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Cutaneous Lymphomas

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (20 August 2022) | Viewed by 24322

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Prof. Dr. Matthias Goebeler

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Guest Editor

Department of Dermatology, University Hospital Wuerzburg, Josef-Schneider-Str. 2, 97080 Wuerzburg, Germany
Interests: Cutaneous lymphomas, molecular biology, dermatopathology, pathophysiology, targeted therapy, skin immunology

Prof. Dr. Marion Wobser

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Guest Editor

Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Josef-Schneider-Straße 2, 97080 Würzburg, Germany
Interests: Cutaneous lymphomas, molecular biology, dermatopathology, pathophysiology, targeted therapy, skin immunology

Special Issue Information

Dear colleagues,

Cutaneous lymphomas are rare and heterogeneous hematological tumors of the skin with a wide spectrum of clinical and histopathological presentation. Close clinicopathological correlation is required to make the diagnosis and attributing the patient to the correct subtype is necessary to choose an adequate stage-adapted treatment regimen. High-throughput sequencing analyses and immunophenotyping enabled us to better understand the molecular landscape of cutaneous lymphomas, to discern the respective neoplastic cell of origin and to decipher the complex interaction of lymphoma cells with other immune cells and the tumor microenvironment. While especially in advanced stages of mycosis fungoides - the most common cutaneous T-cell lymphoma - traditional treatment regimens only achieved temporary remissions, novel insights into the molecular basis and the immunological features of cutaneous lymphomas have recently provided novel and promising targets for personalized treatment approaches.

In this Special Issue, experts in this field will highlight the current approaches to the histopathological diagnosis and clinical management of patients with different subtypes of cutaneous lymphomas. Moreover, original articles will provide novel insight into the molecular pathogenesis and immunological hallmarks of cutaneous lymphomas which may be exploited for innovative treatment strategies in the future.

Prof. Dr. Matthias Goebeler
Prof. Dr. Marion Wobser
Guest Editors

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Keywords

Cutaneous T-cell lymphomas
cutaneous B-cell lymphomas
mycosis fungoides
skin

Published Papers (10 papers)

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Editorial

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4 pages, 203 KiB

Open AccessEditorial

Special Issue “Cutaneous Lymphomas”

by Marion Wobser and Matthias Goebeler

Cancers 2023, 15(5), 1481; https://doi.org/10.3390/cancers15051481 - 26 Feb 2023

Viewed by 975

Abstract

Cutaneous lymphomas comprise heterogeneous subtypes of hematological neoplasms that primarily manifest in the skin [...] Full article

(This article belongs to the Special Issue Cutaneous Lymphomas)

Research

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13 pages, 1294 KiB

Open AccessArticle

Mogamulizumab Combined with Extracorporeal Photopheresis as a Novel Therapy in Erythrodermic Cutaneous T-cell Lymphoma

by Nadia Ninosu, Susanne Melchers, Max Kappenstein, Nina Booken, Inga Hansen, Maël Blanchard, Emmanuella Guenova, Chalid Assaf, Sergij Goerdt and Jan P. Nicolay

Cancers 2024, 16(1), 141; https://doi.org/10.3390/cancers16010141 - 27 Dec 2023

Cited by 1 | Viewed by 981

Abstract

Background: Primary cutaneous T-cell lymphomas (CTCLs) are rare lymphoproliferative malignancies characterized by significant morbidity and mortality in advanced disease stages. As curative approaches apart from allogeneic stem cell transplantation are lacking, establishing new treatment options, especially combination therapies, is crucial. Methods: This retrospective study included 11 patients with SS or MF receiving therapy with mogamulizumab in combination with ECP from four European expert centers. The response rates in the skin and blood as well as treatment use and adverse events (AE) were described. Results: 8/11 patients (73%) showed an overall response (OR) in the skin. The mean mSWAT decreased from 98.2 ± 40.8 to 34.6 ± 23.8. The overall response rate (ORR) in the blood was 64% with two complete responses. During combination therapy, the mean number of Sézary cells decreased from 3365.3 × 10⁶/L before treatment to 1268.6 × 10⁶/L. The mean minimum known period without progress was 7.2 months in the skin and 7.6 months in the blood. The most common AEs were mogamulizumab-associated rash (MAR) (45.5%), anemia (27.3%), lymphocytopenia (27.8%), and infusion related reaction (16.7%). No AE led to treatment discontinuation. Conclusions: Our study presents the combination of mogamulizumab and ECP as an effective therapy in the blood and skin in CTCL with good tolerability, similar to mogamulizumab monotherapy. Full article

