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Background
The chronic myeloproliferative disorders (CMPD) are a collection of blood dyscrasias having similar clinical and histomorphologic findings. Classically, the following disorders are included.
Chronic myelogenous leukemia
Chronic myelomonocytic leukemia
Essential thrombocythemia
Polycythemia vera
Chronic idiopathic myelofibrosis with myeloid metaplasia (Agnogenic myeloid metaplasia)It should be clear that this category of diseases overlaps with several different disease categories including chronic leukemias and myelodysplasia.
OUTLINE
PATHOGENESIS CHARACTERIZATION Clonal disorders Clonal proliferations of myeloid stem cells Bone marrow fibrosis Blood 1981;57:781–7.
Blood 1990;75:1540–8.
Br J Haematol 1991;77:80–6.
Br J Haematol 1997;97:441–8.Proliferation of nonclonal fibroblasts, apparently as a result of inappropriate release of growth factors by clonal megakaryocytes or platelets
Cytokines implicated in the development of myelofibrosis include:
Transforming growth factor
Platelet-derived growth factor
Epidermal growth factor
Basic fibroblast growth factor
Calmodulin20q deletion Am J Clin Pathol 1996;106:680–8.
Characteristic defect in chronic idiopathic myelofibrosis with myeloid metaplasia
Presence of an abnormal karyotype has been shown to be an independent adverse prognostic indicator and a prognostic factor for acute conversion in chronic idiopathic myelofibrosis with myeloid metaplasia
GROSS APPEARANCE/CLINICAL VARIANTS CHARACTERIZATION General VARIANTS AUTOIMMUNE MYELOFIBROSIS Pathology of Autoimmune Myelofibrosis A Report of Three Cases and a Review of the Literature
Randall D. Bass, MD, Vinod Pullarkat, MD, Donald I. Feinstein, MD, Anita Kaul, MD, Carl D. Winberg, MD, and Russell K. Brynes, MD
Am J Clin Pathol 2001;116:211-216 Abstract quote
We identified 3 patients with autoimmune myelofibrosis (AM) lacking American Rheumatism Association criteria for systemic lupus erythematosus (SLE).
They had 1 or 2 cytopenias and lacked serologic evidence for SLE. Autoimmune features included psoriatic arthritis and positive direct Coombs test (DCT) result, DCT-positive autoimmune hemolytic anemia, and synovitis with polyclonal hypergammaglobulinemia.
Bone marrow biopsy specimens from each patient were evaluated by routine morphologic and immunohistochemical examination. They demonstrated marked hypercellularity (2 cases) or hypocellularity (1 case), moderate erythroid hyperplasia (all cases) with left-shifted maturation (2 cases), intrasinusoidal hematopoiesis (all cases), slightly to moderately increased megakaryocytes (2 cases), and grade 3 to 4 reticulin fibrosis (all cases). All lacked basophilia, eosinophilia, bizarre megakaryocytes, clusters of megakaryocytes, and osteosclerosis.
Mild to moderate bone marrow lymphocytosis was noted in all cases. In 2 cases, increased small T cells and B cells formed nonparatrabecular, loose aggregates.
BREAST Am J Surg Pathol 1980;4:281–5.
HISTOLOGICAL TYPES CHARACTERIZATION ESSENTIAL THROMBOCYTHEMIA
CONTEXT: Essential thrombocythemia (ET) is a chronic myeloproliferative disorder (CMPD) characterized predominately by thrombocytosis and abnormal megakaryocyte proliferation. The current diagnostic criteria require a combination of clinical, histologic, and cytogenetic data. The diagnosis relies largely on exclusion of other causes of thrombocytosis.
OBJECTIVE: Describe historical, clinical, and laboratory features of ET in order to understand, clarify, and more accurately diagnose this entity.
DATA SOURCES: Review contemporary and historical literature on ET and other causes of thrombocytosis.
