Whilst peripheral lymphadenopathy may be the most common finding, on examination many other abnormalities may be present, including hepatosplenomegaly, abdominal mass, pallor, effusions, etc.

In the UK, for a dog presenting with peripheral lymphadenopathy the list of differentials is short. Lymphoma is the primary disease to rule out, but other metastatic neoplasia can occasionally present as lymphadenopathy, as can chronic skin disease. When individual nodes are enlarged, especially in the submandibular region, the diagnosis can be more challenging. In other countries with higher incidences of infectious diseases (e.g. Ehrlichia) these must be ruled out by appropriate tests. Fine needle aspirate (FNA) is a useful first diagnostic test, whenever possible avoiding the submandibular lymph nodes. However, it is a quick assessment test and for patients with suspected lymphoma further diagnostics are recommended. Flow cytometry allows detailed characterization of the lymphoid population from an FNA and should be utilized when available or practical (see Chapter 4). In the absence of this facility, or when the sample would be too small, then a biopsy is recommended.

The value of a representative biopsy is that this gives the pathologist much more information about the distribution of neoplastic cells throughout the node, which in turn gives the veterinary surgeon more information when discussing treatment and prognosis with the client. Excisional biopsy is best, especially when the nodes are relatively small. In many instances, tru-cut biopsies can be performed accurately, and a number of samples should be taken. Fast-growing lymph nodes may have large areas of necrosis, so to check that you have a representative sample, gently role the slice of tissue on a slide and examine it microscopically; if the majority of the cells are not identifiable, take a further biopsy or change plan and take an excisional biopsy instead.

For patients with lymphoma involving other organs (e.g. primary hepatic, oral, renal), FNA are usually diagnostic because lymphoblasts would not normally be present in these organs. Care should be taken with FNA of the spleen and intestine in the diagnosis of lymphoma. Malignant effusions containing large numbers of lymphoblasts are also sufficiently diagnostic for starting treatment.

For patients presenting with clinical signs related to a paraneoplastic syndrome (PNS), the diagnostic route might not be obvious. Hypercalcaemia is reported in up to 40% of canine patients and many of these do not have peripheral lymphadenopathy. The most efficient approach to the work-up of a dog with hypercalcaemia (especially a young dog) is good quality thoracic radiographs. The anterior mediastinum is the most common location for lymphoma in patients with hypercalcaemia; the second most common location is the bone marrow. Patients that present with possible immune-mediated haemolytic anaemia (IMHA) or thrombocytopenia (ITP) should be thoroughly worked up to rule out underlying lymphoma as both are common lymphoma-associated PNS.

Patients that are clinically well at the time of diagnosis and starting treatment (substage a) have a better long-term prognosis than those patients that are already ill (substage b). Therefore, treatment should start as soon after diagnosis as possible to prevent a well patient moving from substage a to substage b.

A number of grading systems have been described to categorize canine lymphoma and a detailed discussion of these is beyond the goals of this chapter. Anyone interested in pursuing this further is advised to consult a more advanced text.

Most lymphomas are described as high grade (lymphoblastic), intermediate grade or low grade (lymphocytic). As a general rule, lymphoblastic lymphoma responds well to chemotherapy in the early stages but will more rapidly build up resistance, resulting in earlier relapse compared with lymphocytic lymphomas that may be slower to respond but will have longer remission times.

This is a valuable tool to distinguish between T- or B-cell origin and currently the information can be obtained from either biopsy or cytological preparations. Typically patients with T-cell lymphomas have a poorer long-term prognosis. This does not mean that patients with T-cell lymphomas will not achieve a complete remission but rather the remission may not be as enduring as patients with B-cell lymphomas. Typically, ∼70% of dogs with multicentric lymphoma have disease of B-cell origin.

PNS are common in dogs with lymphoma (Chapter 10), the most common being thrombocytopenia and hypercalcaemia. In some cases the presence of a PNS is a negative prognostic indicator.

