Gastrointestinal neoplasms in dogs and cats (Proceedings)

Primary gastrointestinal (GI) neoplasia is an important differential diagnosis for a dog or cat with vomiting or diarrhea, especially chronic vomiting or diarrhea, anorexia and weight loss, particularly animals that are middle-aged and older. Some GI neoplasms have been associated with paraneoplastic syndromes such as hypoglycemia and polyuria/polydipsia, which could provoke additional clinical complaints. Depending on the tumor type and location, patients with GI neoplasia can have extensive disease at the time of definitive diagnosis, often worsening the prognosis. Thus, early diagnosis becomes important to improving clinical outcomes.

Etiology and pathophysiology

The most common primary gastric tumor in dogs is adenocarcinoma in various forms; lymphosarcoma and smooth muscle tumors (leiomyomas, leiomyosarcomas) are considered the next most common tumors. Dogs with gastric tumors are most commonly middle-aged to older dogs. The antrum and lesser curvature are the most common sites in which adenocarcinomas are found in dogs. Common metastatic sites of gastric adenocarcinomas include regional lymph nodes, liver, spleen, omentum/peritoneal cavity, and lung. The most common primary gastric tumor in cats is lymphosarcoma, which can have a diverse array of appearances from infiltrative to polypoid lesions. Gastric adenocarcinomas can be seen in cats, but are considered rare. In both dogs and cats, gastric lymphosarcoma is commonly a part of more diffuse gastrointestinal lymphosarcoma, but can be seen as a solitary tumor in the stomach. Extramedullary plasmacytomas have been described in both dogs and cats as primary gastric or bowel tumors.

The most common intestinal tumor in cats is lymphosarcoma; in dogs, intestinal lymphosarcoma intestinal adenocarcinoma and intestinal smooth muscle tumors are seen with around the same frequency although lymphosarcoma is reported a bit more often than the other tumor types. Other tumor types that have been described in the bowel include leiomyomas, leiomyosarcomas; gastrointestinal stromal tumors (GIST), plasma cell tumors, mast cell tumors, carcinoids (tumors of neuroendocrine origin) and extraskeletal osteosarcomas. Benign polyps can be found in the duodenum of cats or the rectum of dogs. GISTs have been recently described as tumors that arise from the interstitial cells of Cajal, cells that regulate intestinal motility and peristalsis. GISTs have histological features that are very similar to intestinal smooth muscle tumors, but are distinguished by positive staining for c-kit (CD117). In one report that characterized GIST, there was a predilection for this tumor in dogs to be seen in the cecum and large intestine whereas the smooth muscle tumors were more likely to be seen in the stomach and small intestine; only the dogs with GIST had hypoglycemia. The paraneoplastic syndromes attributed in the older literature to leiomyomas/leiomyosarcomas have the potential to be a result of GIST. Intestinal adenocarcinomas in dogs are seen more often in the large intestine than the small intestine.

Animals with GI tumors are most commonly middle-aged to older. Common metastatic sites of non-lymphoid intestinal tumors include regional lymph nodes, liver, spleen, omentum/peritoneal cavity and lung.

GI tumors can disrupt normal gastrointestinal motility likely as a consequence of disruption of the intestinal smooth muscle wall and/or accompanying inflammatory changes, or cause obstructive disease. Ulceration of the GI mucosa is a feature of GI tumors in some patients, but will not be present in all. In patients with GI bleeding secondary to mucosal ulceration, chronic blood loss can lead to iron deficiency anemia, which can be either regenerative or non-regenerative. Because indices and erythrocyte morphology don't always betray the existence of regenerative responses, obtaining a reticulocyte count in patients with undefined anemia becomes an important diagnostic step as reticulocytosis indicates that anemia is from either hemorrhage, or hemolytic disease.

