In addition, roughly 10% of MDS cases have loss-offunction mutations in the tumor suppressor gene TP53, which correlate with the presence of a complex karyotype and particularly poor clinical outcomes. Both primary MDS and therapy-related MDS are associated with similar recurrent chromosomal abnormalities, including monosomies 5 and 7, deletions of 5q, 7q, and 20q, and trisomy 8.
MORPHOLOGYInMDS,themarrowispopulatedbyabnormal-appearinghematopoieticprecursors.Someofthemorecommonabnormalitiesincludemegaloblastoid erythroid precursors resemblingthoseseeninthemegaloblasticanemias,erythroidformswithirondepositswithintheirmitochondria(ring sideroblasts),granulocyteprecursorswithabnormal granules ornuclearmaturation,andsmallmegakaryocyteswithsinglesmallnucleiormultipleseparatenuclei.
Clinical Features. MDS often is described as rare, but actually is about as common as AML, affecting up to 15,000 patients per year in the United States. Most patients present between the ages of 50 and 70. As a result of cytopenias, many suffer from infections, symptoms related to anemia, and hemorrhages. The response to conventional chemotherapy usually is poor, perhaps because MDS arises in a background of stem cell damage. Transformation to AML occurs in 10% to 40% of patients. The prognosis is variable; the median survival time ranges from 9 to 29 months and is worse in cases associated with increased marrow blasts, cytogenetic abnormalities, or TP53 mutations.
The common pathogenic feature of myeloproliferative neoplasms is the presence of mutated, constitutively activated tyrosine kinases or other acquired aberrations in signaling pathways that lead to growth factor independence. This insight provides a satisfying explanation for the observed overproduction of blood cells and is important therapeutically because of the availability of tyrosine kinase inhibitors. The neoplastic progenitors tend to seed secondary hematopoietic organs (the spleen, liver, and lymph nodes), resulting in hepatosplenomegaly (caused by neoplastic extramedullary hematopoiesis).
Four major diagnostic entities are recognized: chronic myeloid leukemia (CML), polycythemia vera, primary myelofibrosis, and essential thrombocythemia. Their distinctive features are listed below:
CML is separated from the others by its association with a characteristic abnormality, the BCR-ABL fusion gene, which produces a constitutively active BCR-ABL tyrosine kinase.
The most common genetic abnormalities in the “BCRABL–negative” myeloproliferative neoplasms are activating mutations in the tyrosine kinase JAK2, which occur in virtually all cases of polycythemia vera and about 50% of cases of primary myelofibrosis and essential thrombocythemia
Some rare myeloproliferative neoplasms are associated with activating mutations in other tyrosine kinases, such as platelet-derived growth factor receptor-α and platelet-derived growth factor receptor-β.
In addition, all myeloproliferative neoplasms have variable propensities to transform to a “spent phase” resembling primary myelofibrosis or to a “blast crisis” identical to acute leukemia, both presumably triggered by the acquisition of other somatic mutations. Only CML, polycythemia vera, and primary myelofibrosis are presented here, as other myeloproliferative neoplasms are too infrequent to merit discussion.
CML principally affects adults between 25 and 60 years of age. The peak incidence is in the fourth and fifth decades of life. About 4500 new cases are diagnosed per year in the United States.