Print version ISSN 1516-8484
Rev. Bras. Hematol. Hemoter. vol.34 no.1 São Paulo 2012
Monica BelleiI; Carlos Sergio ChiattoneII; Stefano LuminariI; Emanuela Anna PesceI; Maria Elena CabreraIII; Carmino Antonio de SouzaIV; Raul GabúsV; Lucia ZoppegnoVI; Jorge MiloneVII; Astrid PavlovskyVIII; Joseph Michael ConnorsIX; Francine Mary FossX; Steven Michael HorwitzXI; Raymond LiangXII; Silvia MontotoXIII; Stefano Aldo PileriXIV; Aaron PolliackXV; Julie Marie VoseXVI; Pier Luigi ZinzaniXIV; Emanuele ZuccaXVII; Massimo FedericoI
IDepartment of Oncology, Hematology and Respiratory Diseases, L'Università di Modena e Reggio Emilia - UniMoRe, Modena, Italy
IIHematology and Hemotherapy Center, Universidade Estadual de Campinas - UNICAMP, Campinas, SP, Brazil
IIIBone Marrow Transplantation Section, Department of Hematology, Hospital Italiano de La Plata, Buenos Aires, Argentina
IVDepartment of Hematology, Faculdade de Ciências Médicas da Santa Casa de São Paulo - FCSCSP, São Paulo, SP, Brazil
VService of Hematology, Hospital Maciel, Montevideo, Uruguay
VIFundaleu, Buenos Aires, Argentina
VIIDepartment of Medicine, Hospital Del Salvador, Santiago, Chile
VIIIHematology, Hospital San Martín de La Plata, Buenos Aires, Argentina
IXBritish Columbia Cancer Agency - BCCA, Vancouver, Canada
XYale Cancer Center, New Haven, USA
XILymphoma Service, Memorial Sloan-Kettering Cancer Center, New York, USA
XIIDepartment of Medicine, University of Hong Kong, China
XIIIQueen Mary University of London, UK
XIVHaematopathology Unit, Institute of Haematology and Clinical Oncology, L. & A. Seragnoli, L'Università di Bologna, Bologna, Italy
XVDepartment of Hematology, Hadassah MedicalCenter, Tel Aviv, Israel
XVISection of Hematology/Oncology, Nebraska Medical Center, Omaha, USA
XVIIIstituto Oncologico della Svizzera Italiana -IOSI, Bellinzona, Switzerland
Peripheral T-cell lymphomas are a group of rare neoplasms originating from clonal proliferation of mature post-thymic lymphocytes with different entities having specific biological characteristics and clinical features. As natural killer cells are closely related to T-cells, natural killer-cell lymphomas are also part of the group. The current World Health Organization classification recognizes four categories of T/natural killer-cell lymphomas with respect to their presentation: disseminated (leukemic), nodal, extranodal and cutaneous. Geographic variations in the distribution of these diseases are well documented: nodal subtypes are more frequent in Europe and North America, while extranodal forms, including natural killer-cell lymphomas, occur almost exclusively in Asia and South America. On the whole, T-cell lymphomas are more common in Asia than in western countries, usually affect adults, with a higher tendency in men, and, excluding a few subtypes, usually have an aggressive course and poor prognosis. Apart from anaplastic lymphoma kinase-positive anaplastic large cell lymphoma, that have a good outcome, other nodal and extranodal forms have a 5-year overall survival of about 30%. According to the principal prognostic indexes, the majority of patients are allocated to the unfavorable subset. In the past, the rarity of these diseases prevented progress in the understanding of their biology and improvements in the efficaciousness of therapy. Recently, international projects devoted to these diseases created networks promoting investigations on T-cell lymphomas. These projects are the basis of forthcoming cooperative, large scale trials to detail biologic characteristics of each sub-entity and to possibly individuate targets for new therapies.
