Carolyn J. Henry, DVM, MS, DACVIM (Oncology)
Gastrointestinal (GI) cancer is relatively rare in veterinary oncology compared to human oncology, but it is an important differential for companion animal patients presenting with the complaints of vomiting, weight loss, or diarrhea. Prognosis and therapy options vary widely, depending upon tumor histology, location, and stage at the time of diagnosis. For purposes of this discussion, the term "gastrointestinal cancer" will be used to refer to malignancies affecting the GI tract distal to the esophagus, as esophageal malignancies are very rare and oral cancers are beyond the scope of this lecture. Apocrine gland anal sac adenocarcinoma (AGASACA) will also be discussed, time permitting.
Lymphoma is the most common GI malignancy in dogs and cats and will be considered separately here. Diagnosis of GI lymphoma is generally based upon biopsy samples obtained via endoscopy or exploratory laparotomy. Whereas endoscopic biopsies often do not allow discrimination of inflammatory bowel disease (IBD) from intestinal lymphoma in cats, this is not the case for gastric lymphoma.1 With intestinal lesions, a diagnosis of IBD or lymphocytic plasmacytic enteritis may precede an eventual diagnosis of lymphoma and it is unclear if this represents a misdiagnosis or simply disease progression from preneoplastic to neoplastic.
Treatment and Prognosis
Canine GI lymphoma is more often of T-cell origin than B-cell origin, which correlates with the poor prognosis in most cases. In a recent review of 30 cases of canine GI lymphoma2, median survival time (MST) was only 13 days, although two dogs with colorectal lymphoma were still alive at the time of the report, with survival times of 31 and 84 months. Treatment was attempted in all but 3 of the dogs and consisted of surgery, chemotherapy, or a combination thereof. Despite the use of newer chemotherapy protocols compared to those reported in the largest previous report of canine GI lymphoma3, significant improvements in survival were not demonstrated. Somewhat better survival times have recently been reported for cats with GI lymphoma. In a 2002 report4, 11 cats with GI lymphoma (immunophenotype not reported) that were treated with cyclophosphamide (300 mg/m2), vincristine (0.75 mg/m2), and prednisone (COP) as previously reported by Cotter, et al5 had a complete remission rate of 63.6% and the median disease free interval was 245 days. Over 1/3 of the cats were alive at one year. A 2008 report showed that a subset of cats with low-grade lymphocytic GI lymphoma respond well to chlorambucil and prednisone, with an overall median survival time of 765 days.6
Nonlymphoid Gastric Cancer
Epithelial tumors are the most common nonlymphoid gastric neoplasms in dogs, with adenocarcinomas (ACA) predominating. Leiomyomas and leiomyosarcomas are the next most common nonlymphoid tumor types in the canine stomach. Other diagnoses include GI stromal tumors (GIST), histiocytic sarcoma, mast cell tumors (MCT), plasmacytomas, and carcinoids. Most affected dogs are older (median=10 years). Males are reportedly predisposed, although this does not uniformly hold true.7 Certain breeds including chow chows, rough coated collies, some lines of Belgian shepherds, Staffordshire bull terriers, and Norwegian Lundehunds are considered to be predisposed. Gastric carcinomas occur most often in the lower two-thirds of the stomach, especially in the pylorus. Accordingly, the presenting complaint is often vomiting, which is chronic in nature. Associated weight loss and inappetance may occur, as well as hematemesis, melena, anemia, abdominal pain, and polydipsia.7,8
Diagnosis is based on plain film and contrast radiography, ultrasonography (US), fine needle aspiration (FNA), endoscopy or exploratory surgery. Fine needle aspiration is not as reliable for achieving a diagnosis of gastric cancer as it is for intestinal neoplasia. This is thought to be due, in part, to the inflammation and necrosis often associated with gastric cancer.9 As such, endoscopy may be preferred for initial assessment of nonlymphoid lesions. Once a diagnosis of gastric neoplasia is made, complete tumor staging is essential, as metastatic disease may influence treatment decisions.
