From the R.E.A.L. Classification to the upcoming WHO scheme: A step toward universal categorization of lymphoma entities?

Annals of Oncology 9: 607-612. 1998. 1998 Khmer Academic Publishers. Printed in the Netherlands.

Commentary From the R.E.A.L. Classification to the upcoming WHO scheme: A step toward universal categorization of lymphoma entities? S. A. Pileri, M. Milani, G. Fraternali-Orcioni & E. Sabattini Service of Pathologic Anatomy/Haemalopathology Unit, Institute ofHaematology, S. Orsola Hospital. University of Bologna. Bologna, Italy * See Appendix on page 611 for members of the International Lymphoma Study Group

Key words: classification, Hodgkin's disease, malignant lymphoma

Revised European—American lymphoma classification: General principles

In 1991, a group of experienced European and American haematopathologists, none of whom had previously been involved in the writing of a lymphoma classification, founded the International Lymphoma Study Group (ILSG) for discussion of the problems related to the categorization of such tumours. After completion of two pilot studies, on mantle cell lymphomas [1] and Hodgkin's disease [2], the group, which in the meantime had expanded (Appendix), decided to tackle the problem of lymphoma classification and formulate a proposal for overcoming the seemingly endless conflicts between the American and European schools [3-13]. In April 1993, the first draft of a new classification was discussed, since all members felt that the limitations of the two previous schemes (the Working Formulation (WF) and the Updated Kiel Classification (UKQ) [1113] were severe enough to render an update difficult or even impossible. With respect to the WF, its basic concept itself comprised its main limitation: in fact, it was originally intended as a transduction system among the classifications in use in the 1970s [3-9]. This compromise provided for no distinction between B- and T-cellderived neoplasms, while allowing the fragmentation of otherwise homogeneous tumours (e.g., follicle centre cell lymphomas) and, conversely, the lumping together of lymphoma types which are different in terms of histogenesis and clinical course (e.g., diffuse mixed lymphomas). Moreover, the database used for construction of the WF consisted of 1,000 patients treated by chemotherapeutic protocols in use in the 1970s, morphologically diagnosed only on H&E stained slides and grouped according to the type of growth, cell size and mere survival, without consideration of important clinical data (stage, systemic symptoms, presence of bulky disease, monoclonal gammopathy, leukaemic phase) as well as phenotypic and molecular findings. The Updated Kiel Classification (UKC) [11-12], although more refined than the WF because of its

immunology orientation, suffered from limitations such as: a) the absence of the extranodal lymphomas (that actually comprise 40% of all lymphoid neoplasms), b) definition of the grade of aggressiveness on morphological grounds only, and c) a low reproducibility for some categories [14-16]. On the basis of literature reports and the knowledge gained from the late 1980s to the early 1990s, the ILSG stated that: 1. The best approach for a correct lymphoma classification is to simply list all diseases with distinct clinico-pathologic patterns identifiable with the available diagnostic tools. 2. The list should embrace all lymphoid neoplasms (plasmacytoma, leukaemias and Hodgkin's disease included). 3. The lymphoid tumours should be divided into three main categories: B-cell-derived, T-cellderived and Hodgkin's. 4. The first two types of point 3 should be further divided into tumours derived from precursors and peripheral lymphocytes. 5. Each entity should be defined by specific parameters such as morphology, phenotype, molecular characteristics, clinical aspects and, where possible, by the normal counterpart. Accordingly, the ILSG listed all entities, using consensus as the basis and then describing the entities, each termed either accepted or provisional: the latter corresponded to those lymphoma types whose existence is convincing on the basis of the data available in the literature, but for which there is a lack of either complete consensus or sufficient diagnostic experience among the members. The proposal which emerged from this work was termed Revised European-American Lymphoma (R.E.A.L.) Classification, and was published in Blood September 1994 [17] (Table 1). Noteworthy is the fact that this classification carries some original elements while dealing with already known entities:

