Towards understanding the peripheral T-cell lymphomas

J. O. Armitage*, J. M. Vose and D. D. Weisenburger

University of Nebraska Medical Center, Omaha, NE 68198, USA

* Email: eryan{at}unmc.edu

The next, and largely unexplored, frontier in lymphoma management is the problem of T-cell lymphomas. In western countries, T-cell lymphomas represent <10% of all non-Hodgkin's lymphomas or approximately 5000 new cases per year in the USA. However, T-cell lymphomas are not uniform and an increasing number of subtypes are being recognized. Lymphoblastic lymphomas are tumors of precursor T-cells and frequently present as leukemia or with a mediastinal mass in young men. Lymphomas of more mature T-cells are referred to as ‘peripheral T-cell lymphomas’. This name is sometimes confusing as it does not refer to sites of involvement but rather to more mature—or post-thymic—T-cell lymphomas. The current World Health Organization (WHO) classification of the peripheral T-cell lymphomas is listed in Table 1 [1Go]. Most are aggressive neoplasms with only mycosis fungoides and cutaneous anaplastic large-cell lymphoma frequently following an indolent course. Several of these disorders present as distinctive clinical–pathologic syndromes (e.g. enteropathy type in patients with celiac disease), while others are only distinguished from B-cell lymphoma by immunophenotyping. Many of these lymphomas are quite rare, but the frequency of the more common peripheral T-cell lymphomas, as found in a large international study, is shown in Table 2 [2Go–4Go].


View this table:
[in this window]
[in a new window]
 
Table 1. WHO peripheral T-cell lymphomas

 

View this table:
[in this window]
[in a new window]
 
Table 2. Relative frequency of peripheral T-cell lymphoma (excluding anaplastic large cell) in eight countries [3Go]

 
The results of treatment of patients with aggressive T-cell lymphomas have generally been found to be worse than those for patients with diffuse large B-cell lymphoma. With a few exceptions, studies have found patients with peripheral T-cell lymphomas to have a poorer response to therapy and shorter survival than comparable patients with aggressive B-cell lymphomas [5Go–13Go]. Exceptions to this rule might be explained by the inclusion of patients with anaplastic large T/null-cell lymphoma in such comparisons. Anaplastic large T/null-cell lymphoma is a disease usually seen in young males where the lymphoma frequently overexpresses the anaplastic lymphoma kinase (ALK) protein. This lymphoma has a better survival than that seen in diffuse large B-cell lymphoma and a much better survival than seen with other peripheral T-cell lymphomas. However, the improved survival seems to be restricted to those patients whose lymphomas overexpress the fusion protein referred to as the ALK protein [14Go–16Go]. The survival of patients with aggressive non-Hodgkin's lymphomas classified by immunophenotype is presented in Figure 1 [2Go].



View larger version (16K):
[in this window]
[in a new window]
 
Figure 1. Survival of patients with anaplastic large T/null cell lymphoma and other peripheral T-cell lymphomas compared to patients with diffuse large B-cell lymphoma [2Go].

 
The poor outcome of therapy in patients with peripheral T-cell lymphoma is very likely to be, at least partly, the result of the way clinical trials of aggressive lymphomas have been carried out. Patients with T-cell lymphoma and B-cell lymphoma have been lumped together, with the great majority of patients in any particular study being those with aggressive B-cell lymphoma. Thus, regimens found to be effective have been those that particularly benefit patients with diffuse large B-cell lymphoma. There is no reason to expect that the same drugs would be optimal for patients with peripheral T-cell lymphoma—or that all subtypes of peripheral T-cell lymphoma would benefit from the same drugs. The poor treatment results reported to date with CHOP-like regimens have led some investigators to try alternative approaches, including primary therapy with platinum-based chemotherapy regimens and very intensive regimens such as HyperCVAD. Some studies have shown that patients with relapsed aggressive peripheral T-cell lymphoma respond to autologous hematopoietic stem cell transplantation as well as do those with relapsed diffuse large B-cell lymphoma [17Go–19Go]. This has led many clinicians to offer transplant in first remission to patients with high-stage peripheral T-cell lymphoma. A number of newer agents have been shown to benefit some patients with relapsed peripheral T-cell lymphoma and need to be tested as possible primary therapy. These include interferon, depsipeptide, denileukin difitox and others. A signification advance in the treatment of patients with diffuse large B-cell lymphoma came with the combination of the anti-CD20 antibody rituximab with traditional chemotherapy regimens. Finding a similar immunotherapy for use in combination for patients with peripheral T-cell lymphoma would be important.

In this issue of the Annals of Oncology, the lymphoma team from Vancouver present their analysis of peripheral T-cell lymphomas seen at the British Columbia Cancer Agency [20Go]. We know that peripheral T-cell lymphomas frequently vary in incidence geographically [21Go]. In this regard the relatively large number of extra-nodal NK/T-cell nasal lymphomas seen in Vancouver might reflect the large immigrant population from China and Southeast Asia. They found a poorer outcome for patients with the anaplastic large-cell type than has been found in some studies. This might relate to exclusion of the null-cell subgroup, which is often ALK positive. In addition, they found a lower frequency of angioimmunoblastic T-cell lymphoma than has been seen in previous studies. It would be interesting to know if that lymphoma is truly less common in British Columbia and, if so, why. Their paper confirms many previous observations about this difficult group of lymphomas and is an important contribution to stimulate further studies.

