Gastrointestinal Neoplasia in Dogs and Cats
Many gastrointestinal neoplasms in dogs and cats are biologically aggressive with a poor outcome, even with surgical and medical therapy. Intensive therapy is often necessary to improve patients’ clinical status, although longterm prognosis is poor. Diagnostic staging tests are warranted in cases for which surgical resection is elected. In some cases, a relatively favorable prognosis can be achieved with extensive therapy, such as in dogs with adenocarcinoma or lymphoma of the large intestine and cats with low-grade lymphoma.
Gastrointestinal (GI) neoplasms are uncommon in dogs and cats, with gastric tumors representing <1% and intestinal tumors <10% of overall neoplasms in the dog and cat. Specific etiologic agents for GI neoplasia have not been identified. The increased risk of Belgian Shepherds for gastric carcinoma, and of Siamese cats for intestinal adenocarcinoma and lymphoma, may reflect genetic predispositions. Feline leukemia virus has been suggested to be an underlying factor in development of feline GI lymphoma, even in cats with a negative retroviral status. Helicobacter infections are associated with gastric neoplasia in people, but similar direct links have not been established in dogs or cats.
The average age of dogs with GI neoplasms is 6–9 years and of cats 10–12 years, though gastric leiomyomas tend to occur in older dogs (average age 15). There is a slight predominance for male dogs and cats to develop GI neoplasia in some reports. GI neoplasms tend to be malignant in dogs and cats.
In dogs, adenocarcinoma is the most common gastric and large intestinal neoplasm, whereas lymphoma is more frequently seen in the small intestine, followed by adenocarcinoma and sarcomas such as gastrointestinal stromal tumor (GIST) and leiomyosarcoma. Other reported canine GI neoplasms include carcinoid, adenoma, leiomyoma, carcinoma in situ, and inflammatory polyp.
Adenocarcinomas frequently affect the lower 1/3 of the stomach (eg, lesser curvature and pyloric region) and rectum. Gastric and small intestinal adenocarcinomas frequently metastasize to regional lymph nodes, liver, and lung. At the time of diagnosis, up to 58% of intestinal and up to 95% of gastric adenocarcinomas have metastasized.
Gastrointestinal lymphoma most commonly affects the small intestine as well as extra-GI organs such as the liver. Canine GI lymphoma is mostly a high-grade variant with rapid clinical progression. Colorectal lymphomas are predominantly B-cell immunophenotype (92%–100%), whereas other canine GI lymphomas are more commonly T-cell. Small-cell, low-grade GI lymphoma, a slowly progressive indolent lymphoma, occurs less commonly in dogs but can be clinically well-managed. The differentiation of high- versus low-grade lymphoma requires histopathologic and potentially immunohistochemical analysis such as cellular size, mitotic index, and Ki-67 staining. Transition of low-grade GI lymphoma into high-grade lymphoma occurs in approximately 10% of dogs.
Gastrointestinal stromal tumors are mesenchymal in origin. A major diagnostic criterion for GIST is a positive KIT (CD117) reaction on immunohistochemistry. Before the recognition of GIST, many of these tumors were likely classified as leiomyosarcomas. GIST typically occur in the cecum and large intestine. In contrast, leiomyosarcomas occur most commonly in the stomach and small intestine. Overall, GIST and leiomyosarcoma grow slowly and are slow to metastasize, with a reported metastatic rate of up to 30%. For canine GIST, KIT expression does not necessarily accompany exon 11 mutation of its encoding gene c-kit; however, reverse transcription-PCR using RNA from formalin fixed paraffin-embedded tissue can increase the mutation detection rate compared with conventional PCR technique using genomic DNA.
In cats, lymphoma is the most common GI neoplasm, followed by adenocarcinoma and mast cell tumor. Both low-grade and high-grade GI lymphomas are frequently reported, and their clinical behaviors are well-characterized in cats. Low-grade GI lymphomas are mostly mucosal and T-cell immunophenotype, commonly affecting the small intestines. Small intestinal high-grade lymphoma, however, can be either T-cell or B-cell in origin.
