Molecular Markers in Canine Lymphoma
World Small Animal Veterinary Association World Congress Proceedings, 2015
Peter Bennett1, BVSc, FANZCVS (Canine medicine), DACVIM (Oncology, SAIM)
1Veterinary Teaching Hospital, University of Sydney, NSW, Australia

Lymphoma is a relatively common disease in the dog and has been treated successfully with chemotherapy for many years.1 There has been improvement in the management and ability to give the owners of a patient an accurate prognosis, but it has been limited. The recent commercial development of monoclonal antibodies for canine lymphoma will likely have a big influence in the treatment of this disease as the development and use of rituximab in people. This will not be a widely available option in the near future.

Lymphoma should be considered a group of cancers of the lymphoid tissues rather than a single disease. Some of this is reflected in the range of different subtypes that are identified in the histological classifications that have been used in dogs. There is significant overlap between the disease subtypes. To date, the full extent of the differences and their influence on prognosis and ideal treatment has not been explored. In people some further investigations has been done, but there is still a lot more work to be done.

It is possible to get a fairly firm diagnosis of lymphoma from the combination of physical examination and cytology of an aspirate of the node. Histopathological evaluation of biopsies is not always performed. It was recognised many years ago that there was a difference in prognosis between dogs with T cell lymphoma and dogs with B cell lymphoma. Initially, the most readily available means to obtaining the immunophenotype was with immunohistochemistry. This led to an increase in the biopsies and histological classification, but it was not a routine procedure. In more recent years, there has been an increase in the availability of other means of differentiation including immunocytochemistry, flow cytometry, and PCR for antigen receptor rearrangement (PARR), which all can identify the immunophenotype.2 This has led to a decline in the routine use of histopathological evaluation.

Histopathology is still used in cases where there is not clear diagnosis of lymphoma. It is also used commonly when low-grade disease is suspected or possible. In the veterinary literature, there has been little correlation between the histological classifications and prognosis. It is possible that there might be differences in the most effective treatment between the types, but this has not been explored.

Currently when dogs are treated for lymphoma, we get a reasonable response rate of over 90% with combination chemotherapy and a median survival of around one year. But there is a wide range of potential outcomes for an individual patient and this causes problems. So while we can quote to the owner the median or mean survivals and response rates, for their pet the outcome could range from a failure to respond and death within days through to cure. As clinicians, it would really help if we could more accurately predict the outcome for the individual.

In both dogs the most common form of generalised lymphoma seen is diffuse large B cell lymphoma. This is also the most commonly diagnosed variant of non-Hodgkin's lymphoma in people. It is most common in dogs that we will tell the owners the prognosis based on the disease being an intermediate or high-grade B cell lymphoma and modified by other clinical prognostic signs, most importantly the substage. In people, there are at least 13 recognised subclassifications of diffuse large B cell lymphoma with known variations in prognosis. The subclassification is based on a panel of immunohistochemical markers. We currently do not know if these classifications are relevant for the canine patient.

In people with diffuse large B cell lymphoma, they are also classified as to whether they are of the germinal centre variety, activated B cell-like, or unclassified. There are significantly different outlooks for these classifications. The identification of the subtypes can be performed looking at genetic profiling of the lymphoma cells as well as using an algorithm based on a series of immunohistochemical staining.3 It is still not clear if these differences are present in dogs based on genetic analysis. It is clear that we cannot use the same immunohistochemical algorithms.

Despite the dramatic decrease in the cost of genetic analysis and the decrease in the time taken to perform these tests, it is difficult to run them as a routine procedure. The use of microRNA analysis of the lymphomas has identified some differences in these that have a very high correlation with the immunohistochemical and genetic classifications of the lymphoma. It has been shown that the microRNA changes can be identified in blood, which allows for a less invasive, but still accurate test. There has been limited evaluation of microRNAs in canine lymphoma.4

The use of molecular markers in canine lymphoma should help improve the accuracy of differentiating the subtypes of the disease and give indications of the metabolic drivers of the cancer. The latter can then be used to determine the best treatments based on likely drug susceptibility or metabolism. The molecular findings might not be in the involved pathway, but be acting as a surrogate marker.

If these are achieved this will aid improvement in prognostication. If improvements in treatments are found, this will alter the prognosis for some, or possibly many, patients. This work has not been done in people or dogs.

Molecular markers can also be used in the assessment of response. The use of PCR techniques for evaluating minimal residual disease will detect low levels of disease that are not evident on routine examinations.5 This is a sensitive measure of response to treatment, but it is not able to predict cure. Its full value in the management of canine lymphoma has not been elucidated.

Another area of evaluation of genetic and molecular markers is in looking for risk factors in high-risk breeds. There is some early work in this area published for Golden Retrievers6 and studies in other breeds are ongoing. If there are markers of risk identified, then this could be utilised in breeding programs to reduce the incidence of the disease in these breeds.

This is a novel and exciting area in canine lymphoma. More work is required to develop the knowledge of the full advantages of these tools to improve the management of canine patients with lymphoma.

References

1.  Marconato L. The staging and treatment of multicentric high-grade lymphoma in dogs: a review of recent developments and future prospects. The Veterinary Journal. 2011;188:34–38.

2.  Gelain ME, Mazzilli M, Riondato F, Marconato L, Comazzi S. Aberrant phenotypes and quantitative antigen expression in different subtypes of canine lymphoma by flow cytometry. Veterinary Immunology and Immunopathology. 2008;121:179–188.

3.  Hans CP, Weisenburger DD, Greiner TC, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103:272–282.

4.  Albonico F, Mortarino M, Avallone G, et al. The expression of miR-17-5p and miR-155 correlates with grading in splenic lymphoma. Veterinary Immunology and Immunopathology. 2013;155:117–123.

5.  Yamazaki J, Baba K, Goto-Koshino Y, et al. Quantitative assessment of minimal residual disease (MRD) in canine lymphoma using real-time polymerase chain reaction. Veterinary Immunology and Immunopathology. 2008;126:321–331.

6.  Thamm DH, Grunerud KK, Rose BJ, Vail DM, Bailey SM. DNA repair deficiency as a susceptibility marker for spontaneous lymphoma in Golden Retriever dogs: a case-control study. PLoS One. 2013;8:e69192.

  

Speaker Information
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Peter Bennett
Veterinary Teaching Hospital
University of Sydney
Sydney, NSW, Australia


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