Introduction

The term myeloproliferative disease (MPD) was first used in 1951 by Dameshek1 to unify the conditions chronic myeloid leukemia (CML), polcythemia vera (PV), and idiopathic myelofibrosis (MF). This group of entities later included essential thrombocythemia (ET). The revised WHO classification2 also includes some newer entities and recognizes an overlap between myeloproliferative and myelodysplastic disorders (MPD/MDS) (Table 46.1). The WHO classification of these disorders interestingly does not include systemic mastocytosis, which now resides in a new group "mast cell diseases." All these disorders have a predisposition to developing acute leukemia (usually myeloid) and/or MF to a variable extent.

This chapter focuses upon the chronic MPDs, with the exception of CML, and the overlap between

Table 46.1 WHO classification of chronic myeloproliferative diseases

Chronic myeloproliferative disease

■ Chronic myeloid leukemia

■ Chronic neutrophilic leukemia

■ Chronic eosinophilic leukemia (and hypereosinophilic syndrome)

■ Polycythemia vera

■ Chronic idiopathic myelofibrosis (with myeloid metaplasia)

■ Essential thrombocythemia

■ Mastocytosis

■ Chronic myeloproliferative disease unclassifiable

Mixed myelodysplastic/myeloproliferative disorders

■ Chronic myelomonocytic leukemia

■ Atypical chronic myeloid leukemia

■ Juvenile myelomonocytic leukemia

Myelodysplastic/myeloproliferative disease, unclassifiable

MPD/MDS disorders and mastocytosis. For each disorder in turn pathology, cytogenetics, and molecular biology will be discussed. The molecular basis of many of these conditions is becoming increasingly apparent and this has the potential to revise diagnostic pathways and to force the review of classification. For example, the V617F JAK2 mutation discovered in 2005 is present in up to 95% of PV and 50% of ET and MF, respectively.3-7

The WHO classification places more emphasis, than do previous diagnostic criteria, upon pathology, in particular on features of the bone marrow trephine most especially megakaryocyte morphology (Figure 46.1). This remains to be fully validated, and although it is currently undergoing revision, a more substantial revision may be required in the light of rapid advances in molecular knowledge (this is reviewed in detail in the Idiopathic Myelofibrosis Molecular Biology section and Figure 46.2). When all MPDs (excluding CML) are considered, cytogenetic abnormalities in order of frequency are -Y, +8, +9, -7, del(20)(q11q13), del (13)(q12q14), del(5)(q13q33), and del(12)(p12). Conventional cytogenetics remain the evaluation of choice, but for rarer specific abnormalities (e.g., FIP1L1 PDGFRa) either RTPCR or FISH would be required. Deletion of chromosome 20q is probably one of the best characterized abnormalities in MPD and although a minimal common deleted region has been identified, no genes have yet been classified. For the common Philadelphia negative MPDs as discussed in this chapter, the most consistent and highly prevalent molecular abnormality akin to BCR/ABL for CML is V617F JAK2.3-7 The discovery of thrombopoietin triggered further interest in this and other cytokines in MPDs, and much molecular research has relatively fruitfully focussed in this field. Indeed a recent mutation in the cognate receptor cMPL has been identified in a small proportion of patients with ET and MF but thus far not PV.8 9 A pathogenic theme for the common MPDs in particular is that somatic mutations at a stem cell level result in at least two key events—hypersensitivity

Figure 46.1 Examples of marrow pathology features. (A) Large megakaryocyte typical of ET with distinct nuclear morphology; (B) Scanty reticulin in such cases; (C) Megakaryocyte morphology said to be more in keeping with MF indistinct nuclear morphology and clustering; (D) Dense reticulin formation; (E) Large megakaryocytes demonstrating emperipolesis.

Figure 46.1 Examples of marrow pathology features. (A) Large megakaryocyte typical of ET with distinct nuclear morphology; (B) Scanty reticulin in such cases; (C) Megakaryocyte morphology said to be more in keeping with MF indistinct nuclear morphology and clustering; (D) Dense reticulin formation; (E) Large megakaryocytes demonstrating emperipolesis.

to proliferative signals and resistance to inhibitory ones.

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