Bone marrow histopathology and biological markers as specific clues to the differential diagnosis of essential thrombocythemia, polycythemia vera and prefibrotic or fibrotic agnogenic myeloid metaplasia

Abstract 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.

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The Significance of Bone Marrow Biopsy andJAK2V617FMutation in the Differential Diagnosis Between the “Early” Prepolycythemic Phase of Polycythemia Vera and Essential Thrombocythemia

American Journal of Clinical Pathology ◽

10.1309/6bq5k8lhvyakuaf4 ◽

2008 ◽

Vol 130 (3) ◽

pp. 336-342 ◽

Cited By ~ 38

Author(s):

Umberto Gianelli ◽

Alessandra Iurlo ◽

Claudia Vener ◽

Alessia Moro ◽

Elisa Fermo ◽

...

Keyword(s):

Bone Marrow ◽

Differential Diagnosis ◽

Polycythemia Vera ◽

Bone Marrow Biopsy ◽

Essential Thrombocythemia

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

Blood ◽

10.1182/blood.v96.10.3374.h8003374_3374_3380 ◽

2000 ◽

Vol 96 (10) ◽

pp. 3374-3380 ◽

Cited By ~ 11

Author(s):

Ruben A. Mesa ◽

Curtis A. Hanson ◽

S. Vincent Rajkumar ◽

Georgene Schroeder ◽

Ayalew Tefferi

Keyword(s):

Bone Marrow ◽

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Quantitative Methods ◽

Prognostic Significance ◽

Control Group ◽

Prognostic Information ◽

Myeloid Metaplasia ◽

Bone Marrow Disease ◽

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.

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Phenotypic Description of Familial Chronic Myeloproliferative Disorders.

Blood ◽

10.1182/blood.v104.11.658.658 ◽

2004 ◽

Vol 104 (11) ◽

pp. 658-658 ◽

Cited By ~ 4

Author(s):

Albert Najman ◽

Isabelle Chaumarel ◽

Christine Bellann-Chantelot ◽

Veronique Barbu ◽

Myriam Labopin ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Myeloid Leukemia ◽

Myeloproliferative Disorders ◽

Large Network ◽

Myeloid Metaplasia ◽

Chronic Myeloproliferative Disorders ◽

Familial Cases ◽

Agnogenic Myeloid Metaplasia

Abstract Chronic myeloproliferative disorders (CMPD) are rare diseases of the bone marrow characterised by a clonal proliferation of one or several myeloid lineages. Familial clustering are regularly reported suggesting a role for inherited factors. To adress this issue, we collected with the help of a large network of haematologists clinical data and blood samples of 78 families defined by the presence of at least two affected subjects with one of the four CMPD: polycythemia vera, essential thombocythemia, chronic myeloid leukemia and agnogenic myeloid metaplasia. A total of 176 affected subjects including 83 polycythemia vera, 70 essential thrombocythemia, 12 chronic myeloid leukemia and 11 agnogenic myeloid metaplasia were recruited. 449 asymptomatic relatives, mainly first-degrees, were collected and among them 11%were carriers of endogenous erythroid colonies with normal blood counts. Phenotypic spectrum within families was either homogenous (46/78) or heterogeneous (32/78) and the main association (25/32) was polycythemia vera and essential thrombocythemia. A few cases of changes in disease phenotype was also observed during the course of CMPD. Clinical and haematological data of affected subjects at diagnosis and during the course of the disease were similar to sporadic CMPD. However, a marked anticipation of approximatively 20 years/generation at onset age was observed. No excess of carcinomas was noted either in affected subjects or relatives. An excess of acute leukemias, however, was noted in relatives. We did not show evidence of known environmental factors such as exposition to ionic radiations or chemical solvents. Familial cases were restricted to a single generation in 33 families. Occurence was vertical in 45 families involving 2 generations in 36 and 3 generations in 9. In those familial cases consistent with a dominant inheritance, we exluded molecular abnormalities of VHL and EpoR genes involved in particular forms of familial and congenital polycythemia. In conclusion, the analysis of these 78 familial CMPD cases highlights that (i) the observation of mixed phenotypes in a large proportion is consistent with the theory that MPD arise from clonal expansion of a pluripotent hematopoietic precursor cell (ii) no environmental factor is clearly involved in the onset of CMPD and (iii) the observation of familial aggregations and the low incidence of the pathology suggest the implication of genetic predisposition factors in the occurence of myeloproliferative disorders. This large collection of multiplex families enables us to initiate genome-wide linkage analysis.

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