Case 4 -

Prefibrotic Stage, Chronic Idiopathic Myelofibrosis James W. Vardiman University of Chicago Chicago, IL

Click on each slide thumbnail image for an enlarged view

Clinical History This 33-year-old woman's chief complaint was gradually increasing fatigue for about one year. At the time that she sought medical attention the only significant physical finding was a "barely palpable" spleen. Laboratory data included: WBC=14.8 x 109/L, Hb=8.7g/dL, Plt=1,247 x 109/L, Reticulocytes= 4.3% with RPI=1.6. Serum ferritin=29ng/mL (normal 12-201), uric acid 7.5mg/dL (normal 1.0-7.5). A bone marrow biopsy and aspiration was performed. Cytogenetic studies from the marrow aspirate revealed a normal female karyotype. FISH studies showed no BCR/ABL fusion gene. The blood and bone marrow findings were reported as "consistent with Essential thrombocythemia (ET)" and the slides were referred to the University of Chicago for an additional opinion. Case 4 - Figure 1 - Prefibrotic CIMF. Peripheral blood smear showing increased platelets, mild leukocytosis due to neutrophilia, and occasional teardrop-shaped red blood cells. Case 4 - Figure 2 - Prefibrotic CIMF. Representative fields from the peripheral blood smear showing segmented neutrophils with normal morphology, occasional myelocytes, and basophils. In these fields there is minimal red blood cell poikilocytosis. Case 4 - Figure 3 - Prefibrotic CIMF. Representative fields of the bone marrow biopsy demonstrate megakaryocytic proliferation, with the megakaryocytes in clusters. Case 4 - Figure 4 - Prefibrotic CIMF. Representative fields of the bone marrow biopsy demonstrate megakaryocytic proliferation, with the megakaryocytes in clusters. Case 4 - Figure 5 - Prefibrotic CIMF. High power fields of the biopsy demonstrate the variable size and atypia of the megakaryocytes. Naked megakaryocyte nuclei are seen, and in some the N:C ratio is abnormal. There is marked neutrophil proliferation but diminished numbers of erythroid precursors. Case 4 - Figure 6 - Prefibrotic CIMF. The aspirate smear is poorly cellular and cytology was not well preserved. The reticulin stain reveals only minimal increase in reticulin fibers. Case 4 - Figure 7 - Prefibrotic CIMF. The aspirate smear is poorly cellular and cytology was not well preserved. The reticulin stain reveals only minimal increase in reticulin fibers. Case 4 - Figure 8 - Prefibrotic CIMF. This figure summarizes the important findings, including the thrombocytosis in the blood, the hypercellular bone marrow biopsy with predominantly granulocytic and megakaryocytic proliferation, and the atypia of the megakaryocytes. There is a minimal increase in reticulin fibers. Differential diagnoses for thrombocytosis include: Reactive thrombocytosis Myeloproliferative diseases Chronic Myelogenous Leukemia Polycythemia vera Essential thrombocythemia Chronic Idiopathic Myelofibrosis, Prefibrotic stage Other myeloid neoplasms possibly associated with thrombocytosis, including "5q- syndrome," Refractory anemia with ringed sideroblasts associated with marked thrombocytosis, etc. Diagnosis: Prefibrotic stage, chronic idiopathic myelofibrosis Discussion In this case the major challenge is to discover the reason for the markedly elevated platelet count. The first question is whether the platelet elevation is a reactive response to an underlying systemic illness or occult, non-myeloid neoplasm, or due to a clonal myeloid disorder, such as a chronic myeloproliferative disease (CMPD). The clinical history, marked hypercellularity of the bone marrow and atypia and clustering of the megakaryocytes support a diagnosis of a CMPD. Sometimes, however, the marrow findings are equivocal, and the diagnosis of CMPD as the cause of thrombocytosis is not easily made. In such cases a history of persistent thrombocytosis, thrombotic and/or hemorrhagic episodes, and splenomegaly would support a diagnosis of CMPD. Recently, it has been discovered that a large proportion of the BCR/ABL- negative CMPDs are associated with a mutation of JAK2, a gene that encodes a cytoplasmic tyrosine kinase instrumental in mediating signal transduction downstream of cytokine receptors. The mutation, JAK2V617F, is found in ~90% of cases of Polycythemia vera (PV), ~50% of cases of Chronic idiopathic myelofibrosis (CIMF), and ~40% of cases of Essential thrombocythemia (ET). Although JAK2V617F is not specific for a single CMPD, if present