Urothelial cell carcinoma of the bladder causing severe hemorrhage and hypovolemic shock in a cat

Abstract

Case summary

A 7-year-old female spayed domestic shorthair cat was evaluated for a 10-day history of progressive hematuria. Abdominal ultrasound revealed a large non-shadowing echogenic mass in the bladder lumen and multiple small broad-based pedunculated lesions along the luminal urinary bladder wall. The cat was progressively anemic, tachypneic and lethargic, and required a whole blood transfusion. The following morning, peracute bradycardia, bradypnea and unresponsive mentation were noted. A unit of packed red blood cells (pRBCs) was rapidly administered to the patient, resulting in improved cardiorespiratory and mental status. Cystoscopy revealed a blood clot occupying approximately 50% of the bladder lumen, multiple proliferative broad-based masses originating from the bladder wall and two pulsatile bleeding vessels associated with one of the masses. Biopsies of the masses were obtained, followed by electrocautery of the bleeding vessels and sclerotherapy of the entire urinary bladder. Another transfusion with pRBCs was administered the following day, and the patient was discharged 48 h after cystoscopy. The biopsies were consistent with urothelial cell carcinoma, and meloxicam was prescribed. No additional blood transfusions were required, and the cat had resolution of anemia 20 weeks after discharge.

Relevance and novel information

Urothelial cell carcinoma is the most common type of cancer of the bladder wall in cats. However, severe hemorrhage caused by this tumor resulting in hypovolemic shock has been poorly reported in cats. Treatment with electrocautery and sclerotherapy can lead to long-term control of bleeding when definitive treatment is not pursued.

Case description

A 7-year-old female spayed domestic shorthair cat was presented for a 10-day history of hematuria and acute onset of hyporexia with a single episode of vomiting. The cat was obtained 1.5 years before presentation and developed inappropriate urination characterized by periuria at that time, which improved to monthly episodes. Discolored urine had not been previously noted.

The patient had initially been presented to another referral hospital for the acute onset of red discolored urine. The physical examination was unremarkable aside from obesity. A point-of-care ultrasound (POCUS) of the bladder revealed large mobile and non-shadowing masses in the lumen, suspected to be blood clots, with concern for bladder wall polyps. Urinalysis from a cystocentesis sample confirmed too numerous to count red blood cells (RBCs) without evidence of white blood cells (WBCs) or bacteria. A complete blood count (CBC) revealed normal hemato-crit (41%, reference interval [RI] 31–49) and thrombo-cytopenia (41 K/µl, RI 200–500) with a large quantity of platelet clumps. A urine culture showed no growth. The patient received subcutaneous cefovecin (7.7 mg/kg) and was discharged with oral gabapentin (8.8 mg/kg q8h) given as needed for discomfort.

Initially, the hematuria improved for several days, but then worsened significantly, prompting further evalu-ation. Physical examination revealed a moderate amount of blood on the peri-vulvar fur and a grade 2 parasternal systolic heart murmur. POCUS revealed multiple hyperechoic, round structures within the urinary bladder lumen that appeared adhered to the wall. Prothrombin time was normal (19 s, RI 15–22). New anemia (hematocrit 27%, RI 30–52) was noted, without evidence of regeneration (reticulocytes 16 K/µl, RI 3–50). The patient was admitted for hospitalization and received intravenous (IV) maropitant (1 mg/kg q24h), oral gabapentin (8 mg/kg q8h) and transdermal mirtazapine (0.3 mg/kg q24h). IV fluid therapy with lactated Ringer’s solution (LRS) (50 ml/kg/day) was also started, but discontinued after 6 h because the cat was deemed to be euhydrated and normovolemic on reassessment.

The following morning, the patient’s packed cell volume (PCV) was 24%. Abdominal ultrasound performed by a board-certified radiologist revealed a large (approximately 4 × 2.2 cm), mostly well-defined, irregularly marginated, mixed echoic mass within the urinary bladder (Figure 1). In addition, several small (approximately 2–3 mm) broad-based to pedunculated, hyperechoic structures were noted along the luminal surface of the urinary bladder wall. Differentials included chronic hematoma, mineralized neoplasm or chronic granuloma. The hyperechoic structures along the urinary bladder wall were possibly concurrent polypoid cystitis, neoplasia or adhered hemorrhagic material. Progressive lethargy and tachypnea were noted, so a blood transfusion was administered. The patient was type B and received 60 ml of type B whole blood. At 3 h into the transfusion, the patient developed increased respiratory rate and effort, dull mentation and facial twitching. Blood pressure was too low to measure, and hypothermia (94.4°F [34.6°C]) was noted. Because of concern about a transfusion reaction, the transfusion was discontinued, a 60 ml IV LRS fluid bolus was administered, active warming was started and the patient was placed in an oxygen cage with supplemental oxygen (40%). An LRS constant rate infusion (CRI; 20 ml/kg/day) was continued after the bolus. Over the next 2 h, the patient’s mentation and blood pressure normalized, and temperature, respiratory rate and effort improved. Large amounts of hemorrhagic urine were noted overnight.

