Report of the European Task Force on Lymphomas: Workshop on peripheral T-cell lymphomas

Annals of Oncology 9: 835-843, 1998. © 1998 Kluwer Academic Publishers. Printed in the Netherlands.

Commentary Report of the European Task Force on Lymphomas: Workshop on peripheral T-cell lymphomas E. Campo,1 P. Gaulard,2 E. Zucca,3 E. S. Jaffe,4 N. L. Harris,5 J. Diebold,6 B. Schlegelberger,7 A. C. Feller,8 G. Delsol,9 C Gisselbrecht10 & E. Montserrat11 on behalf of the European Task Force on Lymphomas

Key words: extranodal lymphomas, non-Hodgkin's lymphomas, peripheral T-cell lymphomas

Introduction

Peripheral T-cell lymphomas (PTL) comprise a heterogeneous group of neoplasms with different morphological patterns, phenotypes and clinical presentations (Table 1). These tumors have a striking epidemiological distribution, with a lower incidence in Western countries than in Asia [1]. In recent years, several clinicopathologic entities with relatively well-defined characteristics have been identified [2]. However, several studies have recognized the limitations of morphology as the defining criteria for these entities [1]. Phenotype, site of origin, clinical presentation, and their relationships with certain antigens (EBV, gliadin) seem to be very important aspects in the definition of these entities. In addition, these tumors may originate in different subsets of T(oc/p, y/8) or NK cells, and a proportion of them have a cytotoxic antigen profile. However, the relative importance of cell origin in the definition of the different entities is not yet clear. The clinical evolution of these patients is usually very aggressive and current therapeutic strategies are limited. The heterogeneity of these tumors and their relatively low incidence hamper assessment of more appropriate protocols. To bring together the multidisciplinary experience of different groups and to discuss these open questions about peripheral T-cell lymphomas, a workshop was sponsored by the European Task Force on Lymphomas and held in Barcelona, Spain from May 30 to June 1, 1997. The aims of the workshop were to analyze the cytogenetic and molecular genetic alterations associated with the development of these lymphomas, to discuss the more reliable criteria for defining the different entities included in nodal and

extranodal PTL, and to discuss the present status with repect to prognostic factors and therapeutic strategies of these disorders. Forty biologists, cytogeneticians, pathologists, and clinicians participated in the meeting. The program included several lectures and discussion of 50 cases of peripheral T-cell lymphomas provided by the pathologists, histological sections of which were circulated among participants before the workshop. Cytogenetic and molecular cytogenetic Cytogenetic data on peripheral T-cell lymphomas are still limited. This is probably because of the rarity of these diseases in Western countries as well as of technical difficulties in chromosomal analysis of these neoplasms. Cytogenetic and molecular cytogenetic data were presented by Drs. B. Schlegelberger, Ch. Bastard, and I. Wlodarska. Their results could not be directly compared because different classification systems, namely the R.E.A.L. and the updated Kiel Classification, had been used. The only chromosome abnormalities restricted to specific types of T-cell lymphomas were the t(2;5)(p23;q35) associated with the anaplastic large-cell lymphoma (ALCL) and the isochromosome 7q in hepatosplenic y/5 T-cell lymphoma. However, high-grade PTL, predominantly pleomorphic medium- and largecell lymphomas, differ significantly from low-grade PTL (AILD-type T-cell lymphoma, lymphoepithelioid T-cell lymphoma, T-zone lymphoma, and cutaneous T-cell lymphoma) with regard to the presence of normal metaphases, aberrant clones, polyploidy, and complexity of the clones. Moreover, deletions of 6q, total or partial

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'Hematopathology Section, Laboratory of Pathology, "Department ofHematology, Hospital Clinic, University of Barcelona, Barcelona, Spain; Laboratory of Pathology, Centre Hospitalier Universitaire Henri Mondor, Creteil, France; * Division of Oncology, San Giovanni Hospital, Bellinzona, Switzerland; 4Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland, USA; iLaboratory of Pathology, Massachusetts General Hospital, Boston, MA, USA; 6 Laboratory of Pathology, Hotel-Dieu, Paris, France; 7Department ofHuman Genetics, University of Kiel, Kiel; 8Medical University ofLubeck, Lubeck, Germany; 9 Laboratory of Pathology, Hospital Purpan, Toulouse; w Institut d'Hematologie, Hospital St. Louis, Paris, France * Seepage 842 for list of participants 2

836 Table 1. Comparison of the diferent T-cell lymphoma classifications. R.E.A.L.

WHO

T-lymphoblastic

Precursor T cell lymphoblastic lymphoma/ leukemia Mature T-cell and NIC-cell neoplasms

Precursor T cell lymphoblastic lymphoma /leukemia Mature T-cell and NIC-cell neoplasms

T-lymphocytic, prolymphocytic leukemia

T-cell chronic lymphocytic leukemia/prolymphocytic leukemia

T-cell prolymphocytic leukemia

T-lymphocytic, CLL-type

Large granular lymphocytic leukemia - T-cell type - NIC-cell type Angiocentric lymphoma

