Acute Hemobilia and Hemocholecyst in 2 Dogs with Gallbladder Carcinoid

Abstract

Gallbladder neoplasia resulting in hemobilia and hemocholecyst is a rare condition in humans and, to the authors' knowledge, has not been reported previously in the veterinary literature. Hemobilia is defined as upper gastrointestinal bleeding that originates from within the biliary tract and can be caused by any abnormal communication between the biliary tract and blood vessels.1 Hemocholecyst is described as nontraumatic accumulation of blood or a blood clot within the gallbladder.2 About 30–40% of affected human patients present with the classical triad of clinical features attributable to hemobilia or hemocholecyst, which include upper gastrointestinal tract bleeding, abdominal pain, and jaundice. Hemobilia can progress to hemocholecyst, cholecystitis, and extrahepatic biliary duct obstruction (EHBDO).1–3 Neuroendocrine carcinoma (carcinoid) arising from the gallbladder is uncommon in humans and extremely rare in dogs, with only 2 reported occurrences in the veterinary literature.4–7 In humans, primary gallbladder and biliary duct system carcinoids constitute <1% of all carcinoid tumors arising from any tissue or organ in the body.8 This report describes 2 dogs with hemobilia and hemocholecyst secondary to gallbladder carcinoid. Clinical findings include acute vomiting, jaundice, melena, and hematemesis. A 10-year-old, male castrated Rhodesian Ridgeback was referred to Veterinary Centers of America Veterinary Referral Associates (VCA-VRA) for evaluation of vomiting. One day before presentation, the dog was treated supportively for vomiting. There was no history of steroid or nonsteroidal anti-inflammatory drug (NSAID) use. Physical examination abnormalities included pyrexia 103.2°F (39.5°C), jaundice, and melena without demonstrable abdominal pain. Laboratory abnormalities included increased total bilirubin concentration 12.9 mg/dL (reference range, 0.1–0.3 mg/dL), alkaline phosphatase 2,481 U/L (reference range, 5–131 U/L), alanine transaminase (ALT) 906 U/L (reference range, 12–118 U/L), aspartate aminotransferase 109 U/L (reference range, 15–66 U/L), γ-glutamyl transpeptidase 22 U/L (reference range, 1–12 U/L), cholesterol 434 mg/dL (reference range, 92–324 mg/dL), globulin 3.9 g/dL (reference range, 1.6–3.6 g/dL), and ionized magnesium 0.62 mmol/L (reference range, 0.42–0.58 mmol/L). Leukocytosis was present with 19,000 cells/μL (reference range, 4,000–15,500 cells/μL) characterized by mature neutrophilia of 17,100 cells/μL (reference range, 2,060–10,600 cells/μL). The remainder of the serum chemistry and CBC results were within the reference ranges. On urinalysis, pH was 7.5, specific gravity 1.011, with 1 + proteinuria and 3 + bilirubinuria. Leptospirosis titers were also performed and revealed the following titers: pomona 1 : 400, icterohemorrhagiae 1 : 400, canicola <1 : 50, grippophytosa 1 : 400, hardjo <1 : 50, autumnalis 1 : 400, and bratislava 1 : 200. Convalescent leptospirosis titers 2 weeks later were decreased (1 : 100 for icterohemorrhagiae and grippophytosa, ≤1 : 50 for the remaining serovars). The dog was recently vaccinated for leptospirosis, and these titers are consistent with vaccination. Prothrombin and activated partial thromboplastin times were normal. Abdominal and thoracic radiographs were normal. Abdominal ultrasound examination was performed. The liver extended beyond the costal arch with mildly increased echogenicity and mildly nonhomogenous parenchyma. The gallbladder was moderately distended (7.2 × 3.5 cm on longitudinal view) with a moderate amount of biliary sediment. The common bile duct was dilated and measured 1.0 cm in width (normal, <0.3 cm)9 with hypoechoic contents. Both the gallbladder and common bile duct walls were normal. Focal common bile duct obstruction could not be visualized and no focal mass was visualized. No other abnormalities were found on ultrasound examination. These findings were consistent with hepatomegaly, nonspecific mildly hyperechoic liver, and EHBDO. Exploratory laparotomy was recommended for biliary duct catheterization and possible stenting. At the time of surgery, the gallbladder was found to be enlarged and distended. A mass was palpable on the ventral apical region of the gallbladder with adhesion to the medial aspect of the quadrate liver lobe. The liver was mottled in appearance and mildly enlarged with rounded edges. The pancreas and duodenum appeared normal. Duodenotomy was performed over the major papilla. The gallbladder was expressible; bile admixed with blood clot and fresh hemorrhage was noted exiting the duodenal papilla. Common bile duct retrograde catheterization