CONCLUSIONS: ET is a relatively indolent and often asymptomatic CMPD that is characterized primarily by a sustained elevation in platelets > or = 600 x 10(3)/microL (> or = 600 x 10(9)/L), proliferating enlarged and hyperlobated megakaryocytes, and minimal to absent bone marrow fibrosis. Significant changes and revisions to the diagnostic requirements and criteria for ET have occurred during the last 30 years. Recently, a mutation in the Janus kinase 2 (JAK2) gene has been found in a significant number of cases of ET and other CMPDs. In up to 57% of ET cases, a mutation in the JAK2 gene can be detected. In the absence of a JAK2 mutation and features of another CMPD, the diagnosis of ET remains a diagnosis of exclusion after other causes of thrombocytosis have been excluded.MYELOFIBROSIS
CONTEXT: Chronic idiopathic myelofibrosis (CIMF) is a clonal myeloproliferative disease characterized by panmyelosis with intact maturation, progressive bone marrow fibrosis, and multiorgan extramedullary hematopoiesis.
OBJECTIVE: This review article aims to summarize the recent updates regarding the clinicopathologic features, molecular pathogenesis, cytogenetic abnormalities, diagnostic criteria, new diagnostic ancillary tests, and prognostic factors of CIMF.
DATA SOURCES: Important relevant articles indexed in PubMed/MEDLINE (National Library of Medicine) through the end of 2005 and referenced medical texts.
CONCLUSIONS: Because CIMF has a variety of clinical presentations, diagnosis may be challenging; the prefibrotic stage of CIMF has always been a challenging disease for pathologists to diagnose accurately. The recently proposed European Clinical and Pathological criteria can be helpful in the diagnosis of CIMF, especially in its prefibrotic stage. The enumeration of CD34-positive cells in the peripheral blood and the presence of circulating endothelial progenitor cells are the new important ancillary tests for the diagnosis of a small subset of patients with CIMF with atypical presentation. The recent discovery of the new mutation affecting the Janus tyrosine kinase 2 (JAK2V617F), more frequently observed in patients with polycythemia vera, is seen in approximately 35% to 57% of patients with CIMF. This mutation can serve as another diagnostic tool. Important factors affecting prognosis in CIMF are anemia, age of the patient, white blood cell count, degree of fibrosis, and number of blasts in the peripheral blood.
Hongyu Ni, MD, PhD, etal.
The frequency and distribution of CD34+ cells in the bone marrow (BM) of patients with idiopathic myelofibrosis (IM) were determined using an immunohistochemical technique. The percentage and absolute number of circulating CD34+ cells were enumerated.
Patients with IM exhibited a continuum of number of BM CD34+ cells ranging from 1 to 85 per 5 mm2. The frequency of BM CD34+ cells was inversely related to the number of circulating CD34+ cells. The BM biopsy specimens obtained from 4 patients with IM who underwent allogeneic stem cell transplantation were examined sequentially. Quantitative measurement revealed that the reticulin fiber volume was progressively reduced after allogeneic stem cell transplantation. All 4 patients had normocellular marrow with normal numbers of BM CD34+ cells after transplantation.
These findings suggest that the BM fibrosis and abnormal hematopoietic stem cell distribution in patients with IM is a consequence of the progeny of a malignant hematopoietic stem cell clone.
- Chronic idiopathic myelofibrosis: independent prognostic importance of bone marrow microvascular density evaluated by CD105 (endoglin) immunostaining.
Ponzoni M, Savage DG, Ferreri AJ, Pruneri G, Viale G, Servida P, Bertolini F, Orazi A.
1Department of Pathology, San Raffaele H Scientific Institute, Milan, Italy.
Mod Pathol. 2004 Dec;17(12):1513-20 Abstract quote.
Microvascular density (MVD) is substantially increased in bone marrow biopsies of patients with chronic idiopathic myelofibrosis (CIMF). CD105, a useful molecule for assessing MVD in various malignancies, is preferentially expressed by recently formed microvessels. Increased serum-soluble CD105 in patients with chronic myeloproliferative disorders, including CIMF, was documented. CD105 MVD has not so far been investigated in CIMF: to this end, the results in 55 patients with CIMF and 21 controls were compared with the conventional CD34 immunostaining as well as traditional histological and clinical disease features.
