Chronic Vomiting Associated With a Gastric Carcinoid in a Cat

Introduction

Feline, nonlymphomatous, malignant gastric neoplasms and carcinoid tumors are rare. Carcinoid tumors have been documented in a variety of anatomical locations in the cat, including the liver, intestine, and lung. The purposes of this report are to describe the clinical and pathological characteristics of a feline gastric carcinoid and briefly review the pathophysiology, biological behavior, and treatment of carcinoid neoplasms in both humans and small animals.

Case Report

A 15-year-old, 4.6-kg, castrated male domestic shorthair cat was examined for vomiting of 5 months’ duration. Frequency of vomiting varied from one to five times daily, and the vomitus consisted of small volumes of bile-tinged fluid, with hematemesis being observed on two occasions. The cat maintained a normal appetite during the entire course of illness, and no diarrhea was noted by the owner. Four months prior to the onset of vomiting, vaccines for rabies, feline viral rhinotracheitis, calicivirus, and panleukopenia were administered. There was no previous history of other major medical problems, and the cat was housed exclusively indoors with three other healthy, adult cats.

Twenty-two days prior to presentation, the cat was examined by the referring veterinarian. Physical examination findings were normal. Diagnostic tests including a complete blood count (CBC), serum biochemical profile (SBP), fecal flotation, feline leukemia virus and feline immunodeficiency virus enzyme-linked immunosorbent assay, and serum total thyroxine (T₄) concentration were performed. The CBC and T₄ were within reference ranges. The only abnormal biochemical finding was azotemia, characterized by a blood urea nitrogen (BUN) of 39 mg/dL (reference range, 16 to 35 mg/dL) and a serum creatinine of 2.2 mg/dL (reference range, 0.5 to 1.9 mg/dL). Gastroduodenoscopy was performed under general anesthesia on the following day. Grossly, a 4-cm, superficial ulcer was visualized at the pyloric antrum, with the other anatomical areas of the stomach and duodenum appearing normal. Suppurative gastritis was identified during histopathological examination of biopsies obtained from the ulcerated gastric mucosa. Sucralfate^a (250 mg per os [PO] q 8 hours for 10 days) and cimetidine^b (50 mg PO q 8 hours for 10 days) were prescribed by the referring veterinarian. The vomiting decreased in frequency to one to two times daily following this treatment.

Physical examination findings at initial presentation to the Veterinary Teaching Hospital revealed a bright, alert, and responsive cat in good body condition. Temperature, pulse, and respiratory rate were within normal limits. Abdominal palpation revealed kidneys that were small with smooth, regular surfaces. The remainder of the physical examination, including fundic evaluation, was unremarkable.

Initial evaluation included a CBC, SBP, urinalysis, and zinc sulfate fecal flotation. Abnormal findings included azotemia (BUN, 35 mg/dL; reference range, 16 to 34 mg/dL; creatinine, 2.3 mg/dL; reference range, 0.5 to 1.9 mg/dL) and isosthenuria (urine specific gravity, 1.012). Feces appeared normal, and flotation failed to identify any parasitic ova. The cat was determined to be in stable, chronic renal failure based on physical and laboratory assessments. Blood pressure was normal using indirect Doppler methodology. The azotemia in this patient was felt to be of insufficient magnitude to be the sole explanation for the chronic vomiting, and it prompted the pursuit of primary gastrointestinal disease. Abdominal ultrasonography revealed small kidneys, with a loss of renal corticomedullary distinction bilaterally. The gastric wall was thickened (12 mm at maximal diameter; reference range, <4 mm); contained several variably sized (2 to 5 mm), hypo-echoic cavitary lesions; and appeared to have an irregular mucosal surface in the region of the lesser curvature. A 6-mm, hyperechoic nodule was visualized in the margin of the caudate lobe of the liver. Fine-needle aspiration of the hepatic nodule was performed using a 25-gauge, 3.81-cm, hypodermic needle. Cytopathological evaluation of the hepatic aspirate revealed normal hepatocytes.