Keywords: Lymphoma, T-cell/epidemiology; Killer-cells, natural; Prognosis; Lymphoma, T- cell/ pathology; Lymphoma, T-Cell/classification; Hematologic neoplasms; South America; Europe
T-cell Lymphomas constitute a heterogeneous group of rare disorders that have different biological and clinical profiles resulting from clonal proliferation of mature post-thymic lymphocytes, in the majority of the cases from either the CD8+ or CD4+ lineages. Most, therefore, express αβ T cell receptors. Since natural killer (NK) cells are closely related to T-cells, neoplasms derived from these are also placed within this group. Until the 1970s they were not distinguished from lymphomas originating from the B-cell lineages but considered a major histologic subtype within a single group that included all lymphomas that was only poorly described according to growth pattern.(1) Only after the immune system was better characterized, lymphomas began to be subdivided into B and T cell lineages and started to be considered separate entities.(2-4) The role of the immunophenotype in distinguishing disease entities was affirmed by the Revised European-American Lymphoma (REAL) classification published in 1994(5) which was subsequently confirmed by the World Health Organization (WHO) project.(6)
The 2008 WHO classification for hematopoietic malignancies(7) roughly divides the mature forms of T-cell and NK-cell malignancies (otherwise reported as peripheral T-cell lymphomas - PTCLs) into four categories according to their presentation: predominantly leukemic (disseminated), nodal, extranodal and cutaneous. In each category, entities are further differentiated based on morphologic, genotypic, genetic and immunohistochemical criteria, as well as clinical behavior.(7)
Compared to B-cell lymphomas, mature T/NK-cell lymphomas are uncommon malignancies accounting for 10 to 15% of all non-Hodgkin lymphomas (NHL), with well documented geographic variations.(8-10) In the western hemisphere T-cell lymphomas represent 5 to 10% of all NHL(8,11-13) with an overall incidence rate of 0.5-2 per 100,000 inhabitants per year.(14) Surveillance Epidemiology and End Results (SEER) data (2004-2008)(15) report an age-adjusted incidence rate (IR) in the US for T/NK-cell lymphomas of 1.8/100,000 men and women per year. In Europe, data from the Cancer Registry Based project on Haematologic malignancies (HAEMACARE)(16) on lymphoid malignancies diagnosed in 2000-2002 and archived in 44 European cancer registries present a crude IR of 1.13 per 100,000 inhabitants per year for mature T/NK-cell neoplasms. Out of the 66371 cases diagnosed with a lymphoproliferative disorder in the period 2000-2002, 2527 (3.8%) were mature forms of T/NK-cell lymphoma. These patients can be subdivided into two different categories, the first includes cutaneous forms (n = 1208, IR = 0.54 per 100,000 inhabitants per year) and the other grouping disseminated, nodal or extranodal PTCLs (n = 1319, IR = 0.59 per 100,000 inhabitants per year). These two categories have been investigated with respect to survival confirming very different outcomes for the two populations: period estimates for 2000-2002 of 5-year relative survival were calculated on a mean number of 1046.5 cases of cutaneous PTCLs and 987.5 cases of other T/NK-cell lymphomas leading to a 83.4% 5-year relative survival for cutaneous PTCLs and a 38.6% 5-year relative survival for non-cutaneous PTCLs.(17)
PTCLs are relatively more frequent in Asia(12,18,19) and in Central and South America,(20-22) where approximately 15% to 20% of lymphoma are diagnosed as PTCL or NK/T-cell lymphomas, with NK-cell lymphomas (NKCL) occurring almost exclusively in Asia and South America. The differences in the geographic distribution of T-cell lymphoma may result from a real higher incidence in eastern countries as well as the relatively lower frequency in Asia of many B-cell lymphomas such as follicular lymphoma.(23) Indeed, race has been reported to correlate with the incidence of B-cell lymphomas as they are more frequently detected in Whites than in Asians, while the incidences for T-cell lymphomas for Whites and Asians are comparable.(23) In addition to race-linked factors, a possible cause of geographic variations could be the higher prevalence of viral infections, particularly the human T-cell lymphotropic virus type 1 (HTLV-1) in eastern counties compared to Europe and the US, an infection that appears to be related to the onset of adult T-cell leukemia/lymphoma (ATLL) and NK-cell neoplasms.(23-26)
The mature forms of T/NK-cell lymphomas usually affect the adult population, with a median age between 55 to 60 years and a slight predominance in men.(13,14,27,28) Most of the patients present with an advanced stage disease(11,13,2729) and constitutional symptoms(11,13,27) and a non-ambulatory performance status in one third of the cases.(27,29)
PTCLs with cutaneous presentation may have a relatively benign protracted course while nodal and extranodal T-cell lymphomas have an aggressive clinical behavior and poor prognosis. Indeed, with the exclusion of anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma and indolent mycosis fungoides which have good survival rates,(30) the prognosis of PTCLs is dismal with a 5-year survival near to 30% on the whole.
