Gastrinoma

Introduction

A gastrinoma is a rare tumor in small animals, having been reported in only 25 dogs and 5 cats, compared to approxi­mately 250 dogs and four cats with an insulinoma.^20-22

Gastrinomas are most commonly single nodules of small size (Figure 9.19).

Gastrinomas synthesize and release excessive quantities of gas­trin (Figure 9.20), leading to gastric acid hypersecretion, hypertrophy of the gastric mucosa, and eventually gastric and duodenal ulceration (Figure 9.21).^23,25 Persistent hyperchlor- hydria also leads to a decrease in duodenal pH, which in turn leads to mucosal injury and inactivation of digestive enzymes with subsequent maldigestion.

Clinical presentation

Gastrinomas usually develop in middle-aged to older dogs (age range 3.5-12 years in 21 dogs reported) and cats (age range of five reported cats: 8-12 years).²² In dogs, females are anecdotally more commonly affected than males (69% vs. 31%), but this may be a reflection of the small number of cases reported.

The most common clinical signs observed in 25 of the re­ported cases included vomiting (92%), weight loss (88%), ano­rexia (72%), lethargy (64%), and diarrhea (60%).

Figure 9.19:

Gastrinoma. This figure shows a small tumor (arrow) in the pancreas of a dog. This tumor is barely visible and was identified as a gastrinoma by immunohisto­chemistry. (Courtesy of Dr. Kenneth W. Simpson, Cornell University, Ithaca, NY.)

Figure 9.20:

Immunohistochemistry of a gastrinoma. This image shows a pancreatic tumor that was stained for gastrin. Note the massive degree of brown staining on the left side of the picture. The brown stain shows the presence of gastrin, identifying this pancreatic tumor as a gastrinoma. (Courtesy of Dr. Kenneth W. Simpson, Cornell University, Ithaca, NY; magnification: 10?.)

Figure 9.21:

Duodenal perforated ulcer. This figure shows a perforated ulcer in the duodenum of a dog. This dog was diagnosed with a pancreatic tumor that stained positive for gastrin, identifying it as a gastrinoma. (Courtesy of Dr. Kenneth W. Simpson, Cornell University, Ithaca, NY.)

Figure 9.22:

Esophageal ulceration. This image shows an endoscopic view of severe ulceration of the distal esophageal mucosa in a dog with a gastrinoma. (Courtesy of Dr. Kenneth W. Simpson, Cornell University, Ithaca, NY)

Routine laboratory tests do not reveal any specific changes, but up to 50% of affected dogs and cats have a regenerative anemia, indicating ongoing blood loss.

Survey abdominal radiographs are unremarkable in most cases. Upper GI contrast radiography, which is rarely performed these days, may reveal plaque-like defects in the stomach or duodenum, indicating ulceration. In the small number of dogs described, abdominal ultrasonography failed to locate the pri­mary lesion, but abdominal ultrasound may be useful for iden­tifying metastatic lesions. Of the five cats diagnosed with a gastrinoma, two were evaluated by transabdominal ultrasound and in one of these cases the tumor was identified during a repeat ultrasound examination.²² Gastroduodenoscopy allows for direct visualization of esophageal (Figure 9.22), gastric, and duodenal lesions, but cannot identify the underlying cause of these lesions. In human gastrinoma patients, sensitivities and specificities of different localization techniques for gastrinoma have been compared. Abdominal ultrasonography, CT, MRI, or selective angiography all have a rather low sensitivity for the diagnosis of the primary lesion.²³ However, these modalities are all useful in identifying metastatic lesions. Much more promising for localization of the primary lesion are endo­scopic ultrasonography and SRS, which successfully identify the primary lesion in almost all human patients. SRS is the most sensitive technique for localization of both the primary tumor and metastatic lesions in human gastrinoma patients.²³ Currently, endoscopic ultrasonography is not routinely avail­able in veterinary practice. The diagnosis of a gastrinoma by SRS using ¹¹¹In-DTPA-D-Phe¹-octreotide (OctreoScan, Mallinckrodt Medical) has recently been reported in a single dog.²⁶

Diagnosis

Although rare, gastrinomas should be ruled out in all patients with a history of chronic vomiting, weight loss, anorexia, or diarrhea when an alternative diagnosis cannot be arrived at.

