Canine T‐zone lymphoma: an apparent risk factor for adult‐onset demodicosis

We read with interest the recent publication on canine demodicosis by O'Neill et al. (2020). The main objective of the study was to explore epidemiological features of juvenile and adult-onset canine demodicosis in dogs from the UK. Because of our inherent bias as medical oncologists, we could not help but notice one potential risk factor for adult-onset demodicosis that was apparently not detected in the studied population. This letter aims to propose a constructive discussion on this potential risk factor, more prevalent in certain canine breeds, that was not documented in this recent publication. Nodal peripheral T-zone lymphoma (TZL), also referred to as small clear cell lymphoma, is a low grade, indolent lymphoid malignancy that has long been recognised in people and was described in dogs more than 15 years ago (Nakamura & Suchi 1991, Fournel-Fleury et al. 2002, Valli et al. 2005). Compared with large cell (high grade) lymphomas, the reported survival times are much longer, ranging from 622 to >1000 days, with an oral chemotherapy protocol of chlorambucil and prednisone providing better results than the multiagent protocols commonly used for more aggressive lymphomas, including protocol combining of cyclophosphamide, doxorubicin, vincristine and prednisone (Valli et al. 2005, Flood-Knapik et al. 2013, Valli et al. 2013, Seelig et al. 2014, Martini et al. 2016, Mizutani et al. 2016). Not all dogs are treated at diagnosis, owing to the indolent nature, but treatment is recommended when certain criteria are met; there is no consensus, but it may include the presence of clinical signs, visceral involvement, and/or lymphocytosis above 30,000/uL, to name a few. Golden retrievers appear to be overrepresented in many studies, and it was recently demonstrated that senior golden retrievers without a diagnosis of TZL have an increased frequency of circulating T-zone cells (CD45 negative) when compared to other breeds (Flood-Knapik et al. 2013, Seelig et al. 2014, Mizutani et al. 2016, Hughes et al. 2018). Other commonly reported breeds with TZL include the shih-tzu, Labrador retriever, boxer and terrier breeds, but dogs of any breed may be affected (Valli et al. 2005, Flood-Knapik et al. 2013, Seelig et al. 2014, Martini et al. 2016, Mizutani et al. 2016). On clinical presentation, dogs have enlarged and firm peripheral lymph nodes and, occasionally, non-specific clinical signs that may include lethargy, dyspnoea from enlarged lymph nodes, decreased appetite, or other non-specific signs (Martini et al. 2016, Mizutani et al. 2016). Complete blood cell count commonly (>50% dogs) demonstrates mild to marked lymphocytosis in dogs with TZL, and the circulating lymphocytes are also T-zone cells (Flood-Knapik et al. 2013, Seelig et al. 2014, Martini et al. 2016, Mizutani et al. 2016, Hughes et al. 2018). On cytology the neoplastic cell population is composed of small to intermediate lymphocytes, with a clear cytoplasm that often forms a pseudopod (“hand mirror” morphology), while histopathology and immunohistochemistry confirms a paracortical expansion of small cleaved T lymphocytes, with a very low mitotic count, often with no mitosis observed (Fournel-Fleury et al. 2002, Valli et al. 2005). Other tests that are helpful to diagnose TZL include polymerase chain reaction for antigen receptor rearrangement (PARR, clonality testing) and flow cytometry (Valli et al. 2005,Seelig et al. 2014, Martini et al. 2016, Mizutani et al. 2016). The latter is now commonly used to diagnose TZL and shows a characteristic population of T lymphocytes with an aberrant phenotype; the neoplastic cells are CD45 negative and CD25 positive, with various CD4 and CD8 expressions (Seelig et al. 2014, Martini et al. 2016, Mizutani et al. 2016). Of interest to dermatologists and primary veterinary care practitioners, it has been noted that 10 to 50% of dogs with TZL presented with, or eventually developed, adult-onset demodicosis (Flood-Knapik et al. 2013, Mizutani et al. 2016). These percentages are exceedingly high for an adult population of dogs and suggest that TZL is associated with, or results in, an immunosuppressive state. In addition to the two studies describing adult-onset demodicosis in dogs with TZL, a similar frequency of demodicosis in dogs with TZL is anecdotally observed in our oncologic practice, and there are numerous accounts of dogs, most of them golden retrievers, with concurrent TZL and demodicosis discussed on the message boards of a large web-based veterinary network (www.vin.com). Interestingly, demodicosis is occasionally diagnosed in people with lymphoid malignancies (lymphoma, leukaemia), but typically develops during maintenance cytotoxic therapy, suggesting that the immunosuppression is secondary to the long-standing aggressive chemotherapy rather than from the lymphoid malignancy itself, contrary to what is observed in dogs with TZL (van Atteveld et al. 2017). It has been our personal experience that the demodicosis of dogs with concurrent TZL responds well to appropriate therapy, especially if the TZL is also treated. We think it is important to recognise the potential connection between the two diseases; canine TZL appears to be an underlying cause predisposing affected dogs to adult-onset demodicosis. Why this was not observed by O'Neill et al. (2020) in the studied population from the UK may be a matter of geographic distribution differences, sample size, or underreporting of indolent lymphoma (TZL) in the studied population. Specifically, geographic distribution differences of various lymphoma subtypes, including TZL, was recently described in the USA for golden retrievers (Ruple et al. 2017). Recent review articles focusing on canine demodicosis do not allude to TZL as apotential risk factor (Ferrer et al. 2014, Mueller et al. 2020). Future review papers and textbook chapters on canine demodicosis and lymphoma should include this information, and more research is needed to better understand the phenomenon.

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