Conversion of polycythemia vera to refractory anemia with hyperplastic bone marrow

Summary Clinical and morphologic findings in the conversion of treated polycythemia vera to pancytopenia with hyperplastic bone marrow (refractory anemia or pancytopenia with hyperplastic bone marrow) are described in light of our own observation. The nomenclature associated with this condition (pancytopenia, chronic erythroleukemia, preleukemia) is not uniform, whereas the morphologic findings are virtually identical. Some patients subsequently develop acute leukemia. The prognosis in cases of refractory anemia with hyperplastic bone marrow following polycythemia vera is, independent of the subsequent acute leukemia, invariably terminal.     

Delayed manifestation and slow progression of cerebral infarction caused by polycythemia rubra vera

BACKGROUND: Polycythemia rubra vera is often found after the manifestation of cerebral infarction, though the pathogenesis is still controversial. We present a case of cerebral infarction secondary to polycythemia rubra vera, which presented a slow expansion on magnetic resonance imaging despite severe hemiplegia. This case suggests a possible mechanism for development of cerebral infarction in polycythemia rubra vera. METHODS: This case report was conducted in a university hospital. Magnetic resonance imaging and diffusion-weighted imaging were performed to assess the evolution of infarction, and the total blood volume and cerebral blood flow were determined with the use of isotopes, Cr and Tc, respectively. Phlebotomy was performed, but intervention was not applicable. The manual muscle test and sensory disturbance were assessed by the same physiotherapist throughout the clinical course. RESULTS: A 64-year-old male patient with polycythemia rubra vera had a cerebral infarction. A subtle change was observed on CT scan on the third day after the onset of infarction, and a small signal was demonstrated on magnetic resonance imaging on the fourth day. The cerebral infarction expanded slowly in size and reached a maximum on day 24. A diagnosis of cerebral infarction secondary to polycythemia rubra vera was made, and treatment by phlebotomy, hydration, and hydroxyurea was begun. Though the hemiplegia remained, he became ambulatory with a brace, as do patients with atherosclerotic infarction. CONCLUSIONS: It is suggested that the delayed manifestation and slow expansion of cerebral infarction caused by elevated hematocrit might be derived from a pathogenesis different from atherosclerotic infarction.     

Sequential development of chronic lymphocytic leukemia in a patient with polycythemia vera

A patient with a seven-year history of polycythemia vera treated by repeated phlebotomies and intermittent busulfan administration developed gradually lymphocytosis accompanied by thrombocytopenia in peripheral blood and in the bone marrow. A marked pathological monoclonal proliferation of the B-cell population was detected. The sequential development of chronic lymphocytic leukemia in the patient with polycythemia vera could be considered as a coincidence because there is no reliable explanation of this event at present.     

Polycythemia vera with der(15) and der(20) associated with remarkable neutrophilia]

An autopsy case of polycythemia vera with der(15) and der(20) associated with remarkable neutrophilia was reported. A 87-year-old man was diagnosed as polycythemia vera in August 1987. The red blood cell count was 621 x 10(4)/microliters, Ht 58.5% and the white blood cell count 45,400/microliters with 92% neutrophils. The splenomegaly, increased red blood cell volume and the low erythropoietin level were present. The arterial SaO2 value was above 92%. The chromosome analysis of bone marrow cells revealed 46, XY, -15, -20, +der(15)t(15;?)(q13-15;?), +der(20)t(20;?)(q11;?). The breakpoint in No. 20 was in q11. The remarkable leukocytosis with relative and absolute neutrophilia were observed. Particularly late in the clinical course the white blood cell count was 92,900/microliters with 99% neutrophils. The Ph1 chromosome was negative and the bcr rearrangement was not detected. He died of bronchopneumonia in January 1989. At the autopsy findings neither the marrow fibrosis nor the extramedullary leukemic cell infiltration was noticed.     

