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In 1963, Lewis and Szur described five patients whom they considered to have "malignant myelosclerosis" on the basis of a rapidly fatal course. Additional cases were reported under the headings of malignant or acute myelosclerosis. The syndrome is defined as "a rare but distinct accelerated variant of agnogenic myeloid metaplasia that is characterized by marked anemia, peripheral blood myeloblastosis, and normoblastosis, lack of teardrop poikilocytosis, and prominent myelofibrosis. There is usually no palpable hepatosplenomegaly or lymph node enlargement.

It has become clear that the patients originally described as having acute myelosclerosis were heterogeneous. Fibrosis often complicates both classic AML and ALL, and critical review indicates that some of the reported cases were in fact AML with fibrosis. Others appear to have been AMM in transition to acute leukemia. Nevertheless there remained a subset of patients designated as suffering from acute myelosclerosis in whom there was no convincing evidence of these other conditions.

Several reviews have attempted to bring order to the differential diagnosis of acute myelosclerosis. In one proposed scheme all forms of AMM (chronic, accelerated, and transitional) may be distinguished from other entities by the presence of splenomegaly and characteristic red cell morphologic changes. Accelerated and transitional AMM remain confounded.

Other Chronic Myeloproliferative Disorders

AMM must also be distinguished from CML, essential thrombocythemia (ET), and PV. When marrow fibrosis becomes a prominent feature of one of the other CMPDs, diagnosis may be difficult. Furthermore, whether one can always distinguish between AMM and atypical CML, or unclassified CMPD or should consider these

PV terminates in an AMM-like syndrome in 15 to 20% of patients. To be certain that a patient with newly diagnosed myelofibrosis has not had typical but undiagnosed PV in the past could be difficult, but as a practical matter this distinction is not usually necessary. Myelofibrosis in PV most commonly occurs after years of disease. Patients with PV usually become symptomatic as a result of the expanded red cell mass and thus come to medical attention earlier in their course. A patient with

Fibrosis may be present in CML at diagnosis and may also develop as the disease progresses. In most cases differentiation of AMM and CML is straightforward if aspirable bone marrow or a large concentration of circulating mitotic myeloid precursors is available, because the most reliable diagnostic test for CML is cytogenetic analysis. Approximately 95% of patients with typical CML have the t9:22 Philadelphia (Ph1) chromosome abnormality and many of the remainder exhibit molecular evidence of the bcr/abl gene rearrangement. Rarely, patients with what appears to be typical AMM have been reported to have a 9:22 chromosome translocation, but these cases are so rare that this observation does not detract from the value of the Ph1 chromosome in the differential diagnosis of CML and AMM. If the Ph1 abnormality is absent in a patient suspected of having one 

When bone marrow fibrosis is present in ET, this condition may resemble an early phase of AMM. In fact, making a clear distinction may not be possible, and the patient may require observation over time. Fortunately with current therapeutic options, distinguishing between early AMM and early ET is not critical: management is symptomatic for both disorders. Some investigators have noted the similarity in the two conditions and questioned whether they should be considered separate. However, recent studies of oncogene and tumor suppressor gene expression in patients with different CMPDs suggest that there

Secondary Forms of Myelofibrosis

Syndromes similar to AMM occur in association with a variety of neoplasms, infections, and other diseases. These are associated with varying degrees of the blood changes, fibrosis, and extramedullary hematopoiesis typical of AMM . Particularly when nucleated red cells and myeloid precursors are prominent in the blood, the general term myelophthisic anemia or leukoerythroblastosis has been used. In 50,277 consecutive blood smears in patients studied at the Mayo Clinic there was a

The diagnosis of secondary myelofibrosis is based on discovering an appropriate associated disease. Some forms of secondary myelofibrosis are a regular feature of underlying illness, such as the fibrosis that occurs in the postpolycythemic phase of PV. Some constitute a well-described if uncommon syndrome, such as fibrosis associated with systemic lupus erythematosus or vitamin D deficient rickets. Others occur only rarely because of the underlying disease. When myelofibrosis is secondary to infection, the infection usually is chronic, widespread, and easily diagnosed. With the availability of treatment for tuberculosis and