Following a 12-hour fast, the cat was premedicated with glycopyrrolate^c (0.02 mg/kg body weight, subcutaneously [SC]), oxymorphone^d (0.05 mg/kg body weight, intravenously [IV]), and diazepam^e (0.33 mg/kg body weight, IV). Anesthetic induction was performed with propofol^f (3 mg/kg body weight, IV) and maintained with isoflurane^g following endotracheal intubation. Lactated Ringer’s solution was administered IV (10 mL/kg body weight per hour) throughout the procedure. Gastroduodenoscopy was performed using a 104-cm, flexible videoendoscope with 9.8-mm outer diameter and 2.8-mm biopsy channel.^h During visual examination, a 0.5-cm, superficial erosion was present along the ventral aspect of the lower esophageal sphincter. A 4-cm gastric ulcer was identified along the angularis incisura [Figure 1]. The ulcerated area hemorrhaged mildly during the procedure. Other gastric regions and the duodenum were grossly normal. Multiple biopsies of the duodenum, pylorus, angularis incisura, and cardiac and fundic regions of the stomach were obtained. Numerous biopsy samples were also collected from the thickened, nodular margins of the ulcerated lesion; however, no samples were taken from the ulcerated area itself. A rapid urease testⁱ was performed with a biopsy specimen from the angularis, and results were negative. The cat recovered from anesthesia uneventfully and was discharged the following day with instructions for the owner to administer sucralfate suspension^a (250 mg PO q 6 hours) for treatment of gastric ulceration and esophageal erosion, pending histopathological results. Lymphosarcoma, adenocarcinoma, and gastrinoma were considered possible differential diagnoses based on the clinical history and gross endoscopic findings.

Endoscopic biopsies of duodenum, pylorus, cardia, and greater curvature were histopathologically normal. With hematoxylin and eosin (H&E) staining, biopsy samples from the angularis revealed an infiltrating population of small, round neoplastic cells with markedly vacuolated cytoplasm that distorted normal mucosal architecture. The neoplastic cell population demonstrated variable amounts of fine cytoplasmic stippling. A moderate amount of pyogranulomatous inflammation surrounded the round cell population. Grimelius and Steiner silver staining revealed a small population of neoplastic cells with cytoplasmic, silver-positive granules. No mast cells were noted. In the absence of histopathological evidence of gastric mucosal hypertrophy and duodenal ulceration, light microscopic features of this tumor were most consistent with a gastric carcinoid, although lymphoma and gastrinoma could not be completely excluded. Excisional biopsy was recommended for definitive diagnosis.

The cat returned to the Veterinary Teaching Hospital 7 days later for reevaluation in preparation for surgical resection of the gastric neoplasm. The owner documented that the frequency of vomiting had decreased; vomition was observed five times in the previous week and hematemesis was documented once. Physical examination findings were unchanged from the previous visit. Results of CBC and SBP revealed azotemia (BUN, 38 mg/dL; creatinine, 2.0 mg/dL). Results of three view thoracic radiographs were normal.

The cat was anesthetized using the same protocol described previously. Cefazolin^j (20 mg/kg body weight, IV) was administered preoperatively and q 6 hours for the first 24 hours of the postoperative period. An exploratory celiotomy was performed through a ventral midline approach. A firm, approximately 6-cm long, subserosal mass was palpated in the lesser curvature of the stomach, and gastric lymphadenopathy also was noted during gross inspection of the abdomen. The gastric node was completely excised. A partial gastrectomy was performed to excise the gastric mass, followed by a partial lobectomy of the caudate lobe of the liver (caudal 1.5 cm excised). The gastric mass was 6.5-cm long, 2.0-cm wide at its greatest diameter, and had raised, nodular borders with multiple, healed, central, ulcerative mucosal lesions on visual inspection after excision [Figure 2]. Performance of a renal biopsy to further characterize the renal disease and surgical placement of a jejunostomy tube were considered to facilitate postoperative nutritional management, but were declined by the owners.