The MVD mean values estimated by both CD105 and CD34 were significantly higher in CIMF patients than in controls (P<0.00001). In addition, the proportion of CD105-positive megakaryocytes was significantly higher in CIMF than in controls (P<0.0001). A degree of reticulin fibrosis >2 correlated with increased CD105 MVD (P=0.05). A multivariate analysis confirmed that CD105-positive MVD was an independent adverse prognosticator.
This study demonstrates that while MVD, as assessed by both CD34 and CD105 immunostaining, is significantly increased in CIMF, only CD105-determined MVD correlates with the degree of fibrosis and is prognostically relevant. These findings provide a rationale for the investigational use of anti-CD105-targeted drugs in CIMF.
Evolution of myelofibrosis in chronic idiopathic myelofibrosis as evidenced in sequential bone marrow biopsy specimens.Buhr T, Busche G, Choritz H, Langer F, Kreipe H.
Institute of Pathology, Hannover Medical University, Hannover, Germany.
Am J Clin Pathol 2003 Jan;119(1):152-8 Abstract quote 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.
PLASMACYTOID MONOCYTES
Nodal and Extranodal Tumor-forming Accumulation of Plasmacytoid Monocytes/Interferon-producing Cells Associated With Myeloid Disorders.
Vermi W, Facchetti F, Rosati S, Vergoni F, Rossi E, Festa S, Remotti D, Grigolato P, Massarelli G, Frizzera G.
*Department of Pathology, University of Brescia, Brescia, Italy; daggerDepartment of Pathology, University Hospital Groningen, Groningen, The Netherlands; double daggerDepartment of Pathology, Forlanini Hospital, Rome, Italy; section signInstitute of Anatomic Pathology and Histopathology, University of Sassari, Italy; and Department of Pathology, Columbia University, New York, NY, USA.
Am J Surg Pathol. 2004 May;28(5):585-595. Abstract quote
Nodal tumor-forming accumulations of plasmacytoid monocytes/interferon-producing cells (PMs/IPCs) have been described in patients with myeloproliferative disorders.
Here we report a series of 9 additional cases of such association. The patients were predominantly adult (median, 62 years), males (male/female ratio, 7:2), who presented with chronic myelomonocytic leukemia (4 cases), acute myeloid leukemia (1), acute monocytic leukemia (2), unclassifiable chronic myeloproliferative (1), or myeloproliferative/myelodysplastic disease (1). The prognosis was poor (median survival, 24 months) and related to progression of the underlying myeloid neoplasm. We found that in addition to lymph nodes, PMs/IPCs accumulated to bone marrow (8 cases) and skin (4 cases). Immunohistochemical markers typically expressed by PMs/IPCs (CD68, CLA/HECA452, CD123) were found in all cases and shown useful to identify cells with variations from classic morphology. In addition, PMs/IPCs expressed the interferon-alpha (IFN-alpha) inducible protein MxA, the B-cell oncogene TCL1, and granzyme B. The biologic and clinical significance of the association between PMs/IPCs and myeloid disorders remains not clarified.
Using fluorescence in situ hybridization analysis in a case known to harbor monosomy 7 in the myeloid leukemia, we demonstrated that PMs/IPCs share the same chromosomal abnormality, thus indicating that they are clonal, neoplastic in nature, and closely related to the associated myeloid tumor. Recently, a novel CD56+ hematologic neoplasm has been reported and retained to stem from PMs/IPCs. The majority of PMs/IPCs in the present series failed to express CD56, thus indicating that variants of PMs/IPCs neoplasms exist, which might represent parts of a spectrum.POLYCYTHEMIA VERA
CONTEXT: Polycythemia vera (PV) is a clonal myeloproliferative disease characterized by an erythroid dominant trilineage proliferation of hematopoietic precursor cells. Classified as a chronic myeloproliferative disease, PV represents a histopathologic spectrum of 2 recognized stages, the polycythemic and postpolycythemic phase. The clinical manifestations of hemorrhage, thrombosis, and increased red cell mass are directly related to primary bone marrow dysfunction. Prognosis is strongly associated with thrombosis risk and disease progression; thus, treatment is directed toward minimizing coagulopathic complications and preventing leukemic transformation. Recently, a specific point mutation in the Janus kinase 2 (JAK2) gene was described in a majority of PV patients. The potential diagnostic and/or prognostic value of JAK2V617F is discussed.
