Mucinous Gastric Carcinoma With Abdominal Carcinomatosis and Hypergastrinemia in a Dog

Introduction

Gastrinomas in dogs are rare functional tumors of gastrin-secreting cells, usually located in the pancreas; in a single case, a gastrinoma was reported in the duodenum.^1–3 Hypergastrinemia results in excess hydrochloric acid production by gastric parietal cells, leading to gastric and duodenal ulceration. Gastrin also has trophic effects on the gastric mucosa, which may result in diffuse gastric wall thickening. Historically the concurrent findings of gastric hyperacidity, gastrointestinal ulceration, diarrhea, and pancreatic islet cell tumor were referred to as Zollinger-Ellison syndrome, and this term is still occasionally used in the literature.^2–6

Unlike gastrinomas, gastric carcinomas are primary tumors arising from the epithelium of the stomach, and they are the most common primary gastric neoplasms in dogs.⁷ Mucinous gastric carcinomas are an uncommon subtype of gastric carcinoma characterized by marked mucin production and the presence of mucinous lakes. These neoplasms arise from the gastric mucosa, particularly the lamina propria, and they frequently invade the underlying submucosa and metastasize to the regional lymph nodes, mesentery, liver, and spleen.⁸

The veterinary literature includes few case series and case reports of gastrinomas in dogs and cats, and small case series of gastric carcinomas in dogs. The clinical signs from these two tumor types are very similar, with most dogs evaluated for prolonged inappetance or anorexia and vomiting. Differentiation relies on identification of a gastric mass versus a pancreatic mass, histopathological examination, and measurement of fasting serum gastrin concentrations.^2,3,7,9,10 The purpose of this paper is to present a case of mucinous gastric carcinoma that mimicked gastrinoma because of increased fasting serum gastrin, diffuse severe gastric wall thickening, and a peripancreatic mass due to carcinomatosis.

Case Report

A 12-year-old, spayed female Australian cattle dog was presented to the Purdue University Veterinary Teaching Hospital (PUVTH) for further evaluation of a 5-month history of vomiting. Frequency of vomiting had increased over time, ranging from one to six episodes per day. Vomitus consisted of fluid and/or partially digested food, but vomiting episodes were not associated with feeding or time of day. Despite a normal appetite, the dog had lost 2.3 kg since initial presentation to the referring veterinarian 5 months earlier. Diagnostics performed by the referring veterinarian included complete blood count, serum biochemical panel, abdominal radiographs, and gastroscopy (performed approximately 1 week prior to referral). No significant abnormalities were noted, and no biopsies were obtained during the endoscopic examination. Conservative treatment was attempted, which consisted of an oral antiemetic (i.e., metoclopramide), zinc supplementation, pancreatic enzyme supplementation, a bland diet, and H₂ blocker (i.e., famotidine); however, because owner compliance was lacking, effectiveness was difficult to evaluate. According to the owners, famotidine had not been administered for at least 3 to 4 weeks prior to presentation at the PUVTH. At presentation, the dog was slightly thin and approximately 5% dehydrated, but the remainder of the physical examination was unremarkable.

Complete blood count, serum biochemical panel, and urinalysis revealed lymphopenia and eosinopenia (lymphocytes 730 cells/μL, reference range 1000 to 5000 cells/μL; eosinophils 0 cells/μL, reference range 100 to 1250 cells/μL); increases in alanine transaminase (81 IU/L, reference range 3 to 69 IU/L) and alkaline phosphatase activities (554 IU/L, reference range 20 to 157 IU/L); and decreased blood urea nitrogen concentration (6 mg/dL, reference range 7 to 32 mg/dL). Thoracic radiographs were unremarkable. Abdominal radiographs suggested a thickened stomach wall, and a mixture of soft tissue and fat opacity was seen in the cranial abdomen. This resulted in a moderate loss of serosal margins in the abdomen and a mottled appearance to the peritoneum, particularly on the left side [Figure 1]. Abdominal ultrasonography revealed a small amount of free fluid adjacent to the liver. The stomach wall was thickened with loss of normal layering, measuring approximately 1.4 cm in the fundic region [Figure 2]. In the region of the pancreas, a hypoechoic, mass-like lesion that measured approximately 1 cm in thickness was seen, with adjacent hyperechoic fat. A mesenteric lymph node visualized in the same region was slightly enlarged but of normal shape (0.7 cm wide; short:long axis ratio 0.37). Both adrenal glands were at the large end of normal size.

