Lymphoma classification - from controversy to consensus: The REAL and WHO Classification of lymphoid neoplasms

Background: Controversy in lymphoma classification dates back to the first attempts to formulate such classifications. Over the years, much of this co ntroversy arose from the assumption that there had to be a single guiding p rinciple - a 'gold standard - for classification, and from the existence of multiple different classifications. Design: The International Lymphoma Study Group (I.L.S.G.) developed a conse nsus list of lymphoid neoplasms, which was published in 1994 as the 'Revise d European-American Classification of Lymphoid Neoplasms' (R.E.A.L.). The c lassification is based on the principle that a classification is a list of 'real' disease entities, which are defined by a combination of morphology, immunophenotype. genetic features, and clinical features. The relative impo rtance of each of these features varies among diseases, and there is no one gold standard. In some tumors morphology is paramount, in others it is imm unophenotype, a specific genetic abnormality, or clinical features. An inte rnational study of 1300 patients, supported by the San Salvatore Foundation , was conducted to determine whether the R.E.A.L. Classification could be u sed by expert pathologists and had clinical relevance. Since 1995, the Euro pean Association of Pathologists (EAHP) and the Society for Hematopathology (SH) have been developing a new World Health Organization (WHO) Classifica tion of hematologic malignancies, using an updated R.E.A.L. Classification for lymphomas and applying the principles of the R.E.A.L. Classification to myeloid and histiocytic neoplasms. A Clinical Advisory Committee (CAC) was formed to ensure that the WHO Classification will be useful to clinicians. Results: The International Lymphoma Study showed that the R.E.A.L. Classifi cation could be used by pathologists, with inter-observer reproducibility b etter than for other classifications (> 85%), Immunophenotyping was helpful in some diagnoses, but not required for many others. New entities not spec ifically recognized in the Working Formulation accounted for 27% of the cas es. Diseases that would have been lumped together as 'low grade' or 'interm ediate/high grade' in the Working Formulation showed marked differences in survival, confirming that they need to be treated as distinct entities, Cli nical features such as the international Prognostic Index were also importa nt in determining patient outcome. The WHO Clinical Advisory Committee conc luded that clinical groupings of lymphoid neoplasms was neither necessary n or desirable. Patient treatment is determined by the specific type of lymph oma. with the addition of grade within the turner type, if applicable, and clinical prognostic factors such as the international Prognostic Index (IPI ). Conclusions: The experience of developing the WHO Classification has produc ed a neu; and exciting degree of cooperation and communication between onco logists and pathologists from around the world, which should facilitate pro gress in the understanding and treatment of hematologic malignancies.