Treatment and Prognosis
Unfortunately, gastric cancers are highly metastatic; thus long-term responses are uncommon. In one retrospective report of 21 gastric malignancies, 14 of 19 adenocarcinomas had metastasized at the time of diagnosis, as had both of the reported leiomyosarcomas.7 Surgical resection via gastrojejunostomy or Billroth I (gastroduodenostomy) provides rapid symptomatic improvement in most patients. However, presurgical screening for metastatic disease is essential for informed decision making on the part of the client. Survival time for dogs with gastric carcinoma that do not undergo surgery averages less than 3 months. Surgical resection of the primary tumor may improve survival time to greater than 8 months in select cases.7 However, death or euthanasia due to recurrent signs or metastatic disease is the usual outcome. Nutritional management via parenteral or enteral feeding is advised for patients undergoing treatment. Adjuvant chemotherapy protocols have been largely adapted from the human literature and include a combination of 5-fluorouacil, doxorubicin, and cyclophosphamide (FAC) or single agent protocols using cisplatin, doxorubicin or 5-fluorouracil. Given the relative rarity of this disease in dogs, the extent of disease at the time of diagnosis, and the paucity of manuscripts reporting outcome in affected dogs, an advantage to administering adjuvant chemotherapy has yet to be proven.
Benign gastric tumors may warrant a good prognosis. Leiomyomas tend to be discrete, solitary masses that can be completely excised. Dogs with this tumor type may present with paraneoplastic hypoglycemia which resolves immediately with complete resection of the mass.
Nonlymphoid Small Intestinal Cancer
Of the nonlymphoid cancers that occur in the small intestine (SI), carcinomas are the predominant histology in both species. In dogs, any segment of the SI may be affected, although sarcomas occur most often in the jejunum. The jejunum and ileum are affected more often in cats than is the duodenum. Although SI neoplasia is generally a disease of older animals (median age = 9 in dogs and 11 in cats), some tumor types, most notably leiomyosarcomas, are reported to occur in very young animals. With the exception of SI mast cell tumors, for which miniature breeds (especially Maltese) are reportedly predisposed,10 no clear breed predispositions for canine SI cancer are known. The Siamese breed is overrepresented in reports of feline SI neoplasia.
The most common presenting complaints associated with SI cancer are weight loss, vomiting, and anorexia. In dogs, weight loss and vomiting are more common with duodenal or jejunal lesions whereas in cats these clinical signs do not help localize the tumor site. Diarrhea and tenesmus are more typical for ileal masses than for proximal SI lesions.Other clinical signs associated with SI cancer include melena, abdominal distension, and lethargy. Paraneoplastic syndromes may occur secondary to smooth muscle tumors and include hypoglycemia with leiomyoma and leiomyosarcoma and nephrogenic diabetes insipidus with leiomyosarcoma. Dogs with paraneoplastic hypoglycemia may present with seizures and ataxia. Hypoglycemia may also occur secondary to tumor-related peritonitis, especially with smooth muscle tumors that grow quite large and subsequently rupture.8
Initial diagnostic evaluation includes abdominal imaging with radiography and US. Loss of intestinal wall layering can be identified on abdominal US and is a consistent feature that allows tentative diagnosis of intestinal neoplasia.11 Diagnosis is usually confirmed via surgical biopsy after initial evaluation and staging. More than 50% of dogs with intestinal leiomyosarcoma have metastasis within the abdomen at the time of diagnosis.8 As such, presurgical tumor staging is warranted. Metastatic disease occurs not only through hematogenous or lymphatic routes, but also via transcoelomic spread and tumor seeding. Interestingly, some dogs with visceral metastasis of leiomyosarcoma have gone on to experience very long survival after excision of the primary tumor.8
Treatment and Prognosis
Treatment of choice is surgical resection. In one report of 21 dogs with intestinal carcinoma, when outcome was assessed for the 15 dogs that underwent surgical resection of their intestinal mass, gender had an apparent influence on survival. The MST for all dogs undergoing surgery was 233 days, with female dogs living a median of 28 days and male dogs living a median of 272 days.12 Metastatic disease is also highly prognostic for dogs with SI neoplasia. In a report of 39 dogs with intestinal carcinoma (n=23) or leiomyosarcoma (n=16), those without histological evidence of metastatic disease at the time of surgery survived a median of 15 months, compared to 3 months for those with metastatic disease.13 This difference was significant. The MST for all dogs was 10 months, and the one- and two-year survival rates were 40.5% and 33.1%, respectively. It has been reported that 65% of adenomas and 47% of intestinal ACA express COX-2; thus, there may be a role for COX-2 inhibition with drugs such as NSAIDs in the treatment of this disease.14 Chemotherapy has not been adequately studied for its efficacy against SI tumors. Doxorubicin may have activity against SI carcinomas and leiomyosarcomas, but sufficient response data is not available.