Some studies have suggested that females have a better prognosis than males, although this has not been universally agreed upon.

Younger patients typically have more aggressive disease and therefore shorter survival times.

Several mechanisms exist by which tumour cells may acquire resistance and in canine LSA over-expression of P-glycoprotein is one of the major causes leading to the multidrug resistance (MDR) phenotype (Lee et al 1996). Lymphoma cells with the MDR phenotype are resistant to a number of categories of chemotherapeutics, including antimicrotubule drugs (e.g. vincristine), anthracyclines (e.g. doxorubicin) and prednisolone; however, the alkylating agents are not affected by MDR. Drug resistance can be inherent or develop as a consequence of treatment (see Chapter 6 for the mechanisms of drug resistance).

Patients with T-cell lymphomas appear to have more clinical bone marrow suppression that often results in treatment delays or reduced doses that can result in earlier relapse.

The treatment of choice for the majority of patients with lymphoma is combination chemotherapy. Infrequently, surgery or radiotherapy may be more appropriate.

Median survival times (MST) are influenced by the combination of cytotoxics used in the treatment of patients with lymphoma. The more complex the protocol, the better the outcome – for example, using prednisolone alone the MST is 3 months, using COP (cyclophosphamide, vincristine and prednisolone) the MST is 6 months, and using CHOP (cyclophosphamide, vincristine, doxorubicin and prednisolone) the MST is 12 months (Cotter & Goldstein 1987, Piek et al 1999). As a single agent, doxorubicin gives superior survival times when compared to COP (Carter et al 1987). However, the more complex the protocol, the greater the risk of side effects, and so both the client and the veterinary surgeon must be committed to the management of side effects, should they occur.

The authors use a doxorubicin protocol because it is the incorporation of doxorubicin into protocols for canine LSA that have increased overall survival times (Carter et al 1987, Keller et al 1993, Teske et al 1994). However, when choosing the protocol to use the following factors should also be considered: the experience and setup of the veterinary surgeon, equipment available for handling cytotoxics and adequate 24-hour care should a cancer patient be unwell. In cases where all these factors are not in place, referral for treatment should be discussed and offered to the client.

Oncologists are trained and equipped to deal with the problems that may develop and just as importantly have the experience to individualize treatment depending on age, breed, stage, drug resistance and intolerance. The ability or willingness of the client to travel for specialist care may also impact on the protocol used and the veterinary surgeon should never go beyond their comfort level or equipment as this will inevitably result in poor care for the patient. Cost may also be an issue; the more complex protocols inevitably are financially more expensive and for clients with a limited budget this should be considered at the outset.

Personality of the patient has to be considered in some instances. For dogs that become extremely stressed when at the vets the clients may be unwilling to enter into treatment that involves many weekly visits to the surgery for chemotherapy. In such cases a protocol combining outpatient oral medication (with appropriate monitoring and client information) may be beneficial or a single-agent protocol such as doxorubicin every 3 weeks for five treatments may be suitable (Postorino et al 1989).

The debate about the value of a maintenance phase of a chemotherapy protocol is still an area of discussion. The less intense the induction phase, the more valuable is maintenance chemotherapy (e.g. COP). As with any protocol, the question is: ‘How long should the induction phase be?’ Should it be a set number of weeks, e.g. 25 weeks, or should it be for so many treatments after a complete response has been obtained? Should it be different depending on the stage of disease as patients with advanced disease may require longer or more intense treatment to achieve a complete response or a stable partial response? The simple answer to these questions is that the optimal protocol has not yet been developed and breaching the ‘1-year wall’ for median survival remains the objective.

Everyone hopes that his or her dog will be the one to beat the disease. Unfortunately, this is rarely the case and when relapse occurs, the decision of where to go from here can be difficult. For a patient that has had a long first remission the authors would advise re-induction using the same protocol. If the first remission has not been long, or re-induction does not result in a complete response, then a number of salvage protocols can be considered.