T-cell large granular lymphocytic leukemia Aggressive NIC cell leukemia Extranodal NK/T cell lymphoma, nasal and nasal type

Small cell cerebriform (mycosis fungoides, Sezary syndrome) T-zone Lymphoepithelioid Pleomorphic, small, mediumsized, and large T-cell lymphoma T-immunoblastic

Mycosis fungoides/ Sezary syndrome Peripheral T-cell lymphoma (unspecified) Subcutaneous panniculiticT-cell lymphoma (provisional) Intestinal T-cell lymphoma Hepatosplenic y/8 T-cell lymphoma (provisional)

Mycosis fungoides Sezary syndrome Peripheral T-cell lymphoma (unspecified) Subcutaneous panniculitis-like T-cell lymphoma Enteropathy-type intestinal T-cell lymphoma Hepatosplenic y/8 T-cell lymphoma

Angioimmunoblastic (AILD,LgX)

Angioimmunoblastic T-cell lymphoma

Angioimmunoblastic T-cell lymphoma

T-large cell anaplastic (Ki-1

Anaplastic large cell lymphoma, T- and null-cell types

Anaplastic large cell lymphoma, primary systemic type Primary cutaneous CD30 positive lymphoproliferative disorders - Lymphomatoid papulosis - Primary cutaneous ALCL - Borderline lesions

Pleomorphic (HTLV1+)

Adult T-cell leukemia/lymphoma (HTLV1+)

Adult T-cell leukemia/lymphoma (HTLV1+)

EORTC

Mycosis fungoides Sezary syndrome CD30-negative large T-cell lymphoma Pleomorphic, small/mediumsized cell (provisional) Subcutaneous panniculitis-like T-cell lymphoma (provisional)

Lymphomatoid papulosis CD30 positive large cell lymphoma

Abbreviations: R.E.A.L. - Revised European American Lymphoma Classification [2]; WHO - World Health Organization Classification (Draft as of October 1997); EORTC - European Organization for Research and Treatment of Cancer Classification for Primary Cutaneous Lymphomas [32].

trisomies of 7q, and monosomy 13 or changes of 13ql4 are significantly more common in high-grade than in low-grade PTL (B. Schlegelberger) [3] according to the Kiel Classification. Consistent cytogenetic features of cutaneous PTL are inv(14)(qllq32.1) and trisomy 8q, mostly due to i(8)(qlO). These abnormalities as well as complex clones, duplications of 6p, deletions of 6q, and monosomy 13 or changes of 13ql4 are found significantly more frequently than in other low-grade PTL [4]. Trisomy 3 is predominantly found in AILD-type T-cell lymphoma, T-zone lymphoma, and lymphoepithelioid lymphoma. Trisomy 5 and additional X chromosomes are also frequent findings in AILD-type lymphomas (B. Schlegelberger) [5]. It is not known whether these numerical aberrations in PTL are primary or secondary changes. Other alterations found in PTL are the recurrent involvement of lOp and trisomy 21 (C. Bastard). There is evidence that some cytogenetic findings may be of prognostic significance. The presence of aberrant metaphases in unstimulated cultures, complex aberrant

clones, aberrations involving the short arm of chromosome 1 are particularly associated with a significantly shorter survival in AILD-type T-cell lymphomas [6]. In contrast to B-cell lymphomas in which translocations involving the immunoglobulin heavy chain gene at 14q32 are the most common cytogenetic aberrations, alterations involving the T-cell receptor (TCR) a/5 gene at 14qll are rare in PTL. Only lymphoblastic lymphomas show translocations with breakpoint at 14qll and in some PTL Inv( 14) juxtaposed theTCL-1 gene next to the TCR a/5 gene (Dr. I. Wlodarska). In conclusion, the data presented indicated that there are few isolated cytogenetic aberrations associated with specific types of PTL (ALCL, hepatosplenic y/5 T-cell lymphoma and T-PLL). However, different cytogenetic alterations may be of prognostic significance in some lymphomas. Future classic and molecular cytogenetic studies may help to localize new genes important for T-cell lymphomagenesis.

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Kiel

837 Nodal peripheral T-cell lymphomas

Anaplastic large-cell lymphoma (ALCL) ALCL is now a well recognized entity with defined morphology, phenotype, and clinical features [7-9]. However, there is still some controversy regarding different aspects of this lymphoma. The ALCL session of the Workshop addressed some open questions including the terminology of the morphological subtypes, the differential diagnosis of this entity, the relationship between systemic and primary cutaneous lesions, the significance of the recently identified NPM-ALK chimerical gene, and different aspects of clinical presentation and prognostic factors. Several talks and sixteen cases were presented in this session. The cases were classified as common, lympho-histiocytic, small-cell, giant-cell, and mixed subtypes. All of these subtypes were considered to represent variants of a morphological spectrum of the same entity. Whatever the ALCL subtype, upon careful scrutiny all cases showed the presence of a medium- to large-sized cell with highly characteristic features. These included an eccentric nucleus (horseshoe shaped or kidney shaped nucleus), nucleoli that are less prominent than in Reed-Sternberg cells and often an eosinophilic region near the nucleus, probably representing a prominent Golgi apparatus. Certain cases were classified as monomorphic variants by some participants. The discussion clarified that these monomorphic cases could be included in the common type of ALCL. Several cases showed a striking perivascular distribution of neoplastic cells that was helpful in recognizing this neoplasm in lymph nodes with unusual

