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AN INTEGRATED APPROACH TO THE DIAGNOSIS OF LYMPHOID MALIGNANCY

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In the past hundred years there have been numerous classifications of lymphoproliferative disorders. Some of these, such as the National Cancer Institute Working Formulation, the Kiel classification and the French-American-British (FAB) classification of leukaemia have had a major influence on the development of haematological oncology. Many other classifications have been largely forgotten. The publication of the Revised European American Lymphoma (REAL) classification [1] followed by the World Health Organisation (WHO) Classification of Haematological Malignancies in 2001 marked a turning point in the development of haematopathology. For the first time, the largely artificial distinction between lymphomas and lymphoid leukaemias was recognised so that they were considered as different presentations of the same entity. For example, this recognition has effectively ended the confusion caused by the arbitrary separation of B-cell chronic lymphocytic leukaemia (B-CLL) and small lymphocytic lymphoma. The second major impact of the WHO classification was to change the approach to the laboratory diagnosis of leukaemia and lymphoma with much greater emphasis on immunophenotyping, in particular, and other biological parameters. The WHO classification defines each of the diagnostic entities in terms of morphology, immunophenotype, cytogenetics and clinical features. This means that laboratory and clinical protocols can be developed that allow the diagnosis to be approached independently through these routes. Ensuring that the results of these investigations are concordant is now the major guarantee that a particular diagnosis is accurate. This represents an important practical advance towards improving the reliability of the laboratory diagnosis of leukaemia and lymphoma; an area where there has been considerable cause for concern in the past. Effective immunophenotyping is critical to the success of this approach to diagnosis. In the past decade, the number of antibodies that can be used as diagnostic reagents has grown and this has been accompanied by improvements in both immunocytochemistry and flow cytometric techniques. At the same time, there has been a growth in understanding of the detailed immunophenotypes associated with the diagnostic entities of the WHO classification. In many cases it is now possible to make a firm diagnosis based on immunophenotypic criteria alone and this provides a very effective check on the accuracy of a morphologically based diagnosis.

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One of the weaknesses of the WHO classification is that although many of the entities can be diagnosed accurately and reproducibly, they are also highly heterogeneous with respect to clinical behaviour and response to treatment. This means that in many cases, the routine immunophenotypic analysis of lymphoproliferative disorders needs to be extended to include prognostic markers that can be used to stratify patients according to their likely response to treatment. As more therapeutic monoclonal antibodies enter clinical practice, it will become important to assess accurately the extent of expression of cellular targets both at presentation and relapse. It is also becoming clear that in many cases, the immunophenotype is predictive of the presence of specific cytogenetic abnormalities. This can be useful ...

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