However, our results are consistent with a recent molecular classification of the MPDs1 in which it is suggested that reticulin accumulates to a variable extent in patients with ET (Figure 5). In particular, agreement on the frequency of dysplastic megakaryocytes was poor, barely above chance, with agreement on staghorn and cloudlike megakaryocytes little better. Bone marrow transplants can be conducted to treat severe diseases of the bone marrow, including certain forms of cancer such as leukemia. Primary myelodysplastic syndromes: diagnostic and prognostic significance of immunohistochemical assessment of bone marrow biopsies. An overall diagnosis was made according to the WHO criteria and recorded on a 5-point scale: true ET (0), prefibrotic myelofibrosis (1), and manifest myelofibrosis of increasing severity (2-4). The myeloproliferative disorders (MPDs) are clonal hematologic malignancies comprising 3 main disorders: essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (MF).1,–3  In 2005 the JAK2 V617F mutation4,,–7  was shown in 95% of patients with PV and in just more than half of those with ET and MF.4,8,–10  Before this, the diagnosis of these disorders relied on a combination of clinical, laboratory, and histologic features using one of several different sets of diagnostic criteria.

Firstly, the biopsy in MDS gives an exact assessment of the cellularity; secondly, the presence of reticulin fibres, increased in the majority of the cases, can be evaluated; thirdly, dysmegakaryopoiesis is more easily detected in trephine biopsies than in smears; finally, abnormal behaviour of myeloblasts, clustering centrally in the bone marrow, is frequently observed before the smears show an excess of myeloblasts.

However, if such large sample sizes are required to show statistical significance, such differences are unlikely to be clinically relevant. Subjective and objective predictors of WHO diagnosis.

P.J.C.

[27], The stem cells are typically harvested directly from the red marrow in the iliac crest, often under general anesthesia.

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.

Exploratory factor analysis identified 3 underlying processes contributing to the morphologic patterns of ET. This study was registered at http://isrctn.org as #72251782 and at http://eudract.emea.europa.eu/ as #2004-000245-38. Expression of Jak2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. The size of clusters was recorded as no clusters (0), predominantly small clusters of fewer than 6 cells (1) or predominantly large clusters of at least 6 cells (2).

In patients with ET, the JAK2 V617F mutation was associated with increased overall cellularity, increased erythropoiesis, and increased granulopoiesis, but there was no association between JAK2 status and reticulin grade, megakaryocyte clustering, or the presence of staghorn, cloudlike, dysplastic, or pyknotic megakaryocytes.10, The results presented here suggest that current histologic criteria are not sufficient to permit routine separation of ET into biologically distinct subsets. Introduction.

It is possible that even experienced hematopathologists need special training to distinguish subtypes of ET. For instance, erythrocytes, macrophages, and their precursors tend to gather around blood vessels, while granulocytes gather at the borders of the bone marrow.

Plain film x-rays pass through soft tissues such as marrow and do not provide visualization, although any changes in the structure of the associated bone may be detected.

We next compared prefibrotic myelofibrosis and true ET for each of the individual end-point categories that comprised the composite end point, noting that numbers of events were generally low in these individual categories. While much information can be gleaned by testing the blood itself (drawn from a vein by phlebotomy), it is sometimes necessary to examine the source of the blood cells in the bone marrow to obtain more information on hematopoiesis; this is the role of bone marrow aspiration and biopsy.

Biopsies were assessed by experienced hematopathologists (but not directly involved in the development of the WHO criteria) working without a training set of slides, evaluating trephines from all patients in all ET risk categories. These results show that reticulin grade was the major factor determining WHO classification assignment by all 3 hematopathologists. The independent predictors of WHO classification score for each of the 3 hematopathologists were analyzed by Bayesian proportional odds logistic regression.

Each of the 3 hematopathologists assessed the sections independently and without knowledge of patient outcomes, with only the age and sex of the patient provided for each trephine specimen (to allow determination of cellularity). In keeping with this concept, histologic features of bone marrow in ET, as defined by PVSG criteria, show substantial variability. It is particularly weighted toward cellularity criteria, with emphasis on overall cellularity as well as the degree of hypercellularity for each of the 3 lineages separately. To establish the role of bone marrow histopathology in the diagnostic evaluation of a patient seeking treatment for thrombocytosis, bone marrow biopsy specimens were obtained from patients enrolled in 3 prospective trials of ET. (C) Staghorn megakaryocyte (true ET) immediately adjacent to a cloudlike megakaryocyte (prefibrotic myelofibrosis). However, the assessment of other cytologic features was much less reliable (particularly megakaryocyte morphology), as was classification according to WHO disease category, including the distinction between prefibrotic myelofibrosis and true ET. A bone marrow biopsy can take about 60 minutes. The cellularity factor shows significant correlation with JAK2 status, but the other 2 reflect unknown biologic … 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. Similar to blood, smears made from suspensions of bone marrow cells are preferable for the identification of other types of blood cells. This factor analysis suggests that 3 underlying processes describe many of the morphologic patterns evident in the bone marrow trephine histology of patients whose disease is diagnosed as ET (by PVSG criteria), namely cellularity, megakaryocyte clustering, and extent of fibrosis. (A) Subjective estimates of the relative importance of 16 morphologic features in determining WHO diagnosis for each of the 3 hematopathologists. To provide a more objective assessment, a Bayesian proportional odds logistic regression was undertaken (Figure 3B). In 2001, the World Health Organization (WHO) published its criteria for the diagnosis of MPDs.16  This classification scheme is pathology based and, compared with the PVSG criteria, introduced a heavy emphasis on bone marrow trephine morphology together with the concept of “prefibrotic myelofibrosis” and “true ET” as distinct disorders. Normal marrow is either red, consisting of the hematopoietic tissue, or yellow, composed mainly of fat cells (adipose tissue). The WHO monograph lists several histologic features that are said to be characteristic of true ET, such as the presence of staghorn megakaryocytes, normal overall cellularity, and loose megakaryocyte clustering.

In this study, we have evaluated the reproducibility with which individual histologic criteria can be assessed and contribute to the definition of subtypes of ET in a large, prospective, multicenter cohort of patients.

(D) Staghorn megakaryocyte (true ET) in a tight cluster (prefibrotic myelofibrosis). Bone marrow accounts for about 4 – 5% of the total body weight of an individual. 1990 May;75(1):26-33. doi: 10.1111/j.1365-2141.1990.tb02612.x. For clinical outcome, we used a composite clinical end point of time to first arterial or venous thrombosis; major hemorrhage; myelofibrotic, leukemic, or myelodysplastic transformation; or death. Bone … An Inside Blood analysis of this article appears at the front of this issue. Bone marrow is the spongy tissue inside your bones. Bone marrow histology of CALR mutated thrombocythemia in the Seoul and Belgian/Dutch study showed loose clusters of large megakaryocytes (M) with bulky, cloud-like nuclei with a normal or a minor reduction of erythropoiesis and no increase in reticulin fibers grade 0 or 1 (RF 0 or 1). Moreover, obvious advantages of bone-marrow biopsy over bone-marrow smears were found. Events occurring before January 31, 2006, that were notified before June 30, 2006, were included in the analysis, meaning that the median follow-up for the cohort from trial entry was 68 months.

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