Lymphoma in the dog - Bibliovet The Encyclopaedia of Veterinary Medicine

Details: Category: Schede; Published: 27 October 2012; Hits: 10

Disciplina: Oncologia
Specie: Cane

Lymphoma is the most frequent malignant neoplasm of the haematopoietic system in the dog and shares the clinical, cytological, histopathological and biomolecular characteristics of non-Hodgkin’s lymphoma in humans.

In human oncology the Revised European American Lymphoma (REAL) and modified World Health Organization (WHO) classifications are the most recent classifications and take into consideration epidemiological, clinical, morphological, immunophenotypic and genetic features, distinguishing precise clinical entities with their own prognostic and therapeutic characteristics.

In veterinary medicine there are not yet precise guidelines, although attempts must be made to refine the diagnosis of this malignancy, abandoning the generic term “lymphoma” in favour of specific subtypes with their own prognosis and response to treatment.

Various different classification schemes have been proposed over the years. The distinction between B-cell and T-cell lymphomas led to the updated Kiel classification, which takes into account cytological and immunophenotypic features (Table 1). Unfortunately, the Kiel classification does not consider some subtypes of lymphoma.

The Veterinary Lymphoma Study Group, coordinated by Professor Valli, is evaluating whether the REAL/WHO systems can be applied also to dogs, in order to identify specific pathological entities characterized by their own prognostic and therapeutic profiles (Table 2).

Low grade
Small cell	T-cell immunophenotype. The cells are small with clumped chromatin and scant pale cytoplasm. The variants are a centrocytic type (irregular nucleus), clear cell type (irregular nucleus, abundant clear cytoplasm, often extended and unipolar, containing azurophilic granules; hand mirror appearance; Fig. 1), prolymphocytic type (fine chromatin and prominent nucleoli) and pleomorphic type (irregular, indented nuclei and scant pale cytoplasm).
Centrocytic (mantle cell lymphoma)	B-cell immunophenotype. Small or medium-sized cells with round, indented or irregular nucleus, clumped chromatin and scant cytoplasm.
Centroblastic- centrocytic (follicular)	B-cell immunophenotype. Rare lymphoma formed of a heterogeneous population of centrocytes and centroblasts; the mitotic index is low. Often evolves into a lymphoma with a high grade of malignancy.
Lymphocytic	B-cell immunophenotype. The cells seem small and normal, the nucleoli are not visible and mitoses are extremely rare. Lymphocytic lymphoma starts as a leukaemia and subsequently invades lymph nodes.
Lymphoplasmacytic (immunocytoma)	B-cell immunophenotype. Homogeneous lymphoid population. There are cells with an eccentric nucleus and clear perinuclear area which can evolve into immunoblasts and plasma cells (immunoblastic lymphoma).
Prolymphocytic	B-cell immunophenotype. Homogeneous population of small to medium-sized cells with evident nucleoli which infiltrate lymph nodes diffusely. Mitoses are rare. Often leukaemic.
High grade
Lymphoblastic	B- or T-cell immunophenotype. The cells are homogeneous and small or medium-sized, with a usually convoluted or ‘light-bulb’ shaped nucleus, fine chromatin and poorly visible nucleoli. The cytoplasm is scant and moderately basophilic. T-cell lymphoblastic lymphoma is often associated with mediastinal tumours and hypercalcaemia and has a CD4+CD8+ or CD4-CD8- immunophenotype.
Burkitt’s (small, non-convoluted cells)	B-cell immunophenotype. The cells are medium-sized, uniform, with a rounded nucleus and multiple nucleoli (powdery chromatin) and intensely basophilic cytoplasm with thick, unclear margins; they are sometimes vacuolated. The “starry sky” pattern, given by the presence of numerous macrophages with abundant, clear cytoplasm, is common. The mitotic index is high. This lymphoma often involves the intestine. The biological behaviour is very aggressive and the prognosis dismal.
Centroblastic	B-cell immunophenotype. The cells are bulky, with a large, central nucleus, vesicular chromatin and 2-4 prominent nucleoli arranged at the periphery of the nucleus in an eccentric position (Fig. 2). The cytoplasm is scant and intensely basophilic; mitoses are frequent. Three subtypes have been recognized: 1) monomorphic centroblastic lymphoma: formed by at least 60% centroblasts; 2) polymorphic centroblastic lymphoma: formed by centroblasts and immunoblasts, these latter accounting for more than 10% but less than 90% of the cells. It is the most frequent subtype and diffusely infiltrates the lymph node. It is accompanied by the “starry sky” pattern; 3) centrocytoid centroblastic lymphoma: the cells are intermediate between centroblasts and centrocytes). A typical form of lymphoma in dogs and recognized also in humans is macronucleolated medium-sized cell (MMC) lymphoma, which originates from the perifollicular marginal zone. Despite its apparently low grade of proliferation (determined from the mitotic index and expression of Ki-67), MMC lymphoma is biologically aggressive and must be included among the high-grade lymphomas. It takes on a monocytoid form in the gastrointestinal tract.
Immunoblastic	B- or T-cell (CD3+) immunophenotype. The cells are very bulky and have a central nucleus with a single horn or two prominent nucleoli and basophilic cytoplasm which is sometime vacuolated. There is a “starry sky” pattern. The mitotic index is high.
Anaplastic	B- or T-cell immunophenotype. The (bulky) cells often have histiocytic features with a flower-shaped nucleus and vacuolated cytoplasm (pseudo-Steinberg cells). The mitotic index is high. This lymphoma is not considered in the Kiel classification.
Pleomorphic, mixed (small and large cell)	T-cell immunophenotype (often CD4+CD8-). The cells are variably sized, the nuclei are irregular and the cytoplasm is pale or moderately basophilic. The mitotic index is high. Plasma cells can often be seen in the background.
Pleomorphic large cell	T-cell immunophenotype (often CD4+CD8-). This is the most frequent high-grade T-cell lymphoma. The cells are medium-sized or large and are often multinucleated. The nucleus is convoluted or cerebriform and the nucleoli are numerous and prominent. There is abundant, strongly basophilic cytoplasm which may form pseudopodia (“tennis racket” or “hand mirror” appearance) or contain fine azurophilic granules.
Plasmacytoid	B- or T-cell immunophenotype. The cells are small or large with an eccentric nucleus, intensely basophilic cytoplasm and an area of clear perinuclear cytoplasm. There is often an accompanying “starry sky” pattern. This is an aggressive, chemoresistant lymphoma, which does not have a recognized equivalent in humans.

