Leukaemias are neoplastic disorders that develop from a clonal mutation in stem cells at different stages of differentiation. Depending on the cell lineage affected, the leukaemias can be divided into myeloid or lymphoid; they are also divided into acute or chronic forms.
The histopathologist has morphological, cytochemical, immunophenotypic and cytogenetic criteria on which to base the diagnosis and classification of leukaemias. Thanks to the use of Romanosky stains, such as the Wright and May-Grunwald Giemsa stains, morphological criteria are undoubtedly the histopathologist’s first instruments for making a putative diagnosis of leukaemia. The cytochemical criteria exploit the physiological presence of particular enzyme reactions and substances considered specific to certain cell lineages. For example, peroxidase, Sudan black B, chloracetate esterase and leucocyte alkaline phosphatase show that a haematopoietic cell-derived neoplastic proliferation is of myeloid origin.
Immunophenotypic criteria use monoclonal antibodies to surface and/or intracytoplasmic markers able to differentiate between the different cell lineages. Cytogenetic criteria, currently only in use in human medicine, involve the demonstration of congenital or acquired chromosomal anomalies related to the development of different types of leukaemia.
ACUTE MYELOID LEUKAEMIAS
Acute myeloid leukaemias (AML) are acute myeloproliferative disorders defined by the proportion of blasts in the bone marrow being 30% or more of the total nucleated cells, according to the French-American-British (FAB) classification, or 20% or more according to the World Health Organization (WHO) criteria, excluding accessory cells (lymphocytes, plasma cells, macrophages, osteoclasts/osteoblasts, mast cells).
The FAB classification distinguishes the leukaemias on the basis of morphological and cytochemical criteria, unlike the WHO classification which also uses immunophenotypic, genetic and associated clinical features to distinguish the leukaemias. Although genetic studies are gaining ground in veterinary medicine, at present there is insufficient knowledge to allow satisfactory use of the WHO classification in neoplastic haematopoietic disorders in the dog and cat. The combined use of the FAB classification together with immunophenotypic criteria currently represents an excellent compromise.
The acute myeloid leukaemias include (FAB classification):
- Acute undifferentiated leukaemia (AUL)
- Acute myeloid leukaemia without maturation (M0)
- Acute myeloid leukaemia with minimal maturation (AML-M1)
- Acute myeloid leukaemia with maturation (AML-M2)
- Acute promyelocytic leukaemia (AML-M3)
- Acute myelo-monocytic leukaemia (AML-M4)
- Acute monoblastic leukaemia (AML-M5)
- Acute erythroleukaemia (M6)
- Acute megakaryoblastic leukaemia (AML-M7)
Signalment. In veterinary medicine, AML more frequently affects breeds of large dogs, adult/elderly subjects and males.
Aetiology. The aetiology of AML is multifactorial; exposure to viruses, chemical substances, radiation or antineoplastic drugs is considered a risk factor. In the cat Retroviruses are often involved in the development of AML.
Presentation and clinical signs. Affected patients present with non-specific signs of disease, such as weakness, altered appetite, dejection and sometimes lameness; common findings in the clinical examination include splenomegaly and hepatomegaly, while lymph node enlargement is rare and mild. Hyperthermia is often found; this sign is probably a consequence of opportunistic infections. A complete blood count shows trilineage cytopenia: the anaemia, from moderate to severe, is frequently accompanied by leucocytosis, secondary to the presence of numerous undifferentiated cells in the circulation, neutropenia and thrombocytopenia.
Diagnosis. A diagnostic suspicion of leukaemia based on the clinical assessment and blood tests must be followed by a cytological and/or histological evaluation of a sample of haematopoietic bone marrow. The cytopathology examination shows that most of the cells of the erythroid and megakaryocytic lineages are replaced by myeloid cells at various stages of differentiation and in variable percentages depending on the type of leukaemia present. Contextual cytofluorimetry, by showing which receptors are expressed, enables classification of the myeloproliferative disorders according to the FAB classification.
Treatment. Chemotherapy is the treatment of choice; nevertheless, in veterinary medicine there are no effective protocols capable of eradicating the neoplastic population of cells in the bone marrow without the support of a bone marrow transplant, a therapeutic strategy that is unfortunately not applicable, except in Europe. Palliative support treatment (fluid therapy, transfusions of blood or plasma, antibiotic treatment and adequate nutrition) is, therefore, indicated.
Prognosis. The fact that bone marrow transplantation cannot be performed makes the prognosis dismal. Survival ranges from a few days to a few weeks.
CHRONIC MYELOID LEUKAEMIAS
Chronic myeloid leukaemias (CML) are characterized by the proliferation of well differentiated cells of haematopoietic origin with less than 30% (or 20%) of blast cells in the bone marrow and rare blasts in the peripheral blood.
The CML comprise:
- Chronic granulocytic leukaemia or chronic myelogenous leukaemia
- Chronic eosinophilic leukaemia
- hronic basophilic leukaemia
- Chronic monocytic leukaemia
- Chronic myelomonocytic leukaemia
- Polycythemia vera
- Essential thrombocythemia
Signalment. CML mainly affects elderly subjects; there is no breed predisposition.
Aetiology. In human medicine CML is frequently associated with genetic alterations, which have not been reported in veterinary medicine. However, it is suspected that the same risk factors described for AML may also be implicated in the development of CML.
Presentation and clinical signs. CML is manifested by non-specific signs of disease: loss of appetite, weight loss, mild anaemia or erythrocytosis, thrombocytosis, a gradual increase in blood counts, splenomegaly and hepatomegaly are common clinical signs and laboratory findings.
