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The present study illustrates characteristic features of histopathology in the 3 non-leukemic, Ph-negative groups of chronic myeloproliferative diseases (CMPD). Attention is paid to the final outcome of CMPD, especially its transformation into acute leukemias and the occurrence of myelofibrosis from bone marrow biopsies (BMB) in a total of 1,716 CMPD patients. Essential thrombocythemia (ET), polycythemia vera (P. vera), and chronic megakaryocytic granulocytic myelosis (CMGM) can readily be distinguished by histopathology from BMB in the great majority of patients without regarding laboratory data, leaving a compartment of about 12% unclassifiable cases. Histologic patterns of staging are the increase in number and pleomorphism of megakaryocytes (MK), increase in number and density of reticulin fibers and collagen fibrosis, and excess of blasts. These 3 criteria are each graded from 0 to 3 in every biopsy. From these, a staging results by means of the histology of BMB in each of the Ph-negative CMPD. This staging provides a classification by defined criteria which permits comparative studies, the possibility of monitoring the individual patients by follow-up histology, and offers a baseline for reliable evaluation of results from therapy protocols.

BackgroundThe World Health Organization classification of myeloproliferative neoplasms discriminates between essential thrombocythemia and the prefibrotic phase of primary myelofibrosis. This discrimination is clinically relevant because essential thrombocythemia is associated with a favorable prognosis whereas patients with primary myelofibrosis have a higher risk of progression to myelofibrosis or blast crisis. Design and MethodsTo assess the reproducibility of the classification, six hematopathologists from five European countries re-classified 102 non-fibrotic bone marrow trephines, obtained because of sustained thrombocytosis. ResultsConsensus on histological classification defined as at least four identical diagnoses occurred for 63% of the samples. Inter-observer agreement showed low to moderate kappa values (0.28 to 0.57, average 0.41). The percentage of unclassifiable myeloproliferative neoplasms rose from 2% to 23% when minor criteria for primary myelofibrosis were taken into account. In contrast, the frequency of primary myelofibrosis dropped from 23% to 7%, indicating that the majority of patients with a histological diagnosis of primary myelofibrosis did not fulfill the complete criteria for this disease. Thus, over 50% of cases in this series either could not be reproducibly classified or fell into the category of unclassifiable myeloproliferative neoplasms. ConclusionsWorld Health Organization criteria for discrimination of essential thrombocythemia from prefibrotic primary myelofibrosis are poorly to only moderately reproducible and lead to a higher proportion of non-classifiable myeloproliferative neoplasms than histology alone.

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The incidence of myelofibrosis (MF) among the three major Philadelphia chromosome-negative chronic myeloproliferative disorders, i.e. essential thrombocythaemia (ET), polycythaemia vera (PV) and chronic idiopathic myelofibrosis (CIMF), is not well documented since the diagnostic criteria have recently been redefined by the WHO. Therefore we performed a retrospective analysis of follow-up biopsies of 275 patients with ET, PV and CIMF according to the WHO classification of chronic myeloproliferative disorders. In the diagnostic bone marrow biopsies, MF was observed in 57 of the 136 CIMF patients (42%), 4 of the 73 PV patients (5%) and none of the 66 patients with ET. Within a median observation time of 2.9 years, 34 of the 79 patients with CIMF (43%), 13 of the 69 patients with PV (19%) and 1 of the 66 patients with ET (1.5%) – each initially without MF – developed MF regardless of myelosuppressive therapy.

Although the new World Health Organization (WHO) classification acknowledges "prefibrotic" phases, progression of myelofibrosis in chronic idiopathic myelofibrosis (cIMF) is controversial because there are only a few studies about sequential biopsy specimens, and they yield conflicting results. The conflicting results might be due to a mixture of different degrees of myelofibrosis and therapy regimens within the respective groups studied. To prove this hypothesis, we studied sequential bone marrow biopsy specimens from patients with cIMF and compared 3 groups with different degrees of myelofibrosis at initial diagnosis with a group of patients with primarily unfibrosed disease who met the WHO criteria for prefibrotic cIMF. Patients receiving chemotherapy were considered separately from patients without treatment. Our results favor a steady progression of myelofibrosis unrelated to therapy modalities, whereas confusing literature data can be explained: fibrosis may remain static or lessen, especially in more advanced stages of cIMF.

Histologic diagnoses from bone marrow biopsies were analyzed in a total of 1165 patients presenting with thrombocythemic platelet counts at initial examination. Two cut-off points suggested by the Polycythemia Vera Study Group to define thrombocythemia by platelet counts were compared: the former limiting value of 1000 x 10(9)/l platelets versus the recently proposed value of 600 x 10(9)/l. The percentage of all nonproliferative disorders was 41% under the lower, dropping to 11% under the high cut-off point. The respective figures for myeloproliferative disorders increased from 49% under the lower to 74% under the high limiting value. Primary thrombocythemia was included in 72% by the lower, and in only 40% by the high limiting value when classified by its histologic pattern in bone marrow biopsy. A striking decrease of platelet counts occurs, related to fiber increase, among each of three main groups of myeloproliferative disorders: in CML with megakaryocytic predominance from 40% down to 25%, in megakaryocytic-granulocytic myelosis (primary, i.e., agnogenic myelofibrosis) from 36.6% to 10%, and in primary thrombocythemia from 72.6% to 28.6% in cases with reticulin sclerosis.