(This article belongs to the Special Issue Cutaneous Lymphomas)

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12 pages, 909 KiB

Open AccessArticle

Panel Sequencing of Primary Cutaneous B-Cell Lymphoma

by Marion Wobser, Patrick Schummer, Silke Appenzeller, Hermann Kneitz, Sabine Roth, Matthias Goebeler, Eva Geissinger, Andreas Rosenwald and Katja Maurus

Cancers 2022, 14(21), 5274; https://doi.org/10.3390/cancers14215274 - 27 Oct 2022

Cited by 3 | Viewed by 1117

Abstract

Background: Primary cutaneous follicular B-cell lymphoma (PCFBCL) represents an indolent subtype of Non-Hodgkin’s lymphomas, being clinically characterized by slowly growing tumors of the skin and common cutaneous relapses, while only exhibiting a low propensity for systemic dissemination or fatal outcome. Up to now, only few studies have investigated underlying molecular alterations of PCFBCL with respect to somatic mutations. Objectives: Our aim was to gain deeper insight into the pathogenesis of PCFBCL and to delineate discriminatory molecular features of this lymphoma subtype. Methods: We performed hybridization-based panel sequencing of 40 lymphoma-associated genes of 10 cases of well-characterized PCFBCL. In addition, we included two further ambiguous cases of atypical B-cell-rich lymphoid infiltrate/B-cell lymphoma of the skin for which definite subtype attribution had not been possible by routine investigations. Results: In 10 out of 12 analyzed cases, we identified genetic alterations within 15 of the selected 40 target genes. The most frequently detected alterations in PCFBCL affected the TNFRSF14, CREBBP, STAT6 and TP53 genes. Our analysis unrevealed novel mutations of the BCL2 gene in PCFBCL. All patients exhibited an indolent clinical course. Both the included arbitrary cases of atypical B-cell-rich cutaneous infiltrates showed somatic mutations within the FAS gene. As these mutations have previously been designated as subtype-specific recurrent alterations in primary cutaneous marginal zone lymphoma (PCMZL), we finally favored the diagnosis of PCMZL in these two cases based on these molecular findings. Conclusions: To conclude, our molecular data support that PCFBCL shows distinct somatic mutations which may aid to differentiate PCFBCL from pseudo-lymphoma as well as from other indolent and aggressive cutaneous B-cell lymphomas. While the detected genetic alterations of PCFBCL did not turn out to harbor any prognostic value in our cohort, our molecular data may add adjunctive discriminatory features for diagnostic purposes on a molecular level. Full article

(This article belongs to the Special Issue Cutaneous Lymphomas)

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10 pages, 1311 KiB

Open AccessArticle

Treatment of Indolent Cutaneous B-Cell Lymphoma with Intralesional or Intravenous Rituximab

by Christian Menzer, Adriana Rendon and Jessica C. Hassel

Cancers 2022, 14(19), 4787; https://doi.org/10.3390/cancers14194787 - 30 Sep 2022