Serum pre- and postprandial bile acids, canine pancreatic lipase immunoreactivity, trypsin-like immunoreactivity, and cobalamin concentrations were within reference ranges, but serum fasting folate concentration was mildly decreased (5.3 μg/L, reference range 7.7 to 24.4 μg/L). Fasting serum gastrin concentration was increased (127 pg/mL, reference range 10 to 40 pg/mL).^a The pH of the vomitus while the dog was fasted was 4 to 5, as measured with both urine dip-stick and standard laboratory pH paper. Basal endogenous adrenocorticotropic hormone (ACTH) concentration was mildly decreased (14.2 pg/mL, reference range 20 to 100 pg/mL), and an ACTH stimulation test revealed increased serum postcortisol concentration (precortisol 4.2 μg/dL, reference range 1.0 to 6.0 μg/dL; postcortisol 27.1 μg/dL, reference range 7.0 to 17.0 μg/dL).

The previously noted abdominal fluid was sampled using ultrasound guidance. Fluid analysis revealed a modified transudate (3200 nucleated cells/μL, protein concentration 2.5 g/dL) with carcinomatosis. A differential cell count revealed a predominance of neutrophils (73%) and fewer macrophages (23%), which were often highly vacuolated and displayed cytophagia. The remaining cells noted were neoplastic, occurring both individually and in clusters. These cells had a dark blue cytoplasm with occasional blebbing around the cell margins. Many cells had punctate, clear vacuoles with an eccentrically located oval nucleus. An equal number of cells displayed signet-ring morphology with a rim of dark cytoplasm around the periphery of the cell and a lighter blue central area that appeared mottled with indistinct vacuolization; these neoplastic cells were most consistent with either carcinoma or adenocarcinoma. No bacterial growth was identified in the peritoneal fluid or a previously submitted urine culture.

Gastroduodenoscopy was performed 2 days after presentation, using an Olympus 1.0 m × 9.8 mm videoscope. The esophageal mucosa had a cobblestone appearance and was diffusely erythematous, particularly orad to the lower esophageal sphincter. Upon entering the stomach, a largerthan-expected volume of bile-tinged fluid was seen, despite 48 hours of fasting. The gastric mucosa was diffusely erythematous and appeared thickened, and the rugal folds were ill-defined even with minimal gastric insufflation. Subjective impression of the endoscopist was that after insufflation with air, the stomach did not distend as uniformly or as much as expected. Ulcers or erosions were not identified in the stomach, and no abnormalities were seen in the duodenum. Smears of gastric pinch-biopsy samples were cytologically consistent with parietal cell hyperplasia with the presence of many fibroblasts. Results of a point-of-care test^b for detection of Helicobacter sp. were not consistent with infection. Biopsy samples were not submitted for histopathology, because the decision was made to proceed with exploratory laparotomy given the uncertainty of primary gastric disease versus gastrinoma and the owner’s desire for palliative intervention.

Exploratory laparotomy the following day revealed a thickened, firm, and irregular-appearing gastric fundus, pylorus, and antrum [Figure 3]. A nodular, yellow, mesenteric mass extended parallel to the left limb of the pancreas and was closely associated with the vascular root of the spleen. The pancreas itself appeared normal, and no mass lesions were palpable within the parenchyma. Omental adhesions were present between the spleen, stomach, and diaphragm; the jejunum was mildly dilated; and an approximately 7.0 cm-diameter, tan nodule encompassed a large portion of the caudate lobe of the liver. Agastrojejunostomy, splenectomy, and a wedge biopsy of the liver nodule were performed. Because the owners had stressed that they preferred aggressive intervention if it offered hope for control of clinical signs, a subtotal gastrectomy was performed. This left only a relatively small portion of the gastric antrum, which was anastomosed end-to-side to the jejunum. A majority of the peripancreatic mass was removed, and a jejunostomy tube was placed.

Histopathological examination of the surgically obtained samples revealed mucinous gastric carcinoma with metastasis to the mesentery and spleen. Neoplastic cells occurring in clusters with glandular to solid arrangements originated from the lamina propria of the stomach and extended into the submucosa and muscularis [Figure 4]. The gastric fundus was the most severely affected region, and neoplastic emboli within lymphatic vessels were seen in many cut sections. Variably defined nodules of neoplastic cells with extensive mucin production were seen in the spleen. The masses within the mesentery also contained numerous neoplastic cells admixed with free mucin as well as intravascular neoplastic emboli. The liver biopsy revealed hepatic glycogenic and lipidic degeneration. Immunohistochemical staining failed to reveal gastrin within the neoplastic gastric cells.^c Because neoplastic cells in all other examined tissues were identical in appearance to the primary mucinous gastric carcinoma, immunohistochemical staining of other tissue sections was not performed.