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Most non-cutaneous peripheral T-cell lymphomas present as nodal neoplasms. Although different morphologic types may be recognized, their clinical and biological significance are not clear. Among nodal PTL, AILD-type T-cell lymphoma shows a peculiar constellation of morphological and clinical characteristics different from those of other tumors. However, there is still controversy about this lymphoma, particularly regarding the limits of its definition, the need of clinical information to establish this diagnosis, and the possible existence of unusual presentations or evolution. The session on nodal PTL dealt with all of these aspects based on presentations by Dr. A. C. Feller and 13 cases of nodal T-cell lymphomas, eight of which were identified as T-cell lymphomas of AILD-type. The major common features of the classical AILDtype T-cell lymphoma are the total effacement of the lymph node architecture with frequent spreading throughout the lymph node capsule, proliferation of arborizing epithelioid venules frequently associated with PAS-positive material, the admixture of non-neoplastic plasma cells and eosinophils, and an increase of follicular dentritic cells with large irregular networks stained with CD35, CD21, CD23, CNA-42 or KiM4P. The neoplastic cellular content is variable, with a predominance of small to medium sized lymphoid cells with pleomorphic nuclei. The number of blastic cells may vary and, occasionally resemble or even be identical to Hodgkin's and Reed-Sternberg cells. Another unusual feature is the presence of small clusters of epithelioid cells similar to those seen in lymphoepithelioid lymphoma (Lennert's lymphoma). However, in lymphoepitelioid lymphoma the lymphoid cellularity is more uniform than in AILDtype lymphoma and is not associated with proliferation of follicular dendritic cells. There is some evidence that morphologically early phases of lymph node involvement by AILD-type lymphomas may be recognized. These changes occur in the paracortical or interfollicularT-zones of the lymph node and are characterized by an increase of high endothelial venules together with a mixed cellular infiltrate of eosinophils, plasma cells, and lymphocytes. Small clusters of more homogeneous cells intermingled with lymphoid clear cells may also appear in these areas. Similar changes have been described by Suchi as T-zone dysplasia. These changes may represent an early phase of AILD type lymphoma in an otherwise well preserved nodal architecture and in some cases they may be associated with follicular hyperplasia, indicating the differential diagnosis with hyperimmune reactions. The clinical manifestations of AILD-type lymphomas are relatively well known. Although in most cases its biological behavior is aggressive, some patients may have a long history with undulating lymph node enlargement, skin rash, fever, and weight loss. Some patients have spontaneous remissions during such episodes. T-cell lymphoma of AILD-type may acquire addi-

tional morphological and immunohisto-chemical features as the disease progresses. In particular, some cases develop an increase of the large pleomorphic and blastic cells usually associated with a decrease in the vascularity and in the network of follicular dentritic cells. This morphologic aspect may suggest the differential diagnosis with large pleomorphic T-cell lymphomas. Other cases may show small or large sheets of either polyclonal or monoclonal B-cells with morphological aspects of B-immunoblasts. Individual patients may develop a high-grade (large-cell) B-cell lymphoma with a clear predominance of B-blasts, while others may develop a B-cell lymphoma in other organs (case B21 presented by Dr. Ph. Kluin). The pathogenesis of this lymphoma is not clear. The inflammatory background and the follicular dendritic cell proliferation suggest the involvement of different chemokines. The detection of CD8 and CD4 proliferating cells in this neoplasia is unique within the T-cell lymphomas. If both compartments are postulated to be neoplastic, this can be an indication that the genesis of this lymphoma occurs during early thymic or even prethymic T-cell development. In addition, the frequent positivity of EBV and the development of B-cell EBVassociated lymphomas suggest a role for this virus in some aspects of this lymphoma.