Cited by 4 | Viewed by 1898

Abstract

Indolent cutaneous B-cell lymphomas (CBCL) are a rare disease for which the therapeutic recommendations are based on clinical reports. Recommendations for solitary lesions include surgery or irradiation. However, the high relapse rates may require less invasive repeatable therapy. This study seeks to retrospectively assess the efficacy of intralesional rituximab (ILR) for indolent CBCL when compared with intravenous rituximab (IVR). Patients treated for indolent CBCL with ILR or IVR at the Division of DermatoOncology of the University Hospital Heidelberg were eligible for this study. Characteristics of lymphoma, treatment response, and adverse events were assessed. Twenty-one patients, 67% male at a median age of 52 (range 17–80), were included. Nineteen (90%) had only localized lymphoma (stage T1 and T2). Complete response was achieved in 92% (11/12) of ILR after a median of one cycle (three injections) and 78% (7/8) of IVR patients after a median of six cycles. Half of ILR patients and 78% of IVR patients showed relapse after a median of 15 and 23 months, respectively. Adverse reactions were usually mild and were limited to the first injection of ILR. One patient with IVR contracted a pulmonary infection. ILR may be an alternative to the intravenous administration of rituximab for localized indolent CBCL. Full article

(This article belongs to the Special Issue Cutaneous Lymphomas)

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20 pages, 2310 KiB

Open AccessArticle

Diagnostic Outcomes and Treatment Modalities in Patients with Mycosis Fungoides in West Sweden—A Retrospective Register-Based Study

by Karolina Wojewoda, Martin Gillstedt, Hanna Englund, Shada Ali, Catharina Lewerin and Amra Osmancevic

Cancers 2022, 14(19), 4661; https://doi.org/10.3390/cancers14194661 - 25 Sep 2022

Cited by 3 | Viewed by 4452

Abstract

(1) Background: Mycosis fungoides (MF) is a variant of primary cutaneous T-cell lymphoma. The aim of this study was to describe the clinical features and epidemiological and diagnostic findings in addition to the treatment modalities and responses in patients with MF. Furthermore, comparisons between patients in the early stage and the advanced stage were evaluated. (2) Methods: A retrospective register-based study based on data collected from the primary cutaneous lymphoma register and medical records was performed at the Department of Dermatology and Venerology at Sahlgrenska University Hospital, Gothenburg, Sweden. (3) Results: Eighty-four patients with a median age of 55 years with MF were included. Most of the patients (n = 73) were diagnosed at the early stage of the disease (IA–IIA). Overall disease progression was seen in 12.5% (n = 9) of the patients. Nine (10.7%) patients were deceased, out of which four (4.8%) deaths were associated with MF-related causes. (4) Conclusions: This study contributes to the knowledge of the epidemiological and clinical features in addition to the diagnostic findings and treatment responses in patients with MF in Sweden. Full article

(This article belongs to the Special Issue Cutaneous Lymphomas)

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21 pages, 4925 KiB

Open AccessArticle

Combination of Resminostat with Ruxolitinib Exerts Antitumor Effects in the Chick Embryo Chorioallantoic Membrane Model for Cutaneous T Cell Lymphoma

by Fani Karagianni, Christina Piperi, Berta Casar, Dalia de la Fuente-Vivas, Rocío García-Gómez, Kyriaki Lampadaki, Vasiliki Pappa and Evangelia Papadavid

Cancers 2022, 14(4), 1070; https://doi.org/10.3390/cancers14041070 - 20 Feb 2022

Cited by 6 | Viewed by 2608

Abstract

The combination of Resminostat (HDACi) and Ruxolitinib (JAKi) exerted cytotoxic effects and inhibited proliferation of CTCL cell lines (MyLa, SeAx) in previously published work. A xenograft tumor formation was produced by implanting the MyLa or SeAx cells on top of the chick embryo chorioallantoic membrane (CAM). The CAM assay protocol was developed to monitor the metastatic properties of CTCL cells and the effects of Resminostat and/or Ruxolitinib in vivo. In the spontaneous CAM assays, Resminostat and Ruxolitinib treatment inhibited the cell proliferation (p < 0.001) of MyLa and SeAx, and induced cell apoptosis (p < 0.005, p < 0.001, respectively). Although monotherapies reduced the size of primary tumors in the metastasis CAM assay, the drug combination exhibited a significant inhibition of primary tumor size (p < 0.0001). Furthermore, the combined treatment inhibited the intravasation of MyLa (p < 0.005) and SeAx cells (p < 0.0001) in the organs, as well as their extravasation to the liver (p < 0.0001) and lung (p < 0.0001). The drug combination also exerted a stronger inhibitory effect in migration (p < 0.0001) rather in invasion (p < 0.005) of both MyLa and SeAx cells. It further reduced p-p38, p-ERK, p-AKT, and p-STAT in MyLa cells, while it decreased p-ERK and p-STAT in SeAx cells in CAM tumors. Our data demonstrated that the CAM assay could be employed as a preclinical in vivo model in CTCL for pharmacological testing. In agreement with previous in vitro data, the combination of Resminostat and Ruxolitinib was shown to exert antitumor effects in CTCL in vivo. Full article