608 Table I. Revised European-American Lymphoma Classification. B-cell neoplasms I. Precursor B-cell neoplasm: precursor B-lymphoblastic leukaemia/lymphoma II. Peripheral B-cell neoplasms 1. B-cell chronic lymphocytic leukaemia/prolymphocytic leukaemia/small lymphocytic lymphoma 2. Lymphoplasmacytoid lymphoma/immunocytoma 3. Mantle cell lymphoma 4. Follicle center lymphoma. follicular Provisional cytological grades: I (small cell). II (mixed small and large cells), III (large cells) Provisional subtype: diffuse, predominantly small cell type 5. Marginal zone lymphoma Extranodal (MALT type ± monocytoid B cells) Provisional subtype: nodal (± monocytoid B cells) 6. Provisional entity: splenic marginal zone lymphoma (± villous lymphocytes) 7. Hairy cell leukaemia 8. Plasmacytoma/plasma cell myeloma 9. Diffuse Large B-cell lymphoma Subtype: primary mediastinal (thymic) B-cell lymphoma 10. Burkitt's lymphoma 11. Provisional entity: high-grade B-cell lymphoma, Burkitt-like T-cell and putative NIC-cell neoplasms I. Precursor T-cell neoplasm: precursor T-lymphoblastic leukaemia/lymphoma II. Peripheral T-cell and NIC-cell neoplasms 1. T-cell chronic lymphocytic leukaemia/prolymphocytic leukaemia 2. Large granular lymphocyte leukaemia T-cell type NIC-cell type 3. Mycosis fungoides/Sezary syndrome 4. Peripheral T-cell lymphomas, unspecified Provisional cytological categories: medium-sized cell, mixed medium and large cell, large cell, lymphoepithehoid Provisional subtype: hepatosplenic y T-cell lymphoma Provisional subtype: subcutaneous panniculitis T-cell lymphoma 5. AngioimmunoblasticT-cell lymphoma (AILD) 6. Angiocentric lymphoma 7. Intestinal T-cell lymphoma (± entreopathy associated) 8. Adult T-cell lymphoma/leukaemia (ATL/L) 9. Anaplastic large cell lymphoma (ALCL). CD30+.T- and null-cell types 10. Provisional entity: anaplastic large-cell lymphoma, Hodgkin's-like Hodgkin's disease I. Lymphocyte predominance II. Nodular sclerosis III. Mixed cellularity IV. Lymphocyte depletion V. Provisional entity: lymphocyte-rich classical HD

a) it is the product of a consensus among experienced haematopathologists; b) includes both nodal and extranodal lymphomas; c) does not provide grades of malignancy. The latter point deserves a comment. On the basis of all the reports published in the literature, the ILSG members agree that the aggressiveness of a given lymphoma category varies significantly among patients due to different factors such as the indices of proliferation and apoptosis, the activation of oncogenes, the presence

of hybrid fusion genes, the development of multidrug resistance, the microambient, the possible correlation with microorganisms (see the Helicobacter pylori for the peripheral B-cell lymphomas of marginal zone origin), etc. [18-35]. For all of these reasons the ILSG preferred to avoid attributing a grade of malignancy to each entity in the belief that it cannot be defined by pure morphology or statistical analysis; in particular, the latter only informs with respect to the natural history of the disease or its median response to treatment and thus is not predictive of the individual patient's outcome nor helpful in making ad hoc therapeutic decisions (so-called tailored therapy) [36, 37]. Reactions to the R.E.A.L. Classification The R.E.A.L. Classification gave rise to conflicting reactions among clinicians and pathologists [38-49]. In fact, while some have appreciated its innovative basic objective of targeted biological research and more effective therapies, others have cited the absence of a procedure of validation and application for information transference among continents with respect to its interand intrapersonal reproducibilty and its epidemiological impact in the different countries. The missing grade of malignancy has drawn positive attention to the individual pathological entities and thereby encouraged scientists to expand the present knowledge and attempt to formulate new operative proposals. In March 1994, when the R.E.A.L. Classification was first presented at the US National Cancer Institute, the clinicians proposed a validation study that involved hospitals throughout the world, the results of which are as follows. Validation project of the R.E.A.L. Clasification The principal objective of this project was to compare the applicability and the reproducibility of the R.E.A.L. Classification [17] as opposed to the WF [13] and the UKC[11, 12]. Other aims were: 1) to define the incidence of each category in different geographic areas, 2) to determine the actual diagnostic impact of the clinical information and the immunophenotype, 3) define the clinical relevance of the immunophenotype, 4) and verify the inter- and intrapersonal reproducibility in the diagnoses of all entities. For this project, started in 1995 and ended in 1996, 1,379 lymphoma cases were selected from nine clinical and pathology institutions (Omaha, Vancouver, Capetown, London, Bellinzona/Locarno, Lyon, Hong Kong, Wiirzburg, Gottingen), according to the following criteria: a) patients affected by previously untreated lymphoma, b) onset of disease between 1st January 1988 and 31st December 1990, c) geographical representativeness of the various types of lymphoma, d) availability of enough material for the diagnosis and classification of the tumour, e) presence of immunophenotypic studies,

