Lymphoma in Australian cats—Lessons for Europe?

Most feline physicians would agree that lymphoma (synonym: lymphosarcoma; malignant lymphoma) (LSA) is the most common malignancy of cats. Indeed, the discovery in the 1960s that some types of feline LSA were associated with a retrovirus (feline leukaemia virus (FeLV)) resulted in an explosion of knowledge concerning LSA, cats in general and virus-induced cancer.

Substantial literature has been generated in relation to this important feline malignancy, the majority of reports arising from the UK and North America, but with important contributions also from Europe. Although a very large number of papers have covered a variety of aspects of this malignancy, a comprehensive review of the literature provides an insight that LSA may take on different guises in different feline populations, whether they are separated geographically, or in time. In other words, the pattern and epidemiology of LSA appears distinct in different countries or even regions within the same country, and at different points in time. Thus, some series of feline LSA cases have had a preponderance of young cats with mediastinal involvement associated with leukaemia, while others have comprised mainly older cats with involvement of the gastrointestinal tract, mesenteric lymph nodes or kidneys.

A retrospective analysis of feline LSA cases seen in our hospital (Court et al 1997) suggested that the clinical and epidemiologic features of LSA in eastern Australia differed markedly from that which had been reported in the past for UK and North America. Accordingly, we embarked on a large prospective study of feline LSA in order to obtain a more rigorous data set, with a view to precisely define the features of this important malignancy in Australian cats as at 1995/1996.

This project involved myself (a feline physician with expertise in chemotherapy and infectious disease), PC (a veterinary pathologist with an interest in comparative oncology) and an enterprising PhD student (LG). This combination of personnel was very successful in recruiting cases, and we were able to obtain data from 118 cats over an 18-month period. These cases were studied using standard clinical methods (haematology, serum biochemistry, radiology, ultrasonography and necropsy). Immunohistology was used to determine the immunophenotype of the tumours. Daria Love developed a sensitive Western blot test to detect antibodies against FIV (adapting protocols developed originally in Glasgow), while Marion Jackson and colleagues at Saskatoon used their PCR to determine whether FeLV provirus was present in tumours from affected cats. The study had two broad aims: (1) to define risk factors for the development of LSA in our cohort of Australian cats, and (2) to determine patient or tumour factors predictive of a successful outcome using a single multi-agent chemotherapy protocol.

Analysis of the data was initially hindered by our inability to classify cases according to accepted anatomic schemes or staging protocols. This problem arose because many cases had either unusual combinations of tissues affected (eg, gut, nearby mesenteric lymph nodes and one peripheral lymph node) or the involvementof atypical structures (eg, the nasal cavity). For this reason, we developed our own classification system, including separate categories for caseswith mixed and atypical tissue involvement(Gabor et al 1998).

In our study cohort, the age distribution of cases was biphasic with a small group of young cats (less than 4 years of age) and a much larger group of cats about 10 years old (overall range 5–212 months; median age 120 months). The subgroup of young cats tended to have mediastinal involvement, with or without involvement of nearby lymph nodes. Siamese cats and Siamese crosses were over-represented (22 cases) across-the-board in comparison with domestic crossbred cats and were especially conspicuous amongst the group of young cats with mediastinal involvement. Male cats were over-represented, accounting for 72/118 cats (Gabor et al 1998).

Compared with the series from the UK or North America, mixed cases and atypical cases were much more common. Seventy percent of lymphomas were B cell tumours, 26% were T cell tumours, while 4% failed to stain with any T or B cell markers. Medium-grade (66%) and high-grade (24%) tumours predominated, while low-grade tumours (10%) were quite rare. There was no detectable association between histological grade and immunophenotype (Gabor et al 1999).

Haematology and serum biochemistry were generally unhelpful in the diagnostic investigation of these cases, although as expected, cats with renal involvement tended to be azotaemic and cats with alimentary LSA tended to have lowalbumin concentrations. Although 13 cats had detectable neoplastic lymphoid cells in buffy coat preparations of peripheral blood, only five had distinct lymphocytosis (Gabor et al 2000).

Only 2/107 (2%) of cases for which serum was available were positive for FeLV p27 antigen; both of these were young cats with T celltumours and both were leukaemic. Considering this, it was surprising that 25/97 (26%) of cases for which tissue was available for PCR testing had FeLV provirus in tumour tissue (Gabor et al 2001a). Unfortunately, we did not have the foresight to collect age-matched lymphoid tissue from cats without LSA to use as ‘controls’, a deficiency we are currently addressing.

Interestingly, 50/101 (50%) cats were FIV-positive on the basis of Western blot analysis. These cats were more likely to be male, domestic crossbreds and have atypical LSA. Only 39/107 (36%) were positive on the basis of one manufacturer's in house ELISA, and using Western blot analysis as the gold standard this corresponded to five false-positives and 16 false-negatives. The five false-positives were negative using an immunomigration FIV test, and of the 16 sera that were ELISA-negative but Western-positive, nine were positive using immunomigration(Gabor et al 2001b).