838 variants remains unknown. In some RT-PCR- positive cases in which the immunohistochemistry was negative, the t(2;5) was found in small subclones of the tumor (Dr. K. Muller-Hermelink). Some peculiar clinical presentations of ALCL were discussed. Dr. G. Delsol presented an ALCL that developed shortly after a well documented insect sting. A similar association had been observed on different occasions by other participants. The significance of this finding is not clear. ALCL may occur in HIV+ patients. ALK1 expression in these cases seems to be present only in tumors from patients with no AIDS criteria (Dr. B. Falini) and occasionally the patients may have a long survival (Dr. E. Campo). The biological significance of these cases may be different from that of ALK1-negative cases associated with other AIDS manifestations. The clinical manifestations, prognostic factors, and therapeutic strategies were presented by Drs. K. Patte and P. L. Zinzani. The clinical behavior of ALCL in children seems to be relatively favorable, independent of the intensity of the therapeutic regimen. Mediastinal and skin involvement were independent prognostic factors for an aggressive clinical course. In the experience of the Bologna Group, the clinical manifestations, evolution, and response to treatment of ALCL patients were similar to those of Hodgkin's-related ALCL cases. The detection of soluble CD30 in CD30-positive disorders is of potential interest as a tumor marker in the monitoring of these patients. Finally, Dr. MacLennan presented preliminary data showing that T and null ALCL had significantly better prognoses than those of cases diagnosed as B-cell ALCL. By contrast, B-cell ALCL had a survival curve similar to that of other large B-cell lymphomas (B-LCL). These findings support the concept that B-ALCL is a different entity which is more closely related to other B-LCL. Extranodal and T/NK-cell lymphomas Extranodal T- and NK-cell lymphomas are relatively rare diseases, accounting for about 2% of all lymphomas or 15% of lymphomas with aT-cell phenotype [1]. They comprise several recently recognized clinicopathologic entities which were included in the R.E.A.L. Classification as distinct or provisional entities [2]. Among them, angiocentric lymphoma was renamed 'nasal NK/T-cell lymphoma' following a recent workshop [15]. It appears that these entities are defined by their site of origin, their clinical features, their cell origin and/or their possible association with some antigen, whereas their morphology is not specific. However, there is still some controversy regarding different aspects of these lymphomas. The aim of the extranodal session was to address certain open questions, including the composition of the list of extranodal T- and NK-cell lymphoma entities in the future WHO classification, the criteria needed, especially the importance of T-cell subsets for the disease definition, the role of antigens, especially Epstein-Barr

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presentation or strong reactive lymphohistiocytic infiltration. The classic phenotype of these lymphomas was T- or null-cell type with expression of CD30, EMA, and cytotoxic molecules. In addition, most ALCL express H and Y blood group-related antigens detected by BNH.9 antibody. By contrast, CD15, and EBV were negative. This phenotype was identical in all histological variants. Primary cutaneous ALCL were CD30-positive but usually negative for EMA and cytotoxic molecules. The participants discussed the usefulness of this phenotypic profile in the differential diagnosis between primary and systemic ALCL and between ALCL and other morphological similar disorders such as ALCL-related Hodgkin's disease. Two cases contributed by Drs E. Ralfkiaer and K. MacLennan were particularly interesting in the differential diagnosis between systemic and primary cutaneous ALCL. These two cases were primary skin tumors which developed a very aggressive course with late (more than six months) systemic dissemination. Both cases were positive for EMA and cytotoxic molecules. These cases raised the question of whether a classic phenotype in primary skin ALCL may predict a more aggressive behavior. The terminology of the CD30-positive skin lesions was discussed but no clear agreement was reached. Several participants presented information regarding expression of the ALK gene in these lymphomas by the use of the recently developed ALK1 antibody [10]. The studies concluded that ALK1 immunoreactivity was present in 60%-80% of the T and null ALCL. All ALCL histological variants had similar rates of positivity. Primary cutaneous ALCL and Hodgkin's disease were usually negative. The question about the clinical and prognostic significance of ALK1 positivity in these lymphomas is still open. Several studies have shown that the t(2,5) is predominantly found in young patients with better prognoses [11,12]. A previous study using a different antibody (p80) showed that tumors expressing the ALK gene also occur in a younger group of patients with better survivals [13]. However, this study included a significant number of cases with B-cell phenotype, now considered a different entity, that were P80 -negative. The mechanisms leading to ALK expression were analyzed in several presentations and case discussions. ALK immunoreactivity strongly correlated with the presence of the t(2,5) translocation or a NPM-ALK chimerical mRNA detected by RT-PCR. However, several discordances were discussed. In some ALK1positive cases, in which the t(2;5) was not found by classic cytogenetics, other aberrations of the ALK gene or 2p23 region were observed including a cryptic t(2,5) detected by FISH, amplification of ALK gene, and other t(2p23) translocations (Drs. I. Wlodarska, C. deWolfPeters, G. Delsol) [14]. These findings and the fact that the ALK1 antibody is specific for the carboxy-terminal portion of the ALK protein suggest that the ALK gene could be upregulated by mechanisms other than those involving the t(2;5). The significance of these genetic

839 virus (EBV), in their diagnosis and pathogenesis. To that end, several lectures as well as slide discussions of 15 cases were presented in this session. Nasal and 'nasal type' NK/T-cell lymphomas

A few recent studies have pointed out the existence of non-nasal lymphomas that are morphologically, phenotypically and biologically very similar to the nasal NK/T-cell lymphomas [15, 17]. Two cases presenting with major intestinal tumors but also other manifestations (pleural and peritoneal effusion, splenomegaly) were contributed by Dr. F. Berger and Dr. A. Norton. These two cases disclosed many features in common with those of nasal NK-cell lymphomas, i.e., angiocentrism and angioinvasion, EBV association in most tumor cells, and a NK cell immunophenotype with TIA-1 and granzyme B-activated cytotoxic profile. These two cases were also associated with hemophagocytic histiocytosis and displayed a very aggressive clinical course. Cytogenetic analysis performed in one case disclosed a translocation t(X;18)(ql3;pll). Due to the marked similarity with typical nasal NK/T-cell lymphoma, it is proposed that they be referred to as nasal-type NK/T-cell lymphoma. Enteropathy associated T-cell lymphoma (EATCL) Two participants (Dr. H. D. Foss and Dr. A. Norton) presented informations regarding different aspects of these lymphomas and three cases were discussed. Intestinal perforation is the most common clinical presentation. They often present as multiple jejunal tumors or ulcers. A rare case presenting as a gastric mass was contributed by Dr. H. D. Foss. This case was classified by the workshop participants as 'enteropathy-type T-cell

