Representative morphological features of different myeloproliferative neoplasm (MPN) disease types. Bulbous or ‘cloud-like’ megakaryocytic nuclei (A-D) with rounded contours and vesicular chromatin are most characteristic of pre-fibrotic primary myelofibrosis (PMF). ‘Staghorn’ nuclei (E-H) with hyperlobation, elongated contours, and enlarged cell size, are commonly seen in essential thrombocythemia (ET). Hypolobated nuclei (I and J) are typically found in small megakaryocytes and sometimes show widely separated nuclear lobes. Hyperchromatic nuclei (K and L) are commonly found in overtly fibrotic PMF and myeloproliferative neoplasm, Unclassifiable (MPN-U). Note the highly fibrotic stroma in (L). Tight megakaryocyte clusters (M and N) show a syncytial quality in clustered cells. In contrast, loose megakaryocyte clusters (O and P) are characterized by intervening cells or stroma (P). CD34 immunostains demonstrate decreased (Q), normal (R), and increased (S) marrow vascularity.

CML

Epidemiology

• CML accounts for 15% to 20% of cases of leukemia in adults.
• Males are more commonly affected.
• The only well-established risk factor is exposure to ionizing radiation, evident by the increased CML incidence in survivors of the atomic bomb explosions in Japan.

Clinical Presentation

• 20 – 40% are asymptomatic and diagnosed incidentally by WBC count.
• Insidious onset with anemia, fatigue, weight loss, night sweats, bone pain, abdominal pain and fullness.
• Extramedullary hematopoiesis may cause hepatosplenomegaly and lymphadenopathy; may have splenic infarcts.
• Rare patients with excessively high white blood cell counts have symptoms related to leukostasis, such as priapism or neurologic deficits.

Pathobiology

• BCR-ABL1 is detected in cells of all hematopoietic lineages. For unknown reasons, the BCRABL1-induced cellular expansion predominantly targets the myeloid progenitor cell compartment, giving rise to the clinical phenotype, while many newly diagnosed patients have mostly Ph− stem cells.29 As a consequence, the hierarchical organization of hematopoiesis is maintained during the chronic phase, and a substantial number of Ph− stem cells are available to reconstitute the system if CML hematopoiesis is therapeutically suppressed.

• 90-95% have the characteristic cytogenetic Philedelphia Chromosome t(9;22)(q34;q11), which fuses BCR (chromosome 22) with ABL (chromosome 9)
  • Remainder have variant translocations involving a third or fourth chromosome or a cryptic translocation of 9q34 and 22q11 that can’t be identified with routine cytogenetic analysis.