Editorial. Peripheral T-cell lymphoma: A developing concept

Transcription

1 Annals of Oncology 9: , Editorial Peripheral T-cell lymphoma: A developing concept For a long time T-cell lymphomas (TCLs) were thought to be limited to southern Japan and some parts of China and the Caribbean [1-3]. As a result, they gained no mention in the Working Formulation [4], and were only rather rudimentarily treated in the Updated Kiel Classification [5, 6], where their categorisation was based on pure morphology and the existence of new emerging entities was not taken into account. In this context, they gave rise to very poor inter- and intra-personal reproducibility [7]. In 1994, the proposal of the Revised European-American Lymphoma (R.E.A.L.) Classification by the members of the International Lymphoma Study Group [8] (Table 1) aroused new interest in TCLs. The R.E.A.L. Classification was conceived as a list of distinct clinico-pathological entities that could be distinguished by the available techniques [8]. A few of these entities were regarded as 'provisional' in the absence of extensive experience or complete consensus within the Group [8]. Two other underlying principles of the R.E.A.L. Classification were that all lymphoid tumors should be included, irrespective of their solid or leukaemic nature, or of their nodal or extranodal primary location, and that following the assumption that within each category aggressiveness varies from patient to patient, no indication should be given as to the grade of malignancy [8]. Following its initial proposal, the R.E.A.L. Classification has proved its clinico-pathological relevance, easy Table 1. Categorisation of T-cell lymphomas according to the R.E.A.L. Classification. T-cell and putative NK-cell neoplasms Precursor T-cell neoplasm: Precursor T-lymphoblastic leukaemia/ lymphoma Peripheral T-cell and NK-cell neoplasms T-cell chronic lymphocytic leukaemia/prolymphocytic leukaemia Large granular lymphocyte leukaemia T-cell type NK-cell type Mycosis fungoides/sezary syndrome Peripheral T-cell lymphomas, unspecified Provisional cytological categories: medium-sized cell, mixed medium and large cell, large cell, lymphoepithelioid Provisional subtype: Hepatosplenic y5 T-cell lymphoma Provisional subtype: Subcutaneous panniculitis T-cell lymphoma AngioimmunoblasticT-cell lymphoma (AILD) Angiocentric lymphoma Intestinal T-cell lymphoma (± enteropathy associated) Adult T-cell lymphoma/leukaemia (ATL/L) Anaplastic large cell lymphoma (ALCL), CD30+, T- and null-cell types Provisional entity: Anaplastic large-cell lymphoma, Hodgkin'slike applicability and reproducibility [9], and has also represented the basis for the development of the new International Classification Project promoted by the World Health Organisation (WHO) [10, 11]. As far as peripheral T/NK-cell neoplasms are concerned, the final draft of the WHO scheme differs from the R.E.A.L. Classification in the following points: a) the tumoral entities are subdivided into predominantly leukaemic/disseminated, predominantly nodal, and predominantly extranodal categories; b) the term 'peripheral T/NK-cell lymphoma, unspecified' has been included among both nodal and extranodal tumors; c) primary anaplastic large cell lymphomas (ALCLs) of the skin and lymphomatoid papulosis have been separated from nodal ALCLs and independently cited as primary cutaneous CD30+ lymphoproliferative disorders of the skin; d) the terms 'T-cell lymphocytic leukemia', 'intestinal T-cell lymphoma' and 'angiocentric T-cell lymphoma', respectively, have been substituted by the ones 'T-cell prolymphocytic leukemia', 'enteropathy-type intestinal T-cell lymphoma' and 'NK/T-cell lymphoma, nasal and nasal type'; e) subcutaneous panniculitis-like T-cell lymphoma and hepatosplenic T-cell lymphoma have become accepted entities (Table 2) [10, 11]. The introduction of the R.E.A.L. Classification has stimulated the interest of various groups on the problem of peripheral TCLs (PTCLs) in Western countries. This has led to the publication of several reports [9, 12-18] and the organisation of specific meetings, such as the ones held by the European Task Force on Lymphomas and the European Association for Haematopathology in Barcelona (June 1997) and Leiden (April 1998). Annals of Oncology has paid special attention to this topic, and three contributions can be found in the present issue alone [16-18]. The huge amount of work done on PTCLs during the last four years has provided important basic information and has fostered some new concepts which although sometimes still under debate deserve comment. Accepted concepts New studies have shown the relevance of the distinction between T- and B-cell lymphomas, which had been questioned by several groups in the past [19, 20]. In particular, the integration of morphological, phenotypic, molecular and clinical findings contemplated by the R.E.A.L. Classification [8] has made recognition of PTCLs as a whole and of the various specific entities straightforward, and has overcome the problems of reproducibility previously encountered with the Updated