The diagnostic interface between histology and molecular tests in myeloproliferative disorders

PURPOSE OF REVIEW: The sighting of the Philadelphia chromosome in 1960, later shown to harbor the BCR-ABL mutation in chronic myeloid leukemia, is arguably the most seminal contribution to molecular oncology. In the decades that followed, other cytogenetic and molecular disease markers have been described and effectively incorporated into routine diagnostic tests. This review discusses how this process is unfolding in myeloproliferative disorders. RECENT FINDINGS: In 2003, a karyotypically-occult FIP1L1-PDGFRA was reported in a subset of patients with blood eosinophilia and bone marrow mastocytosis; this mutation has since joined several other molecular markers for eosinophilic (e.g. PDGFRbeta- and FGFR1-rearrangements) and mast cell (e.g. KITD816V) disorders. In 2005, JAK2V617F was described in polycythemia vera and other BCR-ABL myeloproliferative disorders; the particular discovery has already had a major impact on current diagnostic approaches in polycythemia vera. These remarkable molecular discoveries are both redefining and reinforcing the diagnostic role of bone marrow histopathology. SUMMARY: Recent progress in the molecular pathogenesis of myeloproliferative disorders calls for a paradigm shift in traditional diagnostics, which is based on subjective technologies or assignment to a 'consensus'-based ever-changing list of inclusionary and exclusionary criteria. Routine clinical practice might be better served by diagnostic algorithms that incorporate molecular disease markers, which complement histological impression.     

Eosinophilic fasciitis after allogeneic bone marrow transplantation

We describe a patient with eosinophilic fasciitis (EF) developing 8 months after an allogeneic bone marrow transplantation for acute myeloblastic leukemia. The patient responded to low dose prednisone. A full thickness skin-muscle-fascia biopsy detected the characteristic fascial changes of EF and distinguished it from other forms of chronic graft-versus-host-disease (GVHD). This distinction may be important since EF after bone marrow transplantation may occur more often and it may respond to treatment with low doses of prednisone whereas chronic GVHD usually requires more extensive immunosuppressive treatment.     

The effect of the JAK2 V617F mutation on PRV-1 expression

JAK2(V617F)an acquired mutation of JAK2, is present in a majority of patients with polycythemia vera and to a lesser extent among patients with the other myeloproliferative disorders. We analyzed the effect of JAK2(V617F) on the expression of polycythemia rubra vera 1(PRV-1), using an in vitro model. Compared to wild-type JAK2, the presence of JAK2(V617F) increased both PRV-1 protein and mRNA levels in murine myeloid cells. A JAK2 inhibitor eliminated the V617F-induced increase in PRV-1 expression.     

Initial bone marrow reticulin fibrosis in polycythemia vera exerts an impact on clinical outcome

We examined the prevalence and prognostic relevance of bone marrow reticulin fibrosis in 526 patients with World Health Organization-defined polycythemia vera evaluated at the time of initial diagnosis. Seventy-four patients (14%) displayed mostly grade 1 reticulin fibrosis, with only 2 cases showing higher-grade fibrosis. Presenting clinical and laboratory characteristics, including JAK2V617F allele burden, between patients with and without fibrosis were similar for the most part, with the exception of a higher prevalence of palpable splenomegaly in patients with fibrosis (P < .01). Patients with fibrosis were less prone to experience thrombosis during their clinical course (1.1 vs 2.7 per 100 patient-years; P = .03) and more prone to develop post-polycythemia vera myelofibrosis (2.2 vs 0.8 per 100 patient-years; P = .01). There was no significant difference between the 2 groups in terms of overall or leukemia-free survival. The present study clarifies the incidence, degree, and prognostic relevance of bone marrow fibrosis obtained at time of initial diagnosis of polycythemia vera.     