Adenocarcinoma is commonly identified in the feline intestinal tract, especially in the jejunum and ileum, but rarely in the stomach or large intestines. Feline adenocarcinomas are also biologically aggressive, with a high metastatic rate. Metastasis commonly occurs to regional lymph nodes (up to 50%) and lungs (up to 20%), while carcinomatosis can be seen in up to 30% of cats.
Other uncommonly reported GI tumors of dogs and cats include leiomyoma, fibrosarcoma, carcinoma in situ, colorectal polyp, and plasmacytoma.
Clinical signs of GI neoplasia depend on the location and extent of the tumor and its possible metastases or paraneoplastic syndromes (eg, hypercalcemia, hypoglycemia). The most common clinical signs associated with GI neoplasia include:
Signs of constipation or tenesmus may accompany colonic and rectal tumors. An abdominal mass or organomegaly may be palpable on physical examination. Abdominal pain and ascites may reflect peritonitis secondary to a ruptured portion of neoplastic bowel.
Routine laboratory studies and plain radiographs do not show specific changes associated with GI neoplasia. Hypoglycemia is often associated with leiomyomas/leiomyosarcomas. Hypercholesterolemia and increased alkaline phosphatase activity has been seen in some nonlymphomatous neoplasia. Microcytic anemia with or without hypoproteinemia is a common finding with ulcerated masses and chronic blood loss. Electrolyte and acid-base disturbances may reflect ongoing vomiting and can include hypochloremia, hypokalemia, and metabolic alkalosis or acidosis. Paraneoplastic hypercalcemia has been associated with lymphoma and intestinal adenocarcinoma.
Contrast abdominal radiographs may reveal mass lesions in the GI tract or areas of ulceration. Abdominal ultrasonography may reveal focal or diffuse thickening of the GI tract and loss of normal layering. Regional lymph nodes may be enlarged, and splenomegaly and/or hepatomegaly may accompany some cases of GI lymphoma. Though ultrasonographically abnormal findings may suggest the presence of neoplasia, a normal appearance does not rule them out, especially for the stomach. In a study of 22 gastric neoplasms in dogs and cats, abnormalities were detected in 50% of the cases with ultrasonography, but 95% with endoscopy. Ultrasound can facilitate fine-needle aspirates or needle biopsy sample collection for cytologic or histologic analysis. Aspirated samples are also suitable for flow cytometric characterization for lymphomas.
Endoscopy of the GI tract can facilitate identification and partial-thickness biopsy of GI neoplasia. However, endoscopic biopsy collection is limited by the small size and superficial nature of the biopsy, because some GI tumors are submucosal, and this technique may only collect superficial mucosa. In one study, endoscopic biopsies were adequate to detect feline gastric lymphoma but not adequate to differentiate inflammatory bowel disease from lymphoma in the GI tract. A recent study suggested that endoscopic ileal biopsies aid in the diagnosis of feline lymphoma and other GI diseases compared with endoscopic duodenal biopsies. Full-thickness surgical biopsies collected via laparoscopy or laparotomy may more suitably establish a diagnosis and will allow for biopsy of regional lymph nodes and liver to evaluate for metastasis.
In addition to histopathology, immunohistochemistry may be required to differentiate between types of neoplasia for GI biopsies. PCR for antigen receptor rearrangement (PARR) detects clonally rearranged antigen receptor genes by amplification of conserved gene segments and can aid in the diagnosis of GI lymphoma when performed on inconclusive biopsy sections, especially in cats. Although the sensitivity of PARR can be as high as 76% for the diagnosis of canine GI lymphoma, comprehensive assessments are necessary because aberrant lymphocyte antigen expression and clonal rearrangements have also been reported in nonlymphoid neoplasms of dogs. Also, in a study of 20 clinically healthy cats, PARR monoclonality was detected in 40% of the duodenal endoscopic biopsy samples.