OBJECTIVE: To review important developments from the recent and historical literature. Modern diagnostic criteria and emerging molecular findings are emphasized.
DATA SOURCES: A comprehensive review was performed of the relevant literature indexed in PubMed (National Library of Medicine) and referenced medical texts.
CONCLUSIONS: Modified clinical, histologic, and laboratory criteria have clarified the diagnosis of PV. Also, continuing studies on the recently discovered JAK2V617F gene mutation may significantly improve our understanding of PV pathogenesis and facilitate its medical management.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES THROMBOPOIETIN Thrombopoietin Administered During Induction Chemotherapy to Patients With Acute Myeloid Leukemia Induces Transient Morphologic Changes That May Resemble Chronic Myeloproliferative Disorders
Vonda K. Douglas, MD,1 Martin S. Tallman, MD,3 Larry D. Cripe, MD,4 and LoAnn C. Peterson, MDAm J Clin Pathol 2002;117:844-850 Abstract quote
Thrombopoietin (TPO), a potent stimulator of megakaryocyte and platelet production, has been used in clinical trials to reduce thrombocytopenia after chemotherapy in patients with acute myeloid leukemia (AML).We report that TPO therapy is associated with peripheral blood and bone marrow findings that can mimic myeloproliferative disorders. Peripheral blood and bone marrow samples of 13 patients with AML who received TPO were examined. A subset of bone marrow samples exhibited hypercellularity, megakaryocytic hyperplasia, and reticulin fibrosis after TPO administration. Cases demonstrated as many as 58.4 megakaryocytes per high-power field (MHPF) compared with 3.7 MHPF in the control group. Megakaryocytic atypia, increased mitoses, emperipolesis, intrasinusoidal megakaryocytes, and thickened trabeculae also were seen. Peripheral blood findings included leukoerythroblastosis, leukocytosis, thrombocytosis, and circulating megakaryocyte nuclei. Changes resolved within 3 months after discontinuation of TPO.
This rapid resolution of the morphologic abnormalities induced by TPO distinguishes these findings from those seen in true chronic myeloproliferative disorders.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS TREATMENT
CONTEXT: Properly managed, the myeloproliferative disorders are generally compatible with prolonged survival. Challenges to the hematologist include knowing when and how best to intervene to prevent and manage complications. The cytoreductive agent of choice for these disorders is currently hydroxyurea, emerging from randomized trials beginning with those of the Polycythemia Vera Study Group.
OBJECTIVE: To examine the roles and shortcomings of interventions (including hydroxyurea, antiplatelet agents, anagrelide, interferon, thalidomide, alkylating agents, cell cytopheresis, erythropoietins, splenectomy, bone marrow transplantation, and imatinib) for myeloproliferative disorders.
DATA SOURCES: This report uses actual case histories to illustrate the roles and shortcomings of these interventions.
CONCLUSIONS: Beyond phlebotomy for polycythemia vera, patients with polycythemia vera and essential thrombocythemia can be stratified by their risk for thrombosis, which guides the institution of cytoreductive therapies. High-risk patients generally benefit from cytoreductive therapy, and hydroxyurea has emerged as the agent of choice, because alkylating agents (and P32) have high leukemogenic potentials. Anagrelide and interferon are second-line agents. The addition of low-dose aspirin is beneficial for most, helping to prevent arterial thrombotic complications. Therapy in any of these disorders should be tailored to the unique characteristics of the individual patient. With myelofibrosis, therapeutic options run the gamut from observation, erythropoietic stimulators, cytotoxic agents, splenectomy, and bone marrow transplantation. Thalidomide and imatinib have shown some utility. Future challenges are the refinement of individualized treatment strategies and the development of targeted therapies based on rapidly expanding understanding of the molecular perturbations in these disorders.
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