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70 years of the JCP-highly cited papers: Proposals for the classification of chronic (mature) B and T lymphoid leukaemias
  1. Mary Frances McMullin1,2
  1. 1Department of Haematology, Belfast City Hospital, Haematology Research Group, Belfast, UK
  2. 2CME, Queen’s University, Belfast, UK
  1. Correspondence to Professor Mary Frances McMullin, Department of Haematology, Belfast City Hospital, Haematology Research Group, Belfast BT9 7AB, UK; m.mcmullin{at}qub.ac.uk

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This paper published in 1989 comes number 8 in the most cited papers in the Journal of Clinical Pathology in this 70th anniversary of the Journal and cited some 631 times in the 27 years since it was published. In this paper, the French–American–British (FAB) group studied specimens from 110 patients who were well characterised with clinical and laboratory studies including electron microscopy.1 They looked at peripheral blood films, bone aspirate and trephine specimens and some lymph node biopsy specimens. On the basis of cytology and membrane phenotype, the disorders were defined. Immunological techniques used included distinguishing between B and T lymphocytes using membrane (SMIg) and cytoplasmic (CyIg) immunoglobulin and rosette tests with sheep erythrocytes and monoclonals against cell surface epitopes. In a series of meetings over 18 months, the group met and reviewed and discussed the cases and agreed on the classification.

The technologies used were the state-of-the-art methods of the time. Morphology, the long-standing foundation of haematology, is the initial technique used. However, it is recognised that morphological appearances in certain entities can be highly variable. In this paper, the experts agree and define the appearances of the different types of chronic leukaemias and in the illustrations give clear examples of the morphology. However, at the time of publication, the new techniques to define membrane phenotype are also used, and this adds a new dimension to the definition of types of disease. From the 1970s, immunological techniques had led to the characterisation of a range on membrane molecules. This was initially done with tests such as rosette tests with sheep erythrocytes to differentiate B and T lymphocytes, but the expanding range on monoclonals against cell surface epitopes available were used in this paper. Other available techniques are included where appropriate in the disease classification. Thus, specific cytochemical techniques such as tartare-resistant acid phosphatase to define Hairy cells and electron microscopy to define Sezary cells are also included. Of note, the increasing importance of cytogenetic studies in the investigation of lymphoid malignancy is commented on, where certain cytogenetic abnormalities are associated with morphological types and are noted such as translocation t(14;18) in follicular lymphoma,2 but these are not yet included in the classification.

On this basis, the paper describes the features of B cell leukaemias: chronic lymphocytic leukaemia (CLL), CLL mixed types where the morphological features are of CLL and prolymphocytic leukaemia (PLL), PLL, hairy cell leukaemia, splenic lymphoma with villous lymphocytes, leukaemia manifestations of non-Hodgkin’s lymphoma (NHL), leukaemic phase of follicular lymphoma, intermediate NHL or mantle zone lymphoma, lymphoplasmacytic lymphoma and plasma cell leukaemia. The T cell leukaemia defined are T cell lymphocytosis and T CLL, T PLL, adult T cell leukaemia/lymphoma and Sezary’s syndrome. In the text and in a series of tables, the cytological and immunological features of each type are described and examples of typical morphological types are shown. Thus, for example in B CLL, the features of the small and large lymphocytes are described, and weak SmIg absent CyIg, M-rosettes and CD5, CD19/20/24 and anti-class II expression is required. These combinations also distinguish from related variants.

With the publication of this paper, it was widely used to define these different types of chronic B and T cell disease, hence the citation index; however, it was much more used than this as the text, tables and figures were used widely in clinical and laboratory practice in making diagnostic decisions. The previous work by this group on classification of acute leukaemia published 4 years previously relied on morphological and cytochemical features and was widely in use by the time of this publication,3 but they considered as was of course widely accepted that the chronic leukaemias required determination of the membrane phenotype as described in this paper. In conclusion, the authors hoped that the proposal would ultimately lead to improved management of patients.

The definitions of disease set out by the FAB group have formed the basis for a number of iterations of disease entities set out by the WHO. These start with the definitions set out in this paper and incorporate new laboratory information in an expanding molecular landscape. The most recent revision is the 2016 classification of lymphoid neoplasms, which define provisional and definite entities based on understanding of the molecular drivers of lymphoid malignancy.4 The WHO classification of mature lymphoid, histiocytic and dendritic neoplasm now covers almost three pages and includes many defined molecular entities. It is interesting to note the many changes with greatly expanding numbers of entities since the 1989 paper.5 Of note, however, some diseases have disappeared such as the much sought-after T CLL, and many are clearly established that were not described originally such as mantle cell lymphoma. Molecular diagnostics are incorporated where available. It is interesting to observe that non-malignant entities are described (in situ follicular neoplasia), which do not need further evaluation of therapy.

The changes in laboratory techniques from 1987 are incorporated. Laborious and inaccurate tests such as the use of sheep erythrocytes have long since disappeared from usage. The range and efficacy of monoclonal antibodies for classification of membrane molecules has greatly expanded. Some promising techniques such as electron microscopy have not delivered on their initial promise. However, the laboratory investigation has moved to the molecular age where cytogenetic/molecular markers define malignant disease and subtypes. This leads to the question as to when morphology, which was of course the initial basis of classification, will become obsolete and classification of disease will move to a completely molecular classification.

As of the 2016 WHO classification and previously, the promise of treatments for certain defined subtypes is delivered in that there are now treatment options available, some of which are tailored to the particular defined disease. For example, the lymphoplasmacytic lymphoma, Waldenstrom’s macroglobulinaemia, with a MYD88 mutation triggering tumour growth by activation of nuclear factor kappa light chain enhancer of B cells by Bruton’s tyrosine kinase responds to the inhibitor of Bruton’s tyrosine kinase ibrutinib.6 Thus, the premise from the 1987 paper is being achieved. The proposals lead to the basis for further work with increasingly clear and defined disease types and improved treatment options for the management of patients.

References

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Footnotes

  • Handling editor Tahir S Pillay

  • Contributors MFM wrote the article.

  • Competing interests None declared.

  • Provenance and peer review Commissioned; internally peer reviewed.

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