Cutaneous T Cell Lymphomas: From Pathology to Treatment

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: 30 June 2025 | Viewed by 4993

Special Issue Editors


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Guest Editor
Department of Medicine, Divison of Hematology and Oncology, University of California, San Francisco, CA, USA
Interests: Hodgkin and non-Hodgkin lymphoma; cutaneous lymphoma; pre-clinical models and targeted therapy for mycosis fungoides and Sezary syndrome

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Guest Editor
Division of Dermatology, City of Hope, Duarte, CA 91010, USA
Interests: tumor microenvironment in cutaneous lymphoma; advancing novel biologic therapies for cutaneous lymphoma; dermatopathology; mycosis fungoides; Sezary syndrome; lymphoma

Special Issue Information

Dear Colleagues,

Cutaneous T cell lymphomas (CTCL) are a rare subtype of non-Hodgkin lymphoma and a malignancy of skin-homing T cells. CTCL represents a heterogenous group of diseases that presents primarily in the skin at the time of diagnosis. Mycosis fungoides, the variants of mycosis fungoides, and Sezary syndrome (MF/SS) are the most common types, accounting for approximately 60% of all CTCLs. Early-stage mycosis fungoides may manifest as wide-spread, intensely pruritic skin lesions that significantly impact both quality of life and daily functioning. Advance-stage MF/SS can be life-threatening with a survival rate of 3.5 to 5.6 years. Due to its rarity, heterogeneous presentation, and clinical course, the clinical care of MF/SS presents unique challenges that are best addressed through a multidisciplinary approach.

In recent years, remarkable progress has been made in the field of CTCL. The revision of classification has contributed to a more precise diagnosis, prognosis, and treatment of CTCL. Employing state-of-the-art molecular and genetic techniques has provided insights into the potential genetic drivers and therapeutic targets. A deeper understanding of the functions of epigenetic modulation and tumor microenvironment has opened avenues for the discovery of novel therapies and the development of strategies to overcome drug resistance. Moreover, gaining insights into the mechanisms of action and treatment responses of novel agents, with the identification of prognostic biomarkers, is propelling us toward a more personalized therapeutic approach.

For this Special Issue of Cancers, we welcome original research and review articles that encompass the recent advances and address the future challenges in the diagnosis, biological insights, and treatment of CTCL.

Dr. Weiyun Z. Ai
Dr. Christiane Querfeld
Guest Editors

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Keywords

  • cutaneous T cell lymphoma
  • mycosis fungoides and Sezary syndrome
  • pathogenesis/biomarker discovery
  • tumor microenvironment
  • pre-clinical and clinical studies
  • biological insights

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Published Papers (4 papers)

