16 MYELODYSPLASTIC SYNDROMES
1 Define the term myelodysplastic syndrome.
The term myelodysplastic syndrome (MDS) refers to a heterogeneous group of hematologic disorders characterized clinically by ineffective and disorderly hematopoiesis. Despite the name, myelodysplastic disorders are not “dysplastic” disorders; rather, MD disorders are neoplastic conditions that result from the clonal expansion of an abnormal hematopoietic stem cell and manifest as peripheral blood cytopenias and dysplastic changes seen in blood and bone marrow.
2 Briefly discuss the etiology of MDS.
In the human literature, MDS can be divided into two major categories based on the etiology: primary or secondary. Primary MD syndromes are spontaneously occurring disorders; the etiology and the initiating cause are unknown. Secondary MD syndromes result from exposure to ionizing radiation, environmental toxins, and chemotherapy treatment. Secondary conditions are seen less frequently than primary disorders, and the majority of secondary MDS cases are therapy related, particularly after treatment with alkylating agents or topoisomerase II inhibitors.
Myelodysplastic syndromes are rare in veterinary medicine and have been reported in the cat (most frequently), dog, and horse (uncommon). In cats, MDS is suspected to be associated with feline leukemia virus (FeLV) infection because about 80% of cats with MDS are FeLV positive. Predisposing events or underlying etiologies have not yet been identified in other species.
3 Explain the pathogenesis of MDS.
The exact pathogenesis of MDS is unknown. However, the development of MDS is thought to arise from deoxyribonucleic acid (DNA) damage in a hematopoietic stem cell that induces a malignant phenotype. The clonal expansion of the malignant pluripotential stem cell can result in the abnormal production of a variety of myeloid cells, including neutrophils, monocytes, erythrocytes, and platelets. In rare human cases of MDS, lymphoid cells may also be clonally derived. The proliferation of the abnormal stem cell results in the accumulation of progenitors in the bone marrow (a hypercellular marrow) with simultaneous peripheral cytopenias. This paradoxical finding may result from the failure of the stem cells to differentiate or from an increased rate of apoptosis in the bone marrow (with many hematopoietic cells undergoing programmed cell death in the marrow, low numbers of mature hematopoietic cells are in the peripheral blood). Defective maturation, dysplastic changes, and functional abnormalities are also noted in many of the progeny of the neoplastic hematopoietic stem cells.
4 List possible functional abnormalities detected in patients with MDS.
In human patients, functional abnormalities have been demonstrated in the hematopoietic cells produced by the abnormal stem cell. Recurrent infections or bleeding tendencies may be seen as a result of abnormal neutrophil or platelet function, respectively. Similar clinical findings have been documented in animals with MDS, although further investigation is necessary to document functional defects. Table 16-1 lists functional abnormalities detected in humans with MDS.
Table 16-1 Functional Abnormalities Documented in Humans with MDS
| CELL TYPE | FUNCTIONAL ABNORMALITY |
|---|---|
| Red cells | |
| Neutrophils | |
| Platelets |
5 Are any chromosomal abnormalities or genetic changes associated with MDS?
In human medicine, clonality has been confirmed using cytogenetic and molecular techniques. However, the genetic changes responsible for the neoplastic transformation of the hematopoietic stem cell have not yet been elucidated. Point mutations in Ras genes (a family of proto-oncogenes) have been found to occur in about 3% to 33% of human patients with MDS. Chromosomal gains, losses, and translocations have also been described in human patients, with chromosomes 5, 7, 8, and Y reported most. None of the chromosomal abnormalities is specific for MDS, but some are highly associated with certain subtypes and have prognostic significance. For example, MDS patients with deletion of long arm of chromosome 5 have a relatively favorable prognosis, longer survival time, and a low rate of transformation to acute leukemia. The use of cytogenetic analysis or molecular techniques as a diagnostic tool has not been thoroughly investigated for veterinary cases of MDS.
6 How is MDS diagnosed?
The diagnosis of MDS is based on the history, clinical signs, and morphologic examination of the peripheral blood and bone marrow. Cytogenetic analysis is an important diagnostic tool in human medicine. Because MDS encompasses a heterogeneous group of disorders, the presenting signs and laboratory abnormalities may vary. The key to diagnosis of MDS is the presence of persistent cytopenias, despite a hypercellular bone marrow (ineffective hematopoiesis), in conjunction with dysplastic changes in one or more hematopoietic cell lines. It is essential to note that transient dysplastic changes may be seen in the bone marrow with other conditions, and these diseases must be excluded before making a diagnosis of MDS.
7 What differential diagnoses should one consider before making a diagnosis of MDS?
Several diseases can be similar in appearance to MDS, and these disorders should be ruled out before MDS is diagnosed. Dysplastic changes in hematopoietic cells may be seen with nutritional deficiencies (e.g., vitamin B12, folate), may be drug induced (e.g., vincristine, chloramphenicol), may be congenital (e.g., poodle macrocytosis, congenital dyserythropoiesis), and may result from lead toxicity or immune-mediated hematologic disorders. Dysplastic changes seen with these disorders are polyclonal (unlike MDS, which is a clonal disorder) and should be excluded first before making a diagnosis of MDS.
8 What are the major history and clinical findings associated with MDS?
The history, clinical signs, and physical examination findings in an animal with MDS may be variable. Clinical signs are frequently attributable to the type and severity of the cytopenias present. Animals may present for nonspecific signs, such as lethargy, anorexia, and weight loss. Because anemia is frequently present, animals may show evidence of pallor and weakness. Less often, animals display clinical signs due to thrombocytopenia, such as petechiae or ecchymoses. Animals with neutropenia may have recurrent bacterial infections. MDS may also be an incidental finding on routine screening tests.
9 Describe the major peripheral blood findings associated with MDS.
The main peripheral blood findings associated with MDS are a persistent cytopenia or cytopenias (bicytopenia or pancytopenia are common). Animals are usually anemic (may be severe), and the anemia is frequently nonregenerative. Thrombocytopenia is a common finding. Neutropenia may also be seen. Dysplastic changes may be observed in the peripheral blood, and various cell lines can be affected. Possible dysplastic changes for the erythroid lineage may include macrocytosis (common finding in cats), poikilocytosis, and normoblastemia (presence of nucleated red blood cells) without polychromasia. Dysplastic myeloid changes may include abnormal cell size (gigantism), hypo/hypersegmentation, and hypo/hypergranulation. Platelets may be seen that are giant, bizarre in shape, or abnormally granulated. In addition, circulating blast cells may be seen in the peripheral blood, although they do not exceed 5% of blood leukocytes.
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