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Rare PTCLs: Treatment Lagging Behind Pathobiologic Advances

Rare PTCLs: Treatment Lagging Behind Pathobiologic Advances

Peripheral T-cell lymphomas, or PTCLs, represent an uncommon and biologically heterogeneous group of hematologic malignancies, accounting for less than 10% of all non-Hodgkin lymphomas worldwide, with marked geographic differences. Due to their low prevalence, variable clinical presentation and phenotypic heterogeneity, these lymphomas have historically been difficult to diagnose and categorize. Since the introduction of immunophenotyping and molecular genetic methods, as well as the development of comprehensive classification systems, there have been significant advances in diagnostic accuracy, classification, and our understanding of the biologic behavior of different PTCL subtypes. However, the molecular pathogenesis of most subtypes of PTCL remains incompletely understood, and treatment outcomes with conventional anthracycline-based chemotherapy regimens are generally significantly inferior to those in aggressive B-cell lymphomas.

Noteworthy Features of Disease

In this review, Roschewski and Wilson provide a comprehensive summary of our current knowledge of the pathobiologic, epidemiologic, and clinical features of three rare subtypes of primary extranodal T-cell lymphomas—hepatosplenic T-cell lymphoma (HSTCL), subcutaneous panniculitis-like T-cell lymphoma (SPTCL), and enteropathy-type T-cell lymphoma (ETTCL). Several particular features of these uncommonly encountered disease entities appear noteworthy. In contrast to natural killer/T-cell lymphoma—which also tends to arise in extranodal sites—they are generally not associated with Epstein-Barr virus (EBV) infection; however, underlying autoimmune conditions or immunodeficiency states have been demonstrated in up to one-third of patients, indicating chronic antigen stimulation or immune dysregulation as a possible pathogenetic mechanism in all of these disorders.

There is a striking association between SPTCL (and less commonly HSTCL) with hemophagocytic syndrome, a potentially life-threatening disorder related to macrophage hyperactivation due to cytokine secretion by activated or neoplastic cytotoxic-like T lymphocytes. Over the past 2 decades, significant progress has been made in the diagnosis and management of this rare but frequently fatal hematologic disorder, and standardized treatment protocols have been developed, such as the HLH-2004 protocol using a combination of decadron, cyclosporine, and etoposide.[1] In our personal clinical experience, prompt recognition and treatment of concomitant hemophagocytic syndrome should be a priority in the management of patients with PTCL and may be lifesaving.

Subtypes and Prognoses

The immunophenotypic and molecular distinction of mature post-thymic T lymphocytes into two major subsets—α/β and γ/δ—has led to an appreciation of clinically and prognostically heterogeneous subtypes of PTCL. According to a report of 83 cases by Willemze et al, these differences are most evident in SPTCL, where the more frequently observed cytotoxic CD4–, CD8+, CD56– α/β T-cell phenotype shows a generally indolent clinical course and favorable prognosis (5-year disease-specific and overall survival > 80%). In contrast, the less commonly encountered CD4–, CD8–, CD56+ γ/δ T-cell phenotype has an aggressive clinical course and poor prognosis (5-year disease-specific and overall survival of 11%).[2] Based on these observations, the World Health Organization/European Organisation for Research and Treatment of Cancer (WHO-EORTC) classification reserves the term SPTCL only for the α/β type, whereas the γ/δ type is included in the separate group of cutaneous γ/δ T-cell lymphomas. On the other hand, among patients with HSTCL, the vast majority demonstrate the γ/δ subtype, which has an extremely poor prognosis. Too few cases of α/β type have been reported to draw any conclusions about prognostic significance of the latter phenotype.

Delays in Diagnosis

With the exception of SPTCL of α/β T-cell type, the T-cell lymphomas reviewed here have a very poor prognosis overall. In a large multicenter study, the International Prognostic Index (IPI) has not proven helpful in predicting outcomes in patients with ETTCL and HSTCL, as even patients in the low-risk groups have poor outcomes.[3] One major contributing issue remains the frequent delay in establishing a diagnosis in these rare types of PTCL. This is particularly so in patients with ETTCL with underlying gluten-sensitive enteropathy, where clinical deterioration may be misinterpreted as dietary noncompliance, the disease may be multifocal, histopathologic features diverse, and distinction from other (benign or malignant) disease entities difficult.

