Myelodysplastic Syndromes: A Diagnostic and Therapeutic Conundrum

    

    

    Figure 8: Same biopsy section as in figure 7 but lower magnification
demonstrating. A- the tip of aspirating needle has encountered an area
where clusters of immature myeloid precursors (blast cells) are present. They
can be easily identified by the presence of nucleoli. B- demonstrates where
the tip of the aspirating needle has encountered an area where blast cells are
absent but predominates with erythroid precursors (E).
    

MDS is primarily a disease of the elderly and most patients are at 65 or over. The disease is characterized by ineffective hematopoiesis and bone marrow failure. Deficiencies in hematopoiesis usually result in peripheral blood cytopenias, of which anemia is the most common. However, neutropenia and thrombocytopenia, either singly or in combination, may dominate the blood picture. The bone marrow usually is hypocellular but sometimes it may be normocellular or hypercellular which may lead to its interpretation or assessment as a myeloproliferative disorder and misleadingly diagnosed as Myelodysplastic/Myeloproliferative Neoplasm (MDS/MPN) [14]. The term MDS/MPN is another diagnostic conundrum that the international working group has led the practicing hematologist into [14]. There is no justification for incorporating myeloproliferative disorders into the category of myelodysplastic syndromes. All patients with myeloproliferative disorder show some degree of myelodysplastic changes and it is perhaps scientifically incorrect and diagnostically ambiguous to combine these two possibly separate diseases under one umbrella.

We have diligently studied well stained bone marrow aspirate and plastic embedded bone marrow biopsy sections from normal adults as well as from patients with various hematological disorders [15]. Normal marrows (aspirates and trephine biopsies) were obtained from normal adults who volunteered to donate marrow for transplantation. Patients with AML, for example were studied at diagnosis, following chemotherapy, during hematopoietic regeneration following chemotherapy and at complete remission [16-18]. Patients with Chronic Granulocytic Leukemia (CGL) were studied in the chronic phase, during blast cell transformation, and following autographing and during hematopoietic regeneration [19- 21]. Bone marrow aspirates and biopsies were also obtained from patients with aplastic anemia, chronic lymphocytic leukemia, non- Hodgkin’s lymphoma and multiple myeloma.

We have observed that some degree of myelodysplastic alteration either in the erythroid, granuloid or megakaryocytic series can be observed in most of these disorders. Even in normal marrows, some dysplastic changes in the erythroid, granuloid or megakaryocytic cells can be observed but they are few and far between. In the original FAB classification [4] it was reported that “in some patients the mere presence of these abnormalities is adequate for their inclusion in the MDS”. This premise requires farther delineation because if this were to be accepted then many of the newly diagnosed patients with AMLs, multiple myelomas, Hodgkin’s lymphomas and other marrow-perturbing neoplastic conditions (where such morphologic abnormalities are not uncommon) would need to be included in MDS.

Cytogenetic abnormalities are present in many of the MDS cases [22] and are believed to have both diagnostic and prognostic significance. Prognostic groups have been proposed on the basis of cytogenetics in the revised international score (IPSS-R) scheme, which include 5 different subgroups including 20 different alterations [23]. The most common cytogenetic abnormalities encountered in MDS are del(5q) [5q-], -7, and -8. Cytogenetic studies are performed on spontaneously dividing cells that are typically cultured for short periods (24-72h). MDS with hypocellular bone marrow may not provide a sufficient number of such spontaneously dividing cells and as a result cytogenetic studies in these cases may not be accurate. Karyotypic changes can also be found in many if not most hematological malignant conditions, and some are non-specific irrespective of the disease in which they are found. Although there is some evidence from both cytogenetic and molecular studies [24] that they have an impact on response and outcome but these findings need to be included in a newly devised, organized classification of MDS to be clinically useful and universally recognized. But until an accurate reproducible diagnostic classification (involving cytology, histology, flow-cytometry, cytogenetics and molecular studies) is established we may not know the actual relevance of these studies with regards to such broad array (enumerated below) of current diagnostic classifications, which are solely based on the morphology of hematopoietic cells observed in the smears of peripheral blood and bone marrow.

In patients with a hypocellular bone marrow it can be difficult to distinguish between severe aplastic anemia and MDS due to the paucity of cells in the aspirate smear and core biopsy to assess dysplastic changes. It has been suggested that in such situations, the presence of abnormal megakaryocytes and MDS-associated cytogenetic changes [25] may favor a diagnosis of MDS. But too often there are hardly any cells on which to carry out appropriate cytogenetic or molecular studies or look for specific dysplastic changes in hematopoietic cells.

Another important diagnostic challenge is to distinguish MDS with bone marrow fibrosis from primary myelofibrosis [25]. Here, the absence of Janus Kinase 2 (Jak2 V617F) mutations and the presence of MDS- associated cytogenetic changes and megakaryocytic dysplasia may be helpful factors in distinguishing MDS from primary myelofibrosis. However, in large majority of cases with essential thrombocythaemia, an excessive proliferation of megakaryocytes occurs; such megakaryocytes are quite often dysplastic and associated with marrow fibrosis. These cases should be diagnosed as a myeloproliferative disorder and not MDS despite the presence of dysplastic megakaryocytes and the absence of Jak2 mutation.

Chronic Myelomonocytic Leukemia (CMML) is believed to be a myeloid neoplasm characterized by an excessive production and accumulation of monocytoid cells in the peripheral blood and bone marrow. This is commonly associated with dysplasia in one or more hematopoietic cell lineages and an increased risk of transformation into acute myeloid leukemia [26,27]. CMML was originally classified as MDS in the FAB classification [4]. However, it has been correctly removed from the current WHO classification. CMML should never have been included in the classification of MDS in the first place. CMML truly belongs to chronic myeloproliferative disorders and the condition is very similar to Chronic Granulocytic Leukemia (CGL), but unlike CGL, where mature granulocytic precursor cells predominate in the bone marrow and peripheral blood, in CMML it is the monocytes and pro-monocytes that predominate in these two sites (Figure 9). Substantial dysplasia in one or more hematopoietic cell lineages are not uncommon in CGL and transformation of CGL to AML known as blast cell crisis is common. The only difference in these two disease entities is perhaps the absence Philadelphia chromosome and its related BCR-ABL1 fusion gene in CMML.

    

    

    Figure 9: Myelo-Monocytic Leukemia (MMOL): Peripheral blood and bone
marrow aspirate smear showing monocytes and promonocytes.