Primary myelofibrosis (PMF; previously known as chronic idiopathic myelofibrosis and myelofibrosis with myeloid metaplasia), is characterized by anemia and leukoerythroblastosis (Figs. 21.1, 21.2, 21.3and 21.4) (24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36). It occurs predominantly in middle-aged to older adults. PMF has been diagnosed in children but it is possible that in these rare cases, the disorder represents a congenital bone marrow failure syndrome, acute leukemia with fibrosis, or other disorder.

PMF occurs as a de novo disorder and as a late stage of PV and ET.

Clinical signs and symptoms are referable to cytopenias, coagulopathy, and excessive extramedullary hematopoiesis. Palpable splenomegaly is found in approximately 75% and hepatomegaly in almost 50% of patients at diagnosis. Massive hepatosplenomegaly occurs late in the disease. The clinical course is usually progressive, with worsening cytopenias and eventual transformation to myelodyplastic syndrome (MDS) or acute leukemia. Rarely, PMF converts to PV. Survival is significantly worse than in PV or ET. The risk of transformation to acute leukemia is related to the type and duration of therapy and is increased by splenectomy. Spontaneous hematologic remission rarely occurs, followed in most cases by leukemic transformation. Survival up to 20 years after diagnosis has been reported.

Laboratory studies usually show normocytic normochromic anemia with an increased red cell distribution width (RDW). The white blood cell (WBC) and platelet counts are variable, and may be either increased or decreased. The majority of cases show neutrophilia and basophilia at diagnosis.

Peripheral blood smears characteristically show teardrop red blood cells and significant aniso- and poikilocytosis. Other findings include immature neutrophils and abnormal platelets, particularly large, irregular, hypogranular platelets. Naked megakaryocytic nuclei and fragments of megakaryocytic cytoplasm are often present. Granulocytes and precursors may show mild dysplastic changes. Basophilia and eosinophilia are often present. Over time, neutropenia, thrombocytopenia, and circulating blasts appear.

Bone marrow aspirate smears may be hypercellular in the early stages of PM and hypocellular in patients with advanced fibrosis. Most patients are diagnosed at the fibrotic stage. Megakaryocytes are increased and atypical, varying in size, maturation, nuclear shape, and nuclear lobation. Stainable iron may be absent, a finding that does not necessarily indicate iron deficiency.

Histologic sections show variable cellularity, depending on the stage of disease. Most cases are advanced at diagnosis and show hematopoietic hypocellularity. The myeloid-to-erythroid (M:E) ratio and blast percentage are often difficult to determine because of compression of hematopoietic cells by marked fibrosis. Megakaryocytes are increased, distributed singly and in clusters, and atypical, with varying size and shape, bizarre forms, enlarged and hyperchromatic nuclei, and abnormal nuclear lobation.

Stromal changes are usually marked. Reticulin fibrosis is present because of local cytokine secretion and proliferation of polyclonal fibroblasts. In advanced cases, collagen fibrosis may be found. Changes in trabecular bone parallel the degree of fibrosis. The trabeculae are thickened and irregular, sometimes to the point of overt osteosclerosis. Other findings include benign lymphoid aggregates, sea-blue histiocytosis, gelatinous transformation, and granulomas. Therapy may reduce the degree of fibrosis.

Early or cellular-stage PMF may be difficult to recognize and classify. Patients present with minimal to modest splenomegaly. The peripheral blood shows mild leukocytosis, therapy-refractory anemia with occasional teardrop forms, thrombocytosis, and relatively few myeloid and erythroid precursors. The bone marrow is hypercellular with an increased myeloid to erythroid (M:E) ratio, increased immature myeloid cells, increased and atypical megakaryocytes, and little or no fibrosis. Cases with these features may be diagnosed as unclassifiable MPD until findings more characteristic of PMF emerge.

Karyotype studies show clonal karyotypic anomalies in approximately 50% of patients, primarily trisomies of chromosome 1q, 8, and 9, and deletions of chromosomes 12p, 13q14, and 20q. Acquisition of additional anomalies is evidence of clonal progression and presages leukemic transformation. BCR’ABL1 translocation is typically absent but has been rarely reported in the course of clonal evolution. It is possible that some PMF cases with BCR’ABL1 are actually examples of CML with marked fibrosis.

Molecular studies show JAK2 V617F mutation in approximately 40% to 50% of patients. JAK2, located on chromosome 9p24, encodes a tyrosine kinase, and this mutation produces constitutive kinase function. Cases with JAK2 mutation tend to show higher WBC and red blood cell counts, lower platelet counts. Such cases also tend to show less prominent megakaryocytic clustering. Cases lacking JAK2 V617F mutations may show mutation of JAK2 exon 12 or MPL, located on chromosome 1p34, which encodes the thrombopoietin receptor. PMF may show either mutated or nonmutated PM; thus, the mutations found to date do not seem to be the initial neoplastic event in PMF.

PMF has been reported with sarcoidosis, amyloidosis, and clonal B-cell and plasma cell neoplasms.

The differential diagnosis includes reactive marrow fibrosis, other MPN, MDS, acute leukemia with fibrosis, and lymphoid and plasma cell neoplasia with fibrosis. In general, PMF is distinguished from PV by a lower hematocrit, more atypical megakaryocyte morphology, and more prominent fibrosis; from ET by more atypical megakaryocyte morphology and prominent fibrosis; and from CML by the absence of BCR’ABL1 translocation. It may be difficult to distinguish PMF from MDS with fibrosis. In general, PMF shows a more insidious clinical course, more prominent splenomegaly, less impressive dysplasia, and fewer cytogenetic anomalies.