A definitive diagnosis of gastrinoma, short of histopathological confirmation, is difficult. A species-specific assay for gastrin is not available, but several assays developed for use in humans have been validated for dogs and cats.²⁷ Few veterinary labo­ratories currently offer serum or plasma gastrin measurements (current reference range for dogs: 10-40 ng/L). According to the diagnostic recommendations for humans, a presumptive diagnosis of a gastrinoma can be made when the 24-hour fast­ing serum gastrin concentration is ten times the upper limit of the reference range. This recommendation is rather conserva­tive and reflects the high prevalence of chronic atrophic gas­tritis in humans, which can cause severely elevated serum gas­trin concentrations in humans. In dogs and cats, differential causes of elevated serum gastrin concentrations are chronic renal failure, gastric outlet obstruction, small intestinal resec­tion, immunoproliferative enteropathy of Basenji dogs, gastric dilation/volvulus, and administration of proton-pump in­hibitors. All of these differential diagnoses are considerably more easy to rule out than atrophic gastropathy in humans.² Therefore, in dogs and cats, a less than 10-fold elevation of serum gastrin concentration may be sufficient to diagnose a gastrinoma if other differential diagnoses have been carefully ruled out.

In cases where serum gastrin concentrations are less markedly elevated, provocative testing may be useful. Secretin can be injected intravenously at a dose of 2 U/kg after withholding food from the patient for a 24-hour period. Blood samples are collected at 0, 2, 5, 10, 15, and 20 minutes. An increase of se­rum gastrin concentration to greater than 200 ng/L or a two­fold increase of the serum gastrin concentration at any time point is considered diagnostic for a gastrinoma.²⁰ Alternatively, calcium is administered intravenously at a dose of 5 mg/kg/h, followed by serial measurements of serum gastrin concentra­tions at 0, 15, 30, 60, 90, and 120 minutes.

calcium challenge test is less sensitive than the secretin chal­lenge test.

Treatment

Symptomatic therapy is started in most cases before a defini­tive diagnosis can be established and should be continued for several weeks after definitive therapy. The mainstay of sympto­matic treatment of human gastrinoma patients are proton­pump inhibitors. The proton-pump inhibitor omeprazole has also been successfully used in the management of canine and feline patients with a gastrinoma (0.7 mg/kg PO q 24 h).^20,22,28 Initially, sucralfate, a mucosal protectant that adheres to the exposed proteins of the ulcer, should be added to the treat­ment protocol (1 g per dog PO q 8 h; 0.25-0.5 g per cat PO q 8 h). Histamine₂ antagonists, such as ranitidine or famo­tidine, at double the standard dose are used if omeprazole is ineffective. Octreotide, a long-acting somatostatin analogue, acts by inhibiting gastrin release and by decreasing gastric acid secretion directly and may inhibit tumor growth, thus affording more than just symptomatic relief. It has been used successfully in two canine gastrinoma patients (2-20 μg∕kg SC q 8 h).^18,20 These two dogs survived for 10 and 14 months, respectively, compared to a reported mean survival time of

5.5 months for other dogs with gastrinoma.²⁰

Before initiating definitive treatment, the patient should be staged, which involves the localization of the primary lesion and the search for metastatic disease. Metastatic lesions serve as a long-term prognostic indicator, and approximately 85% of all dogs and cats with a gastrinoma have metastatic disease at the time of diagnosis. After localization of the primary tumor and after widespread metastatic disease has been excluded, an exploratory laparotomy should be performed. Even if the pri­mary tumor can be identified easily, the rest of the pancreas and abdominal cavity should be carefully inspected for addi­tional primary or metastatic lesions.

If the primary tumor can be identified, it is removed by partial pancreatectomy. The tumor should be submitted for his­topathological examination and immunohistochemical stain­ing for regulatory peptides most commonly found in GI NETs. Metastatic lesions, which are present in most cases, should only be removed if this is possible without radical exci­sion. Postoperatively, the patient should not be given anything per os for 24 to 48 hours, followed by the gradual re-introduc­tion of water and an easily digestible low-fat diet.

If the primary tumor cannot be localized and removed during surgery or if extensive metastatic disease is present, an alterna­tive therapeutic approach should be considered. The use of chemotherapy has not been reported in dogs or cats with a gastrinoma and it has a low success rate in human patients. Radiation therapy using OctreoScan® has been successfully used in humans with a response rate of up to 50%, but has not been attempted in veterinary species.²³ Also, medical therapy as described above may prove useful.

Prognosis

The long-term prognosis for dogs and cats with a gastrinoma is grave. However, with appropriate medical management the short-term prognosis and quality of life can be good. Several canine and feline gastrinoma patients have been successfully managed for more than 1 year after diagnosis.²² With increas­ing awareness leading to earlier diagnosis, improved localiza­tion and staging techniques, and advanced treatment options, survival times are likely to increase further.

9.4.4