Table 1: Cytomorphological and immunophenotypic classification of canine lymphoma according to the modified Kiel classification.

B cells	T cells
Lymphoblastic leukaemia/lymphoma	Lymphoblastic leukaemia/lymphoma
Chronic lymphocytic leukaemia/lymphoma	LGL lymphoma/leukaemia
Lymphocytic lymphoma intermediate type	Cutaneous lymphomas epitheliotropic (mycoses fungoides) non-epitheliotropic
Lymphoplasmacytic lymphoma	Extranodal/peripheral T-cell lymphoma
Follicular lymphomas (mantle cell lymphoma, follicular centre cell lymphoma I-II-III, nodal marginal zone lymphoma, splenic marginal zone lymphoma)	Angioimmunoblastic lymphoma
Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) or monocytoid lymphoma	Angiotropic lymphoma (angiocentric, angioinvasive)
Large B-cell lymphomas (T-cell rich, immunoblastic, diffuse cleaved, diffuse non- cleaved, thymic, intravascular)	Intestinal T-cell lymphoma
Burkitt-type lymphoma	Anaplastic large cell lymphoma

Table 2: Histological classification of lymphomas in the dog (2002).

STAGING

The correct approach to a dog with lymphoma requires a prompt, exact diagnosis and evaluation of the characteristics of both the tumour and the patient. In most cases dogs with lymphoma present with generalised, non-painful, enlargement of peripheral lymph nodes. Less frequently the clinical signs are secondary to neoplastic infiltration of the spleen, liver, gastrointestinal tract or bone marrow. The non-specific signs often delay the diagnosis by weeks or months.

Various forms of lymphoma have been described based on the clinical picture: multicentric lymphomas (Figs. 3 and 4), the most common, are characterized by generalised lymph node enlargement and non-specific symptoms; mediastinal lymphomas (thymic), which are rare, involve the mediastinal lymph nodes and, more rarely, the thymus and are often accompanied by a pleural effusion; alimentary lymphomas (Fig. 5), also rare, are characterized by isolated or widespread infiltration of the gastrointestinal tract with or without involvement of lymph nodes, spleen and liver and signs due to the gastrointestinal tract involvement; extranodal lymphomas (cutaneous, ocular, renal, encephalic, cardiac, bone, nasal, endocrine, muscular, pulmonary, pharyngeal, bladder, urethral and prostatic lymphomas).

The assessment of a dog with lymphoma starts with a careful history-taking and clinical examination. The presence or absence of symptoms, including lethargy, poor appetite, weight loss, polyuria/ polydipsia and fever, must be determined in order to classify the patient into the correct substage (a = absence of symptoms; b = presence of symptoms), this being prognostically relevant. It is also useful to investigate any exposure to known risk factors, including passive smoking, emissions from landfill sites and 2, 4-dichlorophenoxyacetic acid.