Nonlymphoid Large Intestinal Cancer
Even though it comprises only 10% of the length of the intestinal tract, the large intestine is the site of most canine nonlymphoid intestinal tumors, other than MCT. This is true in people as well, where colorectal tumors are more common than small intestinal cancer. The current literature suggests that in cats, by contrast, approximately 90% of intestinal tumors occur in the small intestines.However, a recent review of data from the Veterinary Medical Data Base showed that feline ACA are twice as common in the large intestine than in the small intestine(personal communication, K Rissetto; Proceedings of the 2007 VCS Annual Conference, p.40). Large intestinal (LI) tumors primarily affect middle aged to older dogs (median = 8 years for epithelial tumors and 11 years for mesenchymal masses) and older cats (median >12 years). Adenomatous polyps and carcinoma in situ account for the majority of nonlymphoid canine LI lesions. Others include leiomyomas, leiomyosarcomas, GIST (see below), MCT, plasmacytomas, rectal ganglioneuromas, neurilemomas, and carcinoids. Canine LI leiomyosarcomas and GIST usually occur in the cecum, whereas carcinomas are more common in the rectum and colon. Nonlymphoid colorectal tumors tend to affect purebred dogs, including German Shepherds, West Highland White Terriers, and Collies. In cats, adenocarcinoma (ACA) is the most common LI nonlymphoid tumor. Others include MCT, neuroendocrine carcinomas, leiomyosarcomas, fibrosarcomas, and hemangiosarcomas.
Clinical signs noted in dogs with LI tumors include hematochezia, tenesmus, and dyschezia, or intermittent rectal bleeding that is not associated with defecation. Rectal prolapse may occur in dogs with rectal polyps. Cats present with weight loss, anorexia, vomiting, and diarrhea. Hematochezia and tenesmus are reported less frequently. Due to their site predilection for the cecum, canine leiomyosarcoma, leiomyoma, and GIST may be detected due to clinical signs related to intestinal obstruction or septic peritonitis secondary to tumor rupture.8 Paraneoplastic hypoglycemia may occur with LI smooth muscle tumors, causing central nervous signs including seizures and ataxia. Diagnosis of LI tumors ultimately relies upon biopsy of affected tissue. Masses may be palpated by rectal exam in over half of all affected cats and dogs. Imaging with abdominal radiographs, ultrasonography (US), computed tomography, and endoscopy (rigid proctoscopy or flexible colonoscopy) aide in diagnosis. The gross appearance of lesions on endoscopy or at surgery may be prognostic. In one report of dogs with colorectal ACA, patients with single, pedunculated polypoid masses had longer mean survival time (32 months), than dogs with nodular or cobble-stone appearing masses (12 months) or those with annular masses causing strictures (1.6 months).15
Treatment and Prognosis
Surgery is the treatment of choice for most LI masses and may provide excellent long-term outcome for patients with solitary masses. Dogs undergoing excision for colorectal ACA live significantly longer (an additional 7 to 9 months) than those undergoing biopsy alone.15 Mass excision, along with margins of 4 to 8 cm of normal adjacent intestine is recommended to ensure complete tumor removal. Mean post-surgical survival in 57 dogs with colorectal tumors was 20.6 months and was influenced by tumor type and surgical margins. Dogs with adenomas or carcinoma in situ survived significantly longer than dogs with invasive carcinoma. Also, dogs with clean surgical margins lived significantly longer than those with tumor cells within the surgical margins.16 When tissue is submitted for histopathological examination, immunohistochemistry (IHC) should be requested if needed to differentiate tumor types. Stainsto detect desmin, smooth muscle actin, and c-kit/CD117 help differentiate true smooth muscle tumors from GIST, which have an improved prognosis (see below).17
In cats with nonlymphoid LI cancer, aggressive surgery is indicated. Subtotal colectomy resulted in a MST of 138 days, compared to 68 days achieved with a lesser resection and only 10 days when lesions were only biopsied.18 At the time of surgery, thorough abdominal exploration is advised because metastatic disease warrants a poor prognosis. In one study, cats with nodal or abdominal organ metastasis at the time of surgery had a MST of 49 days, compared to 259 days for those without metastasis.18