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Review

20 pages, 13696 KiB  
Review
Unveiling Primary Cutaneous B-Cell Lymphomas: New Insights into Diagnosis and Treatment Strategies
by Zachary R. Barbati and Yann Charli-Joseph
Cancers 2025, 17(7), 1202; https://doi.org/10.3390/cancers17071202 - 1 Apr 2025
Viewed by 94
Abstract
Background/Objectives: Primary cutaneous B-cell lymphomas (PCBCL) are a rare and heterogeneous group of non-Hodgkin lymphomas that are confined to the skin at diagnosis and exhibit a tendency for cutaneous recurrence. The 5th edition of the World Health Organization and the 2022 International Consensus [...] Read more.
Background/Objectives: Primary cutaneous B-cell lymphomas (PCBCL) are a rare and heterogeneous group of non-Hodgkin lymphomas that are confined to the skin at diagnosis and exhibit a tendency for cutaneous recurrence. The 5th edition of the World Health Organization and the 2022 International Consensus Classification recognize three main subtypes: primary cutaneous follicle center lymphoma (PCFCL), primary cutaneous marginal zone lymphoma/lymphoproliferative disorder (PCMZL/LPD), and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL,LT). These subtypes differ in clinical behavior, histopathologic features, immunophenotype, and molecular alterations. Diagnosis and management remain challenging for clinicians. This review aims to provide a comprehensive overview of the defining features and current treatment strategies for PCBCL. Methods: This narrative review synthesizes current literature on the clinical, morphologic, immunohistochemical, and molecular characteristics of PCBCL. It also evaluates the diagnostic utility of immunohistochemistry, gene expression profiling, and molecular assays, particularly in distinguishing primary cutaneous disease from secondary cutaneous involvement by systemic lymphomas. Results: PCFCL arises from germinal center B-cells and must be differentiated from nodal follicular lymphoma. PCMZL/LPD is derived from post-germinal center B-cells and is often linked to chronic antigenic stimulation. Both PCFCL and PCMZL/LPD are indolent and associated with favorable outcomes. By contrast, PCDLBCL,LT is an aggressive lymphoma characterized by genetic alterations activating the NF-κB pathway, commonly including mutations to MYD88 and CD79B. Treatment strategies vary by subtype, ranging from localized therapies for indolent lymphomas to systemic chemoimmunotherapy for aggressive PCBCL. Emerging therapies, such as Bruton tyrosine kinase inhibitors and immunoregulatory agents, are being investigated for relapsed/refractory disease. Conclusions: PCBCL encompass distinct clinicopathologic entities with subtype-specific diagnostic and therapeutic considerations. While current management is guided by clinical behavior, significant knowledge gaps remain regarding the molecular mechanisms underlying skin tropism, immune evasion, and disease progression. Future research could focus on improving molecular characterization and developing personalized and immune-based therapies to enhance outcomes. This review consolidates current knowledge and highlights innovations aimed at advancing the diagnosis and treatment of PCBCL in clinical practice. Full article
(This article belongs to the Special Issue Cutaneous T Cell Lymphomas: From Pathology to Treatment)
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17 pages, 792 KiB  
Review
Therapeutic Targeting of the Janus Kinase/Signal Transducer and Activator of Transcription Pathway in Cutaneous T-Cell Lymphoma
by Alisha Kashyap, Julia Dai and Xiao Ni
Cancers 2025, 17(4), 568; https://doi.org/10.3390/cancers17040568 - 7 Feb 2025
Viewed by 1384
Abstract
Background/Objectives: Cutaneous T-cell lymphoma (CTCL) is a rare group of non-Hodgkin lymphomas characterized by the clonal expansion of malignant T cells. While current treatments can alleviate symptoms and significant progress has been made in treating leukemic CTCL, a definitive cure remains elusive. [...] Read more.
Background/Objectives: Cutaneous T-cell lymphoma (CTCL) is a rare group of non-Hodgkin lymphomas characterized by the clonal expansion of malignant T cells. While current treatments can alleviate symptoms and significant progress has been made in treating leukemic CTCL, a definitive cure remains elusive. Dysregulation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is a key driver of CTCL pathogenesis. As a result, therapeutic strategies targeting JAK/STAT signaling have gained momentum, with the increasing use of JAK inhibitors and other agents that effectively suppress this pathway. These immune-modulating therapies have broad effects on physiological processes, inflammation, and the pathological changes associated with both inflammatory diseases and cancers. Several JAK inhibitors, originally FDA-approved for inflammatory conditions, are now being investigated for cancer treatment. Methods: In this paper, a brief review of the literature on JAK/STAT pathway dysregulation in CTCL is provided, highlighting both clinical and preclinical studies involving JAK inhibitors and other agents that target this pathway. Results: Specifically, we focus on six JAK inhibitors currently under clinical investigation—golidocitinib, ruxolitinib, cerdulatinib, tofacitinib, upadacitinib, and abrocitinib. Additionally, we discuss preclinical studies that explore the mechanisms underlying JAK/STAT pathway inhibition in CTCL. Furthermore, we review reported cases in which CTCL relapsed or emerged following JAK inhibitor treatment. Conclusions: Collectively, these findings support the potential clinical utility of targeting the JAK/STAT pathway in CTCL. However, further research is needed to evaluate safety risks, minimize adverse effects, and optimize these therapeutic strategies. Full article
