Molecular Profiling Improves Classification of Nodal Peripheral T-Cell Lymphomas 

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One of the primary obstacles we face in caring for patients with peripheral T-cell lymphomas is a too often inadequate response to chemotherapy with low rates of progression-free and overall survival.1 And while more intensive treatment programs and the availability of novel agents give a greater hope for success, the management of these lymphomas remains a significant challenge for clinicians.2 However, a frequently overlooked issue by clinicians—but one well understood by pathologists—is the difficulty in reliably making these diagnoses.

In the International T-cell Project, in which four hematopathologists independently reviewed cases of T-cell lymphoma, a consensus diagnosis among these experts was reached in only 75% of patients with peripheral T-cell lymphoma–not otherwise specified.1 Much of the difficulty in reproducing diagnoses in cases of peripheral T-cell lymphoma stems from the need to interpret a constellation of features of histology, immunohistochemistry, and molecular diagnostics, which, unlike many B-cell lymphomas, can vary widely even within a specific T-cell lymphoma subtype.

Molecular Profiling Strategy

Piccaluga and colleagues report a study using molecular profiling to improve the classification of peripheral T-cell lymphoma.3 From the pathology side of management, this appears to be a clear advance. First off, they report high diagnostic accuracy in their gene-expression profile–based molecular classification among the most common T-cell lymphoma subtypes of peripheral T-cell lymphoma–not otherwise specified, angioimmunoblastic T-cell lymphoma, and ALK-negative anaplastic large cell lymphoma. This supports the concept that these subtypes represent distinct pathologic entities.

Second, their classification system appears to be accurate and feasible from formalin-fixed paraffin-embedded tissue. As such, it has the potential to be clinically useful and more than just a research tool.

And third, there are clues that their system refined the prognostic accuracy among several particularly problematic/overlap areas in T-cell lymphoma: distinguishing subjects with peripheral T-cell lymphoma–not otherwise specified who have a follicular helper T-cell phenotype from angioimmunoblastic T-cell lymphoma, and distinguishing high CD30-expressing peripheral T-cell lymphoma–not otherwise specified from ALK-negative anaplastic large cell lymphoma.

Clinician’s Perspective

From the clinician’s perspective, these results beg the question: Does this matter? The 3-year overall survival ratesl for patients in this series were 16%, 44%, and 19% for patients with angioimmunoblastic T-cell lymphoma, ALK-negative anaplastic large cell lymphoma, and peripheral T-cell lymphoma–not otherwise specified, respectively. And while the addition of gene-expression profiling refined these diagnoses to allow some statistical significance, the median survival for each subtype is still less than 50% at 3 years, and we would still approach all these patients with full-course combination chemotherapy. So, at present this may be a better tool to reliably assign a subtype or to stratify patients for clinical trials than a necessity in routine practice.

Changing Approach

However, there are clues that the “one size fits all” approach that we have used for T-cell lymphomas may be changing. As our experience with T-cell lymphomas grows, we are more frequently seeing differential responses to new agents among the T-cell lymphoma subtypes. The studies tend to be small, so these differences are more hypothesis-generating than conclusive regarding whether one drug is superior for a certain subtype than another.

Nonetheless, pralatrexate (Folotyn), while active in many subtypes of T-cell lymphoma, seems to have stronger activity in peripheral T-cell lymphoma–not otherwise specified compared to angioimmunoblastic T-cell lymphoma, with response rates of 35% vs 8%.4 In a recent phase II study, the investigational HDAC inhibitor belinostat produced a 46% response rate among those with angioimmunoblastic T-cell lymphoma (46%)—higher than in peripheral T-cell lymphoma–not otherwise specified (23%) and significantly higher than in ALK-negative anaplastic large cell lymphoma (15%).5

Brentuximab vedotin (Adcetris) is approved based on an 86% response rate in relapsed anaplastic large cell lymphoma, which universally expresses CD30.6 However, it also showed activity in a small study among other types of T-cell lymphoma with varying degrees of CD30 expression, including responses in 50% of patients with angioimmunoblastic T-cell lymphoma and 25% with peripheral T-cell lymphoma–not otherwise specified.7 Other examples include the use of a highly targeted therapy such as crizotinib (Xalkori) in ALK-positive anaplastic large cell lymphoma and the empirically noted high response rates with L-asparaginase among NK/T-cell lymphomas.8,9


The study by Piccaluga and colleagues demonstrates a useful new tool to refine the diagnostic accuracy of T-cell lymphomas. Its development comes from an increased understanding of these lymphomas and gives us a glimpse into the not-too-distant future, when a greater knowledge of the molecular basis of these diseases may be routinely incorporated into the choice of therapies and hopefully lead to real benefits for our patients. ■

Dr. Horwitz is a medical oncologist at Memorial-Sloan Kettering Cancer Center, New York.

Disclosure: Dr. Horwitz is a consultant for Celgene, Spectrum, Millennium, Amgen, Janssen. He has received research support from Celgene, Kiowa Hakko Kirin, Infinity Pharmaceuticals, Spectrum Pharmaceuticals, Seattle Genetics, and Millennium.


1. Vose J, Armitage J, Weisenburger D: International T-Cell Lymphoma Project: International peripheral T-cell and natural killer/T-cell lymphoma study: Pathology findings and clinical outcomes. J Clin Oncol 26:4124-4130, 2008.

2. d’Amore F, Relander T, Lauritzsen GF, et al: Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma: NLG-T-01. J Clin Oncol 30:3093-3099, 2012.

3. Piccaluga PP, Fuligni F, De Leo A, et al: Molecular profiling improves classification and prognostication of nodal peripheral T-cell lymphomas: Results of a phase III diagnostic accuracy study. J Clin Oncol 31:3019-3025, 2013.

4. O’Connor OA, Pro B, Pinter-Brown L, et al: Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: Results from the pivotal PROPEL study. J Clin Oncol 29:1182-1189, 2011.

5. Horwitz S, O’Connor O, Jurczak W, et al: Belinostat in angioimmunoblastic T-cell lymphoma: Results from the pivotal BELIEF trial. 12th International Conference on Malignant Lymphoma. Abstract 153. Presented June 22, 2013.

6. Pro B, Advani R, Brice P, et al: Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: Results of a phase II study. J Clin Oncol 30:2190-2196, 2012.

7. Oki Y, Horwitz S, Bartlett NL, et al: Safety and efficacy of brentuximab vedotin for treatment of relapsed or refractory mature t-/NK-cell lymphomas. 12th International Conference on Malignant Lymphoma. Abstract 152. Presented June 22, 2013.

8. Gambacorti-Passerini C, Pogliani EM: Crizotinib in anaplastic large-cell lymphoma (correspondence). N Engl J Med 364:775-776, 2011.

9. Matsumoto Y, Nomura K, Kanda-Akano Y, et al: Successful treatment with Erwinia L-asparaginase for recurrent natural killer/T cell lymphoma. Leuk Lymphoma 44:879–882, 2003.

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Molecular Profiling Improves Classification of Nodal Peripheral T-Cell Lymphomas

The differential diagnosis of the most common peripheral T-cell lymphoma subtypes is difficult. In a diagnostic accuracy study reported in the Journal of Clinical Oncology, Pier Paolo Piccaluga, MD, PhD, of the University of Bologna, and colleagues in the European T-Cell Lymphoma Study Group and...