U-Vet Animal Hospital, University of Melbourne, Werribee, Melbourne, VIC, Australia
Alimentary (Gastrointestinal) Lymphoma
The most important distinction is small cell/low grade (indolent clinical course) versus large cell/high or intermediate grade or large granular lymphoma (aggressive clinical course).
- Diagnosis of aggressive subtype versus small cell GI lymphoma: Generally, diagnosis of aggressive GI lymphoma is more straightforward than that of small cell GI lymphoma. Cytology of enlarged lymph nodes or intestinal masses is often diagnostic with surgical biopsies infrequently required. In small cell GI lymphoma, clinical presentation and results of diagnostic tests, e.g., abdominal imaging, cytology and histopathology overlap with inflammatory bowel disease. Cytology cannot reliably diagnose small cell GI lymphoma because of the difficulty in distinguishing neoplastic lymphocytes from a normal/reactive population and because the typical diffuse mild to moderate intestinal wall thickening precludes effective sampling for cytology.
- Collection of biopsies in small cell GI lymphoma: The distal small intestine is commonly involved, and thus the diagnosis may be missed if only the stomach and duodenum are biopsied. For endoscopic biopsy collection, therefore, both upper (stomach and duodenum) and lower (colon and ileum) GI studies should be performed. The jejunum cannot be accessed in routine endoscopy procedures in small animals. Alternatively, exploratory laparotomy and full thickness biopsies of multiple GI sites can be performed. The major benefit of endoscopy is its relative non-invasiveness, but potential drawbacks compared to exploratory laparotomy include inability to assess other abdominal organs or the serosal surface of the GI tract, inability to access the jejunum and higher risk of suboptimal biopsies (e.g., due to superficial sampling or crush artefact) hampering diagnosis. Full thickness intestinal biopsies carry a risk of dehiscence and subsequent septic peritonitis, though this does not appear to be necessarily increased in the setting of alimentary lymphoma specifically.1
- Additional tests on biopsies: No matter the method of biopsy, histopathological diagnosis of small cell GI lymphoma can be challenging. Neoplastic lymphocytes cannot be distinguished from inflammatory infiltrate on the basis of morphology alone. Criteria suggestive for lymphoma over IBD include a more monomorphic lymphocyte population, specific patterns of epitheliotropism and/or lamina propria invasion, extension deep to the mucosa, and intravascular infiltration. In addition to routine H&E, immunophenotyping with immunohistochemistry (IHC) and assessment of clonality via PCR (PARR) can assist in making a final diagnosis of lymphoma. In one study,2 approximately 50% of cases that were initially diagnosed as IBD on H&E alone were re-classified as T cell lymphoma when IHC and PARR were assessed. Although less common, misdiagnosis of IBD as lymphoma can also occur. This study suggested a diagnostic algorithm for these cases—if initial histopathology diagnoses IBD but there is poor response to treatment then IHC +/- PARR should be pursued for definitive diagnosis. If initial biopsy is suspicious for lymphoma then IHC should be performed +/- PARR, if IHC is suspicious but not diagnostic for lymphoma. If initial biopsy diagnoses lymphoma, IHC is still recommended for immunophenotyping as prognosis may differ for B versus T cell disease, and because of the small risk of false positive lymphoma diagnosis. PARR should not be relied upon alone for diagnosis as sensitivity in cats can vary (as low as 60–70%, especially with B cell lymphoma) therefore a negative result cannot conclusively rule out lymphoma.
- How much does the distinction of IBD versus small cell lymphoma matter? Prognosis for IBD is better than small cell lymphoma, and a definitive diagnosis should always be pursued. However, in cases where IBD or small cell lymphoma is strongly suspected based on initial diagnostic tests, and histopathology is either not definitive or is declined by owners, initiating treatment directed at IBD and escalating if response is inadequate (e.g., diet and B12 supplementation if indicated → prednisolone → chlorambucil) may be, in my opinion, very reasonable. Distinguishing between aggressive GI lymphoma and small cell lymphoma is of vital importance as the treatment options and prognosis are dramatically different.
- Does a prior diagnosis of IBD increase the risk of developing lymphoma in the future? In cats with a previous diagnosis of IBD who are later diagnosed with small cell lymphoma, it is unclear whether 1) IBD has ‘transformed’ into lymphoma or the chronic inflammation has potentiated the development of lymphoma or 2) the initial diagnosis was incorrect and the cat had lymphoma all along. In people, inflammatory bowel disease is strongly associated with an increased risk of colorectal cancer. These cancers are typically carcinomas, although there may be an increased risk of lymphoma as well. Chronic immunosuppression may also play a role in cancer risk in these patients.
Lymphoma is the most common intranasal tumour in cats. Clinical signs do not specifically distinguish it from other intranasal diseases. In most cats, it is localised to the nasal cavity at diagnosis, though systemic involvement can occur. Advanced imaging (CT or MRI) and biopsies for histopathology are recommended for diagnosis—while cytology may be diagnostic, false negatives are common due to concurrent inflammation. Radiation therapy is the treatment of choice for localised disease. Complete staging including regional lymph nodes, thoracic and abdominal imaging and ideally bone marrow assessment, is recommended if radiation therapy is to be pursued.