Multiple complications developed in the immediate post-operative period, including severe pancreatitis with secondary disseminated intravascular coagulation (DIC) and hemothorax. Symptomatic therapy included the following: oxygen therapy via nasal cannulae; withholding of oral food and water; chest tube placement and intermittent thoracocentesis in response to dyspnea; and transfusions with packed red blood cells, plasma, whole blood, and serum albumin in response to anemia, anemia with coagulopathy, and severe hypoalbuminemia with secondary subcutaneous edema. Enteral nutrition was provided via the jejunostomy tube. The dog’s hemothorax and clinical signs of pancreatitis slowly decreased in severity over 7 days but never completely resolved. The owners nevertheless insisted on attempting to manage the dog at home, and the dog was discharged 7 days postoperatively with an extremely guarded prognosis. Two days after discharge, the dog became dyspneic because of severe pleural effusion and was euthanized; a necropsy was not performed.

Discussion

This case report describes a dog with mucinous gastric carcinoma that closely mimicked the clinical presentation and diagnostic imaging appearance expected in dogs with gastrinomas. The dog of this report also had a mild increase in fasting serum gastrin concentration that has not been previously reported in a dog with primary gastric neoplasia. As with our case, dogs with gastrinomas classically are presented with vomiting and anorexia presumptively due to hypergastrinemia, thickened gastric mucosa, and gastrointestinal ulceration.⁷ Hypersecreting pancreatic masses are frequently identified via laparotomy or necropsy, and fasting serum gastrin concentrations are above the reference range.

The increased serum gastrin concentration in this dog is consistent with previous reports of gastrinoma, even though gastrin concentrations were not markedly increased. Fasting serum gastrin concentrations from previously reported dogs with histologically confirmed gastrinomas range from 2.6 to 31.7 times the upper end of the reference range (n=5; 90 to 2780 pg/mL [n=16]),^{2,3,5,6,11–14} with concentrations <200 pg/mL in three cases.^3,5,11 Unfortunately, although absolute values of serum fasting gastrin are often reported, direct comparisons of previous reports are difficult, as various assays have been used; therefore, fold-comparisons above reference range are now conventionally considered more appropriate.

Although some authors have suggested that a fasting serum gastrin concentration >1000 pg/mL is necessary for definitive diagnosis of gastrinoma without further provocative testing, results well below this are often encountered.³ Serum gastrin concentrations in dogs with primary gastric neoplasms have not been reported. We suspect that gastric mucosal invasion by neoplastic cells may have decreased the stomach’s ability to produce hydrochloric acid, resulting in reduced negative feedback for gastrin production. Gastric pH in our dog was slightly higher than normal, although fasting gastric content pH is slightly more alkaline than after feeding.¹⁵

Other reported causes of increased serum gastrin in dogs include gastric ulcers, gastric outflow obstruction, renal failure, hyperparathyroidism, short bowel syndrome, and atrophic gastritis—none of which were present in this dog.¹⁶ Helicobacter pylori infection in the antral mucosa has also been associated with hypergastrinemia in humans.¹⁰ This has not been reported in dogs, and the point-of-care test for detection of Helicobacter sp. used here as well as histopathology were not consistent with infection. The point-of-care test for humans used at our institution is 99% sensitive and 95% specific after a 2-hour incubation, although the accuracy of identifying Helicobacter sp. depends on the bacterial load present, and to our knowledge this test has not been studied in dogs.¹⁷ Ultimately it remains unclear why this particular dog had increased fasting serum gastrin concentration.

Although the clinical presentation, many of the diagnostic imaging findings, and hypergastrinemia were supportive of gastrinoma, in retrospect other findings were more suggestive of a primary gastric neoplasm.¹⁸ The reference range for normal canine gastric rugal fold thickness is 0.1 to 0.8 cm—well below the 1.4 cm measured by ultrasonography in this case.¹⁸ Abdominal ultrasonographic gastric wall measurements over 0.6 to 0.7 cm in dogs have been proposed as being highly consistent with pathological lesions, although thickening is not considered specific for gastric neoplasia, and nonmalignant lesions should likely still be considered.^9,19,20 The severity of gastric wall thickening in dogs with gastrinomas has not been reported.