Clinical features

Patients with primary GI neoplasms most commonly present with a history of anorexia, weight loss, diarrhea and/or vomiting; vomiting in patients with gastric or proximal duodenal ulcers may have hematemesis. Melena may be seen in some and if the tumor is located in the large bowel, there may be hematochezia, tenesmus and ribbon-like stools, or frank bleeding from the anus. Dogs especially may exhibit features of both large and small bowel diarrhea when tumors are located in the cecum or ileocecocolic region. As noted above, some patients with intestinal tumors may exhibit polyuria/polydipsia and signs of hypoglycemia (tremors, seizures).

The physical examination in affected patients is variable. Poor body condition will be appreciated in animals with weight loss, and an abdominal mass may be palpable in some patients. Cats with GI lymphoma commonly have enlarged mesenteric lymph nodes appreciated during abdominal palpation. Abdominal distension and a fluid wave are possible findings in animals with hypoalbuminemia or peritoneal carcinomatosis. Animals that have developed anemia secondary to neoplasm-associated GI ulceration may have pale mucous membranes. During rectal examination, rectal masses may be palpable and evidence of melena may be appreciated; in the author's experience, some rectal masses are very soft and friable and can be easily mistaken for a mucosal fold, so a hurried rectal examination in a candidate patient is not advised.

Results of routine laboratory testing (CBC, biochemical profile, urinalysis, fecal flotation) help exclude non-gastrointestinal origins of clinical signs such as hepatic, renal or adrenal gland (hypoadrenocorticism) disease, although results are not always helpful and can, in some cases, be confusing (e.g. pre-renal azotemia and an increase in BUN disproportionate to the serum creatinine, which can reflect gastrointestinal bleeding). Hypoglycemia is a feature of occasional patients with GI tumors. While not a common disease of middle-aged and older patients, dogs with atypical forms of hypoadrenocorticism can have clinical and laboratory features that overlap those with GI tumors, so this becomes an important differential, especially for younger animals that could have GI lymphoma.

Anemia, which can be regenerative or non-regenerative, and may have features of iron deficiency (microcytosis, hypochromasia), may be seen in patients with bleeding GI tumors; anemia could also reflect chronic inflammatory disease. Erythrocytosis has been described in a dog with a cecal leiomyosarcoma (which may have been a gastrointestinal stromal tumor as alluded to above). Inflammatory leukograms (mature neutrophilia, monocytosis), thrombocytosis or thrombocytopenia are also possible on the CBC. Biochemical profile results are usually normal unless there has been large scale bleeding, in which case decreases in albumin and total protein are possible; some patients can develop hypoalbuminemia secondary to enteric protein loss. Increases in liver enzyme activities may be seen in animals with hepatic metastasis, and hyperglobulinemia secondary to monoclonal gammopathy has been occasionally described in dogs with extramedullary intestinal plasma cell tumors. Low urine specific gravity would be expected in those patients with PU/PD as part of their presentation.

Suspicion of a GI tumor may be raised by plain or contrast radiographs, or abdominal ultrasonography. Radiographic findings may include thickened gastric wall, displacement of the stomach, or a mass-like effect in the abdomen with displacement of segments of bowel if the mass is large enough; extraskeletal osteosarcomas may have a mineralized density associated with a segment of bowel. For animals with masses causing partial bowel obstruction, dilated/distended GI segments may also be seen. For those animals having contrast studies performed, filling defects and mucosal irregularity, and delayed passage of contrast material and mass lesions or constrictions of the affected GI segment may be appreciated.