The cat recovered from surgery without complication. Oxymorphone^d (0.05 mg/kg body weight, SC q 6 hours) was administered for 24 hours postoperatively for analgesia. The cat was offered one-half of its daily caloric requirements in multiple, small feedings the day after surgery using a commercial recovery diet,^k which was readily consumed. Caloric intake was increased by 25% daily until calculated maintenance requirements were met, at which time the cat was discharged to the owners (approximately 88 hours postoperatively). The cat vomited once during the postoperative period, immediately after parenteral administration of cefazolin.

Histopathological evaluation of the surgical biopsies of the lymph node and liver revealed reactive hyperplasia and mild hepatic lipidosis with cholestasis, respectively. There was no microscopic evidence of neoplasia in either specimen. The gastric mass consisted of several well-delineated nodules within the gastric wall. The nodules were composed of neoplastic round cells forming packets within a delicate fibrovascular stroma [Figure 3]. The round cells contained moderate amounts of pink, vacuolated cytoplasm. Nuclei of the round cells were round to oval and of varying size, with occasional mitoses. The round cells extended into the mucosa, adjacent to the gastric ulceration. Histopathologically, the gastric mass was diagnosed as a carcinoid neoplasm. Examination of the surgical margins of the biopsy sample revealed no evidence of neoplasia.

Transmission electron microscopy was also performed on tumor tissue. Cubes of tissue (1 mm) were fixed in buffered glutaraldehyde, dehydrated, and embedded in polymer. Uranyl acetate and lead citrate-stained sections were examined. Ultrastructurally, tumor cells showed features typical of neuroendocrine (i.e., carcinoid) cells. There was abundant, rough, endoplasmic reticulum in all cells and free ribosomes in many. Some cells [Figure 4] contained prominent cytoplasmic granules, which are the ultrastructural correlate of the silver-staining granules seen on light microscopic examination. Enlarged and irregular mitochondria, with pseudotubular arrays formed within the mitochondrial inner membranes, were also visualized within multiple tumor cells.

The cat was presented approximately 21 weeks following surgery for evaluation of severe polyuria and polydipsia. Physical examination revealed a 5% dehydrated cat with pale mucous membranes and bilaterally small and irregular kidneys. Laboratory evaluation revealed normocytic, normochromic anemia (hematocrit, 17%; reference range, 32% to 45%), azotemia (BUN, 99 mg/dL; creatinine, 8.6 mg/dL), hyperphosphatemia (9.1 mg/dL; reference range, 2.9 to 7.3 mg/dL), and isosthenuria (urine specific gravity, 1.010). Abdominal ultrasonographic examination revealed small kidneys with hyperechoic parenchyma, irregular capsules, and loss of renal corticomedullary definition. Other ultrasonographic findings were unremarkable, with no evidence of metastases noted. Initial treatment consisted of rehydration and diuresis with IV lactated Ringer’s solution. Progressive, chronic renal failure was suspected as the cause of the polyuria and polydipsia, and therapy with recombinant human erythropoietin was recommended to treat the anemia. The owner declined additional diagnostics and treatment, and the cat was lost to follow-up.

Discussion

Nonlymphomatous gastric neoplasia in the cat is rare.^1–4 Adenocarcinomas are the most commonly reported primary nonlymphomatous tumor of the feline stomach, although gastric mast cell tumors have also been described.¹²⁵⁶ Vomiting, anorexia, and weight loss are the most common clinical signs associated with gastric cancer in cats. Non-lymphomatous tumors of the feline stomach are best treated by surgical resection. However, as most cases have advanced disease precluding complete surgical resection at the time of diagnosis, the long-term prognosis is poor.¹²⁵ Gastric neoplasia commonly affects middle-aged to geriatric cats, and Siamese cats appear to be predisposed to the development of gastrointestinal adenocarcinomas.^13–57 Several veterinary oncology references cite that feline carcinoids occur in the stomach.¹²⁵ However, the original reference referred to in those texts describes a feline foregut carcinoid that originated in the duodenum, not the stomach.⁸ To the authors’ knowledge, this is the first report describing clinical and pathological features of a feline gastric carcinoid.