In addition to the generalized increase in gastric wall thickness, the loss of normal gastric wall layering seen with abdominal ultrasound is also more consistent with a primary gastric neoplasm. In 13 dogs with gastric neoplasia, only one had preserved gastric wall layering.⁹ We presume that the gastric wall hypertrophy that occurs secondary to gastrinomas should maintain normal gastric layering on sonographic evaluation, but this must be systematically evaluated. Interestingly, in human medicine, endoscopic ultrasonography has been used to differentiate mucinous from nonmucinous gastric carcinomas. Mucinous lakes surrounded by reactive fibrous tissue may correlate with reticular, highly echoic speckles; however, these were not seen in this case.²¹

Gastroduodenoscopy was attempted in this dog in the hope of differentiating a primary gastric neoplasm from secondary thickening due to gastrinoma, even though an accurate diagnosis of gastric neoplasia may be difficult to obtain unless neoplastic cells invade the superficial mucosa. Interestingly, we did not note any gastric ulcers or erosions. Gastrointestinal ulceration has been reported in five of seven animals with gastrinoma, and in 18 of 23 dogs with gastric carcinoma.^2,7 The remaining five dogs with gastric carcinoma in this latter report had blanching of the mucosa with loss of the normal submucosal vascular pattern, which is more consistent with our findings. Diffuse infiltration of the gastric wall by carcinomas is referred to as linitis plastica; it is often evident on endoscopic examination as marked thickening of gastric folds, a difficult-to-distend stomach due to wall rigidity, and a “leopard skin” appearance to the mucosa.^22–25 This scirrhous subtype of tumor is highly associated with carcinomatosis in humans, as was seen in this dog.²⁵ Interestingly, in at least one experimental model, hypergastrinemia was associated with development of gastric carcinoma with linitis plastica features in a beagle.²²

Mucinous gastric carcinomas in humans comprise 2% to 5% of all gastric neoplasms.²⁶ This subtype of gastric carcinoma is characterized by a substantial number of mucus lakes (i.e., >50% extracellular mucin) resulting from mucin pooling in the tumor stroma; signet ring cells or carcinomatous glands are frequently seen floating within lakes.^26,27 The potential prognostic relevance of mucin production by gastric carcinomas is controversial. One report suggests that mucinous gastric carcinomas are more deeply invasive tumors, more commonly have lymph node involvement, and reflect a more advanced stage of disease at the time of diagnosis compared to nonmucinous gastric carcinomas. A significant difference in survival time may also be seen between mucinous and nonmucinous gastric carcinomas, although this may be due to the more advanced stage of disease at which mucinous carcinomas are typically diagnosed.²⁶

Some authors further subdivide mucinous gastric carcinomas into undifferentiated and differentiated types, which may also be a prognostic indicator.²⁶ Early-stage mucinous gastric carcinomas may have a similar biological behavior as the nonmucinous form. However, in later stages, lymphatic spread is more common than hematogenous spread, likely because of increased lymphatic permeation in mucinous tumors.^21,28 Early mucinous gastric carcinomas in humans also demonstrate an increased frequency of submucosal invasion (83%) compared with that (43%) in early nonmucinous carcinomas. Finally, mucinous gastric carcinomas have been proposed to originate as adenocarcinomas and later become mucinous with tumor progression.²⁸

The optimal surgical intervention for such an extensive tumor is unclear. In a case series of 21 dogs with malignant gastric neoplasia, two underwent gastrojejunostomy and were euthanized 4 and 5 weeks postoperatively because of recurrence of vomiting and anorexia.⁸ Data regarding survival times for dogs with advanced-stage gastric carcinoma are not available. The development of pancreatitis, DIC with hemorrhagic pleural effusion, anemia, and severe hypoalbuminemia were significant complications in our case. Unfortunately, even though these complications were managed with partial success, the persistent pleural effusion resulted in humane euthanasia being the only viable option because of the dog’s quality of life and owner financial constraints.

Conclusion

Although rare, mucinous gastric carcinoma should be a differential diagnosis in dogs with diffuse gastric wall thickening. As demonstrated by this case, dogs with mucinous gastric wall carcinoma may have mild increases in fasting serum gastrin concentration of unexplained etiology. Therefore, an increased fasting serum gastrin concentration, when less than the published recommendation of >1000 pg/mL, should not be automatically considered diagnostic for gastrinoma. Future studies should more thoroughly investigate fasting serum gastrin concentrations in dogs with neoplastic and nonneoplastic primary gastric diseases, in order to better establish the sensitivity and specificity of various values as predictors for gastrinomas.