Figure 1

Ultrasound of the urinary bladder before cystoscopy. The large, mostly well-defined, irregularly marginated, mixed echoic mass was consistent with an intravesicular blood clot. The mass effaced with the ventral wall of the urinary bladder and was not gravity dependent, but vascular flow was not identified when the mass was interrogated with power Doppler. In addition to the mass, several small (measuring approximately 2–3 mm), broad-based to pedunculated, hyperechoic structures were noted along the luminal surface of the urinary bladder wall

The following morning, approximately 12 h after the transfusion, the patient’s anemia had progressed (PCV 13%), and venous blood gas analysis revealed moderate hyperlactatemia (6.7 mmol/l, RI <2). A few hours later, the patient acutely became minimally responsive and bradycardic (100 beats/min). Atropine (0.04 mg/kg) was administered. A 30 ml unit of type B packed RBCs (pRBCs) was administered over 10 minutes. Heart rate and mentation normalized, and tachypnea developed. After transfusion, the PCV was improved (20%) but hyperlactatemia worsened (12 mmol/l). Aminocaproic acid (30 mg/kg IV q8h) was administered to stabilize clot formation and discontinued after 24 h.

Once stable, the patient was anesthetized for cystoscopy that day. Fentanyl (2 µg/kg IV) and midazolam (0.2 mg/kg IV) were administered as premedication. Alfaxalone (0.5 mg/kg IV) was administered for induction and intubation. An adequate plane of anesthesia was maintained with isoflurane (0.25–0.75%), fentanyl CRI (5–7.5 µg/kg/h) and alfaxalone CRI (0.02–0.07 mg/kg/min). A 1.9 mm × 14 cm rigid 30° telescope with a 10 Fr sheath cystoscope (Hopkins II Telescope; Storz) was used. At the bladder trigone, papillary exophytic proliferative tissue was noted (Figure 2). Within the bladder lumen, a large blood clot was noted. Multifocally along the bladder wall, proliferative sessile lesions were noted. At the bladder apex, two pulsatile bleeding vessels associated with a large proliferative lesion were observed. The pulses of blood exiting these vessels matched the patient’s pulse rate monitored via oscillometric Doppler. The cystoscopic infusion fluid was transitioned from 0.9% sodium chloride to dextrose 5% in water. Monopolar electrocautery was performed to cauterize the bleeding lesions, using a 2 Fr Bugbee flexible electrode (Gyrus) via passage through the cystoscope instrument channel. The cystoscopic video is available in the supplementary material (Videos 1 and 2). Bleeding ceased from both sites after coagulation with the electrode (Video 3). Biopsies of the masses were obtained via cup biopsy forceps. Although gross hemorrhage had stopped after cauterization, top-ical sclerotherapy was performed to further reduce the likelihood of recurrence of hematuria. An 8 Fr Foley catheter was introduced into the bladder so that the ballon occluded the bladder outflow. Liquid silver nitrate 0.5% was drawn up through a 0.2 µm filter and mixed with iohexol in a ratio of approximately 3:1. Under fluoro-scopic guidance, the silver nitrate was instilled into the urinary bladder via the balloon catheter until the bladder was distended (Figure 3). It was allowed to dwell for 10 mins and then removed via gentle suction on the catheter with a syringe. The process was repeated with 10% povidone iodine solution, and then again with a second silver nitrate dwell into the bladder. The balloon catheter was removed after the infusion without removing the silver nitrate. Postoperatively, the patient’s anemia (PCV 24%) and lactate (1.7 mmol/l) were improved, although labored breathing was still noted.

