An unusual clinical presentation of a dog with gastrinoma

Abstract

Gastrinoma is a rare malignant neuroendocrine neoplasia that results in autonomous gastrin secretion that stimulates hypersecretion of gastric acid, resulting in severe gastric and proximal small intestinal ulcerations. The principal clinical manifestation of gastrinoma is persistent vomiting. This report describes an uncommon manifestation of pancreatic gastrinoma in a dog.

Gastrinoma is a rare neuroendocrine tumor that usually arises as a result of malignant transformation of somatostatin-secreting delta cells of the endocrine pancreas to gastrin-producing cells (1). Unregulated secretion of gastrin stimulates excessive secretion of gastric acid, resulting in esophageal and gastroduodenal erosions and ulcerations (2–4). Additionally, enzymatic digestion in the proximal small intestine, which requires an alkaline environment, may be hampered by increased delivery of acid from the stomach. Gastric antral hypertrophy is another consequence of prolonged elevation of circulating gastrin. Antral hypertrophy may in turn delay gastric emptying and, in severe cases, may result in gastric outflow tract obstruction (5). It is therefore not surprising that typical clinical signs of gastrinoma in dogs include vomiting, inappetence, and weight loss. Rarely, regurgitation may be seen as a result of severe esophagitis, which develops secondary to vomiting of acidic fluid (3). In addition, profuse diarrhea may be present secondary to enzymatic maldigestion (6).

The diagnosis of gastrinoma in humans is based on the demonstration of increased basal gastrin levels in the presence of gastric hyperacidity (pH < 2.5), which would normally inhibit gastrin secretion. Alternatively, gastrin levels can be measured following intravenous infusion of secretin (7). There are a few case reports in dogs that describe utilization of these criteria to establish a diagnosis (8). In most of the reports of gastrinomas in dogs, the diagnosis is based on histopathology and immunohistochemistry demonstrating gastrin-producing pancreatic carcinomas (3,6,9–11).

Case description

A 10-year-old female spayed Akita was presented to the University of Illinois at Urbana-Champaign Veterinary Teaching Hospital (UIUC-VTH) for progressive gagging, hacking, weight loss, and decreased appetite of 5 mo duration. The dog had been intermittently vomiting food and bile and had more recently begun regurgitating. Four months prior to presentation at UIUC-VTH, the referring veterinarian had performed a celiotomy for gastric and duodenal biopsies, which showed normal stomach and erosive duodenitis on routine histopathology. Symptomatic treatment with sucralfate, ranitidine, famotidine, amoxicillin, metronidazole, and prednisone was instituted by the rDVM in an attempt to alleviate clinical signs. Minimal response was observed. The patient was current on vaccines and had no history of previous or concurrent medical problems.

Physical examination revealed a rectal temperature of 39°C and a heart rate of 136 beats/min; poor body condition was noted (body condition score 3/9). The dog’s capillary refill time was < 2 s and halitosis was present. Copious amounts of saliva were dripping from the mouth. No other abnormalities were evident on physical examination. Systolic blood pressure measured at presentation (by Doppler) was 115 mmHg. Initial diagnostics included a complete blood (cell) count (CBC), serum biochemistry profile, and urinalysis (Tables 1 to 3), which demonstrated an inflammatory leukogram, decreased blood urea nitrogen (BUN), mild hypoproteinemia, mild hyponatremia, hypokalemia, hypochloremia, hypocholesterolemia, and trace urine protein. A urine protein to creatinine ratio was 0.1 (normal < 0.2). Acid-base status was normal on an arterial blood gas analysis.

Table 1.

Complete blood cell count at the time of admission from a dog with gastrinoma

Test	Result	Reference range
Red blood cell	6.94 × 1018/L	5.5 to 8.5 × 1018/L
Hemoglobin	144 g/L	120 to 180 g/L
Hematocrit	0.44 L/L	0.35 to 0.52 L/L
Mean cell volume	63.2 fl	66.0 to 77.0 fl
Mean cell hemoglobin concentration	329 g/L	320 to 360 g/L
Platelet	246 × 109/L	200 to 900 × 109/L
White blood cell	32.1 × 109/L	6.0 to 17.0 × 109/L
Neutrophils	28.89 × 109/L	3.0 to 11.5 × 109/L
Neutrophilic bands	0 × 109/L	0 to 0.3 × 109/L
Lymphocytes	1.93 × 109/L	1.0 to 4.8 × 109/L
Monocytes	1.28 × 109/L	0.2 to 1.4 × 109/L
Eosinophils	0 × 109/L	0.1 to 1.0 × 109/L
Basophils	0 × 109/L	0 to 2.0 × 109/L

Table 3.

