What Is New in CTCL—Pathogenesis, Diagnosis, and Treatments
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Purpose of Review
Cutaneous T cell lymphoma (CTCL) is a heterogeneous group of non-Hodgkin’s lymphoma primarily affecting the skin, of which mycosis fungoides (MF) and Sézary syndrome (SS) account for the majority of cases. The pathogenesis of CTCL is poorly understood with no strongly associated environmental or genetic risk factors identified to date. As such, the development of disease-specific therapies has been limited by a lack of understanding of potentially actionable targets. Moreover, the diagnosis of CTCL remains challenging with nonspecific diagnostic criteria, especially in early-stage disease.
The advent of high-throughput sequencing techniques and molecular modalities has provided significant insight into disease pathogenesis, diagnosis, and potential therapies.
Here, we review the classic features of CTCL, focusing on MF/SS, and provide updates on our understanding of this disease.
KeywordsCutaneous T cell lymphoma Mycosis fungoides Sézary syndrome T cell receptor Monoclonal antibody Checkpoint inhibitor
Compliance with Ethical Standards
Conflict of Interest
Dr. Dulmage has a patent “Method for diagnosis, prognosis and determination of treatment for cutaneous t-cell lymphoma” pending.
Drs. Betty Y. Kong, Kassandra Holzem and Joan Guitart declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 5.Agar NS, Wedgeworth E, Crichton S, Mitchell TJ, Cox M, Ferreira S, et al. Survival outcomes and prognostic factors in mycosis fungoides/Sezary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010;28:4730–9.CrossRefGoogle Scholar
- 33.Ormsby A, Bergfeld WF, Tubbs RR, Hsi ED. Evaluation of a new paraffin-reactive CD7 T-cell deletion marker and a polymerase chain reaction-based T-cell receptor gene rearrangement assay: implications for diagnosis of mycosis fungoides in community clinical practice. J Am Acad Dermatol. 2001;45:405–13.CrossRefPubMedGoogle Scholar
- 35.Ponti R, Quaglino P, Novelli M, Fierro MT, Comessatti A, Peroni A, et al. T-cell receptor gamma gene rearrangement by multiplex polymerase chain reaction/heteroduplex analysis in patients with cutaneous T-cell lymphoma (mycosis fungoides/Sezary syndrome) and benign inflammatory disease: correlation with clinical, histological and immunophenotypical findings. Br J Dermatol. 2005;153:565–73.CrossRefPubMedGoogle Scholar
- 36.Sandberg Y, van Gastel-Mol EJ, Verhaaf B, Lam KH, van Dongen JJ, Langerak AW. BIOMED-2 multiplex immunoglobulin/T-cell receptor polymerase chain reaction protocols can reliably replace Southern blot analysis in routine clonality diagnostics. J Mol Diagn. 2005;7:495–503.CrossRefPubMedCentralPubMedGoogle Scholar
- 39.Boonk SE, Zoutman WH, Marie-Cardine A, van der Fits L, Out-Luiting JJ, Mitchell TJ, et al. Evaluation of immunophenotypic and molecular biomarkers for Sezary syndrome using standard operating procedures: a multicenter study of 59 patients. The Journal of investigative dermatology. 2016;136:1364–72.CrossRefPubMedGoogle Scholar
- 41.Olsen E, Vonderheid E, Pimpinelli N, Willemze R, Kim Y, Knobler R, et al. Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood. 2007;110:1713–22.CrossRefPubMedGoogle Scholar
- 44.• Scarisbrick JJ, Prince HM, Vermeer MH, Quaglino P, Horwitz S, Porcu P, et al. Cutaneous Lymphoma International Consortium study of outcome in advanced stages of mycosis fungoides and sezary syndrome: effect of specific prognostic markers on survival and development of a prognostic model. J Clin Oncol. 2015;33:3766–73. This is a collaborative multicountry study put on by the Cutaneous Lymphoma International Consortium to identifiy prognostic markers in CTCL. CrossRefPubMedCentralPubMedGoogle Scholar
- 48.Santucci M, Biggeri A, Feller AC, Burg G. Accuracy, concordance, and reproducibility of histologic diagnosis in cutaneous T-cell lymphoma: an EORTC Cutaneous Lymphoma Project Group Study. European Organization for Research and Treatment of Cancer. Arch Dermatol. 2000;136:497–502.CrossRefPubMedGoogle Scholar
- 49.Tok J, Szabolcs MJ, Silvers DN, Zhong J, Matsushima AY. Detection of clonal T-cell receptor gamma chain gene rearrangements by polymerase chain reaction and denaturing gradient gel electrophoresis (PCR/DGGE) in archival specimens from patients with early cutaneous T-cell lymphoma: correlation of histologic findings with PCR/DGGE. J Am Acad Dermatol. 1998;38:453–60.CrossRefPubMedGoogle Scholar
