucosal margins were diffusely irregular. In addition, there was outpouching of the urinary bladder in the left dorsolateral aspect of the apex, with variably rounded, smooth, and poorly defined margins, likely representing a defect and/or intramural extension. No leakage of contrast material into the abdomen was identified.

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An abdominal ultrasound of the bladder was then performed (Figure 1B). A moderate amount of slightly echogenic fluid was present throughout the peritoneal cavity. Within the spleen, there was a focal, ill-defined, heterogeneously hypoechoic nodule, which measured approximately 5.3 mm in diameter. At the level of the urinary bladder apex, the left ventral wall was focally, severely thickened (1.6 cm) and irregularly margined with loss of normal wall layering. In this region within the wall, multiple hyperechoic, reverberating foci, consistent with gas, were identified, and the urinary wall tapered abruptly, focally. A discrete defect in the urinary bladder wall was not identified. Possible differential diagnoses for the changes within the urinary bladder included severe cystitis or a neoplastic etiology.

Medical management consisting of maintenance of an indwelling urinary catheter for 5–7 days and continuation of antibiotics and supportive care was pursued. Surgical options of an exploratory celiotomy with possible partial cystectomy or bladder wall biopsies was recommended but declined because of financial limitations.

The dog remained in the hospital with an indwelling urinary catheter for 5 days. Urine output was compared with the IV fluid rate to ensure adequate kidney function. Sequential A-FASTs were performed daily, and the peritoneal effusion resolved. A central IV line was placed in the jugular vein to enable ease of venous blood sampling. A CBC and serum biochemical analysis were performed on day 3 of hospitalization. The prior leukocytosis and neutrophilia had resolved. A mild monocytosis (1.2 K/μL; referenced interval, 0.1–0.8 K/μL) and thrombocytopenia (104 K/μL; referenced interval, 134–396 K/μL) had developed. There was a mild increase in alanine aminotransferase (115 U/L; referenced interval, 18–64 U/L) and aspartate aminotransferase (70 U/L; referenced interval, 15–52 U/L) as well as a mild hypoproteinemia (4.6 g/dL; referenced interval, 5.6–7.5 g/dL) with a hypoalbuminemia (1.8 g/dL; referenced interval, 2.9–3.8 g/dL). The urine culture had no microbial growth at 5 days, and the dog’s demeanor and appetite improved.

The urinary catheter was removed on day 5 of hospitalization. Scant peritoneal effusion was appreciated on an A-FAST prior to removal of the urinary catheter. Eight hours following removal of the urinary catheter, the dog was noted to be quieter and not interested in food. An A-FAST revealed a large urinary bladder, and he was taken outside to urinate. The dog exhibited stranguria and pollakiuria, with minimal urine production. An A-FAST performed following this event identified a moderate amount of peritoneal effusion and a small urinary bladder. Abdominocentesis was performed and fluid analysis revealed a creatinine of 15.3 mg/dL and a potassium of 15.1 mEq/L. This was compared with a peripheral venous blood sample: creatinine of 1.8 mg/dL and potassium of 5.68 mEq/L, confirming the presence of uroabdomen.¹⁵ An indwelling urinary catheter was replaced, and the dog was transferred to the Soft Tissue Surgery Service. A positive-contrast retrograde cystogram was repeated and urine leakage was noted at the left dorsolateral aspect of the bladder apex.

Prior to surgery, a productive cough was noted, prompting three-view thoracic radiographs that revealed a mild alveolar pattern, suspicious for aspiration pneumonia. No evidence of metastasis was present. The patient was placed on enrofloxacin^b (10 mg/kg [4.5 mg/lb] IV q 24 hr]), in addition to the already prescribed ampicillin sodium/sulbactam sodium^a (30 mg/kg [13.6 mg/lb] IV q 8 hr). Blood oxygen saturation remained above 98%, so supplemental oxygen was not provided.

A CBC revealed a leukocytosis (14.39 K/μL; referenced interval, 5.0–13.0 K/μL) with a neutrophilia (13.0 K/μL; referenced interval, 2.7–8.9 K/μL), monocytosis (0.86 K/μL; referenced interval, 0.1–0.8 K/μL), and lymphopenia (0.9 K/μL; referenced interval, 0.9–3.4 K/μL). A marked thrombocytopenia (45 K/μL; referenced interval, 134–396 K/μL) was present. Slide evaluation identified the presence of 2+ echinocytes and 1+ keratocytes. The platelet slide estimate closely correlated with the analyzer, confirming the thrombocytopenia.