2 798 Table 2. Categorisation of T-cell lymphomas according to the last draft of the WHO International Classification Project. Precursor T/NK-cell neoplasms Precursor T lymphoblastic leukaemia/lymphoma Blastic NK lymphoma Peripheral T/NK-cell neoplasms Predominantly leukaemic/disseminated T-cell prolymphocytic leukaemia T-cell large granular lymphocytic leukaemia NK/T-cell leukaemia/lymphoma Adult T-cell leukaemia/lymphoma Predominantly nodal Angioimmunoblastic T-cell lymphoma Anaplastic large cell lymphoma (Tand null cell types) Nodal peripheral T/NK-cell lymphoma, unspecified Predominantly extranodal Mycosis fungoides Sezary syndrome Primary cutaneous CD30+ lymphoproliferative disorders Anaplastic large-cell lymphoma Lymphomatoid papulosis Subcutaneous panniculitis-like T-cell lymphoma NK/T-cell lymphoma, nasal and nasal-type Enteropathy-type intestinal T-cell lymphoma Hepatosplenic T-cell lymphoma Extranodal peripheral T/NK-cell lymphoma, unspecified Kiel Classification [5, 6]. Retrospective clinico-pathological studies [9, 12-14, 17] on over 600 PTCLs classified according to the R.E.A.L. scheme have highlighted the following points: a) PTCLs represent about 10% of all non-hodgkin's lymphomas in Western Countries, b) in spite of the aggressive therapies adopted, they display a rather unfavourable outcome (CR rate: about 50%, OS at five years: about 40%, FFS at five years: about 20%); c) they should be basically distinguished into anaplastic and non-anaplastic forms, with the former showing far better curability (OS atfiveyears: about 80% vs. 30%). These findings underline the need to design new therapeutical protocols for the non-anaplastic tumors. Three recently published independent studies [9, 13, 17] have shown the International Prognostic Index (IPI) [21] successfully discriminates between more and less aggressive T-cell tumors in all conditions apart from ALCL. In another study [12], where the data on the IPI were not available, besides histology (anaplastic vs. non-anaplastic), bulky disease and advanced stage also turned out to be significant indicators of a worse prognosis. An analytical comparison of the above mentioned contributions clearly indicates that the vast majority of non-anaplastic PTCLs reveal poor prognostic signs or symptoms (advanced age, B-symptoms, stage III IV), while ALCLs do not. Another point that has emerged from recent studies regards the approach to the diagnosis of PTCLs of the skin [15, 22]. It is now accepted that the correct interpretation of lymphoid proliferations primarily presenting in the skin cannot be based on pure morphology alone, but requires the knowledge of clinical findings, as well as the frequent application of ancillary techniques (immunophenotyping and molecular biology, as stated at the Consensus Conference held by the WHO at the Airlie House (Virginia, USA) [10]. The relevance of clinical information is also stressed in an important paper by Bernengo et al. [18], which further strengthens the contention of the R.E.A.L. Classification [8] that the clinical outcome of cases belonging to the same histological category does not depend so much on the category itself as on individual variables. Ongoing concepts Some recently published studies and many of the papers presented at the IX Meeting of the European Association for Haematopathology have focused attention on some emerging data, which although of genuine interest do not at the state of the art seem to justify any modifications to the classification of PTCLs. These observations will be outlined below. Expression of cytotoxic molecules Monoclonal antibodies against fixation resistant epitopes of proteins associated with cytotoxic granules (TIA-1, perforin, granzyme B, metase) have recently become available, thus allowing the detection in paraffin sections of lymphocytes or NK cells with a cytotoxic potential (TIA-1+) or with an activated cytotoxic phenotype (granzyme B+, perforin+, metase+) [23-25]. The extensive application of these antibodies to the different types of PTCL has shown that the vast majority of extranodal tumors do express cytotoxic phenotype (more often activated), while only 20% of nodal non-anaplastic neoplasms show this characteristic [26-31]. As far as ALCL is concerned, the expression of activated cytotoxic phenotype is observed in over 80% of the cases irrespective of their primary nodal or extranodal presentation [32-34]. Most of the currently available data reveal no significant differences in terms of clinical behaviour among the positive and negative cases belonging to the same category [35]. Therefore, while the search for these molecules may be of interest in order to better define the normal counterpart from which each tumor is derived, it does not seem wise to include the cytotoxic phenotype among the guidelines for the classification of PTCLs, as this phenotype crosses the boundaries of otherwise well defined clinico-pathological entities. a//? vs. y/5phenotype When the R.E.A.L. Classification was drafted, the members of the International Lymphoma Study Group thought that PTCLs were basically derived from a/p T-lymphocytes, with the notable exception of y/ hepatosplenic TCL [8]. Recent studies have shown that in large series of cases, some hepatosplenic TCLs can show a/p nature and non-hepatosplenic TCLs y/8 phenotype [31, 36]. However, because of the lack of reliable ways of