For patients that have not received doxorubicin initially, the authors would recommend single-agent doxorubicin ± an initial dose of l-asparaginase. In cases where doxorubicin has already been used, the authors moved to a modified MOPP (mustargen, vincristine, procarbazine, prednisolone) protocol, substituting CCNU for mustargen and vinblastine for vincristine or CCNU alone (Moore et al 1999) in combination with dactinomycin. Both drugs have been shown as effective rescue agents.

Other rescue protocols include dacarbazine (DTIC) in combination with doxorubicin (Van Vechten et al 1990), DTIC and CCNU (Flory et al 2008), and CCNU and l-asparaginase (Saba et al 2007). Eventually, whatever salvage protocol is used, progressive disease will occur.

Does it matter if the patient has a T- or a B-cell LSA? That depends on your perspective and whether you intend to do anything about it! If all patients with lymphoma are treated exactly the same, irrespective of stage, location or immunophenotype, the answer may be no; however, in an attempt to increase survival time in patients with T-cell lymphoma the authors routinely give a longer induction. In addition, it has been suggested that dogs with T-cell lymphoma have better outcomes when alkylating agents are included early in the protocol (Morrison-Collister et al 2003).

The authors routinely incorporate CCNU as a first-line drug in the management of canine patients with T-cell lymphoma (Table 22.3) and this has yielded promising results (unpublished communication). The importance of CCNU in improving the outcome for patients with T-cell lymphoma has been shown in studies using this drug for both epitheliotrophic lymphoma and T-cell cutaneous lymphoma. In the former, good responses have been documented (see Chapter 18); in the latter, two studies demonstrated an 80% partial or complete remission after CCNU (Risbon et al 2006, Williams et al 2006).

Because lymphoma is a systemic disease, surgery other than for obtaining a diagnosis is rarely indicated. Surgical excision of heavily infiltrated spleens may be considered (see Chapter 23), and excision of isolated intestinal lymphoma/gastric lymphoma may facilitate chemotherapy and reduce complications from chemotherapy (Chapter 15). Solitary cutaneous disease may also be treated with surgical excision.

Again because of the systemic nature of lymphoma, radiotherapy has a limited but valuable role in the treatment of canine lymphoma. Isolated disease is seen less frequently in the dog than the cat, but it does occur (e.g. oral, rectal), and because lymphoid tissue is extremely sensitive to radiotherapy it can be the treatment of choice.

Radiotherapy has application in the emergency situation, usually for patients in severe respiratory distress due to a large anterior mediastinal lymphoma. It can also be valuable in shrinking individual lymph nodes causing a problem to the patient when other disease is stable.

Half-body radiation in conjunction with chemotherapy has also been used in the management of canine patients (Rassnick et al 2007, Williams et al 2004). In one study, patients with stage II–V disease were started on a CHOP protocol and then given half-body radiation 2 × 4 Gy fractions to the cranial half of the body and 1 month later the same dose to the caudal half of the body. A median remission time of 486 days was reported; overall treatment was well tolerated (Williams et al 2004).

The tolerance of bone marrow to cytotoxic drugs and radiation is a significant limitation in permitting dose escalation of drugs/radiation known to be effective against lymphoma and other cancers. In the early days of BMT development for human patients, dogs were used to develop the technique and therapeutic model, proving the principle when spontaneous lymphoma in the dog was treated with autologous BMT (e.g. Deeg et al 1985).

Recently, Frimberger et al (2006) reported on the combination of chemotherapy with dose escalation and autologous BMT in the management of LSA. They found that dogs receiving the highest dose of cyclophosphamide (500 mg/m², MST 139 weeks) when supported by BMT had longer survival times compared to dogs on lower doses (300 mg/m², MST 43 weeks and 400 mg/m², MST 68 weeks) and BMT.

Leukaemia is neoplastic disease involving one or more cell types of haemopoietic origin; the primary site of disease is the bone marrow.

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