Figure 2

The proliferative, highly vascularized tissue in the urinary bladder trigone noted during cystoscopy

Figure 3

Dorsoventral fluoroscopic view of the urinary bladder. There is an 8 Fr Foley catheter in the bladder trigone with the balloon filled with iohexol. Liquid silver nitrate 0.5% was mixed with iohexol in a ratio of approximately 3:1 and infused into the bladder until it was mildly distended. Note the space-filling defects from the blood clots and masses within the bladder lumen and attached to the bladder wall

The following day, the patient’s demeanor and respiratory rate were improved, but she remained oxygen dependent and lethargic. CBC revealed mildly progressive anemia (hematocrit 19%, RI 28–53) with evidence of regeneration (reticulocytes 146 K/µl, RI 3–50) and mild thrombocytopenia (96 K/µl, RI 155–641). A blood smear revealed moderate platelet clumping, nucleated RBCs (8 per 100 WBCs), and moderate polychromasia and anisocytosis. Another 30 ml pRBC transfusion was administered over 4 h. After the transfusion, the patient’s energy improved and discontinuation of supplemental oxygen was tolerated. The patient was discharged with Yunnan Baiyao, a Chinese herbal medicine (47 mg/kg PO q12h), 2 days after cystoscopy. The patient’s urine was a brown color just before discharge, likely due to retained silver nitrate, povidone iodine and hemoglobinuria from the prior transfusion reaction, and lysed red blood cells from the intravesicular clots.

Histopathology of the biopsy specimens was consistent with urothelial cell carcinoma (UCC). Three weeks after discharge, urine discoloration had resolved and hematocrit was stable (24%, RI 30–52), with no regener-ation present (reticulocytes 6 K/µl, RI 3–50). No obvious clots were noted in the urinary bladder on POCUS. Meloxicam (0.05 mg/kg q48h) was started, and Yunnan Baiyao (47 mg/kg q12h) was continued. At a 12-week recheck after discharge, the patient was doing well at home, with no recurrence of discolored urine. The patient’s anemia had resolved (hematocrit 42%, RI 30–52). Clinically, the patient clinically did well on meloxicam, with intermittent episodes of discolored urine. One year postoperatively, an acute onset of severe hematuria was noted and the patient was euthanized.

Discussion

UCC is the most commonly reported feline primary bladder tumor,^{1 –4} and hematuria is a common clinical sign, present in 65–95% of cases.^{2,5 –7} Despite the frequency of hematuria, anemia at presentation is uncommon; it is present in 30–40% of cases.^2,8 Severe hemorrhage leading to major adverse clinical outcomes such as hypovolemic shock or acute death are rarely reported.^1,9 In the above case, cystoscopy successfully identified the actively hemorrhaging lesions associated with masses and allowed for cautery to coagulate the bleeding lesions.

Treatment of feline UCC includes administration of non-steroidal anti-inflammatory drugs (NSAIDs),^5,7,8 chemotherapy,^7,8 surgical removal,^3,7,8 radiation therapy ⁸ or some combination thereof.^5,7,8,10 In a case series evaluating 118 cases, median survival time was 151 days. Increased survival was associated with partial cystectomy and treatment with NSAIDs. ⁸ Yunnan Baiyao is considered to have hemostatic properties. Studies in feline patients are scant and show poor efficacy, ¹¹ but it may still be administered to patients with severe bleeding disorders.

Although consensus dictates that the patient should have received a crossmatch before each transfusion, ¹² this was not performed before the first two transfusions because of a lack of other available type B blood product. The first unit was given after hours after failing to procure any additional product. The second unit was administered within minutes of the product arriving at the hospital owing to the rapidly deteriorating clinical status of the patient. The third unit was crossmatched to the patient, found to be a match and administered.

Feline UCC can present in varied locations throughout the bladder. The trigone was the sole location of a mass in 9–27% of cases; however, in 9–18% of cases, masses were present in multiple locations of the urinary system.^5,6,8 In the present case, grossly abnormal tissue covered most of the bladder wall. Attempted surgical resection would have required total cystectomy, or partial cystectomy with known incomplete margins. Electrocautery successfully fulgurated the two actively hemorrhaging vessels. Sclerotherapy was performed to additionally coagulate any smaller areas of bleeding that may have contributed to the hemorrhagic shock.

The use of fulgurating electrocautery has been described in humans for the treatment of bleeding lesions in the urinary bladder secondary to radiation cystitis, ¹³ as well as for treatment of hemangiomas of the urinary bladder. ¹⁴ Sclerotherapy, using silver nitrate and/or povidone iodine, has been reported for the treatment of idiopathic renal hematuria in dogs;^{15 –19} however, neither technique has been reported in cats with renal hematuria or bleeding vessels in the urinary bladder. Sclerotherapy has been reported in humans using intravesicular silver nitrate for the treatment of chemotherapy and radiation induced hemorrhagic cystitis,^20,21 and using povidone iodine for the treatment of recurrent urinary tract infections. ²²

Conclusions

Although hematuria is a common clinical sign associated with feline UCC, severe hemorrhage causing hypovolemic shock has rarely been reported. Management of bleeding vessels with electrocautery and sclerotherapy resulted in sustained attenuation of bleeding. This technique may be especially useful when there is multifocal disease distribution or if a less invasive treatment option is desired.