Urinalysis at the time of admission from a dog with gastrinoma

Test	Results
Urine color	Yellow
Urine clarity	Clear
Urine specific gravity	1.015
Urine pH	6.0
Urine protein	Trace
Urine glucose	Negative
Urine ketones	Negative
Urine bilirubin	1+
Urine blood	Negative
Urine white blood cells	Few
Urine red blood cells	Rare
Urine epithelial cells	Negative
Urine bacteria	Negative

Because of the regurgitation and persistent vomiting, thoracic radiographs were obtained to assess for esophageal disease and secondary aspiration pneumonia. The thorax was radiographically normal. Abdominal sonography demonstrated thickened and dilated small intestines. Ultrasound-guided fine-needle aspiration of the small intestinal wall did not yield diagnostic samples.

Endoscopy and exploratory laparotomy for full thickness intestinal biopsies were planned to further evaluate the esophagus, stomach, and small intestine. The most striking findings during esophagoscopy and gastroduodenoscopy were severe ulceration, marked mucosal irregularity and loss of normal elasticity (firmness and poor distensibility) that involved the entire length of the esophagus. Grossly, there was no normal esophageal mucosa present. The stomach appeared normal without any evidence of ulceration or copious fluid secretion. The duodenum had several focal ulcerations and had decreased distensibility. Endoscopic biopsies were collected from the esophagus, fundus and body of the stomach, pyloric antrum and duodenum for histopathological evaluation. Esophageal and duodenal samples were also submitted for cytological evaluation, which indicated marked suppurative inflammation. Exploratory laparotomy followed immediately after endoscopy. A 1-cm oval pancreatic mass with omental adhesions around the duodenum was identified. No other abnormalities were noted during surgery. The pancreatic mass was resected and a jejunostomy tube was placed. Pancreatic and jejunal biopsies were submitted for histopathologic evaluation.

Histopathologic findings showed multifocal necrosuppurative ulcerative gastritis (Figure 1), jejunitis, duodenitis, and esophagitis. The pancreatic mass was identified as a neuroendocrine pancreatic tumor and immunohistochemical antibody stains for gastrin strongly labeled the cells of the tumor, indicating a diagnosis of gastrinoma (Figure 2). An additional stain for insulin was negative. The dog was sent home with omeprazole and sucralfate for symptomatic management and with owner instructions for jejunostomy tube care and feedings. At that point the dog was regurgitating continuously and was non-responsive to treatment. The owners opted for euthanasia of the dog due to poor prognosis and concern for suffering.

Figure 1.

Multifocal necrosuppurative ulcerative gastritis in the stomach of a dog with gastrinoma. Hematoxylin and eosin (H&E) stain (40×).

Figure 2.

Section of the pancreatic mass labeled with polyclonal rabbit anti-human gastrin; the neoplastic cell population has a stippled to diffuse pattern of cytoplasmic chromagen uptake (100×).

Discussion

Gastrinoma in companion animals is a very rare gastrointestinal neuroendocrine tumor usually seen in middle-aged dogs (average age 8.2 y; range: 3.5 to 12 y). There is no apparent breed predilection; females may be affected slightly more often than males (8). Information about canine gastrinoma in the veterinary literature is sparse. Due to the limited data available, it is hard to make generalizations regarding biological behavior of gastrin-secreting tumors. However, clinical signs in gastrinoma patients result from gastric hyperacidity triggered by unregulated gastrin secretion by tumor cells. Gastric hyperacidity, in turn, results in ulceration of the esophagus, stomach, and proximal small intestine (3). Alterations in intestinal pH may lead to maldigestion, causing weight loss and diarrhea. The most striking clinical findings in this dog were related to a severe generalized esophagitis and included severe to continuous regurgitation in addition to more typical signs of vomiting, weight loss, and inappetence. The finding of grossly normal gastric mucosa during gastroscopy is also atypical, especially if consideration is given to the chronicity of this dog’s clinical signs. More typical findings in cases of gastrinoma include antral hypertrophy secondary to the trophic effect of gastrin and gastric ulcers or erosions secondary to hypersecretion of gastric acid (3,8,10).