Panniculitis-like subcutaneous T-cell lymphoma Four cases of T-cell lymphoma presenting in subcutaneous tissue were presented. One case of a classical subcutaneous panniculitis-like T-cell lymphoma (SPTL) was contributed by Dr M. A. Piris. This case was composed of CD8+ a/p" T-cells. Dr E. S. Jaffe reviewed the subject of SPTCL, and based on a series of 16 cases from her laboratory, nearly all cases are CD8+, and all express the cytotoxic molecules TIA-1, granzyme B and perforin [21]. Most (12 of 16) are derived from a/p T-cells but a y/8 origin is likely in approximately 25% of cases. Two cases of y/8 TCL involving subcutaneous tissue were contributed by Drs A. Feller and A. Norton, one of which was panniculitis-like. Dr. B. Falini also presented a case of PTL unspecified (pleomorphic type) involving subcutaneous tissue. The subcutaneous tissue can be the primary site of presentation or a secondary site of involvement in peripheral T-cell lymphomas. SPTL typically presents on the extremities or trunk with multiple subcutaneous masses. Nodal involvement is rare, either at presentation or during the course of the disease. A hemophagocytic syndrome is a common complication in up to two-thirds of patients and may

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A case contributed by Dr. A. Norton illustrated a nasal lymphoma presenting as a localized disease in the nasal cavity. These lymphomas are characterized [16, 17] by a more or less pleomorphic lymphoid proliferation with frequent features of angioinvasion, a phenotype (CD2+, CD3e+/CD3complex-, CD5-, CD56+, TCR-) and a genotype (usual failure to show rearrangements of the T-cell receptor genes) favoring an NK cell origin, a common expression of cytotoxic (TIA1+, perforin+, granzyme B+) proteins [18] and, finally, a striking association with EBV, found in the majority of neoplastic cells. Some of the patients may show the dramatic features of lethal midline granuloma. Most studies indicate a poor prognosis with a tendency to involvement of other extranodal sites (skin, gastrointestinal tract). The extensive necrosis characteristic of these lymphomas has been attributed in the past to angioinvasion by tumor cells. However, more recent studies have shown upregulation of chemokines and cytokines, such as TNF-a, NFKb, Mig and IP-10, which also appear to play a role in the pathogenesis of the observed necrosis [19]. TNF-a and NFKb may also contribute to the hemophagocytic syndrome commonly observed in this disease.

lymphoma', since it was similar in all respects to the classical enteropathy-associated intestinal T-cell lymphomas (EATCL). EATCL exhibit a morphological spectrum ranging from small-cell variants to tumors composed of large immunoblastic or even anaplastic cells [20]. They are typically associated with villous atrophy and epitheliotropism, and do not show EBV association. Their derivation from intraepithelial cytotoxic lymphocytes is supported by their CD1O3+(HML1) phenotype. They also show frequent expression of TIA1, perforin and granzyme B molecules (as reported by Dr. H. D. Foss). The great majority of the reported cases have an a/p T-cell origin, but can be CD4-/CD8-, CD8+, or even CD4+. Different data support the role of gliadin hypersensitivity in the pathogenesis of the disease, especially the strong association with celiac disease and the in vivo demonstration of increasing and activation of intraepithelial lymphocytes in coeliac disease. In addition, the HLA types of patients with caeliac disease and EATCL are identical. The disease occurs in adults, often with a history of gluten-sensitive enteropathy, malabsorbtion or in patients with asymptomatic villous atrophy. However, as mentioned by A. Norton, in a number of intestinal T-cell lymphomas no clinical (or histological) evidence of enteropathy is found. In these cases, it is difficult to formulate a definitive diagnosis of EATCL. The search for villous atrophy, an increase of intraepithelial lymphocytes in adjacent mucosa, a specific CD103 phenotype on fresh tissue, and the absence of EBV are important features for the diagnosis of EATCL. On the other hand, the presence of an angiocentric pattern, EBV association, and/or NK-cell phenotype are strong arguments for a 'nasaltype' NK/T-cell lymphoma.