The clinical examination involves two-dimensional measurements of all enlarged peripheral lymph nodes in order to evaluate, through serial measurements, the response to treatment. Abdominal palpation can detect any enlargement of organs or abdominal effusion.

The diagnosis of lymphoma usually requires that a cytological preparation is made from a peripheral lymph node and evaluated. Cytology has numerous advantages: it is fast, painless and cheap. Since most lymphomas in the dog are high-grade, cytology is sufficient to make a diagnosis of lymphoma. However, for a more precise pathological classification or in the case of low-grade lymphomas, a histological evaluation of the lymph node is necessary, since this enables an assessment of the lymph node architecture.

Flow cytometry is a laboratory investigation that is being introduced into veterinary medicine. This investigation can confirm the diagnosis of lymphoma and demonstrate its immunophenotype, that is, define whether it is of B-cell or T-cell origin.

Once the diagnosis of lymphoma has been made, the tumour must be staged.

Pre-treatment staging according to the World Heath Organization is essential for the following reasons: it defines the spread of the neoplasm, it facilitates prognostication and it helps when planning treatment. Furthermore, it makes “re-staging” possible at the end of treatment in order to evaluate what response to therapy has been obtained. In veterinary oncology, and in particular in the case of lymphoma, the clinical stage of the disease in dogs is usually determined on the basis of the results of non-invasive investigations.

The first step is to do blood tests, including the complete blood count, flow cytometry of peripheral blood to detect any circulating malignant cells and blood biochemistry tests (including lactate dehydrogenase, uric acid, potassium, calcium, phosphorus). These last four parameters are important for the detection of animals predisposed to tumour lysis syndrome, which is often triggered by the administration of chemotherapy. Hypercalcaemia is a negative prognostic factor and the concentration of calcium must, therefore, always be evaluated during the initial work-up.

The bone marrow must be assessed in order to stage the patient accurately, since bone marrow infiltration does not always accompany leukaemic forms and, vice versa, the finding of immature cells in the circulation does not necessarily indicate bone marrow infiltration (“overspill”). Flow cytometry of medullary and peripheral blood can show even mild bone marrow infiltration and peripheral blood involvement. Furthermore, by studying the CD34 marker, flow cytometry can differentiate between acute lymphoblastic leukaemia (CD34-positive) and lymphoma with bone marrow infiltration (CD34-negative), two haematopoietic disorders with very different prognoses.

Chest X-rays can show intrathoracic lymph node enlargement with or without a pleural effusion and any pleural infiltrates that may be present.

Evaluation of the abdominal organs includes the use of ultrasonography. It is very important to carry out cytological studies of organs that appear, on ultrasound, to be altered as well as routine studies of the liver and spleen since the initial stages of infiltration are not always accompanied by changes in ultrasound images.

Once all the investigations have been carried out, the dog can be assigned a clinical stage:

Stage I: involvement limited to a single lymph node or lymphoid tissue of a single organ (including the cranial mediastinum);
Stage II: regional involvement of several lymph nodes, with or without involvement of the tonsils;
Stage III: widespread involvement of lymph nodes;
Stage IV: involvement of the liver and/or spleen, with or without generalised involvement of the lymph nodes (stages I-III);
Stage V: involvement of the bone marrow, blood and/or other extranodal organs (gastrointestinal tract, skin, kidneys, lungs with or without a pleural effusion, only pleural effusion if not secondary to lymphoadenopathy, eyes, pericardium, spinal cord), with or without the other stages.

Each stage must be further characterized by the letter a or b, which indicate the absence or presence, respectively, of systemic symptoms. The presence of hypercalcaemia makes the patient’s classification substage b.

FIRST-LINE TREATMENT

Chemotherapy is the treatment of choice. It is important to understand – and make the owners understand – that the treatment is not given with a curative intent, since only 10% of dogs survive more than 2 years. Chemotherapy is administered as palliation, aimed at improving the animal’s quality of life and, often, prolonging its survival.

The chemotherapy protocols that offer the greatest success involve the sequential use of vincristine, cyclophosphamide, and doxorubicin, with or without L-asparaginase. It is now clear that dogs with high-grade B-cell lymphomas do not need protocols including long maintenance phases, since these do not prolong either the remissions or survival. In contrast, relatively short protocols are preferable, since these are associated with less toxicity and, therefore, a better quality of life for the treated dogs.

While there are beginning to be some therapeutic guidelines for the treatment of high-grade B-cell lymphomas in the dog, the same cannot be said for T lymphomas. The T-cell immunophenotype is a significant, independent negative prognostic factor. CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) protocols are frequently used to treat T-cell lymphomas, often with sub-optimal results.