Carcinoid neoplasms originate from cells of the enterochromaffin system and are often referred to as amine precursor uptake and decarboxylation (APUD) tumors or APUDomas.⁸⁹ The APUD nomenclature is based upon the ability of cells of the enterochromaffin system to synthesize, secrete, and metabolize biologically active amines. APUDomas are further classified by their anatomical location and particular secretory products.^8–11 The advent of new immunohistochemical, immunological, and molecular biological diagnostic techniques that have allowed for further identification and characterization of the secretory products of many neuroendocine tumors has led to a proposed name change from APUDomas to tumors of the diffuse neuroendocrine system. Specific orthoendocrine and paraendocrine syndromes resulting from tumor secretion of various vasoactive amines are common in humans.¹⁰¹²¹³ In humans, foregut carcinoid tumors originate from the bronchi, pancreas, stomach, or duodenum and are associated with marked, intermittent erythema of the torso and head. Chronic usage of inhibitors of gastric acid secretion, particularly proton-pump inhibitors, for the treatment of gastric reflux disease has been demonstrated to be a risk factor for the development of gastric carcinoid neoplasms in humans and laboratory animals.¹⁴ Midgut carcinoids are associated with the classic carcinoid syndrome in humans, which consists of diarrhea, erythema, asthenia, organomegaly, and right-sided congestive heart failure secondary to tricuspid or pulmonic insufficiencies, and are located in the jejunum, ileum, and colon. The carcinoid syndrome is caused by the synthesis, release, and delayed hepatic metabolism of 5-hydroxytryptamine (5-HT, serotonin) and tachykinins by tumor cells.⁸¹¹¹² Rectal (i.e., hindgut) carcinoids have also been reported in humans but have not been associated with specific secretory products.¹⁰¹¹

In the veterinary literature, carcinoid tumors affect older dogs and cats, and orthoendocrine and paraendocrine syndromes have not yet been identified.^7–911 Because of the existence of unique paraneoplastic syndromes in many humans with carcinoid tumors, a tentative diagnosis of carcinoid neoplasia is often made following recognition of appropriate clinical signs, measurement of urinary serotonin metabolites, provocative pentagastrin testing, specialized radionucleotide imaging, computed tomographic studies, or a combination of the above, although definitive diagnosis requires biopsy and histopathological examination of tumor tissue.¹⁰¹³¹⁵ In humans with poorly differentiated neuroendocrine tumors, immunohistochemical staining for neuropeptides (i.e., bombesin, somatostatin, or both) or ultrastructural examination can facilitate the diagnosis of carcinoid neoplasia. The finding of multiple cytoplasmic granules is a classic electron microscopic feature of neuroendocrine neoplasia. As demonstrated in human medicine, these prominent cytoplasmic granules contain the various vasoactive products of neuroendocrine tumor cells. In the absence of recognizable orthoendocrine or paraendocrine syndromes in dogs and cats, diagnosis of carcinoid neoplasia in veterinary patients requires histopathological examination of tumor tissue. As carcinoid tumors may resemble mast cell neoplasia or undifferentiated epithelial neoplasia on routine H&E preparations, special silver stains, immunohistochemistry, electron microscopy, or a combination of the above may be required for definitive diagnosis.^3616–18 In this case, the presence of argyrophilia in tumor cells examined using routine histopathology techniques, and the results of electron microscopic evaluation were felt to be sufficient to confirm the diagnosis of carcinoid neoplasia; therefore, immunohistochemistry was not performed.

