Myelofibrosis pathophysiology: Difference between revisions

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==Microscopic Pathology==
==Microscopic Pathology==
===On Light Microscopy===
===On Light Microscopy===
*Low RBC count manisfesting as anemia.<ref name="pmid16202684">{{cite journal |vauthors=Thiele J, Kvasnicka HM |title=Hematopathologic findings in chronic idiopathic myelofibrosis |journal=Semin. Oncol. |volume=32 |issue=4 |pages=380–94 |date=August 2005 |pmid=16202684 |doi=10.1053/j.seminoncol.2005.04.010 |url=}}</ref><ref name="pmid26891375">{{cite journal |vauthors=Cervantes F, Correa JG, Hernandez-Boluda JC |title=Alleviating anemia and thrombocytopenia in myelofibrosis patients |journal=Expert Rev Hematol |volume=9 |issue=5 |pages=489–96 |date=May 2016 |pmid=26891375 |doi=10.1586/17474086.2016.1154452 |url=}}</ref><ref name="pmid28009442">{{cite journal |vauthors=Hernández-Boluda JC, Correa JG, García-Delgado R, Martínez-López J, Alvarez-Larrán A, Fox ML, García-Gutiérrez V, Pérez-Encinas M, Ferrer-Marín F, Mata-Vázquez MI, Raya JM, Estrada N, García S, Kerguelen A, Durán MA, Albors M, Cervantes F |title=Predictive factors for anemia response to erythropoiesis-stimulating agents in myelofibrosis |journal=Eur. J. Haematol. |volume=98 |issue=4 |pages=407–414 |date=April 2017 |pmid=28009442 |doi=10.1111/ejh.12846 |url=}}</ref>
*Erythroblastosis<ref name="pmid12412736">{{cite journal |vauthors=Tóth P, Tóth Z |title=Idiopathic myelofibrosis with prominent postsplenectomy erythroblastosis terminating in acute myeloid transformation |journal=Haematologia (Budap) |volume=32 |issue=2 |pages=155–61 |date=2002 |pmid=12412736 |doi= |url=}}</ref><ref name="pmid8638637">{{cite journal |vauthors=Osman Y, Kishi K, Narita M, Saito H, Masuko M, Koike T, Shibata A |title=Idiopathic myelofibrosis with unusually high erythroblastosis in the peripheral blood |journal=Am. J. Hematol. |volume=52 |issue=2 |pages=122–3 |date=June 1996 |pmid=8638637 |doi=10.1002/(SICI)1096-8652(199606)52:2<122::AID-AJH12>3.0.CO;2-J |url=}}</ref>
*Fish-shaped RBCs on peripheral blood smears<ref name="pmid28731851">{{cite journal |vauthors=Robier C, Körber C, Quehenberger F, Neubauer M, Wölfler A |title=The frequency of occurrence of fish-shaped red blood cells in different haematologic disorders |journal=Clin. Chem. Lab. Med. |volume=56 |issue=2 |pages=323–326 |date=January 2018 |pmid=28731851 |doi=10.1515/cclm-2017-0378 |url=}}</ref>
*Fish-shaped RBCs on peripheral blood smears<ref name="pmid28731851">{{cite journal |vauthors=Robier C, Körber C, Quehenberger F, Neubauer M, Wölfler A |title=The frequency of occurrence of fish-shaped red blood cells in different haematologic disorders |journal=Clin. Chem. Lab. Med. |volume=56 |issue=2 |pages=323–326 |date=January 2018 |pmid=28731851 |doi=10.1515/cclm-2017-0378 |url=}}</ref>
*Micromegakaryocytes on the peripheral blood smears<ref name="pmid8435338">{{cite journal |vauthors=Reilly JT, Barnett D, Dolan G, Forrest P, Eastham J, Smith A |title=Characterization of an acute micromegakaryocytic leukaemia: evidence for the pathogenesis of myelofibrosis |journal=Br. J. Haematol. |volume=83 |issue=1 |pages=58–62 |date=January 1993 |pmid=8435338 |doi= |url=}}</ref>
*Micromegakaryocytes on the peripheral blood smears<ref name="pmid8435338">{{cite journal |vauthors=Reilly JT, Barnett D, Dolan G, Forrest P, Eastham J, Smith A |title=Characterization of an acute micromegakaryocytic leukaemia: evidence for the pathogenesis of myelofibrosis |journal=Br. J. Haematol. |volume=83 |issue=1 |pages=58–62 |date=January 1993 |pmid=8435338 |doi= |url=}}</ref>

Revision as of 18:54, 13 November 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2], Sujit Routray, M.D. [3]

Overview

Myelofibrosis, a myeloproliferative disorder, is characterized by the proliferation of megakaryocytes in the bone marrow, disrupted cytokine production, and reactive fibrosis resulting in bone marrow failure. The fibrosed and scarred bone marrow produces fewer and fewer normal functioning blood cells leading to pancytopenia and extramedullary hematopoiesis. It can mainly be associated with somatic mutation of the myeloproliferative leukemia virus (MPL) oncogene, the calreticulin (CALR) gene, or Janus kinase 2 (JAK2) gene but other genes can also be involved and it can also result in the setting of another primary insult.