Ultrasonographic features of GI tumors include wall thickening, which can be focal or somewhat diffuse, focal masses, mucosal craters that suggest ulceration, or disruption of the normal layering of the GI wall. In one study, loss of normal wall layering of the small intestine was highly associated with the presence of an intestinal tumor, but animals with severe inflammatory intestinal disease also had a loss of normal wall layering. Animals with obstruction can have dilated GI segments that exhibit hyper- or hypomotility. Regional lymph nodes may be enlarged as a consequence of either hyperplasia secondary to inflammation, or metastasis to these nodes; aspiration cytology may help clarify the status of such lymph nodes. Nodules in the liver or spleen may be indicative of metastatic disease. Because nodular hepatic changes are commonly observed ultrasonographic findings in older animals, especially dogs, conclusions regarding metastatic disease are better made based on cytology or histopathology of suspicious lesions. Abdominal effusion can be a consequence of peritoneal carcinomatosis, which can lend a thickened to nodular and hyperechoic appearance to the mesentery, or hypoalbuminemia secondary to enteric protein loss.

Endoscopic findings in animals with GI tumors vary with the site and tumor type. Endoscopic findings with gastric tumors include ulcers and erosions, polypoid lesions, obvious thickening of the gastric wall (usually best appreciated in the incisura angularis), inability to distend the stomach with air, and retention or prominence of rugal folds. A normal appearance to the gastric mucosa during endoscopic examination does not rule out a gastric neoplasm as some tumors may be deep to the gastric mucosa. Many focal small intestinal tumors are not endoscopically visible given the working length of most endoscopes. Endoscopic findings of intestinal lymphosarcoma can include increased friability (usually manifest as increased tendency for mucosal bleeding), prominent villous tips creating a cobblestone appearance, or solitary mass-like lesions. Erosions and ulceration with focal GI lymphoma are also possible; in the author's experience, these changes are uncommonly seen in patients with diffuse mucosal lymphoma. Large intestinal tumors may appear polypoid, ulcerated or as cauliflower-like lesions; bleeding from the surface may be observed. It is possible for multiple masses to be found during colonoscopy so examination of the entire colon is important even in patients with rectal or distal colonic masses.

Definitive diagnosis of GI tumors is based on cytological or histological demonstration of neoplastic cells. It may be possible to obtain material for cytology from rectal scrapes in patients with rectal masses; on some occasion, the author has had pieces of tissue exfoliate onto a glove during rectal examination, and such pieces of tissue can be submitted for cytological examination, or histology if large enough. Ultrasound-guided needle aspiration cytology of an intestinal mass or enlarged mesenteric lymph node can provide a diagnosis of lymphosarcoma in dogs and cats, and occasionally be strongly suggestive of adenocarcinoma. Nodules in the liver and spleen are also candidates for aspiration and can provide cells for definitive diagnosis, and further stage the patient. Occasionally, rafts of overtly neoplastic cells will be recovered from an abdominal effusion, so it is worth performing abdominocentesis and submitting a portion of the sample to a clinical pathology laboratory for analysis. Biopsies for histopathology can be obtained by endoscopic pinch biopsy if the lesion is considered endoscopically accessible, or during surgical exploration of the abdomen.

Patients that are suspected of GI tumors should be clinically staged with abdominal imaging, ideally abdominal ultrasound, and thoracic radiographs; we have seen patients at WSU that had metastatic lesions detected during abdominal computed tomographic scans that were not detected with abdominal ultrasound. Nodules observed ultrasonographically in other organs, or enlarged abdominal lymph nodes, may be aspirated as noted above for cytological examination to assess for metastasis. It is important to remember that negative results of any staging procedure do not guarantee an absence of tumor, something this author feels that the owners should be warned of before surgical interventions. The role of advanced cross sectional abdominal imaging (abdominal computed tomography or magnetic resonance imaging) for staging patients suspected of having intestinal tumors needs to be explored. Thoracic CT scans are more sensitive for detection of pulmonary metastasis and could be considered where available prior to taking an animal with suspected intestinal neoplasia to surgery.

Treatment

Surgical resection is the preferred treatment of dogs or cats for most forms of GI neoplasia, particularly for those without overt evidence of metastatic disease; animals with evidence of intestinal obstruction and metastatic disease may need surgical resection for palliative treatment of the intestinal obstruction. Reliably effective chemotherapeutic protocols for all intestinal neoplasms save lymphoma have not been established, although many agents have been tried.

