Myelofibrosis pathophysiology

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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][10]
  • 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][11]
  • 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.[12][13][14][14][15]
  • 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.[16]

Sites of Extramedullary Hematopoiesis

  • The main sites of extramedullary hematopoiesis include the spleen and liver.[15][17][18][19][20]
  • 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)
  • Neuroblastoma RAS viral oncogene homolog (NRAS)
  • Kirsten rat sarcoma viral oncogene homolog (KRAS)
  • Protein-tyrosine phosphatase, non-receptor type 11 (PTPN11)
  • GATA-binding protein 2 (GATA2)
  • Tumor protein p53 (TP53)
  • Runt-related transcription factor 1 (RUNX1)

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)[33][34][35][36][37][38][39][40][41][42][43]
  • Infections (tuberculosis [TB], HIV infection, disseminated trichosporon infection, and dengue fever)[44][45][46][47][48]
  • Autoimmune diseases (systemic lupus erythematosus [SLE], multiple sclerosis [MS], Sjogren's syndrome, and juvenile idiopathic arthritis)[49][50][51][52][53]
  • Endocrine disorders (primary hyperparathyroidism)[54]
  • Delta-storage pool deficiency (SPD)[55]
  • Ghosal syndrome[56]
  • Gray platelet syndrome[57]
  • Chromosome 14q32 duplication syndrome, 700-kb[58]

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.[59][60][61][62][30][63][64][65][66]

Microscopic Pathology

On Light Microscopy

  • Low RBC count manisfesting as anemia.[67][59][68]
  • Erythroblastosis[69][70]
  • Fish-shaped RBCs on peripheral blood smears[71]
  • Micromegakaryocytes on the peripheral blood smears[7]
  • Fibroblast-like and myofibroblast-like reticulum cells on bone marrow study[72]
  • Teardrop cells[73]
  • Increased microvascular density, bizarre vessel architecture, and increased number of pericytes on bone marrow study[74][75]
  • Leukocytosis and thrombocytosis in the initial stages followed by leukopenia and thrombocytopenia in the advanced stages.[76][77][78][79][80][81][82][83]
  • Basophilia[84][85][86]

On Confocal Microscopy

  • Proplatelet (pseudopodia of megakaryocyte which extend into bone marrow sinuses to release platelets) formation[87]
  • CD14+ cells and monocytes expressing the angiopoietin-2 receptor (Tie2) lie close to the vessels in the spleen tissue.[16]
  • Vessels show increased density, tortuous architecture, and increased branching on bone marrow study.[75]
  • Thrombospondins (TSP) overexpression[88]

On Electron Microscopy

  • Micromegakaryocytes with mature cytoplasm containing alpha granules and the associated proteins.[7]
  • Megakaryocytes in the peripheral blood with leukoerythroblastosis studied on the vertically cut section of the buffy coat of blood[89]
  • Significant atypicalities of the neutrophilic, basophilic and megakaryocytic cell lines such as:
  • Nuclear-cytoplasmic asynchrony[90]
  • Partial arrest of maturation
  • Ultrastructural abnormalities in platelets such as:
  • Hypoplasia of surface connecting system with few orifices[91]
  • Hyperplasia of the dense tubular system
  • Considerable variety in the number of granules
  • Splenic findings can consist of the following:
  • No alteration in the basic structure[92]
  • Degenerative atrophic changes in the white pulp
  • Erythropoietic and granulopoietic cells along with megakaryocytes in the sinuses and cords of the red pulp
  • Cytoplasmic (degenerative in nature) and nuclear (nuclear blebs and loops) changes in the hematopoietic cells

References

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