609 f) complete clinical data (with special reference to: age, sex, race, date and site of biopsy, nodal/extranodal involvements, stage, presence of bulky disease, laboratory findings, immunological status, performance status, first therapy, response to treatment, follow-up). A group of experienced haematopathologists (J. Diebold, K.A. Mac Lennan, H.-K. Muller-Hermelink, B. Natwani, D. Weinsenburger), only one of them a member of the ILSG (HKMH), visited the above-mentioned centres classifying the selected cases according to the R.E.A.L. Classification [17], the UKC [11, 12] and the WF [13]. The statistical analysis was performed by J. R. Anderson and P. Roy. The study was organized in the following four diagnostic steps: a) review of the histological slides (bone marrow biopsies included) with minimal clinical information (age, sex, site of biopsy and stage); b) comparison of the histopathological data with the immunophenotypic and cytogenetic/molecular data; c) comparison of the data of point b with the clinical information; d) review of 20% of all cases in light of the abovementioned parameters. Consensus was achieved when four out of five of the panel pathologists made the same diagnosis; every day a multi-headed microscope discussion was conducted about controversial cases. The results of this validation study were published in Blood [50] and discussed in Omaha last September at an international meeting. The results showed that the R.E.A.L. Classification [17] possesses the highest correspondence index between the diagnoses of the individual panelists and the consensus diagnoses: this index ranges from 86% to 95%, 20 and 40 points higher than that obtained when the UKC [11, 12] and the WF [13], respectively, were applied. Moreover, it was demonstrated that morphology per se is more often diagnostic for categories such as the B-cell chronic lymphocytic leukaemia and the extranodal marginal zone lymphomas, while for the remaining types, the exact diagnosis cannot be made without the employment of ancillary techniques (immunohistochemistry and molecular biology). A knowledge of clinical data is essential only in cases of primary mediastinal large B-cell lymphomas. Regarding the epidemiological point of view, the study established that the most common type of lymphoma worldwide is the diffuse large B-cell (30%) followed by the follicle center-cell type (22%), the marginalzone (8%), the small B-cell and the unspecified peripheral T-cell lymphomas (7%), the mantle cell type (5%), Burkitt's lymphoma (3%), and the anaplastic large-cell, primary mediastinal large B-cell, and precursor T-celltype lymphoblastic lymphomas (2%), with the remaining categories occurring more rarely, corresponding globally to 12% of all lymphoid neoplasms. The survival curves, as determined by application of the R.E.A.L. Classification [17], provided new important

hints: the group of peripheral small B-cell lymphomas that would have been classified as low-grade malignacies in the WF [13] and the UKC [11, 12], showed a wide range of eight-year survival: the latter, in fact, corresponded to 80% for marginal zone lymphoma, 50% for B-cell chronic lymphocytic leukaemia and 18% for mantle cell lymphoma, and likewise for the large cell types that would have been classified as high-grade neoplasms in the UKC [11, 12] and the WF [13] (eight-year survival: anaplastic large cell type 80%, diffuse large B-cell type 50%, peripheral T-cell types < 20%). Furthermore, when considering the patients belonging to the same category and alive after five years, and subdividing them according to the International Prognostic Index (0.1 vs. 4-5), statistically significant differences emerged, for instance, the values for the mantle cell lymphoma were 59% vs. 12% while those for the large B-cell diffuse type were 72% vs. 22%. These data support the concept of avoiding making a precise prognosis for each lymphoma entity, since the course of the same type of tumour can vary among patients. In line with this concept, if the histotypes according to five-year survival were revealed, it would be possible for three prognostic groups to be recognized: the first, with a fiveyear survival > 50%, comprises the follicle centre cell lymphoma, the small B-cell type/B-chronic lymphocytic leukaemia, the marginal zone lymphoma and the anaplastic large cell type, the second group, with an intermediate prognosis (five-year survival from 30% to 50%), includes large B-cell diffuse lymphoma, Burkitt's lymphoma and precursor lymphoblastic lymphomas, and the third group, with a poor prognosis (five-year survival < 30%) is composed of the mantle cell and the peripheral T-cell lymphomas. As a matter of fact, this stratification of histotypes contrasts with the grades of malignacies of both the UKC [11, 12] and WF [13]. Finally, the validation project provided the same results as other independent studies made simultaneously by other groups on B- and T-cell lymphomas [51-54]. The WHO project For production of a blue book on tumours of the haematopoietic system, in 1994 the WHO established an expert committee that included the ILSG members. A series of meetings followed and, in November 1997, the Consensus Conference, held in Airlie House in Virginia, proposed the categories listed in Table 2, which basically represent a slightly modified R.E.A.L. Classification [17]. With respect to the peripheral B-cell-derived lymphomas, the main differences can be summarized as follows: 1. Immunocytoma was re-termed 'lymphoplasmacytic lymphoma' to avoid the ambiguities existing between the R.E.A.L. Classification [17] and the UKC [11, 12]: in fact, lymphoplasmacytoid lymphoma of the UKC has become part of the B-cell chronic lymphocytic leukaemia in the R.E.A.L. Classification due to expression of the CD5 and

