Keith P. Richter,     San Diego, California

Epidemiology

Lymphoma is the most frequently diagnosed feline cancer and the most common gastrointestinal (GI) neoplasm in cats (Rissetto et al, 2011). Lymphoma occurs in several anatomic locations; the GI tract is the most common site, accounting for 32% to 72% of total cases. Discrepancies in the reported incidence of the various forms of lymphoma may be the result of the differences in classification schemes used, a change in incidence over time, differences in feline leukemia virus (FeLV) subtypes in various geographic areas, and a decreased incidence of non-GI forms since the introduction of an FeLV vaccine. An increase in the proportion of lymphoma of the GI tract over time is apparent by comparing incidences in the same institutions over different time periods. For example, in the New England area the percentage of lymphomas in cats that occurred in the GI tract increased from 8% in 1979 to 18% in 1983 and to 32% in 1996 (Francis et al, 1979; Cotter, 1983; Moore et al, 1996). Likewise, in the New York City area the percentage increased from 27% in 1989 to 72% in 1995 (Mooney et al, 1989; Mauldin et al, 1995). This increased incidence in the GI form over time could be due to a decreased incidence of FeLV infection, and therefore fewer cats died at a young age secondary to FeLV-induced diseases. Thus more cats are living longer, and they may then develop the GI form. Another explanation is that cats may be undergoing more complete evaluations more recently than in the past.

The association between FeLV and lymphoma in cats is well established. The incidence of FeLV antigenemia in cats with GI lymphoma ranges from 0 to 38%. However, such estimation of FeLV infection rate is influenced significantly by the method of testing. Underestimation of FeLV incidence with immunohistochemistry (IHC) versus polymerase chain reaction (PCR) has been suggested. In one study PCR testing detected FeLV viral nucleic acid sequences in up to 63% of cats with GI lymphoma, whereas only 38% of cats were positive by IHC (Jackson et al, 1993). Generally cats with leukemia or mediastinal lymphoma tend to be young and FeLV positive, whereas those with GI lymphoma typically are older and FeLV antigen negative. An association between lymphoma and feline immunodeficiency virus (FIV) also has been proposed, especially when coinfected with FeLV, although most cats with GI lymphoma in the author’s experience are negative for FIV exposure.

Gross Pathologic Findings

The gross appearance of feline GI lymphoma varies with the specific anatomic location. Many segments of the GI tract, including the liver, may be involved. There can be a focal mass or diffuse infiltration. In some cases, especially with low-grade lymphocytic lymphoma, the gross appearance may be normal. When a focal alimentary tract mass is present, there is usually transmural thickening with or without mucosal ulceration. Mural thickening is often eccentric, resulting in preservation of the lumen, although a functional obstruction may develop. This contrasts with intestinal carcinoma, which often results in a mechanical obstruction from decreased luminal diameter, often appearing as a “napkin ring.” With diffuse infiltration the intestinal wall may be visibly and/or palpably thickened. Mesenteric lymphadenopathy is often obvious grossly or on ultrasonographic examination. Intussusception can develop secondary to intestinal lymphoma; the jejunum is the most common location. Hepatic involvement can have a variable appearance. In some cases the liver appears to be grossly normal, whereas in others there may be an enhanced lobular pattern, a mottled appearance, or a gross nodular appearance. In summary, the appearance of lymphoma is extremely variable in all regions of the GI tract. In light of how commonly this neoplasm develops in cats, lymphoma should be considered as a differential diagnosis for GI illness with normal or grossly abnormal organ appearance.

Histopathology and Immunohistochemistry

There are different grades of GI lymphoma, commonly referred to as low grade (lymphocytic or small cell), high grade (lymphoblastic, immunoblastic, or large cell), and intermediate grade. Less common descriptions such as large granular lymphocytic lymphoma also exist (which behave in a manner similar to high-grade lymphoma). Many published reports are either of undetermined grade or predominantly high-grade lymphomas, although low-grade lymphocytic lymphomas have been described more recently in large case series (Fondacaro et al, 1999; Kiselow et al, 2008; Moore et al, 2012; Stein et al, 2010). In the study by Fondacaro et al (1999) 50 of 67 cats (75%) diagnosed with GI lymphomas had low-grade lymphocytic lymphoma. Criteria used to classify lymphoma as lymphocytic have been described (Fondacaro et al, 1999; Moore et al, 2012). In marked contrast to palpable masses of lymphoblastic lymphoma, masses formed by lymphocytic lymphoma are not distinct microscopically, because the mucosa beyond the apparent mass also is involved. The use of a standard grading scheme for GI lymphoma may lead to a greater recognition of low-grade lymphocytic lymphoma. However, criteria have been difficult to establish because of the difficulty in interpreting small endoscopic biopsies, differences in pathologists’ opinions, a lack of characterization using IHC, and only recent availability of polymerase chain reaction (PCR) clonality studies (see Chapter 65). Consequently further studies are needed to define specific criteria for differentiating lymphocytic lymphoma, lymphocytic inflammation, and T-cell infiltrative disease and to correlate such classifications with clinical outcome. In addition, the role of endoscopic biopsies versus full-thickness biopsies must be better defined. The results of one study suggested that surgical biopsies are superior to endoscopic biopsies for the detection of GI lymphoma (Evans et al, 2006). However, many cats in that study did not have their duodenum entered endoscopically (many were blind biopsies), few biopsies were obtained, the quality of the biopsies were not described, histologic grading was not reported, and clonality studies were not performed. Many pathologists are comfortable making the diagnosis on endoscopic biopsy analysis, whereas others believe that full-thickness biopsies are necessary. The author relies heavily on the analyses of endoscopic biopsies in his practice. Although it is customary to consider a continuum from inflammatory bowel disease to lymphoma, there are little supporting data.

Recently IHC has been used to better characterize feline lymphoma. In some studies GI lymphomas were more likely to be of B cell rather than T-cell phenotype, whereas other studies describe a predominantly T-cell phenotype. Notably, most cats with low-grade GI lymphoma have a T-cell phenotype. In a limited number of studies immunophenotype did not appear to correlate with response to chemotherapy treatment or survival, although more recently one study reported a better outcome in cats having the T-cell phenotype (Moore et al, 2012). Thus further study is necessary to determine the clinical value of immunophenotyping.

More recently, detection of lymphoid neoplasia has been accomplished by detecting antigen receptor gene rearrangements. This method is especially useful to determine if the lymphocyte population is monoclonal or oligoclonal (thus suggestive of lymphoma) versus polyclonal (which is more suggestive of inflammation). It is especially helpful to detect the presence of low-grade lymphoma when present concurrently with inflammatory disease. This technique employs PCR to amplify the hypervariable regions of immunoglobulin or T-cell receptor genes. In the absence of neoplasia, this region differs from cell to cell. Amplifying this region can help determine if the products are monoclonal (or oligoclonal) or polyclonal based on their appearance on polyacrylamide gel electrophoresis. This method has been named PARR (PCR for antigen receptor rearrangements) or TCRG (T-cell receptor gamma gene rearrangements). This appears to be a more sensitive and objective method for detection of lymphoma (especially the low-grade form or in less severe lesions) compared with conventional histopathology (Moore et al, 2005; Moore et al, 2012). In one study, detection of TCRG rearrangements had a 91% sensitivity in detecting mucosal T-cell lymphoma regardless of the severity of the lesion (Moore et al, 2012).