Delays in diagnosis may result in worsening performance status due to malnutrition and higher rates of disease- and treatment-related complications. In a series by Abouyabis et al, only 20% of patients with ETTCL presenting with stage I and II disease but none of those with stage III and IV disease survived 5 years.[4] On the other hand, over 90% of patients with HSTCL present with stage IV disease. Considering the lack of effective treatment options, it is questionable whether earlier diagnosis would indeed result in improved patient outcomes.

Treatment Challenges

Due to their low incidence and lack of randomized clinical trials, there are no established standards of care to guide the practicing oncologist in the treatment of these rare PTCL subtypes. Given the overall disappointing outcomes with conventional chemotherapy regimens, we agree with Roschewski and Wilson that there is an urgent need for novel therapeutic approaches and agents. However, we would like to expand beyond the authors’ viewpoints in several aspects: Patients with SPTCL of α/β T-cell type generally have a fairly indolent clinical course and favorable prognosis, particularly when not complicated by hemophagocytic syndrome (5-year overall survival of 91%).

In the series by Willemze et al, treatment of these patients with low-dose prednisone was equally efficient to CHOP(-like) chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone), with 55% sustained complete remissions, thus challenging the need for upfront treatment with multiagent chemotherapy. In patients presenting with associated hemophagocytic syndrome, the outcomes with CHOP(-like) chemotherapy appear to be less favorable (5-year overall survival of 46%).[2] Treatment with oral cyclosporine, in combination with steroids, has reportedly been successful in patients with SPTCL and would be our preferred initial approach in the setting of concomitant hemophagocytic syndrome.[5,6]

For patients with HSTCL, most published reports involve aggressive anthracycline-based chemotherapy regimens, with or without subsequent allogeneic stem cell transplantation. Several recent case reports have highlighted the efficacy of alternative treatment approaches, including interferon-α, purine analogs (cladribine, pentostatin) and the anti-CD52 monoclonal antibody alemtuzumab (Campath).[7-10] However, no general treatment recommendations can be given based on the small number of cases, and therapy must always be tailored to the individual patient.


In conclusion, progress in developing effective treatment options for PTCL and its subtypes has been lagging behind our understanding of the pathobiology of these rare diseases. Novel analytic approaches such as gene expression and proteomics may lead to identification of targetable molecules.

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.



1. Henter JI, Horne A, Arico M, et al: HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 48:124-131, 2007.

2. Willemze R, Jansen PM, Cerroni L, et al: Subcutaneous panniculitis-like T-cell lymphoma: Definition, classification, and prognostic factors: An EORTC Cutaneous Lymphoma Group study of 83 cases. Blood 111:838-845, 2008.

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

4. Abouyabis AN, Shenoy PJ, Lechowicz MJ, et al: Incidence and outcomes of the peripheral T-cell lymphoma subtypes in the united states. Leuk Lymphoma 49:2099-2107, 2008.

5. Al Zolibani AA, Al Robaee AA, Qureshi MG, et al: Subcutaneous panniculitis-like T-cell lymphoma with hemophagocytic syndrome successfully treated with cyclosporin A. Skinmed 5:195-197, 2006.

6. Rojnuckarin P, Nakorn TN, Assanasen T, et al: Cyclosporin in subcutaneous panniculitis-like T-cell lymphoma. Leuk Lymphoma 48:560-563, 2007.

7. Humphreys MR, Cino M, Quirt I, et al: Long-term survival in two patients with hepatosplenic t cell lymphoma treated with interferon-alpha. Leuk Lymphoma 49:1420-1423, 2008.

8. Soldini D, Mora O, Cavalli F, et al: Efficacy of alemtuzumab and gemcitabine in a patient with enteropathy-type T-cell lymphoma. Br J Haematol 142:484-486, 2008.

9. Corazzelli G, Capobianco G, Russo F, et al: Pentostatin (2’-deoxycoformycin) for the treatment of hepatosplenic gammadelta T-cell lymphomas. Haematologica 90:ECR14, 2005.

10. Jaeger G, Bauer F, Brezinschek R, et al: Hepatosplenic gammadelta T-cell lymphoma successfully treated with a combination of alemtuzumab and cladribine. Ann Oncol 19:1025-1026, 2008.

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