Spontaneous hematologic recovery from bone marrow aplasia after accidental tenfold overdosage with radiophosphorus

Two patients with polycythemia vera received intravenously an accidental tenfold overdosage of radiophosphorus therapy (60 and 50 mCi 32P, respectively). In both patients, the occurrence of hemorrhagic complications 3 wk after the 32P medication led to detection of the error and referral to our hospital. Upon admission they showed an agranulocytosis, severe thrombocytopenia, and bone marrow aplasia. In both cases, spontaneous recovery of the hematopoiesis was observed from day 40 posttreatment onward. In one patient, a slow but ultimately complete normalization of blood counts and marrow morphology took place, whereas in the other, a mild thrombocytopenia persists. Nearly 5 yr after the accidental overdosage, both patients are clinically well. Symptoms of polycythemia vera have not reappeared up to now. Attempts were made to evaluate the radiation dose absorbed by the bone marrow. In the first patient, the daily 32P excretion was determined from day 22 to day 60, whereas in the other patient a whole body count was performed on day 78 after administration. From these results, an approximate cumulative bone marrow dose of 10 Sv (1000 rem) could be calculated.     

Evaluation and clinical correlations of bone marrow angiogenesis in myelofibrosis with myeloid metaplasia

Recent observations have underscored the biologic relevance of intratumoral angiogenesis and its potential impact on prognosis. Increased bone marrow angiogenesis has been demonstrated in a variety of hematologic disorders, including multiple myeloma. The extent and prognostic significance of bone marrow angiogenesis in 114 patients with myelofibrosis with myeloid metaplasia (MMM) was investigated. A control group of 44 patients without bone marrow disease, 15 patients with polycythemia vera, and 17 patients with essential thrombocythemia was also studied. Bone marrow microvessel density was assessed by a semiquantitative method, visual microvessel grading, and 2 separate quantitative methods, visual count and computerized image analysis. Angiogenesis estimation by all 3 methods was highly comparable. On visual microvessel grading, a grade 3 or 4 increase in bone marrow angiogenesis was demonstrated in 70% of patients with MMM, 33% of patients with polycythemia vera, 12% of patients with essential thrombocythemia, and 0% of normal controls. In a multivariate analysis, increased angiogenesis in MMM correlated significantly with increased spleen size and was found to be a significant and independent risk factor for overall survival. Increases in marrow angiogenesis correlated with hypercellularity and megakaryocyte clumping. In contrast, these 2 features were inversely proportional to reticulin fibrosis, whereas increases in marrow angiogenesis were independent of reticulin fibrosis. These preliminary findings suggest that neo-angiogenesis is an integral component of the bone marrow stromal reaction in MMM and may provide useful prognostic information and a rationale for the therapeutic investigation of anti-angiogenic agents.     

Retroperitoneal hemorrhage following bone marrow biopsy

We report the case of an elderly woman with polycythemia vera submitted to bone marrow biopsy who developed retroperitoneal hemorrhage as a result of direct penetration of the needle through the iliac crest, with damage to the iliolumbar artery, the first branch of the hypogastric artery.     

Reversal of bone marrow fibrosis and subsequent development of polycythemia in patients with myeloproliferative disorders

Bone marrow fibrosis is a characteristic finding in agnogenic myeloid metaplasia and in the spent phase of polycythemia vera. It is commonly believed that the reticulin deposition is irreversible. However, we report four patients who demonstrated clinical and laboratory evidence of transition from myelofibrosis to polycythemia. The transition was documented by improvement in the hemoglobin concentration and by determination of the Cr51 red blood cell mass, accompanied by a resolution of the fibrosis on serial bone marrow biopsies. Two of the patients had been treated with alkylating agents and splenectomy, one with myelosuppressive therapy without splenectomy, and one with splenectomy alone. These findings indicate that bone marrow fibrosis in the chronic myeloproliferative disorders is not always an irreversible phenomenon. Pathogenetic implications will be discussed.     

