It is believed that the characteristic marrow fibrosis is caused by the inappropriate release of fibrogenic factors from neoplastic megakaryocytes. Two factors synthesized by megakaryocytes have been implicated: platelet-derived growth factor and TGF-β. As you recall, platelet-derived growth factor and TGF-β are fibroblast mitogens. In addition, TGF-β promotes collagen deposition and causes angiogenesis, both of which are observed in myelofibrosis.
As marrow fibrosis progresses, displaced hematopoietic stem cells take up residence in niches in secondary hematopoietic organs, such as the spleen, the liver, and the lymph nodes, leading to the appearance of extramedullary hematopoiesis. For incompletely understood reasons, red cell production at extramedullary sites is disordered. This factor and the concomitant suppression of marrow function result in moderate to severe anemia.
Fig.12.29 ).Redcellsoftenexhibitbizarreshapes(poikilocytes, teardrop cells),andnucleatederythroidprecursorsarecommonlyseenalongwithimmaturewhitecells(myelocytesandmetamyelocytes),acombinationoffindingsreferredtoasleukoerythroblastosis.Abnormallylargeplateletsoftenarepresentaswell.Thebonemarrowinadvancedcasesishypocellularanddiffuselyfibrotic,whereasearlyinthecourseitmaybehypercellularandhaveonlyfocalareasoffibrosis.Throughoutthecourse,marrowmegakaryocytesarepresentinclustersandhavecharacteristichyperchromaticnucleiwith“cloudlike”outlines.Markedsplenomegaly resultingfromextensiveextramedullaryhematopoiesis,oftenassociatedwithsubcapsular infarcts, alsoistypical.Thespleenmayweighasmuchas4000g,roughlytwentytimesitsnormalweight.Moderatehepatomegaly,alsoduetoextramedullaryhematopoiesis,iscommonplace.Lymphnodesalsoareinvolvedbyextramedullaryhematopoiesis,butnottoadegreesufficienttocauseappreciableenlargement.
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Fig. 12.29 Primarymyelofibrosis—peripheralbloodsmear.Twonucleatederythroidprecursorsandseveralteardrop-shapedredcells(dacryocytes)areevident.Immaturemyeloidcellswerepresentinotherfields.Anidenticalhistologicpicturecanbeseeninotherdiseasesproducingmarrowdistortionandfibrosis.
Primary myelofibrosis usually occurs in individuals older than 60 years who come to attention because of progressive anemia and splenomegaly. Nonspecific symptoms such as fatigue, weight loss, and night sweats are common. Hyperuricemia and secondary gout resulting from a high rate of cell turnover also are frequently seen.
Laboratory studies typically show a moderate to severe normochromic normocytic anemia accompanied by leukoerythroblastosis. The white cell count is usually normal or mildly reduced, but can be elevated early in the course. The platelet count is usually normal or elevated at diagnosis, but thrombocytopenia often supervenes as the disease progresses. These blood findings are not specific, and bone marrow biopsy is essential for diagnosis.
Primary myelofibrosis is more difficult to treat than polycythemia vera and CML. The median survival is in the range of 4 to 5 years. Threats to life include infection, thrombosis and bleeding related to platelet abnormalities, and transformation to AML, which occurs in 5% to 20% of cases. JAK2 inhibitors are effective at decreasing the splenomegaly and constitutional symptoms, even in those without JAK2 mutations, presumably because increased JAK/STAT signaling is common to all molecular subtypes. Hematopoietic stem cell transplantation may be curative in those young and fit enough to withstand the procedure.