(This article belongs to the Special Issue Cutaneous Lymphomas)

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17 pages, 2106 KiB

Open AccessArticle

Contemporary Treatment Patterns and Response in Relapsed/Refractory Cutaneous T-Cell Lymphoma (CTCL) across Five European Countries

by Chalid Assaf, Nathalie Waser, Martine Bagot, Mary He, Tina Li, Mehul Dalal, Francois Gavini, Fabrizio Trinchese, Athanasios Zomas, Meredith Little, Nicola Pimpinelli, Pablo L. Ortiz-Romero and Timothy M. Illidge

Cancers 2022, 14(1), 145; https://doi.org/10.3390/cancers14010145 - 29 Dec 2021

Cited by 7 | Viewed by 1862

Abstract

The treatment pattern of cutaneous T-cell lymphoma (CTCL) remains diverse and patient-tailored. The objective of this study was to describe the treatment patterns and outcomes in CTCL patients who were refractory or had relapsed (R/R) after a systemic therapy. A retrospective chart review study was conducted at 27 sites in France, Germany, Italy, Spain and the United Kingdom (UK) of patients who received a first course of systemic therapy and relapsed or were refractory. Data were collected longitudinally from diagnosis to first-, second- and third-line therapy. The study included 157 patients, with a median follow-up of 3.2 years. In total, 151 proceeded to second-line and 90 to third-line therapy. In the first line (n = 147), patients were treated with diverse therapies, including single- and multi-agent chemotherapy in 67 (46%), retinoids in 39 (27%), interferon in 31 (21%), ECP in 4 (3%), corticosteroids in 3 (2%) and new biological agents in 3 (2%). In the second line, the use of chemotherapy and retinoids remained similar to the first line, while the use of new biologics increased slightly. In sharp contrast to the first line, combination chemotherapy was extremely diverse. In the third line, the use of chemotherapy remained high and diverse as in the second line. From the time of first R/R, the median PFS was 1.2 years and the median OS was 11.5 years. The presented real-world data on the current treatments used in the management of R/R CTCL in Europe demonstrate the significant heterogeneity of systemic therapies and combination therapies, as expected from the European guidelines. Full article

(This article belongs to the Special Issue Cutaneous Lymphomas)

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16 pages, 1523 KiB

Open AccessArticle

Targeted Deep Sequencing of Mycosis Fungoides Reveals Intracellular Signaling Pathways Associated with Aggressiveness and Large Cell Transformation

by Marion Wobser, Sabine Roth, Silke Appenzeller, Roland Houben, David Schrama, Matthias Goebeler, Eva Geissinger, Andreas Rosenwald and Katja Maurus

Cancers 2021, 13(21), 5512; https://doi.org/10.3390/cancers13215512 - 02 Nov 2021