The different responses observed may be due to the drug resistance shown by lymphomas with the T-cell immunophenotype. It is, therefore, necessary to stratify future chemotherapy protocols on the basis of immunophenotype.

In the last few years progress has been made in terms of stratifying treatment according to clinical stage. The addition of cytosine arabinoside to the CHOP protocols improved the complete remission rate and survival of dogs with bone marrow infiltration, independently of the immunophenotype.

TREATMENT OF RELAPSES

Recurrent or refractory disease is a therapeutic challenge. Salvage protocols must be used for relapsed disease or disease which seems initially resistant to treatment (primary refractory disease) Second-line treatment involves the use of chemotherapeutic agents which are not included in first-line protocols and which are, possibly, not substrates for glycoprotein P-170. Salvage protocols commonly used in dogs are: MOPP, DMAC, lomustine and dacarbazine, lomustine and L-asparaginase, dacarbazine or temozolomide monochemotherapy, lomustine monochemotherapy.

The complete remission rates obtained by these protocols range between 20 and 50%, with median remission times of 2-3 months. It seems clear from these data that recurrent disease is a problem. Salvage protocols would be much more effective if used in the setting of minimal residual disease rather than when the relapse is already clinically apparent.

Minimal residual disease
Various different studies are underway to try to detect minimal residual disease, with the aim of treating a relapse when this is still clinically silent and, thereby, improving the prognosis. The search for minimal residual disease involves the use of molecular biology techniques on peripheral blood or lymph nodes.

The possibility of exploiting serum markers to anticipate clinical recurrence has also been evaluated. a-1 glycoprotein acid (AGP) is an acute phase protein that can be found in serum. AGP levels decrease drastically in dogs receiving chemotherapy and increase again about 3 weeks before a clinical relapse.

High levels of glutathione S-transferase have been found in the plasma of dogs with lymphoma at the time of diagnosis and just before a relapse.

Thymidine kinase is a cellular enzyme that is active during the G1 and S phases of the cell cycle and is implicated in proliferation of neoplastic cells. The serum concentrations of thymidine kinase increase in dogs with lymphoma, reflecting the clinical stage of the disease. Thymidine kinase is, therefore, a valid marker that can be used to monitor for early relapses in dogs with lymphoma undergoing chemotherapy, before the relapse become clinically evident.

Lactate dehydrogenase is a serum enzyme, assayed in humans with non-Hodgkin’s lymphoma for prognostic purposes. One prospective study has shown that serial assays of lactate dehydrogenase in the serum of dogs with lymphoma can predict relapses. In particular, if the levels are high at the end of treatment and 30 days after the end of chemotherapy, it is probable that the lymphoma will relapse within 45 days. In contrast, high levels at diagnosis are not correlated with prognosis.

OTHER THERAPEUTIC STRATEGIES

In humans with relapsed non-Hodgkin’s lymphoma, bone marrow transplantation in combination with high-dose chemotherapy has given encouraging results. Candidates for bone marrow transplantation are patients with chemosensitive lymphoma and minimal residual disease. The purpose of bone marrow transplantation is to enable intensification of standard chemotherapy doses (myeloablative regimen) and/or radiotherapy, making the myelotoxicity tolerable, overcoming the mechanisms of drug resistance and, finally, prolonging survival.

Autologous transplantation has also been attempted in veterinary medicine in order to facilitate dose-escalation of cyclophosphamide, thus prolonging remission and survival.

Since stem cells from the bone marrow circulate in the peripheral blood before returning to the bone marrow, the peripheral blood is an important source of these cells, eliminating the need for autologous transplantation.

The veterinary hospital of North Carolina State University(USA) is currently carrying out a clinical trial on bone marrow transplantation.

Radiotherapy is widely used in humans with Hodgkin’s and non-Hodgkin’s lymphomas as consolidation after chemotherapy, in association with bone marrow transplantation, or as palliative treatment. Radiotherapy is effective in the treatment of localised forms of lymphoma (nasal, spinal, cutaneous, rectal, bone, mediastinal) but has also been used, together with chemotherapy, to treat multicentric forms (half or total body). Low-dosage half-body radiotherapy has recently been used to treat minimal residual disease in the setting of consolidation, with encouraging results.

Immunotherapy (essentially monoclonal antibodies and vaccines) can be used as an alternative or complementary to chemotherapy; however, it has still been little explored in veterinary medicine. The results are comparable to or better than those obtained with chemotherapy used alone, suggesting that stimulation of the immune system, if accompanied by more conventional therapy, can be a useful and effective adjuvant treatment.

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