Geographic distribution: the international projects
The first attempt to systematically study the distribution of NHL subtypes across geographic regions based on collaborative international efforts was performed after the NHL Classification Project was carried out.(31) The project collected 1403 cases (diagnosed from 1988-1990) from nine institutions in eight different geographic regions thought to have a case base representative of their geographical location. Out of the cases collected, upon a review process involving five expert hematopathologists, 25 (1.8%) were found to have diagnoses other than NHL and were excluded from the analysis and 1378 were confirmed to be NHL. Analyses confirmed statistical evidence that the distribution among the major histologic subtypes of NHL differed substantially by geographical region. According to the consensus diagnosis, a greater percentage of follicular lymphoma was seen in North America, London and Cape Town (28%-32%) than at the other sites (8%-18%). PTCLs made up a higher percentage of the cases from London (8%), Cape Town (8%) and Hong Kong (10%) than from the other sites (1%-6%). Primary mediastinal large B-cell lymphomas and mantle cell lymphomas were more common in Locarno and Bellinzona (9% and 14%, respectively) than at the other sites (0%-4% and 1%-8%, respectively). Angiocentric nasal T/NK-cell tumors were only seen in Hong Kong (8%) and, to a lesser extent, in Lyon (2%).
The project included 129 cases (9.4% of 1378) of PTCLs, 33 of which were anaplastic large cell lymphomas (ALCLs: 2.4%).(12)
The frequencies of the 96 cases of non-anaplastic PTCLs reported in the project varied geographically ranging from 1.5% in Vancouver to 18.3% in Hong Kong.(8) According to the consensus diagnosis, most of the 96 non-anaplastic cases were reported as PTCL not otherwise specified (NOS) (53 patients, 55%), followed by angiocentric nasal type (19 patients, 20%), which were almost exclusively recorded in Hong Kong (16 cases), and angioimmunoblastic T-cell lymphoma (AITL) (17 cases, 18%), whereas the other subtypes were rare.
Later on, the International T-cell Lymphoma Project (ITLP) collected 1314 cases of T/NK-cell lymphomas from 22 Institutions worldwide(28) with diagnoses made from 19902002. The results confirm those reported by the NHL Classification Project with respect to the geographical distribution of subtypes: higher rates of leukemic and NKcell neoplasms were recorded in Asia (25% and 22.4%, respectively) than in North America (2% and 5.1%, respectively) and in Europe (1% and 4.3%, respectively). On the other hand, PTCL-NOS were more frequent in both North America and Europe (34.4% and 34.3%, respectively) than in Asia (22.4%). ALK-positive ALCLs were most common in North America (16%) whereas the enteropathy subtype was most common in Europe (9.1%). Notably, AITL were reported to be more common in Europe (28.7%) compared to North America (16%) and Asia (17.9%). With respect to rarer extranodal forms (excluding primary cutaneous ALCL), most of the cases were diagnosed in Europe (2.8%) and only a few cases were reported in North America and Asia (1.6% and 1.5%, respectively).
More recently the ITLP launched the T-Cell Project, a study aimed at investigating clinical and biological characteristics of aggressive nodal and extranodal PTCLs by means of prospective data collection. An overview of the study is described elsewhere.(32,33) The study started enrolling patients at the end of 2006 and so far 790 patients have been registered from 63 Institutions distributed in four different geographic regions: Europe (Italy: 38 sites; UK: 4; Switzerland: 3; Slovakia: 1; Spain: 1), United States (Memorial Sloan-Kettering Cancer Center, M. D. Anderson Cancer Center, University of Nebraska Medical University, Stamford University, Cleveland Clinic Foundation, Fred Hutchinson Cancer Research Center), South America (Argentina: 3 sites; Brazil: 2; Chile: 1; Uruguay: 1) and the Middle/Far East (South Korea: 1; Hong Kong: 1; Israel: 1) with total patients of 338, 136, 170 and 146, respectively. Four additional sites recently joined the project, but up to now no patients have been registered. The preliminary analysis of the first 524 patients included in the T-Cell Project and presented at the 11th International Conference on Malignant Lymphoma in Lugano(34) supports the previously described geographical variations for these disorders.