Cited by 6 | Viewed by 1847

Abstract

Introduction: Large-cell transformation (LCT) of mycosis fungoides (MF) has been associated with a higher risk of relapse and progression and, consequently, restricted prognosis. Its molecular pathogenesis has not been elucidated yet. Materials and Methods: In order to address molecular mechanisms of LCT, we performed hybrid capture panel-based sequencing of skin biopsies from 10 patients suffering from MF with LCT versus 17 patients without LCT including follow-up biopsies during clinical course, respectively (51 samples in total). The analyzed patients were attributed to three different groups based on the presence of LCT and clinical behavior. Results: While indolent MF cases without LCT did not show pathogenic driver mutations, a high rate of oncogenic alterations was detected in patients with LCT and aggressive clinical courses. Various genes of different oncogenic signaling pathways, including the MAPK and JAK-STAT signaling pathways, as well as epigenetic modifiers were affected. A high inter-individual and distinctive intra-individual mutation diversity was observed. Oncogenic RAS mutations were exclusively detected in patients with LCT. Conclusion: Our data demonstrate that LCT transition of MF is associated with increased frequency of somatic mutations in cancer-associated genes. In particular, the activation of RAS signaling—together with epigenetic dysregulation—may crucially contribute to the molecular pathogenesis of the LCT phenotype, thus conveying its adverse clinical behavior. Full article

(This article belongs to the Special Issue Cutaneous Lymphomas)

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13 pages, 11462 KiB

Open AccessArticle

Epidemiology of Cutaneous T-Cell Lymphomas: A Systematic Review and Meta-Analysis of 16,953 Patients

by Gabor Dobos, Anne Pohrt, Caroline Ram-Wolff, Céleste Lebbé, Jean-David Bouaziz, Maxime Battistella, Martine Bagot and Adèle de Masson

Cancers 2020, 12(10), 2921; https://doi.org/10.3390/cancers12102921 - 11 Oct 2020

Cited by 56 | Viewed by 4669

Abstract

Cutaneous T-cell lymphomas (CTCL) are a heterogenous group of rare diseases. Many studies have reported on local epidemiology or geographic clustering, however we lack information from a global perspective. A systematic review and meta-analysis was conducted in Medline and the Cochrane Library based on a previously registered protocol and according to the preferred reporting of items for systematic reviews and meta-analyses (PRISMA). We selected publications that enrolled at least 100 patients with primary cutaneous lymphomas according to the current classifications. The relative frequencies (proportions) of subtypes were compared between studies and geographic regions in a meta-analysis. In total, 26 studies met our inclusion criteria, reporting on altogether 16,953 patients. Within primary cutaneous lymphomas, CTCL appeared to be 15% more frequent in Asian populations. Mycosis fungoides (MF) accounted for 62% of CTCL, with an important heterogeneity in frequencies between studies and continents. The proportion of Sézary syndrome (SS) was 3%, stable worldwide. Rare CTCL, such as NK/T-cell lymphoma or subcutaneous panniculitis-like lymphoma, were more frequent in Asian studies. This global meta-analysis of CTCL confirmed the predominance of CTCL among primary cutaneous lymphomas (83% on average) in the three analyzed continents, most of which were MF cases. It revealed the same proportions of SS across continents, and the heterogeneity of MF frequencies, suggesting the possible role of environmental factors in the pathophysiology of the latter. Registration number: CRD42020148295 (PROSPERO). Full article

(This article belongs to the Special Issue Cutaneous Lymphomas)

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Review

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11 pages, 779 KiB

Open AccessReview

The Skin Microbiome and Influencing Elements in Cutaneous T-Cell Lymphomas

by Marion Jost and Ulrike Wehkamp

Cancers 2022, 14(5), 1324; https://doi.org/10.3390/cancers14051324 - 04 Mar 2022

Cited by 9 | Viewed by 2792

Abstract

Since the 1970s, a connection between the skin’s microbiota and cutaneous T-cell lymphomas (CTCL) was suggested. New techniques such as next-generation sequencing technologies enable the examination of the nuanced interplay between microbes and their host. The purpose of this review is an updated description of the current knowledge on the composition of the microbiome, relevant bacteria, or other stimuli, and their potential role in CTCL with a focus on the most frequent subtype, mycosis fungoides. Some findings suggest that the skin barrier—or the deficiency hereof—and host-microbiota might be involved in disease progression or etiopathogenesis. In addition, information on the current knowledge of antimicrobial peptide expression in CTCL, as well as treatment considerations with antiseptics and antibiotics, are included. Further studies are needed to provide more insight and potentially contribute to the development of new treatment approaches. Full article

(This article belongs to the Special Issue Cutaneous Lymphomas)

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