A serum biochemical analysis identified a continued mild increase in alanine aminotransferase (83 U/L; referenced interval, 18–64 U/L) as well as mild hypoalbuminemia (2.7 g/dL; referenced interval, 2.9–3.8 g/dL), for which a 500 mL (10.8 mL/kg [4.9 mL/lb]) fresh frozen plasma transfusion was given over 5 hr at a rate of 10 mL/hr; a mild hyperphosphatemia (6.3 mg/dL; referenced interval, 2.7–5.6 mg/dL) and mild hyperkalemia (5.8 mEq/L; referenced interval, 3.5–5.2 mEq/L) were also present.

The dog was anesthetized, a ventral abdominal celiotomy was performed, and 200 mL of serosanguinous peritoneal effusion was removed. The greater omentum was adhered to the apex of the urinary bladder, and numerous (>5), small (1–2 cm), black cyst-like structures were identified on the serosal surface. The urinary bladder was thickened (1–2 cm) and irregular, extending caudally to just cranial to the trigone. Stay sutures were placed medially and laterally in the mid-body of the bladder. A #15 blade was used to excise the apex and cranial portion of the mid-body of the urinary bladder, and approximately 65% of the bladder was removed. The cysts present within the serosa were found to extend to the bladder mucosa (Figure 2). The bladder wall containing the cyst-like tissue was resected; the remainder of the bladder wall was thickened, but no gross disease remained. The partial cystectomy was closed in two layers with 3-0 glycomer 631^c in a simple interrupted pattern. A 12-French Foley catheter was placed in surgery. The remainder of the abdomen was explored. The splenic nodule identified on ultrasound could not be appreciated on gross examination of the spleen. The abdominal lymph nodes were evaluated and were normal in size, color, and consistency. The abdomen was lavaged with 3 L of sterile 0.9% saline. An incisional gastropexy was performed prior to closure. The bladder wall was submitted for histopathology.

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The dog recovered well from surgery, and a venous blood gas analysis identified a resolution of his hyperkalemia (4.54 mEq/L; referenced interval, 3.5–5.2 mEq/L). He was managed supportively with LRS (150 mL/hr), an indwelling Foley urinary catheter, methadone (0.1 mg/kg [0.05 mg/lb] IV q 6 hr), metoclopramide (2 mg/kg/day [0.91 mg/lb/day] continuous rate infusion), maropitant^d (1 mg/kg [0.45 mg/lb] IV q 24 hr), ampicillin sodium/sulbactam sodium^a (30 mg/kg [13.6 mg/lb] IV q 8 hr), and enrofloxacin^b (10 mg/kg [4.5 mg/lb] IV q 24 hr). No pigmenturia was noted the day following surgery, and the dog’s appetite returned.

Two days following surgery, the urinary catheter was removed, and the dog urinated a normal stream with no stranguria. A mild hyperthermia (39.4°C [103°F]) was appreciated and repeat thoracic radiographs were performed. Mild progression of his previous alveolar pattern was appreciated. The central IV line in the jugular vein was removed, and 2 hr after removal, the hyperthermia resolved. The dog continued to improve and was discharged from the hospital 3 days following surgery with tramadol (4.4 mg/kg [1.9 mg/lb] PO q 8–12 hr), amoxicillin-clavulanic acid^e (13.8 mg/kg [20.8 mg/lb] PO q 12 hr), and enrofloxacin^b (8.9 mg/kg [4.1 mg/lb] PO q 24 hr).