3 799 demonstrating y/8 on paraffin sections and of definite evidence that in any single entity the expression of the particular type of T-cell receptor phenotype has any real clinical significance, once again it is felt that there is no point of creating new categories based on this factor. t(2;5) (p23;q35) translocation Some years ago, the t(2;5)(p23;q35) translocation was proposed as a characteristic of ALCL [37]. This translocation produces the formation of a hybrid gene, termed NPM/ALK, which encodes for a chimeric protein consisting of the N-terminal portion of the nucleophosmin protein (numatrin/b23) joined to the entire cytoplasmic domain of the novel neural receptor tyrosin kinase ALK [38-44]. For a long time, the translocation or the hybrid gene possible only by cytogenetics or RT-PCR, which depended on the availability of fresh tissue samples. More recently, new antibodies raised against fixative-resistant epitopes of a cytoplasmic (kinase) domain of the ALK protein and of different portions of the NPM protein have become available and have been applied to large series of cases of ALCL, Hodgkin's disease and other types of malignant lymphoma [45-51]. In particular, the studies so far conducted have shown that these antibodies give rise to a nuclear and cytoplasmic positivity in all the cases carrying the t(2;5) translocation [49, 51], while they can also produce a cytoplasmic staining in rare cases which carry translocations other than the t(2;5), anyhow involving chromosome 2 at p23 [49]. It is noteworthy that until now the translocation (assessed by cytogenetics, molecular biology or immunohistochemistry) has been found in a ratio of ALCLs of Tor null phenotype, while it has never been observed in other types of malignant lymphoma, including Hodgkin's disease and diffuse large B-cell lymphomas with anaplastic morphology [49, 51, 52]. These findings support the decision taken by the members of the International Lymphoma Study Group to limit the term ALCL to T-cell/null neoplasms [8]. Furthermore, the search for the translocation or its product seems to represent a very effective tool for the differential diagnosis between anaplastic large-cell lymphoma and Hodgkin's disease in borderline cases. When dealing with ALCLs of T-cell/null phenotype, it should be underlined that the translocation is strictly limited to nodal tumors, and is absent in most if not all CD30+ lymphoproliferative disorders of the skin [53]. In particular, recent immunohistochemical studies on very large series of nodal T/null ALCL have revealed that the hybrid protein is expressed by the majority (60%-85%) of ALCLs of the common type and in almost all the lympho-histiocytic and small-cell variants [49, 51]. On the other hand, only a minority (16%-25%) of ALCLs of the Hodgkin's-like type have been found to show a similar positivity [49, 51, 54]. This further reinforces the need for additional studies on the latter variant of ALCL in order to better define its relationship to Hodgkin's disease in the negative cases. Interestingly enough, the application of the newly developed antibodies has demonstrated that the translocation is not confined to large anaplastic cells, but does also occur in small- to medium-sized elements [51]. The ratio between anaplastic large cells and small elements can vary remarkably from case to case and also within the same case at presentation and relapse [49]. Therefore, the histological variants of ALCL can be actually regarded as a continuous spectrum reflecting this ratio. The search for clinico-pathological correlations has underlined that the vast majority of the cases carrying the t(2;5) translocation occur in childhood or in patients younger than 30, whereas ALCL patients over 50 very rarely have the translocation [45, 49, 55, 56]. Another interesting feature observed in the course of some independent studies [45,46, 55, 56], is the very good response to therapy and favourable clinical outcome in the t(2;5) positive cases: by contrast, the negative ones seem to run aggressively (OS at five years 25% vs. 80%). These findings have prompted an ongoing review of the concept of to see whether the ALK positive cases (so called ALKomas) should be kept separate from the remaining ALK negative ALCLs. Acknowledgements This paper was supported by grants from A.I.R.C. (Milan) and M.U.R.S.T. (Rome). References S. A. Piled, 1 S. Ascani, 1 E. 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