The biological behavior of carcinoid tumors in humans has been well described.^1012131920 Gastrointestinal carcinoids tend to be slow growing and locally invasive. Common metastatic sites include local and regional lymph nodes, liver, pancreas, and lung. The preferred treatment in humans is surgical resection, but palliation of clinical signs associated with the carcinoid syndrome can be achieved with the use of long-acting somatostatin analogues.¹²¹⁹ Combination therapy with intra-arterial chemotherapy, arterial chemoembolization techniques, and somatostatin analogues has been beneficial in humans with distant metastases.¹⁹ The long-term prognosis for humans with gastrointestinal carcinoid tumors is fair to good, with one study reporting a median survival time of 8 years following the recognition of the carcinoid syndrome.¹⁰

Carcinoid neoplasms in companion animals tend to be locally invasive and metastasize to liver, local lymph nodes, lung, pleura, and peritoneal cavities.³¹¹¹⁸ Surgical excision remains the treatment of choice. To the authors’ knowledge, no studies have been performed that evaluate survival times in large groups of animals with carcinoid tumors. There is also a lack of current literature on the use of cytotoxic chemotherapeutic agents for treatment of metastatic carcinoid neoplasms, although use of octreotide for the treatment of neuroendocrine tumors of the gastrointestinal tract has been previously reported.²¹

Attempts to measure vasoactive substances in blood or urine were not made in this case because of the lack of clinical evidence of an orthoendocrine or paraendocrine syndrome, the relative unavailability of assays for substances such as urinary serotonin metabolites, and the lack of established reference values for those assays in the cat. In addition, accurate interpretation of elevated basal concentrations of certain tumor-elaborated substances (i.e., gastrin) may have been further complicated by the concurrent renal failure. Hypergastrinemia occurs in renal failure secondary to reduced renal clearance of gastrin.²² Diagnosis of gastrinoma can be further facilitated by the demonstration of a marked increase in basal serum gastrin above the reference range, response to provocative secretin or calcium infusions, or both.²² However, in humans, extremely elevated serum gastrin concentrations have also been associated with atrophic gastritis, and the diagnostic sensitivity and specificity of provocative testing in veterinary species for the diagnosis of neuroendocrine neoplasia has not been definitively established.²²

In the first 4 months following surgery, the cat remained free of clinical signs of gastrointestinal disease and gained weight (1.2 kg). Considering that the current human literature demonstrates the slow growth potential of gastrointestinal carcinoid neoplasms,^12131920 the histopathological evidence of complete excision and the lack of demonstrable metastases with thoracic radiography, abdominal ultrasonography, and hepatic and regional lymph node histopathology, the cat was scheduled for examinations consisting of thoracic radiographs and abdominal ultrasonography every 6 months to screen for metastatic disease. However, the cat was lost to follow-up 4 months after surgery, following the identification of progressive chronic renal failure.

The possibility exists that the neoplasm described in this case could represent a different specific neuroendocrine tumor (i.e., gastrinoma) other than a carcinoid. Immunohistochemical studies to identify specific secretory products (i.e., gastrin, neuron-specific enolase) or the demonstration of elevated blood concentrations of gastrin, or both, would have been required to definitively diagnose a gastrinoma;²² neither were performed in this case. In the event that this neoplasm was actually a gastrinoma, the case remains extremely unusual, as gastrinomas are exceedingly rare in the cat, and extrapancreatic forms of this tumor have not been previously reported in the veterinary literature.

Conclusion

Although an isolated report, this case demonstrates that significant clinical improvement may occur with aggressive, complete surgical excision of locally confined carcinoid tumors, and this is the first report to describe the clinical and pathological features of feline gastric carcinoid neoplasia. Additional study of a larger number of cases is required before any conclusions can be drawn regarding the long-term prognosis associated with carcinoid neoplasia in cats.