it indicates the myeloid proliferation is neoplastic rather than reactive, which is often a major issue in the diagnosis of the CMPDs. Other findings that would support a neoplastic process include abnormal c-Mpl expression by megakaryocytes and platelets, EEC formation, abnormal platelet function studies, and a clonal cytogenetic abnormality. In our case, the history and bone marrow morphology indicate that the thrombocytosis is associated with a BCR/ABL -negative CMPD. But which one? A markedly elevated platelet count can be associated with any CMPD. In the past, the guidelines of the Polycythemia Vera Study Group (PVSG) were most frequently used to sub-classify the CMPDs. Those guidelines were based mainly on clinical and laboratory findings, and histopathology of the bone marrow was never considered in the diagnosis. More recently a number of investigators have carefully correlated the histologic findings of marrow biopsies with clinical and laboratory features in the CMPDs and have reported that the lineages involved in the proliferation, the megakaryocyte topography and cytology, and marrow fibrosis are key histologic parameters that aid in accurate classification. In PV, for example, the characteristic morphologic features include panmyelosis with loose clusters of relatively normal megakaryocytes of variable sizes. In CIMF, although most patients present with a classic leukoerythroblastic blood picture and a depleted, fibrotic bone marrow, some patients have a pre-existing, or prefibrotic phase, characterized by granulocytic and megakaryocytic proliferation, with clustering of highly atypical megakaryocytes, minimal fibrosis, and often marked thrombocytosis with no or minimal leukoerythroblastosis in the blood. In contrast, ET is characterized by a proliferation of uniformly large megakaryocytes with deep nuclear lobulation, but most often no significant neutrophil or erythroid proliferation. These histologic criteria were included along with other clinical and lab findings in the WHO classification of the CMPDs, and are useful guidelines in distinguishing one CMPD from another. Still, "unclassifiable" cases with overlapping features do exist, which is not surprising in view of the overlap of some of the genetic lesions, such as JAK2 mutations, that occur in these diseases. In Case 4, the findings satisfy the PVSG criteria for ET (platelet count > 600k/uL, Hct <40%, normal serum ferritin, no BCR/ABL fusion gene, no or less than one/third the area of the biopsy occupied by fibrosis, no reactive cause for thrombocytosis). In contrast, when WHO guidelines are applied that include the histology of the bone marrow (hypercellularity of marrow, marked granulocytic and megakaryocytic proliferation, clustering of highly atypical megakaryocytes of variable sizes, no or minimal fibrosis) as well as the clinical and laboratory data, the diagnosis is prefibrotic stage of chronic idiopathic myelofibrosis rather than ET. In one recent study in which the PVSG and the WHO systems were compared, nearly one-half of cases classified as ET by the PVSG criteria were reclassified as prefibrotic-CIMF using the WHO criteria. The latter group of patients had a significantly worse outcome than patients classified as ET by the WHO guidelines. References Florena AM, Tripodo C, Iannitto E, et al. Value of the bone marrow biopsy in the diagnosis of essential thrombocythemia. Haematologica 2004;89:911-919 Jaffe E, Harris NL, Stein H, Vardiman JW (eds.) World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press: Lyon 2001 James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signaling causes polycythemia vera. Nature 2005;434:1144-1148. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Eng J Med 2005;352:1779-1790. Michiels JJ.Murphy S. Diagnostic criteria and prognosis in polycythemia vera and essential thrombocythemia. Semin Hematology, 1999; 36:9-13 Murphy S. Diagnostic criteria and prognosis in polycythemia vera and essential thrombocythemia. Semin Hematology, 1999;36 (suppl 2):9-13 Thiele J, Kvasnicka HM. Chronic myeloproliferative disorders with thrombocythemia: a comparative study of two classification systems (PVSG, WHO) on 839 patients. Ann Hematol 2003;82:148-152 Tefferi A, Gilliland DG, et al. The JAK2V617F mutation in myeloproliferative disorders: Stauts report and immediate implications for disease classification and diagnosis. May Clin Proc 2005;80:947-958