Surgical excision of the tumor is the gold standard for nonmetastatic, nonlymphomatous neoplasms, though it can be also performed as palliative care in cases of mechanical ileus secondary to an obstructive mass, even if metastatic disease is confirmed. Curative resection, with margins of ≥4 cm, should be attempted. Careful preoperative discussion is needed before surgery because the perioperative mortality rate is reportedly as high as 50% in cats with intestinal carcinoma. In cats with splenic mast cell tumor with intestinal involvement, splenectomy may also improve the outcome.
Prognosis of dogs with GI adenocarcinoma varies depending on the tumor location. Most dogs with gastric adenocarcinoma succumb to the disease within 6 months after surgery. Median survival times of small-intestinal adenocarcinoma in dogs is reported as 4–18 months, with a 1-year survival rate of 40%–60%. On the other hand, dogs with colorectal adenocarcinoma typically have a favorable prognosis, with a median survival time of 2–4 years after surgery. Effective chemotherapy for treatment of GI adenocarcinoma has not been established. Use of adjuvant carboplatin, doxorubicin, or gemcitabine has been reported, although efficacy is unknown.
In contrast, prognosis of feline GI adenocarcinoma is poor regardless of tumor location. For cats that survived to discharge after surgery, reported mean survival ranges from 5 to 15 months for small intestinal carcinomas and from 4.5 to 9 months for large-intestinal carcinomas with or without adjuvant chemotherapy.
Dogs with GIST or leiomyosarcoma without gross metastasis tend to have a long remission time if the tumor is surgically resectable. In a study of leiomyosarcoma and GIST, overall median survival time was 37 months after complete resection, while one report suggested that dogs with GIST can have an increased survival rate compared with dogs with leiomyosarcoma. Molecular targeted therapy such as tyrosine kinase inhibitors can specifically target aberrantly expressed proteins such as KIT in canine GIST and mast cell tumors. Toceranib phosphate is a veterinary-approved tyrosine kinase inhibitor against canine mast cell tumors that works by inhibition of multiple receptor tyrosine kinases including KIT, VEGFR2, and PDGFR2. The reported response rate is 40%–50% in canine cutaneous mast cell tumors, and a recent study reported measurable tumor response in 4 of 7 dogs with GIST, with a median progression-free interval of approximately 2 years.
Gastrointestinal lymphoma is typically treated with chemotherapy. Poorly differentiated, high-grade GI lymphoma is poorly responsive to chemotherapy. If treatment is attempted, a multi-drug chemotherapy protocol (eg, Wisconsin-Madison) is recommended, but median survival time is usually <3 months, though the initial remission rate can be as high as 80%. Large-intestinal lymphoma in dogs is an exception, with median survival times of 5.5–6 years reported after systemic chemotherapy with or without surgical removal of the tumor. Focal lymphoma may be surgically excised, and follow-up chemotherapy may be recommended.
Small-cell (well-differentiated, low-grade) lymphoma is treated with steroids and alkylating agents. Commonly used protocols include prednisolone (1–2 mg/kg, PO, once daily) and chlorambucil (either 2 mg, PO, every other day or 15 mg/m2, once daily, for 4 days, every 3 weeks) with reported median survival times of 2–3 years in cats and 14–21 months in dogs. When resistance is acquired, successful rescue therapy with cyclophosphamide (200–250 mg/m2 given over two days on Day 1 and 3, every 2 weeks) has been reported in cats.
For patients with GI lymphoma confined to the abdominal cavity, radiation therapy may be effective, because most lymphomas are radiosensitive. Two studies have reported its efficacy in feline GI lymphoma as a rescue or consolidation therapy, but further studies are warranted because of the small sample sizes.
Malignant GI neoplasms are associated with a poor prognosis (survival <6 months), even with surgical and medical therapy. Benign lesions, such as leiomyomas and colorectal adenomas, have a good prognosis with surgical excision.
Many GI neoplasms are biologically aggressive, with a poor outcome.
Intensive therapy is often necessary to improve patients’ clinical status.
A relatively favorable prognosis can be achieved with extensive therapy in some cases, such as with canine adenocarcinoma or lymphoma of the large intestine and with feline low-grade lymphoma.