In the absence of clonal markers or excess blasts, MDS is a diagnosis of exclusion (Table 1), requiring the exclusion of other potential contributors to cytopenias and dysplasia.3 Since cytopenias are the most common presenting clinical feature and cytopenias have many potential causes, the differential diagnosis is broad and includes numerous other entities covered in more detail elsewhere in this text. All patients suspected of having MDS should undergo a bone marrow aspirate and biopsy, since the diagnostic criteria are almost entirely pathologic and marrow findings are critical for risk stratification and treatment planning.
Table1. Diagnostic Criteria for Myelodysplastic Syndromes
Several nutritional deficiencies can cause cytopenias and morphology similar to MDS (see chapter on nutritional deficiencies). Folate deficiency can cause macrocytosis and, in extreme cases, megaloblastic morphology in the marrow. Vitamin B12 (cobalamin) deficiency is a more classic cause of megaloblastic changes, and patients with severe B12 deficiency can have bizarre morphology with an abundance of early forms that can occasionally be confused with evolving AML, especially erythroleukemia. Since the hematologic changes of B12 deficiency can occur in the absence of classic neurologic symptoms, B12 and folate levels should be checked on all patients in whom a potential diagnosis of MDS is being entertained, and methylmalonic acid and homocysteine levels may help clarify whether deficiency is truly present in cases with borderline levels.
Copper deficiency is less common than B12 /folate deficiency but can also be mistaken for MDS. It classically arises in patients who have had gastrectomies or certain forms of gastric bypass surgery, particularly biliopancreatic diversion, but is uncommon in newer forms of gastric bypass, including gastric sleeve procedures and Roux-en-Y procedures. It can also develop in patients with malabsorption syndromes such as uncontrolled celiac disease or those taking high doses of zinc, which competes with copper for absorption in the small bowel. Clinically, patients with copper deficiency develop an anemia that can be normocytic or macrocytic and can occasionally be profound. Mild neutropenia can also be seen, while clinically significant thrombocytopenia is rare. Such patients can also develop neurologic symptoms similar to those seen in B12 deficiency, including peripheral neuropathy and in advanced cases myelopathy, demyelination, and rarely optic neuritis. In the marrow, copper deficiency is classically associated with ring sideroblasts and erythroid and neutrophil vacuolization.
Alcohol is a marrow toxin and a common cause of hematologic abnormalities, especially macrocytic anemia.321 Bone marrow examination often reveals ring sideroblasts, and sometimes megaloblastic morphology, but frank dysplasia that would suggest MDS is uncommon. Patients with borderline marrow findings who consume alcohol heavily should be advised to completely abstain from drinking (such advice is sometimes heeded), with a repeat marrow examination in 2 to 3 months if they are abstinent and cytopenias persist.
Other drugs and toxins have also been associated with dysplastic changes in the marrow. Well-described offenders include valproic acid, mycophenolate mofetil, ganciclovir, alemtuzumab, and the antimetabolites mercaptopurine and methotrexate. These tend to cause macrocytic anemias and can also cause neutropenia and thrombocytopenia. On the other hand, isoniazid and chloram phenicol, and to a lesser extent cycloserine and pyrazinamide, have been associated with modest sideroblastic anemia. The anemia associated with isoniazid, in particular, can often be reversed with high doses of vitamin B6 (pyridoxine). Chloramphenicol can also cause an idiosyncratic pancytopenia distinguished by prominent vacuolization of erythroid precursors.
HIV infection has specifically been associated with trilineage dysplasia that is most predominant in the erythroid line.334 The erythroid hematopoiesis almost always is megaloblastic, and reticulin fibrosis can be seen. The marrows also often have polyclonal plasma cell expansion and lymphoid aggregates, and sometimes granulomas. The differential diagnosis of erythrodysplasia in patients with HIV infection includes the influence of medications, opportunistic infections, or a direct effect of HIV on the hematopoietic progenitor cells.
Other primary hematologic disorders are also on the differential diagnosis with MDS. Hypoplastic MDS, for example, can be difficult to distinguish from aplastic anemia, as described above. Similarly, some patients with MDS may have a significant degree of co-existing fibrosis, which can complicate the dis tinction from MPN.
Some patients have cytopenias for which no cause is apparent despite extensive evaluation, including marrow aspiration and biopsy. These patients with “idiopathic cytopenias of undetermined significance” (ICUS) can progress to MDS; the cytopenias may also be due to a non-clonal cause (e.g., immunologically mediated) and may be non-progressive, giving ICUS a variable natural history. Detection of a somatic mutation in these patients—so-called “clonal cytopenias of undetermined significance” (CCUS)—is associated with a higher likelihood of progression to overt WHO-defined MDS or AML, especially if the multiple mutations are present at a high VAF and there are red cell abnormalities such as broad RDW.