Pathogenesis

  • Polyclonal mesenchymal cells of the bone marrow such as, fibroblasts, osteoblasts, pericytes, endothelial cells, adipocytes, and reticular cells create a functional microenvironment, which maintains hematopoiesis. This maintenance takes place through cellular interactions via growth factors, adhesion molecules, cytokines, and extracellular matrix components along with the help of oxygen and calcium.[1]
  • Myelofibrosis is the result of pathologic interaction between hematopoietic progenitor and stromal cells leading to the activation and expansion of the stroma and the accumulation of reticulin and collagen fibers produced by mesenchymal cells.[1]
  • The development and progression of myelofibrosis involves the activation of Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway, which paves the way for the overproduction of abnormal megakaryocytes.[2][3][4]
  • The abnormally proliferated megakaryocytes produce cytokines such as platelet-derived growth factor (PDGF), transforming growth factor (TGF) beta, and basic fibroblast growth factor (bFGF) which are involved in the abnormal proliferation of fibroblasts, resulting in fibrosis.[5][6][7][8][9]
  • Myelofibrosis can result in the setting of somatic mutations in specific genes or it can also be secondary to other primary disorders.
  • The somatic mutations driving the disorder can mainly involve the myeloproliferative leukemia virus (MPL) oncogene, the calreticulin (CALR) gene, or Janus kinase 2 (JAK2) gene.[3][10]
  • The fibrosis of bone marrow leads to extramedullary hematopoiesis involving the reticuloendothelial organs such as the liver and spleen. Rarely, the extramedullary hematopoiesis can also involve ectopic hematopoietic tissue which includes the skin, lymph nodes, lungs, gastrointestinal tract, peritoneum, central nervous system, and genital and urinary tracts.[11][12][13][13][14]
  • Extramedullary hematopoiesis in the spleen of patients with primary myelofibrosis (PMF) can lead to abnormal angiogenesis in the organ and it has been documented that monocytes expressing the angiopoietin-2 receptor (Tie2) play a role in starting/maintaining this pathological angiogenesis.[15]

Sites of Extramedullary Hematopoiesis

  • The main sites of extramedullary hematopoiesis include the reticuloendothelial organs, the spleen and liver.[14][16][17][18][19]
  • Hematopoiesis can rarely also occur in the following locations:

Genetics

Most commonly involved

  • Janus-kinase 2 (JAK2)
  • Calreticulin (CALR)
  • Myeloproliferative leukemia virus (MPL) oncogene
  • These mutations are found in approximately 90% of the patients.

Less commonly involved

  • Additional sex combs-like 1 (ASXL1)
  • Slicing factor, serine/arginine-rich 2 (SRSF2)
  • Enhancer of zeste, drosophila, homolog 2 (EZH2)

Associated Conditions

  • Myelofibrosis belongs to a group of disorders collectively called myeloproliferative disorders. Other members of this group include chronic myelogenous leukemia (CML), polycythemia vera (PV), and essential thrombocythemia (ET).
  • Myelofibrosis can be associated with a variety of medical conditions such as:
  • Malignancies and hematologic disorders (Hodgkin lymphoma, non-Hodgkin lymphoma, essential thrombocythemia, polycythemia vera, multiple myeloma, and malignancies with metastases to the bone)[31][32][33][34][35][36][37][38][39][40][41]
  • Infections (tuberculosis [TB], HIV infection, disseminated trichosporon infection, and dengue fever)[42][43][44][45][46]
  • Autoimmune diseases (systemic lupus erythematosus [SLE], multiple sclerosis [MS], Sjogren's syndrome, and juvenile idiopathic arthritis)[47][48][49][50][51]
  • Endocrine disorders (primary hyperparathyroidism)[52]
  • Delta-storage pool deficiency (SPD)[53]
  • Ghosal syndrome[54]
  • Gray platelet syndrome[55]
  • Chromosome 14q32 duplication syndrome, 700-kb[56]

Gross Pathology

  • On gross pathology, pancytopenia and extramedullary hematopoiesis are the characteristic findings. These are manifested as anemia, susceptibility to various infections, lymphadenopathy, hapatomegaly, and splenomegaly.[57][58][59][60][28][61][62][63][64]

Microscopic Pathology

On Light Microscopy

  • Low RBC count manisfesting as anemia.[65][57][66]
  • Erythroblastosis[67][68]
  • Fish-shaped RBCs on peripheral blood smears[69]
  • Micromegakaryocytes on the peripheral blood smears[7]
  • Fibroblast-like and myofibroblast-like reticulum cells on bone marrow study[70]
  • Teardrop cells[71]
  • Increased microvascular density, bizarre vessel architecture, and increased number of pericytes on bone marrow study[72][73]
  • Leukocytosis and thrombocytosis in the initial stages followed by leukopenia and thrombocytopenia in the advanced stages.[74][75][76][77][78][79][80][81]

On Confocal Microscopy

  • Proplatelet (pseudopodia of megakaryocyte which extend into bone marrow sinuses to release platelets) formation[82]
  • CD14+ cells and monocytes expressing the angiopoietin-2 receptor (Tie2) lie close to the vessels in the spleen tissue.[15]

References

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  4. de Freitas RM, da Costa Maranduba CM (2015). "Myeloproliferative neoplasms and the JAK/STAT signaling pathway: an overview". Rev Bras Hematol Hemoter. 37 (5): 348–53. doi:10.1016/j.bjhh.2014.10.001. PMC 4685044. PMID 26408371.
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