Diagnosis.The diagnosis is based on an assessment of the full blood count with differential and cytopathology and/or histology of the bone marrow. Since cytogenetic studies are not yet available, the definitive diagnosis requires exclusion of other pathological processes that could cause an increase in the number of cells of the affected haematopoietic cell line.
The evolution of CML involves a transition from a chronic form to an accelerated phase of disease followed by a blast crisis, with transformation into a form of acute leukaemia.
Treatment. CML is treated with hydroxyurea and, as needed, with supportive therapy.
Prognosis. Given the low index of neoplastic proliferation, the prognosis is generally good, with affected animals surviving for months.
ACUTE LYMPHOBLASTIC LEUKAEMIAS
Acute lymphoblastic leukaemias (ALL)develop from a clonal proliferation of lymphoid progenitor cells (blasts and prolymphocytes) in the bone marrow. There is often a marked leucocytosis in the peripheral blood secondary to the presence of numerous blasts in the circulation. ALL can be associated with diffuse infiltration of organs (spleen, liver, lymph nodes, etc.). Depending on the type of proliferating cell, the ALL can be divided into B-cell or T-cell types. B-cell ALL are more frequent.
Signalment. ALL occur more frequently in adult dogs from large breeds without a gender predisposition.
Aetiology. It is suspected that mutations of genes controlling the development of lymphoid precursors underlie the appearance of ALL.
Presentation and clinical signs. Subjects with ALL frequently present with non-specific clinical signs such as lethargy, fever, anorexia, loss of weight, petechiae, ecchymoses, pale mucosae, splenomegaly and hepatomegaly.
Diagnosis. A putative diagnosis of ALL is based on an evaluation of the complete blood count and bone marrow aspirate. The cytological evaluation can show that the three resident haematopoietic cell lineages have been partially or completely replaced by the neoplastic population, with consequent trilineage peripheral cytopenia being a common finding.
Treatment. In human medicine the treatment of choice for ALL is myeloablative chemotherapy followed by a bone marrow transplant. In veterinary oncology the chemotherapy must be started as soon as possible, using the various drugs in combination (generally L-asparaginase, vincristine, cyclophosphamide, doxorubicin and cytosine arabinoside). Support therapy is equally important: the purpose of this treatment (broad-spectrum antibiotics, fluid therapy, blood transfusions and bone marrow stimulators) is to prevent and/or treat any complications.
Prognosis. The prognosis is very poor, with the median survival being 4 months.
CRONIC LYMPHOCYTIC LEUKAEMIAS
Chronic lymphocytic leukaemias (CLL) are characterized by the production of a neoplastic clone of mature lymphocytes with a marked, persistent (for at least 3 months) lymphocytosis and diffuse infiltration of bone marrow and secondary lymphoid organs.
Signalment. CLL mainly affect adult/elderly subjects and are more common among males. CLL is the most common form of leukaemia; in the dog, the most frequent cytotype is the large granular lymphocyte variant (LGL-CLL), which is characterized by the presence of large lymphocytes with intracytoplasmic azurophilic granules in the peripheral blood.
Aetiology. The aetiology of CLL is not known; however, as for the acute leukaemias, it is thought that exposure to viruses, chemical substances, radiation or antineoplastic drugs could be a risk factor. It has also been hypothesised that Retroviruses may be involved in the pathogenesis of CLL in the dog.
Presentation and clinical signs. Affected patients have non-specific signs of disease such as weakness, altered appetite, dejection and lameness; often, however, the subjects are asymptomatic and the lymphocytosis is found incidentally. The clinical examination often reveals splenomegaly, while lymph node enlargement is rare and mild. The most significant changes in the full blood count are found in the white blood cell differential which shows a marked lymphocytosis; anaemia is usually mild to moderate and generally accompanied by a mature neutrophilia (but in rare cases, by neutropenia) and an adequate platelet count (but in rare cases, by thrombocytopenia). In humans neutropenia is a common finding: the development of immune-mediated pathologies and early neoplastic infiltration of the bone marrow are, in fact, common events.
Diagnosis. A putative diagnosis based on the findings of the clinical assessment must be followed by a cytological evaluation of a bone marrow sample and haematological immunophenotyping in order to determine the receptor expression of lymphocytes to differentiate reactive conditions from a neoplastic disease.
Treatment. CLL usually has an indolent course and does not require any treatment, at least initially. Indications for chemotherapy are: a progressive reduction in bone marrow function, recurrent infections, persistent or progressive systemic symptoms, gammopathy with hyperviscosity syndrome, marked lymph node enlargement, marked hepatosplenomegaly or splenomegaly and a short doubling time of total lymphocytes. The treatment of choice includes chlorambucil combined with prednisolone.
Prognosis.The survival of treated dogs and cats is variable, ranging from 1 to 3 years. The prognosis is guarded for those patients which have organ failure or severe peripheral cytopenias at diagnosis.
Suggested readings
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8. Valli V. E., Jacobs R. M., Parodi A. L., Vernau W., Moore P. F. – WHO Histological classification of hemopoietic tumors of domestic animals- second series, edition Schluman FY 2nd series, vol. VIII, 2002
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10. Withrow S.J., Vail D.M.., Withrow & MacEwen’s – Small animal clinical oncology, 4° edition, W.B. Saunders Company, 2007
11. Workman H.C., Vernau W. – Chronic lymphocytic leukemia in dogs and cats: the veterinary perspective. Vet. Clin. North. Am. Small. Anim. Pract 2003, 33:1379-1399.