610 Table 2 WHO classification of lymphoid tumours. B-cell neoplasms Precursor B-cell lymphoblastic leukemia/lymphoma Peripheral B-cell neoplasms B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma B-cell prolymphocytic leukemia Lymphoplasmacytic lymphoma Mantle cell lymphoma Follicular lymphoma Marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT) type (± monocytoid B-cells) Nodal marginal zone B-cell lymphoma (± monocytoid B-cells) Splenic marginal zone B-cell lymphoma (± villous lymphocytes) Hairy cell leukemia Diffuse large B-cell lymphoma" Sutypes: mediastinal (thymic), intravascular Burkitt lymphoma Plasmacytoma Plasma cell myeloma T-cell neoplasms Precursor T-cell lymphoblastic leukemia/lymphoma Peripheral T-cell and NK-cell neoplasms T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia NK cell leukemia NK/T cell lymphoma, nasal and nasal-type Mycosis fungoides Sezary syndrome Angioimmunoblastic T-cell lymphoma Peripheral T-cell lymphoma (unspecified)11 Adult T-cell Leukemia/lymphoma (HTLV-1+)3 Anaplastic large cell lymphoma (T- and null cell types) Primary cutaneous CD30-positive T-cell lymprolipherative disorders" Subcutaneous panniculitis-hke T-cell lymphoma Enteropathy-type intestinal T-cell lymphoma Hepatosplenic y/8 T-cell lymphoma Hodgkin's lymphoma (Hodgkin's disease) Nodular lymphocyte predominance Hodgkin's lymphoma Classical Hodgkin's lymphoma Hodgkin's lymphoma, nodular sclerosis (grades I and II) Classical Hodgkin's lymphoma, lymphocyte-rich Hodgki'ns lymphoma, mixed cellularity Hodgkin's lymphoma, lymphocytic depletion a

Morphologic and/or clinical variants of these diseases are not listed, for the purpose of clarity and ease of presentation.

CD23 molecules, while the lymphoplasmacytic immunocytoma of the UKC (CD5 negative) corresponds to the lymphoplasmacytoid immunocytoma in the R.E.A.L. Classification. The term lymphoplasmacytic means that most neoplastic cells are IgM-producing small lymphocytes and plasma cells, as observed in the Waldenstrom syndrome. 2. On the basis of the data published in the literature since 1994, the categories 'nodal marginal lymphoma' and 'splenic marginal zone lymphoma', previously defined as provisional, were changed to accepted [55, 56]. 3. The B-cell prolymphocytic leukaemia was kept separated from the B-cell chronic lymphocytic leukaemia because of its major aggressiveness, greater number of circulating lymphocytes, slight