- Definitive diagnosis: IHC is the most reliable way to distinguish nasal lymphoma from carcinoma (the second most common feline intranasal tumour) and should be considered for definitive diagnosis in all feline nasal tumours.3 Although the recommended treatment for both is radiation therapy and the error rate of routine H&E is not especially high, lymphoma has a higher risk of systemic involvement and therefore more extensive staging is indicated prior to treatment, and the prognoses differ (generally longer survival time with lymphoma than carcinoma). IHC on feline nasal tumours, especially those diagnosed as carcinoma on H&E, would therefore seem prudent.
- Treatment options: Although radiation is standard of care, it is not widely available. In that case, chemotherapy can be effective. The majority of cats will respond to COP/CHOP chemotherapy and extended survivals can be seen, especially in those achieving a complete response (approximately 1–2 years).4
- Combining radiation with chemotherapy: Given the risk of systemic disease and the effectiveness of chemotherapy, it is tempting to treat with both radiation therapy and chemotherapy. In one study using radiation therapy and chemotherapy for cats with localised nasal lymphoma, the median survival time was approximately 2.5 years, longer than that published for either treatment alone.5 The one study comparing cats treated with radiation therapy, chemotherapy, or both, for nasal lymphoma did not show a statistically significant difference between the treatments, though when cats receiving any radiation therapy were compared to cats receiving chemotherapy alone, radiation therapy was found to improve overall survival time. Again, improved survival was seen in cats with a complete response to treatment.6
Peripheral Nodal Lymphoma
Lymphoma limited to the peripheral nodes represents <10% of all feline lymphoma cases. Nodal lymphoma in cats includes both small and large cell variants, and there is a specific subtype referred to as “Hodgkin’s-like” which typically involves one or more of the lymph nodes of the head and neck.
- Diagnosis: Unlikely canine nodal lymphoma, cytology alone is often insufficient for diagnosis and histopathology is often required. IHC should be pursued to assist in diagnosis, especially of Hodgkin’s-like lymphoma and in any equivocal cases. The histological designation ‘T cell rich B cell lymphoma’ is used interchangeably with Hodgkin’s-like lymphoma by some pathologists, but the clinical presentation (single or regional lymph nodes, usually not disseminated disease) must be considered to diagnose Hodgkin’s-like lymphoma and choose appropriate treatment. I have seen a case of a drug reaction in a cat with marked peripheral lymphadenopathy that was diagnosed as emerging large B cell lymphoma on H&E, however, IHC showed reactive hyperplasia. The inciting drug was discontinued with rapid resolution of lymphadenopathy.
- Treatment: In general, although data is lacking, nodal lymphoma in cats is treated as for dogs, i.e., depending on whether it is a large or small cell variant. In the specific case of Hodgkin’s-like lymphoma, surgery is often pursued as an initial treatment, but whether or not chemotherapy should be used at all, as an adjuvant treatment, after progression, or instead of surgery is undefined.
Vail DM, Withrow SJ, editors. Withrow and McEwen’s Small Animal Clinical Oncology (5th edition) W.B. Saunders, Philadelphia, 2012 is recommended as a general resource.
1. Smith AL, Wilson AP, Hardie RJ, Krick EL, Schmiedt CW. Perioperative complications after full-thickness gastrointestinal surgery in cats with alimentary lymphoma. J Vet Surg. 2011;40:849–852.
2. Kiupel M, Smedley RC, Pfent C, Xie Y, Xue Y, Wise AG, DeVaul JM, Maes RK. Diagnostic algorithm to differentiate lymphoma from inflammation in feline small intestinal biopsy samples. Vet Pathol. 2011;48:212–222.
3. Nagata K, Lamb M, Goldschmidt MH, Duda L, Walton R. The usefulness of immunohistochemistry to differentiate between nasal carcinoma and lymphoma in cats: 140 cases (1986–2000). Vet Comp Oncol. 2014;12:52–57.
4. Taylor SS, Goodfellow MR, Browne WJ, Balding B, Murphy S, Tzannes S, Gerou-Ferriani M, Schwartz A, Dobson JM. Feline extranodal lymphoma: response to chemotherapy and survival in 110 cats. J Small Anim Pract. 2009;50:584–592.
5. Sfiligoi G, Theon AP, Kent MS. Response of nineteen cats with nasal lymphoma to radiation therapy and chemotherapy. J Vet Radiol and Ultrasound. 2007;48:388–39.
6. Haney SM, Beaver L, Turrel J, Clifford CA, Klein MK, Crawford S, Poulson JM, Azuma C. Survival analysis of 97 cats with nasal lymphoma: a multi-institutional retrospective study (1986–2006). J Vet Intern Med. 2009;23:287–294.