Bone marrow pathology in essential thrombocythemia: interobserver reliability and utility for identifying disease subtypes

Abstract

The role of histopathology in the diagnosis of essential thrombocythemia (ET) is controversial, and there has been little attempt to quantitate interobserver variability. Diagnostic bone marrow trephine biopsy specimens from 370 patients with ET by Polycythemia Vera Study Group (PVSG) criteria were assessed by 3 experienced hematopathologists for 16 different morphologic features and overall diagnosis according to the World Health Organization (WHO) classification. Our results show substantial interobserver variability, particularly for overall diagnosis and individual cellular characteristics such as megakaryocyte morphology. Reticulin grade was the dominant independent predictor of WHO diagnostic category for all 3 hematopathologists. Factor analysis identified 3 independent factors likely to reflect underlying biologic processes. One factor related to overall and lineage-specific cellularity and was significantly associated with JAK2 V617F status (P < .001), a second factor related to megakaryocyte clustering, and a third was associated with the fibrotic process. No differences could be discerned between patients labeled as having "prefibrotic myelofibrosis" or "true ET" in clinical and laboratory features at presentation, JAK2 status, survival, thrombosis, major hemorrhage, or myelofibrotic transformation. These results show that histologic criteria described in the WHO classification are difficult to apply reproducibly and question the validity of distinguishing true ET from prefibrotic myelofibrosis on the basis of subjective morphologic criteria. This study was registered at http:// isrctn.org as #72251782 and at http:// eudract.emea.europa.eu/ as #2004-000245-38. (Blood. 2008;111:60-70)

Prodromal myeloproliferative neoplasms: The 2008 WHO classification

“…Additionally, in a recently published study of the same group [124], on 361 cases with ET mostly derived from the UK-PT 1 trial [27], 60% of patients presented already initially with increased BM fibrosis (including 20% with moderate to overt MF). Although in both studies [27,122] patients were entered following the PVSG criteria for ET that allow a certain amount of BM fibrosis at the beginning, the latter cohort of 80 patients with outright MF [124], i.e., Grades 3 and 4 [123] is neither consistent with the original [125] nor the updated diagnostic guidelines [5,21]. Regarding the phenotype of ET it is generally assumed that features like overt myelofibrosis or osteosclerosis do not characterize ET at onset, but are more in keeping with PMF [95][96][97]102,112,126] or post-ET MF [118].…”

“…Moreover, in this study, there was a disturbing inability to reach a significant level of concordance on basic morphological features such as quantity of erythropoiesis and remarkably, no selfassessment (intra-observer evaluation) was described (i.e., learning effect). Furthermore, description of characteristic megakaryocyte features excerting a diagnostic impact were occasionally not in full agreement with the correspondingly shown figures [122], suggesting a failing standardization of morphological parameters [62,93,95]. Finally, in 37-76% of patients higher levels of MF, implicating Grades 3 and 4 on a four-graded scale [123] were found including even new bone formation, i.e., osteosclerosis.…”

“…However, several groups confirmed their ability to discriminate between the thrombocythemic manifestations of early stage PMF versus ET [96,97,99,100,114]. On the other hand, in a blinded study among three hematologists/pathologists partially using BM specimens from the UK-PT 1 trial [27], the reproducibility and validity of distinguishing so-called true ET according to the WHO classification [1,2] from prefibrotic PMF [122] was questioned. Unfortunately, the results of this investigation are impaired by a number of inconsistencies.…”

High concordance in grading reticulin fibrosis and cellularity in patients with myeloproliferative neoplasms

“…42,43 However, there has been some controversy as to the reproducibility of reticulin grading and its applicability to routine diagnosis setting outside of a clinical trial setting. [44][45][46][47][48] In order to address this issue, we examined the concordance of reticulin grading in a large number of patients with primary myelofibrosis, post-thrombocythemic myelofibrosis, and post-polycythemic myelofibrosis, in the context of clinical fedratinib trials. Our goal was to determine the reproducibility of the WHO-adopted reticulin grading system in patients before and on treatment with a JAK2 inhibitor.…”

Uses and Abuses of JAK2 and MPL Mutation Tests in Myeloproliferative Neoplasms

“…Overt bone marrow fibrosis is absent in prefibrotic PMF, which is otherwise characterized by the aforementioned PMF-associated changes in megakaryocyte morphology and increased granulocyte proliferation. 11 Controversy is ongoing about the utility of morphology alone to distinguish ET from early PMF 12 ; however, this is irrelevant because clinical pathologists never base their diagnostic impressions on morphology alone, and they also consider clinical, cytogenetic, and molecular information. 1,11 Clinically, PV and ET are characterized by erythrocytosis and thrombocytosis, respectively, and leukocytosis, splenomegaly, thrombohemorrhagic complications, vasomotor disturbances, pruritus, and a small risk of disease progression into acute leukemia or myelofibrosis.…”