Introduction

Lymphoma is the most common feline neoplasm and the most common gastrointestinal neoplasm. Older studies suggested that the gastrointestinal location was less common than other anatomical locations, however more recent studies suggest that a gastrointestinal location is the most common site. The differences in reported incidences may also be associated with differences in classification schemes, change in incidence over time, and differences in feline leukaemia virus (FeLV) subtypes in various geographic areas. For example, some schemes describing feline gastrointestinal lymphoma (GI LSA) include hepatic or splenic involvement, whereas others include this pattern as multicentric. Most cats with GI LSA test negative for FeLV. The reported incidence of FeLV antigenaemia ranges from 0-38%. In general, cats with leukaemia or mediastinal lymphoma tend to be young and FeLV positive, while cats with GI LSA tend to be older and are FeLV antigen negative.

Pathological Findings

Lymphoma can be seen in any region of the gastrointestinal tract. The gross appearance of GI LSA is extremely variable, and in some cases may be normal (especially with low-grade lymphoma). There are different grades of lymphoma, referred to as low-grade (lymphocytic), intermediate grade, or high-grade (lymphoblastic or immunoblastic). Few reports describe grade, and most of the reports that include a grading scheme describe high-grade lymphoma. More recently, a series of cats from our hospital was described that had primarily low-grade lymphoma (50 of 67 cats: 75%). Immunohistochemistry has recently been used to better characterise feline lymphomas, though in a limited number of studies, immunophenotype does not correlate with response to chemotherapy treatment or survival.

Clinical Findings

Clinical signs are variable, and include weight loss, anorexia, vomiting and diarrhoea. Notably many cats have minimal or no vomiting or diarrhoea. Physical examination findings may or may not include an abdominal mass and thickened loops of bowel. Laboratory findings are non-specific. Radiographic findings are also non-specific.

The distribution of lesions in gastrointestinal lymphoma can be nodular (focal or multifocal) or diffuse. The most common ultrasonographic abnormality is thickening of the gastric or intestinal wall. Loss of normal intestinal wall layering, localised mass associated with the intestine, decreased intestinal wall echogenicity, localised hypomotility, regional lymphadenopathy and ascites are also commonly seen. Ultrasonography supplies information about the lesion and the entire abdomen, thus helping to stage the extent of disease and screen for other concurrent diseases. Furthermore, ultrasonography allows guidance of fine needle aspiration or biopsy for procuring specimens for cytological or histopathological examination. Ultrasonography may also represent a non-invasive means for assessing response to therapy. A limitation of ultrasonography includes the inability to assess the exact anatomical location and extent of certain lesions. Ultrasound examination findings may also be normal, especially in cases of low-grade lymphoma.

Endoscopy has been shown to be an effective tool for diagnosing gastrointestinal mucosal lymphoma in people, and in dogs and cats. In our study, endoscopy was performed in 61 of 67 cats, and was the main ancillary test performed leading to the diagnosis of lymphoma.

Treatment

Reports of treatment of feline gastrointestinal lymphoma are limited. Only some of these studies described detailed results in cats specifically with gastrointestinal lymphoma. This is further clouded because many reports do not describe histological grade or results of complete anatomical staging and various combination of chemotherapeutic agents were used. Figure 1 summarises treatment results in various studies. These references are cited in the article in the further reading list.

Some conclusions and recommendations can be made from these studies. In general, response to chemotherapy for high-grade gastrointestinal lymphoma is poor whereas the response for low-grade lymphoma is good. For cats with high-grade gastrointestinal lymphoma, the addition of doxorubicin to the chemotherapeutic regime seems to improve survival time as illustrated by the improved survival times reported in studies that incorporated doxorubicin into the treatment regimen. On the other hand, cats treated with CVP had poor survival times. Other studies suggest that doxorubicin cannot be recommended as a single agent for treatment of feline lymphoma. It seems that by incorporating doxorubicin with other agents (such as CVP and l-asparaginase) in a multi-agent combination protocol, longer remission and survival times can be achieved compared with single-agent doxorubicin or CVP alone.

For cats with low-grade lymphoma, excellent results can be achieved with oral prednisolone and oral chlorambucil. The author currently uses chlorambucil at a dosage of 15 mg/m² once daily for 4 days, repeated every 3 weeks, and 10 mg prednisolone once daily indefinitely. It is unknown whether these cats would do better with a higher-grade protocol. The use of a 'slow alkylating agent' such as chlorambucil may be justified because of the lower mitotic rate of low-grade lymphoma cells. Therefore, a multi-agent protocol using cell cycle-specific drugs may not be necessary.

Chemotherapy is tolerated well by cats in general. The results of an owner survey suggest that cats generally cope well with high-grade chemotherapy protocols and have a good quality of life. Self-limiting anorexia, vomiting, diarrhoea and myelosuppression may be seen in some cats. It may be difficult to distinguish some of these chemotherapy-related side effects from active or progressive lymphoma. If there are abnormalities on abdominal palpation or ultrasonography, these can be used to assess progress or regression. An unusual side effect of chlorambucil has recently been described. A cat with low-grade lymphoma receiving chlorambucil developed generalised myoclonus. The author has seen three cats that developed grand mal seizures after chlorambucil. In all three cats, this apparent chlorambucil-induced neurotoxicity was self-limiting after the drug was discontinued.

Figure 1. Summary of reports describing treatment of feline gastrointestinal lymphoma

(CR: complete remission. NR: not reported. C: cyclophosphamide. V: vincristine. P: prednisone. M: methotrexate. L: L-asparaginase. D: doxorubicin. Cl: chlorambucil. HG: high grade. LG: low grade).

Prognostic Factors

There are very few prognostic factors that have been defined for cats with gastrointestinal lymphoma. Histological grade is a strong indicator of outcome. Our study showed that compared with cats with high-grade lymphoma treated with a multi-agent chemotherapy regime, cats with low-grade lymphoma treated with oral prednisone and chlorambucil had a significantly better remission rate (69% versus 18%) and survival time (17 months versus 2.7 months). Since other studies did not compare low-grade and high-grade lymphoma, this finding has not been described by others.

In most studies, the most significant prognostic indicator for successful outcome is initial response to chemotherapy. In general, cats who survive the initial induction period generally have a better long-term outcome. Though this may seem intuitively obvious, it may give clinicians and owners encouragement to continue chemotherapy treatment in cats that attain a complete remission. Otherwise, despite rigorous data analysis in multiple studies, there is no consistent association with any patient or tumour characteristic that is predictive of outcome (including sex, immunophenotype, clinical stage, age and bodyweight). Recently, investigators have looked at molecular markers and immunophenotype to try to determine prognostic factors, but these have provided no useful information regarding response to treatment or survival.

Conclusions

When prognosticating or treating gastrointestinal lymphoma, grade must be considered. Low-grade and high-grade gastrointestinal lymphomas in many ways represent different disease entities and must be considered separately. Statements about feline gastrointestinal lymphoma may in some cases be over-generalisations. Limitations of many published studies include incomplete staging, inconsistent grading, multiple gastrointestinal locations are not sampled, cats are not prospectively randomised to different chemotherapy protocols, there is a lack of a control (untreated) group and confirmation of remission is not by follow-up biopsy. Controlled, randomised, cohort studies investigating the response of each grade of gastrointestinal lymphoma to single chemotherapeutic regimens seem warranted. Furthermore, additional studies to correlate clinical outcome with immuno-phenotyping and molecular markers are warranted.

References

1.  Richter KP. Feline gastrointestinal lymphoma. Veterinary Clinics of North America Small Animal Practice 2003; 33(5): 1083-1098.