840 cause the patient's death [21]. The hemophagocytic syndrome is most likely secondary to cytokine production by neoplastic cells [22]. Hepatosplenic y/ 5 T-celllymphoma

Peripheral (mature) T-cell leukemias

This term refers to malignancies which result from the clonal proliferation of a mature (TdT-, CDla
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The classical clinical, morphological and phenotypic features of this rare lymphoma entity were presented (Drs. F. Reyes and P. Gaulard), on the basis of a series of 15 patients [23]. It occurs mainly in young adults, presenting with splenomegaly and hepatomegaly, but without lymphadenopathy. Thrombocytopenia is a constant feature. The possible association with hemophagocytic syndrome was illustrated in one case contributed by Dr. P. Gaulard. The neoplastic cells are monomorphic medium-sized, and located preferentially in the sinusoids of the liver, the cords and the sinuses of the red pulp of the spleen and the sinuses of the bone marrow. The latter sinusal marrow infiltration, which often requires immunohistochemistry for its demonstration, is a very useful diagnostic criteria. Another characteristic feature is the non-activated cytotoxic profile (TIA-1+, perforin-, granzyme B-) of the y/8 neoplastic cells [18, 23, 24], Cytogenetic analysis of several cases in the literature indicates a frequent association with isochromosome 7q. Some cases are found in patients with a context of immune defect. A typical case of hepatosplenic y/8 T-cell lymphoma occurring five years after a liver transplantation, and showing the characteristic loss of the short arm of chromosome 7 (7q) was contributed by Dr. C. de Wolf-Peters. The disease has a highly aggressive course notwithstanding the use of intensive chemotherapy regimens. In conclusion, despite the heterogeneity of their clinical presentation, it appears from the information given by the participants, the cases discussed and the literature, that most entities of extranodal T/NK cell lymphoma have certain common features: 1) The tumors show a broad cytologic spectrum from small to large cells with frequent necrosis/apoptosis; 2) Lymph node involvement, even in recurrences, appears to be rare, whereas spread to other extranodal sites is common; 3) Hemophagocytic syndrome is a relatively frequent complication in all of these tumors; 4) All of these tumors seem to have a common derivation from T- or NK-cells with cytotoxic capacities; 5) The disease definition is heavily dependent upon clinical features - not on morphology. However, several unanswered questions were debated, particularly the importance of cell origin (a/p, y/5 T cells, NK cells) in the definition of the disease and the potential role of tissue-restricted antigen stimulation in the pathogenesis of these lymphomas. The importance of cell origin (a/p, y/8 T cells, NK cells) in disease definition was especially discussed on the basis of a series of 11 patients with a non-hepatosplenic y/8 T-cell lymphoma presented by Dr. P. Gaulard [25]. All patients had initial involvement of different mucosae or skin: nasal cavity (three cases), gastrointes-

tinal tract (three cases), lung (one case), larynx (one case), skin (three cases). They were clinically heterogeneous, including cases belonging to different entities of extranodal lymphomas, such as the nasal T/NK-cell lymphoma entity, EATCL, subcutaneous panniculitislike T-cell lymphoma. Thus, it was suggested that these non-hepatosplenic y/8 T-cell lymphomas do not represent a distinct entity but rather a model of activated cytotoxic lymphoma, preferentially occurring in mucosae or skin. A past history of chronic antigen stimulation in several patients, and the possibility of some immune defect in some of them, may suggest a role for an antigen in the pathogenesis of these lymphomas. Thus, the cellular cytotoxic properties and functions may be more important than the cell subset (a/p, y/8 T cells, NK cells) in the definition of disease entities of extranodal T/NK-cell lymphomas. Extranodal T/NKcell lymphomas may develop from tissue-restricted a/p, y/8 T cells or NK cells that have important functions in the immune surveillance of some epithelia in response to antigens. Why most nasal lymphomas are derived from NK cells, depending on the site and /or the nature of the antigen, whereas most EATCL are a/p T-cell lymphomas is unknown. In these extranodal T/NK tumors, a tissue-restricted antigen stimulation (EBV, gliadin, others) may play a major role in the development of the diseases (Figure 1). For instance, gliadin and EBV are known to induce proliferation and activation of cytotoxic cells which might be favored by some local or general immune defect. However, the role of additional molecular events in their transformation is unknown. In particular, to date no recurrent cytogenetic abnormality has been reported, except for the iso7q in hepatosplenic y/8 T-cell lymphoma. Regarding the putative role of EBV, the primary site of the lymphomas seems to be important since nasal lymphomas (T/NK) are invariably EBV-positive, irrespective of their NK- or T- (y/8) cell origin. This parallels the finding that nasopharynx is the reservoir for EBV. However, we have already discussed the fact that EBV-positive lymphomas, resembling nasal NK/T-cell lymphoma (i.e., 'nasal type') may occur in non-nasal sites. In addition, the oncogenic properties of EBV, as shown in B cells, is not established in T and NK cells.