Essential thrombocythemia (ET) is characterized primarily by thrombocytosis (Figs. 21.5, 21.6, 21.7and 21.8) (37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64). ET occurs as a de novo disorder, a therapy-related disease, and a transformation of polycythemia vera (PV).

ET occurs in both children and adults, more often in females. Clinical signs and symptoms are referable to coagulopathy
and excessive hematopoiesis, and include thromboembolism and mild hepatosplenomegaly. Many patients are asymptomatic. The clinical course is usually indolent, with increased fibrosis and osteosclerosis; acute leukemia occurs in approximately 1% to 5% of patients. The risk of transformation is related to the type and duration of therapy. Spontaneous remission has been reported during pregnancy.

Laboratory studies reveal thrombocytosis, neutrophilia, and normal to decreased hematocrit. The neutrophil alkaline phosphatase score is increased. Mild eosinophilia and basophilia are usually present. The platelet count is usually more than 500 × 10⁹‘L, but symptomatic ET has been reported with platelet counts as low as 300 × 10⁹‘L. ET usually shows of 500-2000 × 10⁹‘L. Platelet function studies are often abnormal. Serum thrombopoietin is normal to increased. Circulating hematopoietic precursors capable of spontaneous erythroid colony formation are increased; however, in practice, this is a difficult test to perform reliably and is neither sensitive nor specific enough to use as a diagnostic criterion.

The peripheral blood smear shows normal red blood cell morphology in uncomplicated ET. Neutrophils may be morphologically normal or slightly dysplastic, with subtle abnormalities and increased nuclear lobation. Platelets are often normal in appearance but may include large and hypogranular or agranular forms.

Bone marrow aspirate smears show a variable M:E ratio. Hematopoietic maturation is essentially unremarkable in the untreated patient. Blasts typically comprise less than 3% of nucleated cells. Megakaryocytes are plentiful and mature and include large forms with hyperlobated nuclei. Iron stores are decreased to absent, a finding that does not necessarily reflect true iron deficiency.

Histologic sections of the bone marrow show increased cellularity. This is prominent in megakaryocytes, which are usually present in clusters. Megakaryocytes range from abnormally small to very large, with larger cells showing increased atypical nuclear contours, abnormal nuclear lobation, and densely clumped or almost pyknotic chromatin. Reticulin fibrosis may be present. The trabeculae show irregular thickening and thinning. Other reported findings include pure red cell aplasia, necrosis (possibly because of antiphospholipid antibody syndrome), and reactive histiocytosis.

Genetic studies show monoclonality in some, but not all, cases. Cases with monoclonality (as evidenced by chromosome X inactivation or other means) tend to show overexpression of CD177 (formerly PRV1); the significance of this finding is not known. The appearance of clonal karyotypic anomalies indicates clonal evolution, and correlates with an increased risk of leukemic transformation. Commonly acquired anomalies include deletion of chromosome 17p and’or P53 mutation. BCR’ABL1 translocation is absent. The JAK2 V617F gain-of-function mutation is found in approximately 50% of patients. Such cases tend to show higher white blood cell and red blood cell counts, as well as lower platelet counts and less prominent megakaryocytic clustering.

ET may transform to PV, PMF, and systemic mastocytosis.

ET has been reported with sarcoidosis and with clonally related and unrelated B-cell and plasma cell neoplasms.

The differential diagnosis includes reactive thrombocytosis; other MPN, especially PV, the early (cellular) stage of PMF, and CML with thrombocytosis; and MDS with thrombocytosis. ET is distinguished from PV primarily by a higher platelet count and lower hematocrit; from PMF by thrombocytosis and less marked fibrosis; and from CML by the absence of BCR’ABL1 translocation. It may not always be possible to distinguish ET from PV or from MDS with thrombocytosis.

Polycythemia vera (PV) is characterized primarily by erythrocytosis (Figs. 21.9, 21.10, 21.11, 21.12, 21.13and 21.14) (65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94). PV occurs as a de novo disorder, a therapy-related disease, and a transformation of (or in conjunction with) primary myelofibrosis (PMF), essential thrombocythemia (ET), systemic mastocytosis, and chronic myelogenous leukemia (CML).

PV usually occurs in middle-aged and older adults, rarely in adolescents, and more often in males. Clinical signs and symptoms are referable to hyperviscosity, coagulopathy, and excessive hematopoiesis. These include arterial and venous thromboembolism, vasculopathy, neurologic deficits, and mild hepatosplenomegaly. Many patients are asymptomatic.

The clinical course is usually indolent, with eventual transformation to fibrosis and osteosclerosis, another MPN, MDS, or acute leukemia in approximately 1% to 5% of patients. The risk of transformation is related to the type and duration of therapy. Spontaneous remission has been rarely reported.

Laboratory studies reveal an increased packed red blood cell volume or hematocrit (>60% in males, >56% in females), neutrophilia (>10 × 10⁹‘L in nonsmokers), and thrombocytosis (>400 × 10⁹‘L). The neutrophil alkaline phosphatase score is increased. Mild eosinophilia and basophilia are usually present. The red blood cell mass is increased but is difficult to measure and may be falsely low due to obesity. Serum erythropoietin is decreased. Circulating hematopoietic precursors capable of endogenous erythroid colony formation are increased. However, in practice this is a difficult test to perform reliably, and it is neither sensitive nor specific enough to use as a diagnostic criterion.

Red blood cell and platelet counts may be affected in PV by concomitant hematopoietic disorders or other factors. The platelet count may be increased by iron deficiency and the hematocrit increased by hypoxia or renal disorders. Conversely, the hematocrit may be decreased by expanded
plasma volume, megaloblastic anemia, iron deficiency, or renal failure.