was performed with an 8-Fr polyvinyl catheter. There was no resistance to catheterization; bile and blood clot were suctioned from the gallbladder. Additional bile, blood clot, and fresh hemorrhage were manually expressed from the gallbladder after catheter removal. A common bile duct stent was then placed by means of a 6-cm segment of polyvinyl catheter sutured into the papilla. After the duodenotomy site was routinely closed, the gallbladder was again found to be enlarged and distended. A cholecystotomy was performed lateral to the apical mass and fresh blood clot and hemorrhage were suctioned from the gallbladder. Routine cholecystectomy followed by liver biopsy was then performed. The gallbladder was examined after abdominal closure and found to have an approximately 2 × 3 cm ulcerated broad-based nodule in the apex. The gallbladder also was filled with fresh blood and clot. Histopathology of the gallbladder revealed a broad, irregularly expanding, and locally infiltrative multilobular intramural mass composed of neoplastic polygonal cells. These cells had central round vesicular nuclei with occasional prominent nucleoli and 1–3 mitotic figures/hpf. Fine vascular stromal septa dissect throughout the mass, producing a packeted pattern. These finding were suggestive of gallbladder carcinoid.6 The neoplastic cells were found to be immunoreactive for chromogranin A and protein gene product 9.5 (PGP 9.5) confirming the diagnosis of neuroendocrine carcinoma or carcinoid.10 Mild chronic cholecystitis also was evident on histopathologic evaluation characterized by moderate hyperplasia and papillary proliferation of the mucosal epithelial surface with mild infiltrates of a mixture of inflammatory cells. Histopathology of the liver revealed moderate infiltrates of mixed lymphocytes, plasma cells, and some scattered neutrophils in the portal areas accompanied by bands of increased fibrous stroma and proliferative bile ducts. There was expansion of the portal tracts with prominent fibrosis extending from the portal triads to the central veins. No neoplastic cells were identified in the liver biopsy sample. These findings were consistent with moderate chronic active hepatitis with bridging fibrosis. A bile culture was positive for Escherichia coli and α hemolytic Streptococci. The dog's postoperative care was uneventful and included IV fluid therapy, antibiotic therapy, and pain management. The dog was discharged from the hospital 5 days after surgery. A 12-year-old, female spayed Beagle mixed breed dog presented to VCA-VRA for 4 days of progressive lethargy, anorexia, and acute onset hematemesis and melena on the day of presentation. Prior medical history included chronic, stable mitral regurgitation requiring no current medication. Thirteen days before presentation, the dog was treated supportively for an isolated episode of hematemesis. There was no history of steroid or NSAID use. Physical examination abnormalities included pyrexia 104.2°F (40.1 °C), bilateral lenticular sclerosis, jaundice, grade III/VI apical holosystolic heart murmur, generalized abdominal pain, and melena. Laboratory abnormalities included increased total bilirubin concentration 3.1 mg/dL (reference range, 0.1–0.6 mg/dL), alkaline phosphatase >2,400 U/L (reference range, 20–150 U/L), and ALT 887 U/L (reference range, 10–118 U/L). Leukocytosis was present with 24,000 cells/μL (reference range, 6,000–16,000 cells/μL) characterized by neutrophilia of 17,520 cells/μL (reference range, 3,720–12,480 cells/μL) with left shift (band neutrophils 1,200 cells/μL; reference range, 0–320 cells/μL) and monocytosis 2,880 cells/μL (reference range, 0–960 cells/μL). Anemia was present with a PCV of 33% (reference range, 36–52%). The remainder of the serum chemistry and CBC results were within the reference ranges. Blood smear cytology revealed polychromasia, anisocytosis, and target cells (codocytes). On urinalysis, pH was 7.5, specific gravity 1.039, with 1 + hematuria and 3 + bilirubinuria. Prothrombin and activated partial thromboplastin times were normal. Thoracic radiographs indicated ventral spondylosis deformans but were otherwise normal. Abdominal radiographs indicated hepatosplenomegaly and ventral spondylosis deformans. Abdominal ultrasound examination was performed. The gallbladder was moderately distended (5.6 × 2.3 cm on longitudinal view) with a well-defined, mildly hyperechoic echogenic mass measuring 3.5 × 2.1 cm arising from the apical and cranioventral wall. On cine-loop evaluation, the mass separated from the dorsal gallbladder wall with each respiratory movement, but remained static at its apical and ventral margins. On the caudal (intraluminal) edge of the