Regurgitation is a localizing clinical sign of esophageal disease and dysmotility which prompted diagnostic evaluation of the esophagus by thoracic radiography and subsequent esophagoscopy in this patient. When thoracic radiographs failed to show structural abnormalities in the esophagus, further assessment of esophageal function with a positive contrast esophagram was considered but not performed because administration of contrast material was considered a significant risk for this continuously regurgitating patient and would have required a delay of the esophagoscopy and exploratory laparotomy, which were considered to be of higher priority in determining a specific etiology of the patient’s disease. In the absence of an evaluation of esophageal function, it is unclear if esophageal dysmotility and/or lower esophageal sphincter dysfunction, whether primary or secondary to esophageal injury by acidic gastric contents, contributed to the relative severity of esophageal versus gastric signs; the basis for the relative sparing of the stomach, which typically manifests dramatic abnormalities in gastrinoma patients, in this dog is unclear.

The dog in this report had several hematologic and biochemical abnormalities that are consistent with clinical and necropsy findings. Leukocytosis with mature neutrophilia was attributed to the severe esophagitis and necrotizing enteritis. Hypokalemia was likely secondary to loss through vomiting and regurgitation of acidic stomach contents. Hypochloremia was relative as, when it was corrected relative to serum sodium concentration, chloride was in the normal reference range. Hyponatremia was likely due to a combination of ongoing gastrointestinal losses together with avid water retention by the kidney to counteract dehydration, leading to dilution of serum sodium.

The diagnosis of gastrinoma is based on the demonstration of low gastric pH (< 3) and concurrently high gastrin levels. Alternatively, intravenous infusion of calcium or secretin may be used to distinguish gastrinoma patients, which show a 3-fold greater increase in gastrin levels relative to normal individuals (7,8,12). These diagnostic criteria are commonly used in human patients; however, they have been applied in only 4 dogs and therefore should be interpreted cautiously (8,13). Gastric pH and baseline levels of gastrin were not measured in our patient because the dog had been treated with various antacids at the time of presentation and discontinuation of these medications was considered to be unethical. Infusion with secretin was not attempted because exploratory laparotomy and histopathology combined with immunohistochemistry led to a definitive diagnosis.

Attempts at medical management of this case were limited because the owners opted to have the dog euthanized. Reported medical treatments include inhibitors of gastric acid secretion (proton pump inhibitors and H2-blockers), gastro-protectants (sucralfate and misoprostol) and somatostatin analogs (octreotide) to suppress gastrin secretion (6,8,14,15). Surgical resection of the gastrin-secreting tumor is the treatment of choice; however, it does not provide a cure, as this is a malignant condition that commonly has metastasized by the time of evaluation. Additionally, surgery has not been shown to improve the outcome in comparison to standard medical treatment (8).

In addition to contributing another observation to the limited number of reports of canine gastrinomas, this case is significant in demonstrating an atypical presentation in which 1) the stomach was endoscopically free of any ulcerative and proliferative lesions characteristic of this disease, and 2) the predominant clinical sign at presentation at the UIUC-VTH was intractable regurgitation rather than vomiting. CVJ

Table 2.

Chemistry profile at the time of admission from a dog with gastrinoma

Test	Results	Reference range
Creatinine	44.2 μmol/L	44.2 to 141.44 μmol/L
Blood urea nitrogen	1.96 mmol/L	2.5 to 11.07 mmol/L
Total protein	42 g/L	54 to 80 g/L
Albumin	24 g/L	21 to 43 g/L
Globulin	18 g/L	27 to 44 g/L
Total calcium	2.03 mmol/L	1.98 to 2.88 mmol/L
Phosphorous	1.16 mmol/L	0.78 to 2.1 mmol/L
Sodium	139 mmol/L	141 to 161 mmol/L
Potassium	3.1 mmol/L	3.9 to 5.7 mmol/L
Chloride	98 mmol/L	104 to 125 mmol/L
Glucose	6.11 mmol/L	3.61 to 7.05 mmol/L
ALP	32 U/L	12 to 110 U/L
ALT	24 U/L	17 to 87 U/L
GGT	3 U/L	1 to 11 U/L
Total bilirubin	1.71 μmol/L	1.37 to 8.55 μmol/L
Cholesterol	2.18 mmol/L	2.82 to 8.16 mmol/L
Triglycerides	0.67 mmol/L	0.28 to 1.64 mmol/L
Bicarbonate	21.8 mmol/L	17 to 29 mmol/L
Anion gap	22.3	8 to 25
Lipemic index	12
Hemolytic indicator	13
Icterus indicator	0