Multiple sections of the formalin-fixed, paraffin-embedded urinary bladder were examined by a veterinary pathologist after staining with hematoxylin and eosin and Factor VIII immunohistochemical staining. Histopathology of the bladder mass identified an unencapsulated, poorly circumscribed, densely cellular mass infiltrating the outer muscular layers of the urinary bladder. The mass was composed of pleomorphic spindle to cuboidal cells that occasionally wrapped around small collagen bundles and formed irregular vascular channels containing blood. There was mild to moderate anisocytosis and anisokaryosis, and 17 mitoses were observed in ten 400× fields (2.37 mm²) with rare atypical mitoses. The mass was excised with narrow margins (1 mm); however, small numbers of cells infiltrated the serosa. The diagnosis was HSA of the bladder wall with chronic neutrophilic and hemorrhagic cystitis. A second opinion was sought, which identified grade III HSA of the bladder wall. The endothelial cell origin of the mass was confirmed with weak to moderate cytoplasmic immunoreactivity for Factor VIII–related antigen. Chemotherapy and consultation with a medical oncologist were recommended but were declined by the owner.

Follow-up by phone was performed weekly for the first 2 wk following discharge. The dog recovered well, and the incision healed without complication. An initial increase in urination frequency was observed; however, this resolved within 2 wk from discharge. No hematuria was appreciated. The owner initiated treatment with Apocaps^f, a nutraceutical supplement containing luteolin, apigenin, curcumin, silymin, beta-glucans, and gingerols and purported to initiate apoptosis of neoplastic cells. The dog receives three capsules, three times a day, by mouth. A follow-up phone call was performed 9 mo following surgery; the dog had shown no recurrence of clinical signs and was eating, drinking, and behaving normally. The owner was still administering Apocaps.

Discussion

Canine bladder HSA is uncommon, and there have only been four previous case reports in the literature, with no successful treatment previously described.^4–7 Presenting signs of canine bladder HSA appear to be variable. Uroabdomen, secondary to bladder rupture, has been described in one previous case.⁵ The most common presenting signs for the equivalent disease in humans, bladder angiosarcoma, are hematuria and dysuria.¹⁶

The prognosis for dogs with canine bladder HSA is difficult to assess owing to the rarity of the disease and the reconstruction issues associated with excision of bladder masses. In previous reports of canine bladder HSA, neoplastic nodules have extended into the trigone and encircled the ureteral orifices, requiring ureteral reimplantation and partial cystectomy to remove macroscopic disease.^5,7 In the case report by Liptak et al., partial cystectomy and ureteral reimplantation were performed; however, urinary bladder necrosis was identified 10 days following surgery and the dog was euthanized, preventing long-term follow-up.⁷ Although a partial cystectomy and ureteral reimplantation were recommended in the case report by Martinez and Schulman, the owners elected euthanasia at the time of surgery, preventing assessment of outcome.⁵

Human bladder angiosarcoma is also infrequent, with only 14 cases described in the literature.^15–18 Treatment options have been varied, including both partial and radical cystectomy, chemotherapy, and radiation therapy.^16–18 Despite treatment, bladder angiosarcoma carries a poor prognosis, with a mean survival time of 8.5 months.¹⁶ Current recommendations for the treatment of bladder angiosarcoma include a rapid and aggressive approach, with multimodal therapy consisting of radical surgery, followed by adjunctive radiotherapy and chemotherapy.¹⁶

In this present case, macroscopic neoplastic tissue did not extend to the lateral ligaments of the bladder, where the ureter, ureteral and urinary bladder vascular supply, and innervation to the bladder and vesicourethral junction are located. Because of the location of the tumor at the bladder apex and mid-body, a less radical approach was necessary to remove gross disease, lowering the risk of postoperative complications, such as uroabdomen, from leakage around implanted ureters, or bladder necrosis, from damage to the caudal vesicular arteries. The good outcome associated with bladder HSA in this case may be attributed to the location of the tumor allowing for complete resection.

The exact percentage of the bladder that may be excised in dogs without resulting in long-term pollakiuria or incontinence is unknown. In humans undergoing subtotal cystectomy, bladder volume increases within 4–6 mo.¹⁹ In canine cases of partial cystectomy, when 40–70% of the bladder was excised, pollakiuria following surgery occurred in 6/11 dogs and resolved within 2 mo in 4/6 dogs.²⁰ Consistent with these findings, pollakiuria associated with excision of 65% of the bladder in this case resolved within 2 wk.

Conclusion

This case report describes the first successful treatment of canine bladder HSA by partial cystectomy and documents a good medium-term outcome following removal of gross disease.