There is great room for improvement in our management of patients with the peripheral T-cell lymphomas. Studies of gene and protein expression need to be done to refine our ability to classify T-cell lymphomas, to find subgroups that are especially likely to benefit from our current treatments, and to identify possible targets for new therapies. We are desperately in need of clinical trials that focus specifically on T-cell lymphomas. However, their relative rarity will make it difficult for any individual institution to carry out these trials. Cooperative studies, perhaps on an international basis, might be necessary to improve our understanding of the biology and the treatment of the peripheral T-cell lymphomas. Our patients need us to undertake these efforts in an expeditious manner.

References

1. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. In: Jaffe E, Harris N, Stein H, Vardiman J (eds): World Health Organization Classification of Tumors. Lyon: IARC Press 2001.

2. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood 1997; 89: 3909–3918.

3. Rudiger T, Weisenburger DD, Anderson JR et al. Peripheral T-cell lymphoma (excluding anaplastic large-cell lymphoma): results from the Non-Hodgkin's Lymphoma Classification Project. Ann Oncol 2002; 13: 140–149.[Abstract/Free Full Text]

4. Weisenburger DD, Anderson JR, Diebold J et al. Systemic anaplastic large-cell lymphoma: results from the non-Hodgkin's lymphoma classification project. Am J Hematol 2001; 67: 172–178.[CrossRef][ISI][Medline]

5. Armitage JO, Weisenburger DD. New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project. J Clin Oncol 1998; 16: 2780–2795.[Abstract]

6. Armitage JO, Vose JM, Linder J et al. Clinical significance of immunophenotype in diffuse aggressive non-Hodgkin's lymphoma. J Clin Oncol 1989; 7: 1783–1790.[Abstract]

7. Brown DC, Heryet A, Gatter KC, Mason DY. The prognostic significance of immunophenotype in high-grade non-Hodgkin's lymphoma. Histopathology 1989; 14: 621–627.[ISI][Medline]

8. Cheng AL, Chen YC, Wang CH et al. Direct comparisons of peripheral T-cell lymphoma with diffuse B-cell lymphoma of comparable histological grades—should peripheral T-cell lymphoma be considered separately? J Clin Oncol 1989; 7: 725–731.[Abstract]

9. Shimizu K, Hamajima N, Ohnishi K, Hara K, Kunii A. T-cell phenotype is associated with decreased survival in non-Hodgkin's lymphoma. Jpn J Cancer Res 1989; 80: 720–726.[ISI][Medline]

10. Lippman SM, Miller TP, Spier CM, Slymen DJ, Grogan TM. The prognostic significance of the immunotype in diffuse large-cell lymphoma: a comparative study of the T-cell and B-cell phenotype. Blood 1988; 72: 436–441.[Abstract]

11. Coiffier B, Brousse N, Peuchmaur M et al. Peripheral T-cell lymphomas have a worse prognosis than B-cell lymphomas: a prospective study of 361 immunophenotyped patients treated with the LNH-84 regimen. The GELA (Groupe d'Etude des Lymphomes Agressives). Ann Oncol 1990; 1: 45–50.

12. Kwak LW, Wilson M, Weiss LM et al. Similar outcome of treatment of B-cell and T-cell diffuse large-cell lymphomas: the Stanford experience. J Clin Oncol 1991; 9: 1426–1431.[Abstract]

13. Shimoyama M, Oyama A, Tajima K et al. Differences in clinicopathological characteristics and major prognostic factors between B-lymphoma and peripheral T-lymphoma excluding adult T-cell leukemia/lymphoma. Leuk Lymphoma 1993; 10: 335–342.[ISI][Medline]

14. Gascoyne RD, Aoun P, Wu D et al. Prognostic significance of anaplastic lymphoma kinase (ALK) protein expression in adults with anaplastic large cell lymphoma. Blood 1999; 93: 3913–3921.[Abstract/Free Full Text]

15. Brugieres L, Deley MC, Pacquement H et al. CD30(+) anaplastic large-cell lymphoma in children: analysis of 82 patients enrolled in two consecutive studies of the French Society of Pediatric Oncology. Blood 1998; 92: 3591–3598.[Abstract/Free Full Text]

16. Falini B, Pileri S, Zinzani PL et al. ALK + lymphoma: clinico-pathological findings and outcome. Blood 1999; 93: 2697–2706.[Abstract/Free Full Text]

17. Rodriguez J, Munsell M, Yazji S et al. Impact of high-dose chemotherapy on peripheral T-cell lymphomas. J Clin Oncol 2001; 19: 3766–3770.[Abstract/Free Full Text]

18. Rodriguez J, Caballero MD, Gutierrez A et al. High-dose chemotherapy and autologous stem cell transplantation in peripheral T-cell lymphoma: the GEL-TAMO experience. Ann Oncol 2003; 14: 1768–1775.[Abstract/Free Full Text]

19. Vose JM, Peterson C, Bierman PJ et al. Comparison of high-dose therapy and autologous bone marrow transplantation for T-cell and B-cell non-Hodgkin's lymphoma. Blood 1990; 76: 424–431.[Abstract]

20. Savage KJ, Chhanabhai M, Gascoyne RD, Connors JM. Characterization of peripheral T-cell lymphomas in a single North American institution by the WHO classification. Ann Oncol 2004; 15: 1467–1475.[Abstract/Free Full Text]

21. Anderson JR, Armitage JO, Weisenburger DD. Epidemiology of the non-Hodgkin's lymphomas: distributions of the major subtypes differ by geographic locations. Non-Hodgkin's Lymphoma Classification Project. Ann Oncol 1998; 9: 717–720.[Abstract]