Identification of masked polycythemia vera from patients with idiopathic marked thrombocytosis by endogenous erythroid colony assay

We used the methylcellulose-culture technique to determine the utility of the erythroid progenitor growth in vitro from nonadherent T-depleted bone marrow and peripheral blood cells in distinguishing polycythemia vera (PV) from essential thrombocythemia. Thirty patients with PV (group A) and 30 patients who presented with idiopathic marked thrombocytosis with platelet count greater than 1,000 x 10(9)/L and a normal or reduced hemoglobin (Hb) level (group B) were studied at initial presentation. Endogenous (erythropoietin-independent) erythroid colonies (EEC) were found in all patients in group A and 13 in group B. The numbers of EEC were comparable between patients in group A and the 13 patients with EEC in group B, 11 of whom with initial Hb levels ranging between 6.4 g/dL and 12.6 g/dL were found to have PV 2 to 45 months after initial evaluation. The number of EEC did not correlate with the time to the progression of polycythemia, whereas myelosuppression delayed the subsequent development of PV. Of the two patients with EEC in group B who did not develop PV, both received chemotherapy soon after presentation, which might preclude the evidence of polycythemia evolution. None of the other patients in group B who did not form EEC developed PV with a median follow-up of 24 months. This study indicates that the assessment of EEC in bone marrow or blood is helpful in early identification of PV or prediction of polycythemia evolution in patients with marked thrombocytosis in whom polycythemia has been initially masked or anemia is present.     

Eosinophilic fasciitis

Two patients with clinical and pathologic features of eosinophilic fasciitis manifested serologic and systemic abnormalities that raised the question of the fundamental nature and relationship of eosinophilic fasciitis to scleroderma. In addition to the characteristic features of eosinophilic fasciitis, both patients exhibited arthritis, a predominantly mononuclear cell infiltration of muscles with normal serum muscle enzyme levels, weakly positive serum antinuclear factor, IgA deficiency, and abnormalities of pulmonary function. In addition, one patient had wide-mouthed colonic diverticulae and synovial deposits consistent with amyloid; the second patient had bone marrow hypoplasia. Although corticosteroid therapy was of benefit, hydroxychloroquine and potassium para-aminobenzoate were of further help in controlling the disorder. Biopsies from the two patients revealed inflammatory lesions to be heaviest deep in the skeletal muscle; fascia was only minimally inflamed with mild fibrosis. The findings suggest that striking fibroinflammatory lesions noted in the fascia in some patients with eosinophilic fasciitis may derive largely from spillover of lesions in neighboring skeletal muscle.     

Erythropoietin-dependent primary pure erythrocytosis.

We investigated the pathogenesis of isolated erythrocytosis of 14 yr duration in a 28-yr-old man. The increase in red cell mass was attributed to increased erythropoietin production. An extensive search for recognized causes of secondary erythrocytosis was unrevealing. Family members were found to be hematologically normal. After reduction of the circulating red cell mass by 20%, erythropoietin activity nearly quadrupled, thus suggesting a normal erythropoietin response to phlebotomy. When bone marrow cells of the patient were cultured in plasma clots in the absence of added erythropoietin, endogenous erythroid colony formation was observed, a pattern previously believed to be specific for polycythemia vera bone marrow cells. Our observations suggest that the erythrocytosis in this individual is best explained by an abnormal "servoregulatory" mechanism of erythropoietin production. In addition, this is the first instance in which the rule that endogenous erythroid colony formation is correlated with the diagnosis of polycythemia vera has not held.     

真性红细胞增多症120例临床研究

目的：对多项指标进行分析,提高对本病的认识。方法：真性红细胞增多症是发病率较低的（０．６～１．６／１０ 万）血液病,患者来自我国１７ 省市。着重做了血流变、血动力、微循环及骨髓细胞培养。结果：骨髓生成ＢＦＵ－Ｅ集落数明显高于正常,在无ＥＰＯ情况下仍有较多ＢＦＵ－Ｅ生长。结论：对发病及疗效发挥原理的研究有重要意义。     

Myelodysplastic syndrome with trisomy 11 associated with polycythemia vera

A 52-year-old male with myelodysplastic syndrome (MDS) who had a prior history of polycythemia vera is reported. Chromosome analysis revealed that the bone marrow and blood cells at the MDS phase contained trisomy of chromosome 11 as the sole cytogenetic change. Trisomy 11 is rarely found in hematologic neoplasia, and all of the reported cases with trisomy 11 were diagnosed as having nonlymphocytic neoplasia. In this report, a correlation between the chromosome change and leukemia/MDS developed in polycythemia vera is discussed.