- 50.Zhang B, Beck AH, Taube JM, Kohler S, Seo K, Zwerner J, et al. Combined use of PCR-based TCRG and TCRB clonality tests on paraffin-embedded skin tissue in the differential diagnosis of mycosis fungoides and inflammatory dermatoses. J Mol Diagn. 2010;12:320–7.CrossRefPubMedCentralPubMedGoogle Scholar
- 52.•• Kirsch IR, Watanabe R, O'Malley JT, Williamson DW, Scott LL, Elco CP, et al. TCR sequencing facilitates diagnosis and identifies mature T cells as the cell of origin in CTCL. Sci Trans Med. 2015;7:308ra158. This is a landmark study of TCR sequencing for identification of malignant T cells in CTCL. CrossRefGoogle Scholar
- 55.Feng B, Jorgensen JL, Jones D, Chen SS, Hu Y, Medeiros LJ, et al. Flow cytometric detection of peripheral blood involvement by mycosis fungoides and Sezary syndrome using T-cell receptor Vbeta chain antibodies and its application in blood staging. Mod Pathol. 2010;23:284–95.CrossRefPubMedGoogle Scholar
- 57.Dulmage B O, Akilov O, Vu J R, Falo L D, Geskin L J. Dysregulation of the TOX-RUNX3 pathway in cutaneous T-cell lymphoma. Oncotarget 2015.Google Scholar
- 60.• Rook AH, Gelfand JM, Wysocka M, Troxel AB, Benoit B, Surber C, et al. Topical resiquimod can induce disease regression and enhance T-cell effector functions in cutaneous T-cell lymphoma. Blood. 2015;126:1452–61. Important initial study of the topical immunomodulator resiquimod in the treatment of early-stage CTCL. CrossRefPubMedCentralPubMedGoogle Scholar
- 62.Ogura M, Ishida T, Hatake K, Taniwaki M, Ando K, Tobinai K, et al. Multicenter phase II study of mogamulizumab (KW-0761), a defucosylated anti-cc chemokine receptor 4 antibody, in patients with relapsed peripheral T-cell lymphoma and cutaneous T-cell lymphoma. J Clin Oncol. 2014;32:1157–63.CrossRefPubMedGoogle Scholar
- 63.•• Prince HM, Kim YH, Horwitz SM, Dummer R, Scarisbrick J, Quaglino P, et al. Brentuximab vedotin or physician’s choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial. Lancet (London, England). 2017;390:555–66. This is a phase 3 clinical trial that demonstrated the effectiveness of brentuximab vedotin, an anti-CD30 monoclonal antibody conjugated to a tubulin inhibitor, compared with physician’s choice for treatment of CTCL. CrossRefGoogle Scholar
- 65.Khodadoust M, Rook AH, Porcu P, Foss FM, Moskowitz AJ, Shustov AR, et al. Pembrolizumab for treatment of relapsed/refractory mycosis fungoides and Sezary syndrome: clinical efficacy in a CITN multicenter phase 2 study. Blood. 2016;128:181.Google Scholar
- 73.• Ni X, Jorgensen JL, Goswami M, Challagundla P, Decker WK, Kim YH, et al. Reduction of regulatory T cells by Mogamulizumab, a defucosylated anti-CC chemokine receptor 4 antibody, in patients with aggressive/refractory mycosis fungoides and Sezary syndrome. Clin Cancer Res. 2015;21:274–85. This study highlights the treatment potential of mogalmulizumab, an anti-CCR4 antibody, in treatment of CTCL. CrossRefPubMedGoogle Scholar
- 75.Kim YH, Tavallaee M, Sundram U, Salva KA, Wood GS, Li S, et al. Phase II investigator-initiated study of brentuximab vedotin in mycosis fungoides and Sezary syndrome with variable CD30 expression level: a multi-institution collaborative project. J Clin Oncol. 2015;33:3750–8.CrossRefPubMedCentralPubMedGoogle Scholar
- 81.Duarte RF, Canals C, Onida F, Gabriel IH, Arranz R, Arcese W, et al. Allogeneic hematopoietic cell transplantation for patients with mycosis fungoides and Sezary syndrome: a retrospective analysis of the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2010;28:4492–9.CrossRefPubMedGoogle Scholar
- 82.Benjamin J, Chhabra S, Kohrt HE, Lavori P, Laport GG, Arai S, et al. Total lymphoid irradiation-antithymocyte globulin conditioning and allogeneic transplantation for patients with myelodysplastic syndromes and myeloproliferative neoplasms. Biol Blood Marrow Trans. 2014;20:837–43.CrossRefGoogle Scholar
- 84.Baron F, Labopin M, Peniket A, Jindra P, Afanasyev B, Sanz MA, et al. Reduced-intensity conditioning with fludarabine and busulfan versus fludarabine and melphalan for patients with acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Cancer. 2015;121:1048–55.CrossRefPubMedGoogle Scholar
- 85.Dulmage B, Geskin L, Guitart J, Akilov O E. The biomarker landscape in mycosis fungoides and Sezary syndrome. 2017; 26:668–676.Google Scholar