Chemotherapy is largely unexplored as a treatment option for canine and feline LI cancer, although one small report suggested an improvement in clinical outcome for cats (n=4) receiving adjuvant doxorubicin for colonic carcinoma (280 day survival compared to 56 days for 12 cats not receiving adjuvant chemotherapy).18 Nonsteroidal anti-inflammatory agents may play a role in the management of colorectal neoplasia in dogs. Seven of eight dogs with tubulopapillary rectal polyps treated with piroxicam (dose equivalent: 0.24 to 0.46 mg/kg/day administered per rectum q3 days or 0.34 mg/kg PO on alternate days) demonstrated symptomatic improvement in hematochezia and tenesmus.19 This therapy has yet to be evaluated in cats with LI neoplasia.
Gastrointestinal Stromal Tumors (GIST)
Gastrointestinal stromal tumors are a unique group of mesenchymal tumors that are derived from the interstitial cells of Cajal, which regulate GI motility. Many of these tumors were misdiagnosed as leiomyosarcomas in the past, due to their similar morphology and a lack of appropriate immunohistochemical markers to distinguish the two tumor types. More recent work has demonstrated that GISTs may be differentiated from leiomyosarcomas by their negative staining for desmin and positive staining for c-kit/CD117 on IHC. To the author's knowledge, there has been only one report of feline GIST to date.20
Treatment and Prognosis
Prognosis for GISTs may be better than that for other intestinal malignancies. In a report last year, for dogs that survived the immediate post-operative period, the MST for 17 dogs with GIST was 37.4 months, compared to 7.8 months for 5 dogs with leiomyosarcoma and 2.9 months for 4 dogs with undifferentiated carcinomas.17 Although this difference was not statistically significant, the prolonged survival of dogs with GIST, as with human GIST patients suggests that further evaluation of the prognostic significance of this diagnosis is warranted. Therapies that target c-kit may play a role in the treatment of GISTs in the future, but are largely unexplored at this time. Treatment and prognosis for feline GIST has not been reported.
Apocrine Gland Anal Sac Adenocarcinoma (AGASACA)
Apocrine gland ACA of the anal sac (AGASACA) occurs with approximately equal sex distribution and affects primarily older dogs (10 to 11 years of age). However, the disease has been reported in dogs as young as 5 years of age. The disease is characterized by paraneoplastic hypercalcemia in approximately one third of all affected dogs and regional lymph node metastasis is present at diagnosis in > 50% of all cases. Even when nodal metastasis and hypercalcemia are present, the primary tumor can be very small; thus careful rectal examination is necessary for detection.
Treatment and Prognosis
In a retrospective study of 80 cases of AGASACA published last year21 four statistically significant negative prognostic factors were found: primary tumor size > 2.5 cm, presence of lymph node metastases, presence of distant metastatic disease, and lack of therapy. Using these prognostic factors, the authors developed a clinical staging system that was used in a case management algorithm and tested prospectively in 50 affected dogs. The staging system was shown to be relevant to case management, and survival times were significantly associated with clinical stage. Although the 2007 Polton study and a 2003 report by Williams, et al, demonstrated lymph node metastasis to be prognostic, a 2005 study in the Australian Veterinary Journal did not.21-23 All three reports suggest a role for surgery in improving the prognosis for affected dogs. Furthermore, two of the three reports suggested there is a role for chemotherapy (especially Carboplatin) in conjunction with cytoreductive surgery for this disease.21,23 Radiation is often recommended for AGASACA, based in part on promising responses reported with radiation and mitoxantrone.21,24
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