phenotypic differences and shorter survival [12]; nonetheless, it was equally acknowledged that the B-cell chronic lymphocytic leukaemia can have a prolymphocytic evolution with a significantly worse clinico-pathological course [12]. 4. The Burkitt's-like type of B-cell lymphoma was abolished as a separate entity and included in the one of the peripheral large B-cell lymphomas, diffuse type, due to their identical responses to therapies [50]. 5. The grading of follicle centre cell lymphomas was decreased from 3 to 2, by grouping of grades I and II, although its use is optional. 6. The entity of peripheral large B-cell lymphoma, diffuse type, can be further subclassified, although not obligatorily, into the following histological categories (those in bold are not included in the R.E.A.L. Classification) [17]: centroblastic, immunoblastic (so-called if immunoblasts comprise > 90% of the neoplastic cells), anaplastic, rich in reactive lymphocytes and/or histiocytes [57-59] (lymphomatoid granulomatosis included) [60], Burkitt's-like [50]; on clinical grounds, it is possible to identify the following types: primitive mediastinal [61-63], intravascular [64, 65], pyothorax-associated [66]. The latter variant can also be WHO classified among the lymphoproliferative disorders of immunodepressed subjects that autonomously considers such processes according to their clinical and pathological peculiarities, the first of which is the fact that they represent a spectrum of diseases ranging from polyclonal to frankly lymphomatous [67]. Regarding the peripheral T-cell lymphomas, the differences listed below were reported: 1. The term T-cell chronic lymphocytic leukaemia/ prolymphocytic leukaemia was changed to prolymphocytic leukaemia to underscore the aggressiveness of this category while acknowledging the existence of morphological variants that do not fulfill the reported criteria for a prolymphocytic process. 2. The angiocentric T-cell lymphoma (R.E.A.L. Classification) was renamed 'nasal/nasal-type', as angiocentric lymphomas do not always recognize T-cell derivation [60]: the term 'nasal/nasal type' T-cell lymphoma is more appropriate, as this tumour characteristically arises in the nose and more frequently in Oriental populations, with analogous histological patterns also being observed in Western countries at other extranodal sites [68, 69]. 3. The entities hepato-splenic 7/8 T-cell lymphoma and the subcutaneous panniculitis-like T-cell lymphoma [17], previously termed provisional, were included among the accepted types. 4. In the WHO scheme, the NK lymphomas and the skin lymphomas are considered separately (while in the R.E.A.L. included as subvarieties). 5. A specific position is reserved for the CD30+

611 lymphoproliferative disorders of the skin, including diseases with various degrees of clinical and pathological aggressiveness (lymphomatoid papulosis, regressing atypical histiocytosis, anaplastic large cell lymphoma) [70]. 6. Recognition of subclasses among peripheral unspecified T-cell lymphomas has been considered optional until now.

3.

4. 5. 6. 7.

Conclusions 8.

Hopwood claims that "the urge to classify is a fundamental human instinct: like a predisposition to sin, it accompanies us into the world at birth and stays with us to the end" [71]. It has, however, been of benefit in diagnosis and therapy. The R.E.A.L. Classification and its subsequent results appear to be examples of how pathologists can be of help to clinicians by providing them with a useful tool for both operative and speculative purposes.

Acknowledgements

9.

10. 11. 12.

13.

This study was supported by grants from A.I.R.C. (Milan) and M.U.R.S.T. (Rome). 14

* Appendix

15.

International Lymphoma Study Group members

16.

P. M. Banks, Carolinas Medical Center, Charlotte, NC, USA; E. Campos, Hospital Clinic, Barcelona, Spain; J. K. C. Chan, Queen Elisabeth Hospital, Hong-Kong, R. Dalla Favera, College of Physicians and Surgeons, New York, USA; G. Delsol, Faculty of Medicine Purpan, University Paul Sabatier, Toulouse, France; C. De WolfPeeters, University of Leuven, Leuven, Belgium; B. Falini, University of Perugia, Perugia, Italy; K C. Gatter, John Radcliffe Hospital, Oxford University, Oxford, UK; P. Kluin, Leiden University Hospital, Leiden University, The Netherlands; P. Gaulard, Hopital Henri Mondor, Creteil, France; T. M. Grogan, University of Arizona Medical School, Tucson, AZ, USA; P. G. Isaacson, University College London Medical School, London, UK; E. S. Jaffa, National Cancer Institute, Bethesda, MD, USA; D. M. Knowles, New York Hospital, Cornell University Medical Center. New York, USA; N. Lee Harris, Massachusetts General Hospital, Harvard University, Boston, MA, USA; D. Y. Mason, John Radcliffe Hospital, Oxford University, Oxford, UK; S. Mori, Institute of Medical Science, University of Tokyo, Japan; H.-K. Miiller-Hermelink, University of Wiirzburg, Wurzburg, Germany; S. A. Pileri, University of Bologna, Bologna, Italy; M. A. Piris, Hospital Virgen de la Salud, Toledo, Spain; E. Ralfkiaer, University of Copenhagen, Herlev, Denmark; H. Stein, Klinikum Benjamin Franklin, Free University of Berlin, Berlin, Germany; I. J. Su, National Chen Kung University, Taiwan; R. A. Warnke, Stanford University Medical School, Stanford, CA, USA; L. M. Weiss, City of Hope National Medical Center, Duarte, CA, USA.

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18.

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20. 21.

22.

23. 24. 25.

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Correspondence to: S. A. Pileri, MD Universita degli Studi di Bologna Servizio di Anatomia Patologica Sezione di Emolinfopatologia Policlinico S. Orsola Via G. Massarenti 9 40138 Bologna Italy E-mail, pileri'a almadns.unibo.it