Agnogenic myeloid metaplasia-myelofibrosis has been described by at least 37 different names, such as idiopathic myelofibrosis with myeloid metaplasia.124,125 Patients with this entity generally present with anemia, massive splenomegaly, and nucleated and tear-drop red cell forms in the peripheral blood. Basophilia and an elevation of the white count with a left shift are not uncommon although as the disease progresses, leukopenia may supervene.126 Early in the disease (before marrow fibrosis occurs) the marrow may be simply hypercellular and the disease unclassifiable. The platelet count may be high, normal, or decreased. Serum B12 and B12 binding proteins tend to be elevated as is the uric acid level, each suggestive of a significant degree of cell turnover.
The bone marrow aspiration in patients with agnogenic myeloid metaplasia-myelofibrosis is frequently unsatisfactory, due either to profound hypercellularity (early disease) or to the fibrous tissue itself, which may be hard and difficult to penetrate. As such, a bone marrow biopsy is required for accurate diagnosis. Several patterns of findings on bone marrow biopsy examination may be noted. Early in the disease, panhyperplasia is common. Clusters of megakaryocytes, erythroblasts, and granulocytic hyperplasia with normal maturation are present. Small mononuclear megakaryocytes have been observed that may be confused with atypical lymphocytes but can be defined due to characteristic demarcation membranes and bullseye granules. Even in this early stage, a minimal increase in reticulum fibers can be demonstrated on silver staining. However, collagen fibers, detectable by the Mallory reagent, are not increased. Such findings are typical of all the myeloproliferative disorders and do not definitively indicate agnogenic myeloid metaplasia-myelofibrosis. In more advanced cases, myeloid atrophy and fibrosis ensue.128,129 The marrow cavity becomes fibrotic with small areas of hyperplastic hematopoietic tissue arising above the amorphous background substance, which contains reticulin fibers, collagen fibers, plasma cells, and other residual stromal cells. Endothelial cell proliferation due to angiogenic factors has been noted to accompany the progressive fibrosis.130 Erythroid progenitors tend to become quite sparse.131 The cellularity is predominantly megakaryocytic. Fat spaces are usually absent and most patients do not have an increase in bone trabeculae. The most advanced stage of myelofibrosis is defined by myelosclerosis in which bone tra-
beculae occupy 30 percent or more of the biopsy section leaving minimal residual foci of myeloid tissue (composed mainly of megakaryocytes). The noncellular marrow consists of myelofi-brotic areas with increased reticulum and myelosclerotic tissue composed of collagenous fibers. This mesenchymally derived tissue is usually adjacent to bone trabeculae, which may be broad, irregular, and contain thickened osteoid seams (Plates 3-1M,N). Despite the presence of new bone formation, osteoblasts and osteoclasts are usually not present.
The degree of bone marrow fibrosis also correlates with the degree of bone marrow osteoscelerosis, suggesting that osteosclerosis and megakaryocyte hyperplasia may both have a common origin, potentially due to a factor secreted by the malignant stem cell in this disease. Deposition of extensive amounts of endothelially produced fibronectin, laminin, and collagen type 4 suggests that endothelial cell proliferation as well as fibroblastic proliferation occur.129 Precisely what cytokines are responsible for the fibroblastic, endothelial, and osteoblastic proliferation in agnogenic myeloid metaplasia remains speculative.
Extramedullary hematopoiesis causing splenomegaly is the hallmark of even moderately advanced AMM. Circulating clon-ally derived progenitor cells accumulate in splenic cords. Progressive splenomegaly may lead to a huge abdominal mass. The average spleen weight in patients with advanced myeloid metaplasia is 1.5 to 3 kg. Splenic infarcts result in a thickened and scarred capsule. Microscopically, extramedullary hematopoiesis, which involves the red pulp, is always present. A mild to moderate fibrosis of the red pulp may occur with disease progression. The lymphatic follicles in the white pulp usually become atrophic but are uninvolved by myeloid metaplasia. The splenic histopathology at the time of removal for intractable syndromes may have prognostic value; those with a nodular pattern of extramedullary hematopoiesis (EMH) live longer than those with diffuse EMH or primary immature cells.132,133
Hepatic myeloid metaplasia (extramedullary hematopoiesis) also commonly occurs in patients with agnogenic myeloid meta-plasia-myelofibrosis and may occupy up to 30 percent of the hepatic lobule134 (Plate 3-1O-Q). The basic liver architecture is preserved, but erythroblasts and megakaryocytes occupy the hepatic sinusoids and granulocytic precursors reside in the portal tracts. This distribution mimics normal mammalian embry-otic hematopoiesis. As the disease progresses, the hematopoiesis becomes more immature but neoplastic invasion of the liver does not occur. Hepatic fibrosis is generally minimal, although patients with portal hypertension and cirrhosis have been described.134,135 Such severe complications may be due to postsi-nusoidal obstruction (Budd-Chiari syndrome), presinusoidal thrombotic obstruction, or sinusoidal obstruction secondary to EMH coupled with a high portal blood flow.135
Patients with agnogenic myeloid metaplasia-myelofibrosis may exhibit EMH in nonreticuloendothelial sites. Areas of myeloid metaplasia consist of two to three committed cell lines (usually erythroid and megakaryocytic) and do not destroy or invade adjacent structures. With lymph node invasion, the architecture remains intact and the cortical follicles are not destroyed.
A leukoerythroblastic blood picture, possibly including up to 10 percent myeloblasts at diagnosis is typically noted.136 Basophils may be increased. Tear-drop-shaped red cells are the hallmark of this disease (Plates 3-1R,S). Although the degree of bone marrow dysplasia is often minimal, in contrast to the low leukocyte alkaline phosphatase score in CML, the LAP score in agnogenic myeloid metaplasia is usually increased as it is in PCV and ET.
Cytogenetic abnormalities occur in approximately one-third of cases.137,138 20q- deletion, interstitial 13q- deletion, and acquired trisomy 20 are the most common abnormalities. Patients with abnormal karyotypes have a significantly shorter survival than those with a normal cytogenetic study (median of 30 months vs. greater than 6 years).137 Evolution to more complex karyotypic findings may accompany clinical progres-sion.138 Transition to acute leukemia occurs in less than 10 percent of cases,139 with some of these patients being previously exposed to alkylating agents.
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