841 ing cells are small and the nucleolus is seen in only a few cells by light microscopy, but can be identified by electron microscopy. This group has been designated a small-cell variant of T-PLL. Although there is debate as to whether these latter cases should be designated I T-CLL, it seems justified to include them within the spectrum of T-PLL as the patients have clinical and laboratory features identical to those of the typical T-PLL, including molecular genetics. Immunological markers demonstrate the mature T-cell nature of the cells in T-PLL and in the majority of Proliferation of cytotoxic LGL-leukaemia. Although there is no phenotype unique cells (NK, Ty/8, to each of these diseases, certain marker profiles are more charateristic of one or another disease. T-PLL immune defect -b '^-genetic alterations? cases are CD2+, CD5+, CD7+ and approx. 80% exi (local/general), EBV press membrane CD3 and anti-TCR alpha-beta. The I most common marker profile is CD4+CD8- seen in 61% of cases, while cases with a CD8+CD4- phenotype are rare, representing 12% of cases; a distinct subgroup Transformation which accounts for 25% of cases has a CD4+CD8+ phenotype. Natural killer cell markers are, as a rule, negative. In contrast, cells in LGL-leukaemia are CD2+ but up to one-third of cases lack expression of CD5 and CD7; CD3 is always expressed in cases with a T-cell phenotype but is negative in the NK type LGL-leukae"Mucosa-associated " T/NK mia. The most common phenotype is CD8+CD4—, a cell lymphoma CD4+CD8- phenotype being rare (< 10% cases); in the latter, CD4 is usually coexpressed with NK-associated -intestinal: fig NK, 76 markers. The McAb CDllb, CD16, CD56, CD57 are NK - nasal: expressed in a variable proportion of T-cell LGLleukaemia cases and CD56 and often CD 16 are positive Figure 1. Hypothetical model of antigen-driven tumor development in those classified as NK-type LGL-leukaemia. for extranodal T/NK-cell lymphomas. Cytogenetics and molecular studies have shown two consistent abnormalities in T-PLL: inv(14)(qll;q32) or T-PLL and LGL-leukemia is relevant in terms of prog- complex translocations between the two chromosomes nosis and clinical management. T-PLL is an aggressive 14, seen in 75% of cases and iso8q and/or trisomy 8 disease with a median survival of seven months in the present in close to two-thirds of cases. Although such original series of 78 patients. The disease is manifested abnormalities may be seen in other lymphoid malignanby organomegaly and up to one-third of the patients cies, the frequency in the latter conditions is significantly may have cutaneous lesions. The white blood cell count lower than in T-PLL and thus, it could be considered is high - usually over 100 x 109/l although in a few characteristic of T-PLL. The presence of iso8q or tripatients, the disease evolves with a slowly progressive somy 8 seems to relate to an overexpression of the c-myc lymphocytosis. In contrast, LGL-leukemia presents protein but no rearrangement of the c-myc oncogene. In with mild lymphocytosis, ranging from 5 to 15 x 109/l, LGL leukaemia, there is no consistent chromosome splenomegaly but no lymphadenopathy; cytopenias are abnormality, and cytogenetics fail in up to one-third of common. The clinical course is often indolent and prob- the cases. DNA analysis investigating the configuration lems are mainly derived from cytopenias. In rare instan- of the TRC chain genes is crucial for demonstrating ces, the disease runs an aggressive clinical course and clonality to rule out a reactive condition due to viral this may be associated with morphological features infection, splenectomy or other causes, particularly in suggestive of transformation. Cases with the NK-type patients who are asymptomatic and present with mild LGL-leukemia are more common in Eastern countries lymphocytosis. Still, cytogenetics are important in cases and usually, but not always, have a more aggressive of NK type, as they have the TCR chain genes in germcourse. line configuration. The laboratory features are also distinct in T-PLL The other type of T-cell leukaemia, designated and LGL-leukaemia. T-prolymphocytes are of medium Sezary-like cell leukaemia, might represent a variant, size, have a regular or irregular nuclear outline, a single cerebriform type, of T-PLL. Patients present with organucleolus and a basophilic irregular cytoplasm. Overall nomegaly, no evidence of skin lesions and a leukaemic the size of T-prolymphocytes is smaller than that of picture with lymphocytes having the morphological feaB-prolymphocytes. In about 20% of cases, the circulat- tures of Sezary cells by both light and electron microEnvironmental ANTIGEN (EBV, gliadin, infectious agent...)

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842 scopy. Cytogenetic analyses are available in three such cases and show the abnormalities seen in T-PLL, e.g., invl4 or iso8q. The clinical course is very similar to that of T-PLL and therefore it seems that biologically this entity is close to T-PLL. Prognosis of peripheral T-cell lymphomas

Acknowledgements The Workshop on Peripheral T-cell lymphomas was supported in part by grants from the Spanish Ministry of Health (FIS 97/8006), Spanish Ministry of Culture and Education (Direction General de Ensehanza Superior CO94-1145), and Generalitat de Catalunya (1997XT 00023).