mass, a small amount of mineralization was noted with no acoustic shadowing. The mass was vascularized on color Doppler flow (Fig 1). The common bile duct was dilated and measured 1.1 cm in width (normal, <0.3 cm) with hypoechoic contents. Both the gallbladder and common bile duct walls were normal. Focal common bile duct obstruction could not be visualized. The liver appeared mottled with homogenous mixed echogenicity, and an approximately 4 × 3 cm mixed echogenicity mass was present in the cranial abdomen and appeared to be associated with the central liver region. No other abnormalities were found on ultrasound examination. These findings were consistent with a vascular gallbladder mass, EHBDO, and a mass within the cranial abdomen (possibly associated with the liver). Ultrasonographic image of the gallbladder mass in dog 2 with color Doppler flow. Right longitudinal view. The dog became progressively more anemic (PCV, 18%) and hypoproteinemic (5.0 g/dL), requiring a 170-mL packed red blood cell transfusion. Based on the diagnostic findings and progressive blood loss, exploratory laparotomy to evaluate the hepatobiliary system was recommended. A mass was observed arising from the apex of the gallbladder. Gallbladder expression was performed with minimal resistance. Routine cholecystectomy was performed. A mass was observed arising from the ventral aspect of the caudate liver lobe near the gallbladder. The liver appeared enlarged, pale, and mottled with irregular surfaces and grey tapered edges. Caudate liver lobectomy and liver biopsy were performed. The gallbladder was examined after abdominal closure and was filled with a blood clot originating from an approximately 3 × 2 cm ulcerated mass. Histopathology of the gallbladder revealed a broad and locally infiltrative polypoid intramural mass composed of hypertrophic, hyperchromatic, and neoplastic polygonal cells. These cells had large oval vesicular nuclei with scattered mitotic figures. The cell nests and packets were supported by fibrovascular stromal septa. These findings were suggestive of gallbladder carcinoid. The neoplastic cells were found to be immunoreactive for chromogranin A and PGP 9.5 confirming the diagnosis of neuroendocrine carcinoma or carcinoid. Histopathology of the liver mass revealed a large expanding nodule of hypertrophic, well-differentiated, and ordered hepatocytes. Within the mass there was maintenance of microlobular structures with well-formed portal triads and central veins bridged by narrow hepatic cords and sinusoids. These findings were consistent with nodular hepatocellular hyperplasia. Histopathology of a liver biopsy specimen separate from the site of the liver mass revealed mild infiltration of mononuclear inflammatory cells in the portal areas but was otherwise normal, a finding consistent with mild acute hepatitis. The dog's postoperative care was uneventful and included IV fluid therapy, antibiotic therapy, and pain management. The dog was discharged from the hospital 3 days after surgery. In these 2 dogs, hemobilia and hemocholecyst secondary to gallbladder neoplasia resulted in distention of the gallbladder and common bile duct mimicking EHBDO. Hemobilia and hemocholecyst are descriptions of 2 distinct entities. Hemobilia refers to biliary system intraluminal hemorrhage. Hemocholecyst occurs when there is hemorrhage or a blood clot filling the gallbladder. Because both of these patients had evidence of upper gastrointestinal bleeding (melena in both, hematemesis in one), evidence of blood within the common bile duct, and blood clot within the gallbladder lumen, both hemobilia and hemocholecyst were present. A differential diagnosis of gastrointestinal ulceration also should be considered as a cause of upper gastrointestinal bleeding because ulceration has been reported with gastrin-producing carcinoids (ie, Zollinger-Ellison syndrome) in 1 cat and in humans.11,12 In both cases, gastrointestinal ulceration could not be definitively ruled out given the limited enterotomy in case 1, no enterotomy in case 2, and no definitive visualization of upper gastrointestinal mucosa via endoscopy. Measurement of gastrin concentrations were not performed in either. However, both recovered uneventfully without treatment directed at gastrointestinal ulceration. Malignant gallbladder neoplasia is an uncommon cause of hemobilia, accounting for only 1.5% of reported human cases and has not been reported in the veterinary literature.2 Other etiologies for hemobilia include trauma (including iatrogenic), gallstones, inflammatory disorders, vascular lesions, and other neoplasms.1–3 The most common clinical signs in humans with hemobilia are gastrointestinal