WHO Classification of Hematologic Malignancies
Summary of Key Points
• The World Health Organization (WHO) classification of hematologic neoplasms includes tumors of lymphoid, myeloid, histiocytic, and dendritic cell lineages.
• Each disease is defined as a distinct entity based on a constellation of morphologic, clinical, and biological features.
• The cell of origin is the starting point of disease definition.
• Some lymphomas and leukemias can be identified by routine morphologic approaches. However, for many diseases, knowledge of the immunophenotype and molecular genetics/cytogenetics plays an important role in the differential diagnosis.
• The sites of presentation and involvement are an important clue to underlying biological distinctions. Extranodal lymphomas differ in many respects from their nodal counterparts.
• Many lymphoma entities display a range in cytologic grade and clinical aggressiveness, making it difficult to stratify lymphomas according to clinical behavior. A number of prognostic factors influence clinical outcome, including stage, international prognostic index, cytologic grade, gene expression profile, secondary genetic events, and the host environment.
• The WHO classification includes five major categories of myeloid diseases, all of which are clonal stem cell disorders exhibiting variable maturation in the affected lineages and either effective or ineffective hematopoiesis:
Myeloid (and lymphoid) neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1
• Among myeloid neoplasms, genetic features predict behavior better than morphology alone, necessitating genetic studies for accurate diagnosis.
1. The Revised European-American Classification of Lymphoid Neoplasms (REAL)/World Health Organization (WHO) classification includes which of the following features in the definition of a lymphoma?
2. Follicular lymphoma, one of the most common subtypes of lymphoma in adults, is characterized by translocations involving which of the following genes?
3. Which of the following myeloid proliferations is a clonal disorder?
4. The peripheral blood cells of a 70-year-old woman with leukocytosis are reported to carry the JAK2 V617F mutation. This finding proves:
A The patient does have polycythemia vera.
B The patient does not have chronic myelomonocytic leukemia.
5. In cytogenetically normal AML, the most significant prognostic information is likely to be:
1. Answer: D. The REAL classification departed from traditional schemes by emphasizing that each disease was a distinct entity, defined by a constellation of laboratory and clinical features—that is, morphology, immunophenotype, genetic features, clinical presentation, and course. The same approach was adopted by the WHO classification, first published in 2001.
2. Answer: C. The BCL2/IGH@ translocation is identified in approximately 85% to 90% of adult follicular lymphomas, but is adult in the pediatric variant of follicular lymphoma. The translocation can also be found by sensitive PCR-based techniques in a proportion of healthy adults, a number that increases with age.
3. Answer: D. All myelodysplastic and myeloproliferative neoplasms are clonal stem cell disorders that arise through aberrations of multiple genes that control the proliferation, survival, and maturation of normal hematopoietic cells. They show differences in the degree of maturation and differentiation, but nevertheless, all are derived from a clonal stem cell.
4. Answer: D. The finding of the JAK2 mutation indicates that there is a clonal proliferation present, but by itself it is not diagnostic of any single disease. It is found in almost 95% of cases of polycythemia vera and 50% to 60% of cases of essential thrombocythemia and primary myelofibrosis. It is also found in about 5% to 10% of cases of chronic myelomonocytic leukemia and even in rare cases of acute myeloid leukemia (AML). As with virtually all other mutations in hematopoietic neoplasms, its diagnostic significance must be considered in the context of the clinical and morphologic findings.
5. Answer: C. A number of genetic mutations clearly affect the prognosis of cytogenetically normal AML. Usually, mutated NPM1 and CEBPA are associated with a favorable outcome if they occur as the sole abnormality, whereas the FLT3 ITD mutation infers a worse prognosis, even when it occurs in the presence of other mutations that by themselves carry a good outcome. In general in persons with AML, genetic findings usually outweigh morphologic classification as prognostic factors.