*Appendix List of participants C. De Wolf-Peters, I. Wlodarska (Belgium); E. Ralfkiaer (Denmark); C Bastard, F. Berger, A. Cambiaggi, B. Coiffier, G. Delsol, J. Diebold,

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The prognostic significance of the immunophenotype has been explored in several studies and conflicting results have been reported regarding the outcome of PTL compared to that of aggressive B-cell lymphomas (BCL). PTL patients were found to have the same [26, 27] or poorer [28, 29] prognoses than BCL patients. Recently, the prognostic value of immunophenotype, using the REAL classification, was evaluated with stratification of other prognostic factors [26]. Although the T-cell phenotype was an independent and significant prognostic factor, it was not possible to demonstrate a statistically significant effect on overall survival among the different histologic subtypes. In order to describe the series of PTL of the GELA and to compare with BCL patients, Dr. C. Gisselbrecht presented data on 288 patients with confirmed T-cell immunophenotype included in the prospective LNH87 protocol and 1,595 aggressive BCL patients of comparable histological grades. According to the Kiel classification, most PTL were angioimmunoblastic (23%), pleomorphic medium and large T-cell (49%) or anaplastic large cell (ALCL) (20%) lymphomas. The median ages of the PTL and BCL patients were 56 and 57 years, respectively. Several parameters were significantly more prevalent in PTL patients: male gender, advanced stage, B symptoms, bone marrow involvement, hepatosplenomegaly and skin lesions. Moreover, significantly more PTL patients presented with anemia, hypereosinophilia and hypergammaglobulinemia. The CR rates were 54% and 63% for PTL ad BCL, respectively (P = 0.005). However, ALCL patients had a CR rate of 72%, which was significantly different from that of the other PTL (49%) (P = 0.002) and similar to that of BCL. The overall five-year survival rates differed between PTL (41%) and BCL (52%) (P = 0.004). However, ALCL patients had afive-yearsurvival of 64% which was better than that of any other subgroup of T- or B-cell lymphomas and immunoblastic T-cell lymphoma had significantly lower survival rates when compared to diffuse large cell (centroblastic and immunoblastic) BCL patients. The remaining subgroup, including angioimmunoblastic, lymphoepitheliod and pleomorphic small cell lymphomas, had a worse outcome, with a 31% probability of survival, than diffuse mixed B-cell lymphomas (46%). Because of the better survival advantage for ALCL, multivariate analysis was performed only on patients with non-ALCL PTL and BCL. Analysis was done using the International Prognostic Index (IPI) (age, stage, LDH, performance status) as one factor. Non-ALCL T-cell lymphoma remained a significant (P - 0.0004) adverse prognostic factor. This study con-

firmed that PTL presents as severe disease, as previously described, which might explain the lower CR rate observed in non-ALCL T-cell lymphoma as compared to BCL. Not surprisingly, this poorer response was translated into shorter overall and disease-free survival. These results are in agreement with those of a previous study of the GELA [30], but were not found in other retrospective studies. In fact in the analysis of Kwak et al. [26] based on 98 diffuse large-cell NHL patients, there was a trend favoring a better outcome for T-cell lymphomas. The better prognosis of ALCL among PTL patients was confirmed in the meeting by Dr. P. L. Zinzani in a large series of cases, as well as by the Spanish experience. The latter was presented by Dr. A. LopezGuillermo. The distribution according to the R.E.A.L. Classification of 154 patients with PTL was: PTL unspecified, 53.5%; ALCL, 17%; angioimmunoblastic, 13%; angiocentric, 9%; intestine T-cell, 7%; and hepatosplenic y—8 T cell, 0.6%. This distribution was close to others previously described [31]. In this series the poor initial prognostic features of PTLs, excluding ALCL, were also observed (poor performance status, advanced stage, extranodal involvement, high serum J2-microglobulin and high-risk IPI). Overall CR rate was 47% (69% for ALCL), and the risk of relapse at four years was 50%. Median survival was 21 months (65 months for ALCL). In the univariate analysis the variables related to poor survival were: non-ALCL histology, older age, poor performance status, B-symptoms, extranodal involvement, advanced Ann Arbor stage, bone marrow infiltration, high serum LDH and P2-microglobulin, and high/intermediate or high-risk IPI. In the multivariate study, the histology, the presence of B-symptoms and the IPI maintained independent prognostic value. When the analysis was restricted to the PTL unspecified, the IPI was the only independent variable predicting survival. In summary, PTL patients, with the exception of ALCL, usually present with unfavorable features, respond poorly to treatment and have short survivals, with no sustained responses. Such a poor outcome cries out for new strategies in the treatment of these patients.

843 P. Felman. P. Gaulard, C. Gisselbrecht, K. Patte, F. Reyes (France): A. C. Feller, H.-D. Foss, H. K. Muller-Hermelink, B. Schlegelberger (Germany); B. Falini, P. Luigi Zinzani (Italy); F. Bosch, E. Campo, A. Lopez-Guillermo, J. Garcia-Conde, C. Montalban, E. Montserrat. M. Angel Piris, T. Vallespi, S. Woessner (Spain): B. Borisch, E. Zucca (Switzerland); P. M. Kluin, C. J. L. M. Meijer (The Netherlands); N. Lee Harris, E. S. Jaffe (USA); K. MacLennan, E. Matutes, A. Norton, G.Vaughan-Hudson, B.Vaughan-Hudson (UK).

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Received 11 March 1998; accepted 24 June 1998.

Correspondence lo: E. Campo, MD Hematopathology Section Hospital Clinic Villarroel 170 08036-Barcelona Spain E-mail: campofemedicina.ub.es

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