bleeding (100%), abdominal pain (70%), and jaundice (60%).3 In this report, dog 1 had no demonstrable abdominal pain but was jaundiced and had evidence of gastrointestinal bleeding. Dog 2 had all 3 clinical signs. Although rare, a differential diagnosis of gallbladder neoplasia resulting in hemobilia should be considered in veterinary patients that present with these clinical signs with or without evidence of a gallbladder mass. Hemocholecyst is a very unusual presentation of gallbladder neoplasia, is not well documented in the human literature, and has not been reported in the veterinary literature. In humans, hemocholecyst occurs most commonly secondary to gallstones. Other causes include vascular disorders, malignancy, polyps, and heterotopic gastrointestinal mucosa within the gallbladder.2,13 Hemocholecyst is especially unusual given the fibrinolytic properties of bile, which are thought to prevent complete obstruction of the bile ducts by clotted blood. Slow bleeding may be more likely to cause blood-clot formation that will resist breakdown by the bile and lead to bile duct obstruction. Rapid mixing of blood and bile may create a dispersion in which no discrete clots develop.2,3 Acute severe hemorrhage, however, may overwhelm the fibrinolytic capacity of bile resulting in clot formation and outflow obstruction, which has been noted in human patients.14 Acutely increased cholecystic intraluminal pressure caused by rapid hemorrhage (observed as rapid gallbladder redistension after surgical decompression) may have limited hemorrhage in dog 1. The patency of the bile duct in dog 2 presumably allowed for ongoing hemorrhage. It is difficult to diagnose hemobilia or hemocholecyst of gallbladder origin before surgical exploration. Ultrasound examination currently is the most practical and least invasive imaging modality to identify changes within the biliary tract consistent with these syndromes. Abdominal ultrasonographic imaging may reveal the presence of echogenic material or intraluminal, fixed, and nondependent hyperechoic lesions without acoustic shadows within the gallbladder.1,2 A dilated common bile duct with hypoechoic contents also may be present. Histopathology and immunohistochemistry of both gallbladder masses were consistent with a diagnosis of neuroendocrine carcinoma, or carcinoid. Carcinoid tumors arise from dispersed cells of the neuroendocrine system in the gastrointestinal tract, biliary system, pancreas, and lung. Gallbladder neuroendocrine carcinomas arise from the preexisting neuroendocrine cells in the epithelium.11 These cells belong to one of 2 functional groups: (1) the amine precursor uptake and decarboxylation (APUD) cells that produce serotonin and adrenocorticotrophic hormone, or (2) cells capable of synthesizing low molecular weight polypeptide or protein hormones such as chromogranin, cholecystokinin, and secretin.6 In human medicine, prognostic factors have not been identified in patients with gallbladder carcinoids because the usual criteria for diagnosing malignancy, such as anaplasia and number of mitotic figures, are unreliable. In these cases, malignancy is determined by evidence of tumor invasion into adjacent tissues. If the tumor is localized to the gallbladder wall with no evidence of intraperitoneal or metastatic spread, the patient has a better prognosis.15 Because of the difficulty in diagnosing malignancy based on histopathologic assessment, these tumors should be considered potentially malignant. Chemotherapy options include gemcitabine, doxorubicin, and 5-flourouracil.16 Neither of these dogs had evidence of intraperitoneal or distant metastases at the time of diagnosis. In conclusion, we have described 2 cases of hemobilia and hemocholecyst secondary to gallbladder carcinoid in the dog. Differential diagnosis for this constellation of signs should include other neoplasia (eg, elsewhere in the biliary tract, hepatic, intestinal), liver failure, pancreatitis, ulceration or foreign body within the duodenum, gastrointestinal ischemia, and coagulopathy.17 Although confirmation of hemocholecyst and hemobilia from gallbladder origin in these cases were discovered intraoperatively, relatively noninvasive techniques such as computed tomography, endoscopic retrograde cholangiopancreatography, and magnetic resonance cholangiopancreatography may be of diagnostic assistance.18 Clinicians should be aware of this disease syndrome when presented with a patient exhibiting upper gastrointestinal bleeding, abdominal pain, and jaundice. The authors thank the following doctors for providing compassionate care for these hospitalized patients: Anne Stoneham, Christopher Byers, Heather Cook, and Kayleen Gloor.