Surgical resection is the preferred treatment of patients with adenocarcinomas, smooth muscle tumors, GISTs, extramedullary plasmacytomas and other solitary tumors, particularly for those without overt evidence of metastatic disease. Whether patients with solitary GI lymphoma should have surgical resection as a first intervention is a matter of some debate. Locally extensive disease and/or metastatic disease in most patients with adenocarcinoma, especially gastric adenocarcinoma, usually precludes surgical cure, but surgery may still be of palliative benefit for the relief of gastric obstruction if present. Reliably effective chemotherapeutic protocols for gastric adenocarcinomas have not been established, although many agents have been tried.

Chemotherapy is the preferred treatment approach to both dogs and cats with intestinal lymphoma. Multiple protocols have been used in dogs and cats with intestinal lymphosarcoma. The type of protocol selected is often influenced, especially in cats, by the grade of the lymphosarcoma. Cats with mature (lymphocytic) forms of intestinal lymphoma are often treated with relatively less aggressive protocols that rely on prednisone, vincristine and an alkylating agent (cyclophosphamide or chlorambucil) while lymphoblastic forms are treated with more aggressive multi-agent protocols. Consultation with a veterinary oncologist can be of great value in deciding the best chemotherapeutic approach to the patient with intestinal lymphosarcoma. Plasma cell tumors of the GI tract have also been treated with chemotherapy (prednisone, melphalan) although there is not enough information in the literature to determine if there is any advantage to treating these animals with chemotherapy after a clean surgical resection; however, recurrence is generally expected following incomplete resection of plasma cell tumors.

In cases in which surgery is not possible, it is reasonable to consider administration of a non-steroidal anti-inflammatory drug (NSAID), particularly for those patients that have carcinomas. Increased cyclooxygenase-2 (COX-2) expression has been documented in dogs with colorectal polyps, and clinical responses (reduction in tumor) realized from treatment with nonsteroidal anti-inflammatory drugs (NSAIDs). Larger, prospective clinical studies of the role for NSAIDs in treating dogs with intestinal epithelial neoplasms, both benign and malignant, are needed. The presence of GI ulcers secondary to a tumor can present a treatment dilemma, but the author has proceeded with such therapy, usually with a COX-2 selective NSAID, after careful discussions with owners.

Prognosis

The prognosis for patients with GI neoplasms varies with the tumor type. Dogs with gastric adenocarcinoma typically have a poor to grave prognosis because of extensive disease at the time of diagnosis. Cats with lymphocytic lymphosarcoma can live for many months to years; the prognosis for cats with the lymphoblastic form of lymphoma have a worse prognosis with median survivals with multi-agent protocols in the 8 month range. Dogs with GI lymphosarcoma are generally viewed as having a poor prognosis, although some recent papers suggest the possibility of a better prognosis for dogs with lymphoma limited to the colon. Extramedullary plasma cell tumors of the intestine generally carry a good prognosis provided that surgical resection gives clean margins and there is no evidence of metastatic disease (especially to regional lymph nodes). Dogs with GIST that survive the initial perioperative period reportedly can have a good prognosis with median survivals of 37.4 months after surgical resection alone. By comparison, median survival of dogs with intestinal leiomyosarcomas treated with surgical resection was 7.8 months. In contrast to soft tissue sarcomas in other locations, there is little information regarding the prognostic value of the histological grade of intestinal leiomyosarcomas. The prognosis associated with extraskeletal osteosarcomas of the intestine has been uniformly poor (median survival times less than 2 months for the GI forms), although the author recently treated a patient with a jejunal extraskeletal osteosarcoma that lived for 7 months with surgical resection and chemotherapy before metastatic disease was detected. The prognosis associated with intestinal adenocarcinomas in cats is considered poor as most have advanced disease at the time of diagnosis; intestinal adenocarcinomas in dogs generally carry a guarded prognosis.

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