34. Myeloproliferative neoplasms

Last updated on April 15, 2019 at 18:38

General

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The myeloproliferative neoplasms (MPNs) are a group of disorders characterized by increased proliferation of neoplastic haematopoietic stem cells of the myeloid cell lineage. The neoplastic cells tend to seed to secondary haematopoietic organs like the spleen, liver and lymph nodes.

The subtypes are:

  • Chronic myeloid leukaemia
  • Polycythaemia vera
  • Primary myelofibrosis
  • Essential thrombocythaemia
  • Chronic neutrophilic leukaemia
  • Mastocytosis
  • Myeloproliferative neoplasm with eosinophilia

Only the bolded ones are important and will be discussed. All subtypes except CML are associated with mutations of Janus kinase 2 (JAK2). All MPNs are diseases of old age. The excessive proliferation causes high blood counts of different blood cells.

All MPNs can transform into acute leukaemia (blast crisis) or to bone marrow fibrosis.

Chronic myeloid leukaemia

Chronic myeloid leukaemia (CML) most frequently affects people around 50 to 60 years old. It involves excessive proliferation of the myeloblast cell line; granulocytes, promyelocytes and myeloblasts are found in high numbers.

The clinical picture involves non-specific symptoms like fatigue, weakness and weight loss. Extreme leukocytosis, even above 100 000/µL can occur, which is more than 20 times the normal value. Thrombocytosis and anaemia may also occur. Splenomegaly, sometimes extreme, is characteristic.

CML has three phases:

  • Chronic phase – often clinically unremarkable
  • Accelerated phase
  • Blast crisis

The blast crisis is the terminal stage of CML. The symptoms resemble those of acute leukaemia. During the accelerated and blast phases thrombocytopaenia may occur instead.

All cases of chronic myeloid leukaemia involve the infamous Philadelphia chromosome t(9;22). This translocation fuses the BCR and ABL genes, forming a BCR-ABL protein. This protein is a non-receptor tyrosine kinase that is constitutively active, which mimics the effects of continuous growth factor receptor activation. This translocation increases the survival and proliferation of the cells without inhibiting their differentiation.

There exist drugs that inhibit the BCR-ABL protein. These drugs have dramatically improved the prognosis of CML.

Polycythaemia vera

Polycythaemia vera (PV) is an MPN characterized by excessive proliferation of erythrocyte, thrombocyte and granulocyte cell lines, but the clinical symptoms are related to the erythrocytosis. We say that the proliferation is trilinear, as it involves the three cell lines of the myeloid cell line.

The erythrocytosis causes haemoglobin and haematocrit levels to be elevated compared to normal. There is mild neutrophilia and basophilia. The erythrocytosis causes the blood to become more viscous. Hyperviscocity increases the risk for thrombosis and vascular stasis. The increased RBC count causes splenomegaly. The serum level of EPO is low and can be used to differentiate PV from other causes of polycythaemia.

Mutations of JAK2, which is usually bound to the EPO receptor, causes haematopoietic stem cells to be independent of EPO for proliferation.

The prognosis of PV is very good.

Primary myelofibrosis

Primary myelofibrosis (PMF) is an MPN that is characterised by fibrosis of the bone marrow, causing myelophthisis. This causes haematopoiesis to shift from the bone marrow to extramedullary sites in the spleen, liver and lymph nodes. Extreme hepatosplenomegaly occurs.

Fibroblasts in the bone marrow are not neoplastic but are stimulated by growth factors secreted from neoplastic megakaryocytes. Mutations of JAK2 are involved in the pathogenesis. The neoplastic megakaryocytes produce more thrombocytes than normal and therefore cause thrombocytosis.

Essential thrombocythaemia

Essential thrombocythaemia is similar to PMF in both pathogenesis and clinical symptoms. Megakaryocytes produce more platelets than normal; the reason is unknown. It often involves mutations in JAK2. The prognosis is very good.

The thrombocyte level is above 450 000/µL. Thrombosis or bleeding is common.

Histiocytic neoplasms

These neoplasms don’t have their own topic and are therefore just mentioned here.

Histiocytic neoplasms originate from dendritic cells or macrophages. They’re very rare and therefore not important to know any details of. The most common type is Langerhans cell histiocytosis.


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