At present, 755 patients have been validated in the study. Out of these, 18 were considered after review as misdiagnosed by the local pathologist and were excluded. Out of the remaining 737 patients, PTCLs-NOS account for 285 cases (38.7%) and AITL for only 127 cases (17.2%); on the other hand, 94 (12.7%) cases of ALK-negative ALCL were registered. The AITL and ALK-negative ALCL cohorts are about half and twice, respectively of what was expected. The distribution of cases for the whole population according to histologic subtypes is summarized in Table 1.
Table 2 shows the distribution of histologic entities by geographic region according to reviewed diagnosis. PTCLs-NOS represent the most common subtype in Europe, North America and South America (40%, 42% and 42%, respectively), whereas NKCL is the most common subtype in Asia (31%). Both ALK-negative and ALKpositive ALCLs are prevalent in South America (23% and 8%, respectively).
So far, the European cohort of the T-Cell Project includes 317 validated cases. The overall distributions of histologic subtypes in the European countries - Italy, UK and others counties (Switzerland, Slovakia and Spain, grouped together) - are presented in Table 3. About three quarters of the European patients have been diagnosed with PTCLs-NOS (40%), AITL (20%) or ALK-negative ALCLs (14%).
Table 3 shows that significant differences between countries are evident. ALK-negative ALCL is the most common subtype in the UK (20%) and rarely diagnosed in Switzerland, Slovakia and Spain. In Italy they represent 14% of the cases and are less frequent than their ALKpositive counterpart (8%); Italy has the highest rate for this subtype. Extranodal forms of PTCLs reported in Europe have singular distributions for all countries: the majority of NKCL and enteropathy-type PTCL (11% in both cases) and two out of three cases of gamma/delta peripheral PTCL were registered in Switzerland, Slovakia and Spain, while three out of the four European cases of subcutaneous panniculitis-like PTCL were diagnosed in Italy.
Clinical characteristics of patients registered by European sites are summarized in Table 4.
At present, 152 patients from South American countries were registered in the T-Cell Project. The overall distribution and the distribution by country - Chile, Brazil and Argentina/Uruguay - of different histologic entities are shown in Table 5.
As expected, the rate of PTCLs-NOS is similar to that of Europe (42%) and the percentages of ALK-negative ALCL and of NKCL are higher than in Europe (23% and 13%, respectively). Considering the distribution by country, the PTCL-NOS rate ranges from 19% in Brazil to 51% in other countries. Relative high rates of both ALK-negative (23%) and ALK-positive (8%) ALCLs have been registered in this area compared to Europe. The highest rate of ALKnegative ALCL was recorded in Brazil with 39% of cases, while in Argentina/Uruguay the percentage (11%) is lower than the mean value of South America for this subtype. Similarly, the highest rate of ALK-positive ALCLs (12%) was reported in Brazil. The rate of NKCLs in South America is on the whole double of that in Europe at 15% in both Brazil and Argentina/Uruguay. Interestingly, no extranodal forms of PTCLs other than NKCL were reported for Brazil, while these forms are more common in Chile; the only case of enteropathy-type PTCL and five out of the six cases of subcutaneous panniculitis-like PTCL were diagnosed in this country.
Of note, AITL is confirmed as a rare subtype in this geographic region accounting for a maximum of 10% of cases registered in Brazil.
Clinical characteristics of patients registered by South American sites are summarized in Table 6.
In conclusion the preliminary data coming from the T-Cell Project confirm the characteristic and peculiar profiles for Europe and South America in the distribution of all subtypes of aggressive PTCLs except PTCL-NOS. AITLis confirmed as a distinctive disorder in Europe, while in South America, NKCL and ALK-negative ALCL represent the most common subtypes.
The authors wish to thank Maria Angela Sirotti for her assistance in the T-Cell Project review process.
This study was supported by grants from the Fondazione Cassa di Risparmio di Modena, Modena, Italy, the Associazione Angela Serra per la Ricerca sul Cancro, Modena, Italy, and Allos Therapeutics, Inc., Westminster, CO, USA.
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Department of Oncology, Hematology and Respiratory Diseases, University of Modena and Reggio Emilia COM - Centro Oncologico Modenese
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41124 Modena, Italy
Phone: 39 (0)59 422 4020
Conflict-of-interest disclosure: The authors declare no competing financial interest