(This article belongs to the Special Issue Cutaneous T Cell Lymphomas: From Pathology to Treatment)
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17 pages, 908 KiB  
Review
Antibody–Drug Conjugates Targeting CD30 in T-Cell Lymphomas: Clinical Progression and Mechanism
by Yi Jiang, Sai Dong and Yang Wang
Cancers 2025, 17(3), 496; https://doi.org/10.3390/cancers17030496 - 2 Feb 2025
Viewed by 943
Abstract
CD30 is overexpressed in many T-cell lymphoma (TCL) entities, including subsets of peripheral T-cell lymphomas (PTCL) and cutaneous T-cell lymphomas (CTCL). The antibody–drug conjugate brentuximab vedotin (BV), targeting CD30-positive cells, has been approved for the treatment of relapsed or refractory (R/R) systemic anaplastic [...] Read more.
CD30 is overexpressed in many T-cell lymphoma (TCL) entities, including subsets of peripheral T-cell lymphomas (PTCL) and cutaneous T-cell lymphomas (CTCL). The antibody–drug conjugate brentuximab vedotin (BV), targeting CD30-positive cells, has been approved for the treatment of relapsed or refractory (R/R) systemic anaplastic large cell lymphoma (sALCL), and primary cutaneous anaplastic large cell lymphoma or mycosis fungoides in patients who have received previous systemic therapy. However, many patients still experience disease progression after BV monotherapy. Extensive efforts have been dedicated to investigating effective combinations of BV. A phase III clinical study demonstrated that the combination of BV with cyclophosphamide, doxorubicin, and prednisone (CHP) is superior to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for CD30-positive PTCL. This study led to the approval of BV with CHP as the first-line therapy for CD30-positive PTCL (sALCL in Europe). We summarize the encouraging combination applications of BV in this review. Ongoing studies on combination therapies of BV are also listed, highlighting potential directions for the future application of BV. We focus on dissecting the underlying mechanisms of BV, discussing its effects on both tumor cells and the tumor microenvironment. Exploring resistance mechanisms in TCL provide valuable insights for optimizing BV-based therapies in the future. Full article
(This article belongs to the Special Issue Cutaneous T Cell Lymphomas: From Pathology to Treatment)
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18 pages, 1579 KiB  
Review
The Tumor Microenvironment as a Therapeutic Target in Cutaneous T Cell Lymphoma
by Louis Boafo Kwantwi, Steven T. Rosen and Christiane Querfeld
Cancers 2024, 16(19), 3368; https://doi.org/10.3390/cancers16193368 - 1 Oct 2024
Cited by 1 | Viewed by 1912
Abstract
Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of non-Hodgkin lymphomas, with mycosis fungoides and Sézary syndrome being the two common subtypes. Despite the substantial improvement in early-stage diagnosis and treatments, some patients still progress to the advanced stage with an elusive [...] Read more.
Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of non-Hodgkin lymphomas, with mycosis fungoides and Sézary syndrome being the two common subtypes. Despite the substantial improvement in early-stage diagnosis and treatments, some patients still progress to the advanced stage with an elusive underpinning mechanism. While this unsubstantiated disease mechanism coupled with diverse clinical outcomes poses challenges in disease management, emerging evidence has implicated the tumor microenvironment in the disease process, thus revealing a promising therapeutic potential of targeting the tumor microenvironment. Notably, malignant T cells can shape their microenvironment to dampen antitumor immunity, leading to Th2-dominated responses that promote tumor progression. This is largely orchestrated by alterations in cytokines expression patterns, genetic dysregulations, inhibitory effects of immune checkpoint molecules, and immunosuppressive cells. Herein, the recent insights into the determining factors in the CTCL tumor microenvironment that support their progression have been highlighted. Also, recent advances in strategies to target the CTCL tumor micromovement with the rationale of improving treatment efficacy have been discussed. Full article
(This article belongs to the Special Issue Cutaneous T Cell Lymphomas: From Pathology to Treatment)
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