We concluded from these virological studies that persistent FeLV antigenaemia was very rare in Australian cats with LSA, but there was insufficient data upon which to assess the importance of FeLV infection in relation to lymphomagenesis. Overall, FeLV appeared to be much less important as a cause of LSA than in studies emanating from UK and North America in the 1970s and 1980s. In contrast, FIV infection was very prevalent in Australian cats with LSA and circumstantial evidence points to Australian FIV strains playing a role in the development of LSA. Although a number of studies had previously described a link between FIV and LSA, particularly in small groups of experimentally infected cats, this was the first large study to emphasise this potential association. The influence of FIV as a predisposing cause gives some explanation on a number of the epidemiologic features of LSA in our study cohort, such as the preponderance of males, the commonness of B cell tumours and the large number of atypical and mixed forms of LSA. Mediastinal LSA in young cats, especially in Siamese/Oriental cats, is usually linked with neither FeLV nor FIV in Australian cats, and is likely a genetic disease based on recent data from North America.

An important aim of this study was to correlate patient, tumour, retroviral status and other measurable factors with clinical outcomes in response to a single multi-agent chemotherapy protocol. We used a modified Wisconsin protocol, using slightly different doses of drugs, given in a slightly different order and sometimes using different routes of administration, so that owners were only required to attend the veterinary clinic every second week for the first 16 weeks of therapy, and monthly thereafter. Doxorubicin was given at a dose of 1 mg/kg, l-asparaginase was given more frequently than is customary and via the intramuscular route at a dose of 450 U/kg, cyclophosphamide and methotrexate were given orally (rather than intravenously), routine haematological monitoring was notattempted and intravenous chemotherapy was typically given into the jugular vein under sedation or sevoflurane anaesthesia (Tzannes et al 2000).

A total of 61 cats were treated, 60 with chemotherapy (of which seven had surgery also), while one was treated with surgery alone. The complete remission rate for chemotherapy was 80%. The median survival time of 116 days was disappointing, perhaps reflecting the fact that cats were treated irrespective of their disease severity at presentation. Considering only cats that went into complete remission, the median survival was 187 days. Importantly, 20 cats were long-term survivors and indeed perhaps 25–30% of cases were ‘cured’ (Malik et al 2001).

Despite a rigorous analysis of variables, only three factors had a discernable impact on prognosis. The predictors of a favourable outcome were: (1) attainment of complete remission; (2) a T cell phenotype; and (3) being less than 4 years of age. Surprisingly, FIV status had no impact on survival. Interestingly, one cat with solitary nodal (mandibular) LSA was cured by surgical excision alone. Two cats died of recrudescent toxoplasmosis during therapy (Malik et al2001).

As one of the best predictors of a successful outcome was the attainment of complete remission; we strongly recommend that cats with LSA be given induction therapy with vincristine and l-asparaginase before making a definitive decision about embarking on a full course of chemotherapy. FeLV-negative young cats (less than 4 years old) are good candidates for chemotherapy (especially if they have mediastinal involvement) and we believe a majority of these cases can be cured. Recent work from the Netherlands (Teske et al 2002) suggests that these tumours may respond equally well to simpler protocols without doxorubicin or l-asparaginase, and if this is proven by subsequent work, a doxorubicin-free protocol would probably be preferable to minimise renal and cardiac toxicity.

It may be inappropriate to extrapolate our results for chemotherapy in Australian cats to that in cats in other countries where the clinical features and epidemiology of LSA are different. Thus, comparing outcomes of LSA therapy in different places may be like comparing apples with oranges! For example, the outstanding outcomes obtained in Teske's retrospective probably reflects the high proportion of young Siamese cats with mediastinal involvement in the study cohort.

The pattern of disease observed in our Australian study is similar in some respects to what has been reported more recently for cats in the USA, in contradistinction to what is recorded in veterinary texts. This may reflect a lesser impact of FeLV more recently, as a result of widespread vaccination in North America, or more likely other factors. Therefore, it is probably wise to consider LSA to be an evolvingdisease, reflecting both changes in the genetic constitution of cats in successive generations and changes in the prevalence and virulence of FeLV and FIV over time.

More work is required to further refine guidelines for chemotherapy of LSA in cats (Vail et al 1998). It is the impression of the authors that cats almost never require more than 1 year of chemotherapy and that perhaps 6 months of intensive chemotherapy is sufficient to effect a cure in many cases. There is no doubt in our mind that prednisolone contributes to complications, but we are not convinced it makes an additionalcontribution to efficacy, based on good success in some cases where prednisolone was not included in the protocol because of contraindications based on pre-existing disease conditions.

Since the completion of this study, the broad brushstrokes of these 60 cases have been confirmed. Additionally, we have seen three cases of gastric LSA that were cured using radical surgical excision and limited follow-up chemotherapy. Nasal cases continue to be seen, including a substantial proportion that have a prominent nasopharyngeal component (Hunt et al 2002); many of these do well with cytoreduction (by massage/flushing) and follow-up chemotherapy. Also, many cats, especially older cats, cope better with the chemotherapy regimen if the drugs are administered at longer intervals, typically with intravenous chemotherapy given every 3 weeks rather than every 2 weeks.