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Mycosis fungoides (MF) is a rare, primary cutaneous T-cell lymphoma that is challenging to diagnose due to its heterogeneous clinical presentation and complex histology. The subtlety of the initial clinical appearance of MF can result in diagnostic delays and hesitancy to refer suspected cases to specialist clinics. An unmet need remains for greater awareness and education. Therefore, an international expert panel of dermatologists, oncologists, hematologists, and dermatopathologists convened to discuss and identify barriers to early and accurate MF diagnosis that could guide clinicians toward making a correct diagnosis. Confirmation of MF requires accurate assessment of symptoms and clinical signs, and subsequent correlation with dermatopathological findings. This review summarizes the expert panel's guidance, based on the literature and real-life experience, for dermatologists to help include MF in their list of differential diagnoses, along with simple clinical and histopathologic checklists that may help clinicians to suspect and identify potential MF lesions and reduce diagnostic delays.

PDF file - 67K, Supplementary table 1; Primer sequences. Supplementary figure 1; Effects of immunosuppressive drugs on epidermal proliferation in HSEs (n=3-4) as % of Ki-67 positive (supra-)basal cells. Supplementary figure 2: Mice on Aza diet (A) show more extensive burning 72 hours after UV irradiation compared with mice on control diet (C). Supplementary figure 3; No effect of Aza on tumor yields induced by daily UVA irradiation.Supplementary figure 4; Tumor-free survival (Kaplan-Meier) plots of the different treatment groups (n=12-13)

Supplementary Table 4 from Novel and Highly Recurrent Chromosomal Alterations in Sézary Syndrome

Supplementary Table 2 from Novel and Highly Recurrent Chromosomal Alterations in Sézary Syndrome

Supplementary Figure 1 from Novel and Highly Recurrent Chromosomal Alterations in Sézary Syndrome

Supplementary Table 1 from Novel and Highly Recurrent Chromosomal Alterations in Sézary Syndrome

Supplementary Table 3 from Novel and Highly Recurrent Chromosomal Alterations in Sézary Syndrome

Background: Erythrodermic cutaneous T-cell lymphoma (E-CTCL) is associated with a poor prognosis and severe symptoms. Objective: To establish insights into the quality of life (QoL), expectations, and treatment satisfaction of E-CTCL patients receiving mogamulizumab. Methods: Outcomes of this prospective cohort study conducted between September 2020 and August 2021 at the Leiden University Medical Center included the dermatology-specific QoL (Skindex-29), health-related QoL (RAND-12), degree of itch, pain, and fatigue (Visual Analogue Scale), patient’s expectations, and treatment satisfaction (Client Satisfaction Questionnaire-8 (CSQ-8)), measured at baseline and after six months. Results: 13 patients with E-CTCL were included. Most patients anticipated a positive treatment effect on symptoms. Five patients (46%) improved one or more clinical categories regarding the symptoms domain, six (55%) regarding emotions, four (36%) regarding functioning, and four (36%) regarding the overall Skindex-29 score compared to baseline. The Mental Component Score clinically improved from 31 (IQR 29–51) at baseline to 38 (IQR 25–51). The median VAS itch improved significantly from baseline (8 (IQR 7–10) vs. 3 (IQR 1–8), p = 0.024). Most patients (n = 7) were “very satisfied” with their treatment. Limitations: There was a limited number of patients due to the rarity of the disease. Conclusion: In general, mogamulizumab has a favorable effect on biochemical- and dermatology-specific QoL and physical functioning in some patients, with high treatment satisfaction. Itch especially improved over time in most patients. The treatment satisfaction was generally high. Mogamulizumab seems to be an effective treatment that improves the QoL in patients with E-CTCL.

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is a rare, aggressive cutaneous lymphoma with a 5-year disease-specific survival of only ~55%. Despite high response rates to initial immune-polychemotherapy, most patients experience a disease relapse. The genetic evolution of primary and relapsed/refractory disease has only scarcely been studied in PCDLBCL-LT patients. Therefore, in this retrospective cohort study, 73 primary/pre-treatment and relapsed/refractory biopsies of 57 patients with PCDLBCL-LT were molecularly characterized with triple FISH and targeted next-generation sequencing for 52 B-cell-lymphoma-relevant genes, including paired analysis in 16 patients. In this cohort, 95% of patients harboured at least one of the three main driver alterations (mutations in MYD88/CD79B and/or CDKN2A-loss). In relapsed/refractory PCDLBCL-LT, these oncogenic aberrations were persistently present, demonstrating genetic stability over time. Novel alterations in relapsed disease affected mostly CDKN2A, MYC, and PIM1. Regarding survival, only MYC rearrangements and HIST1H1E mutations were statistically significantly associated with an inferior outcome. The stable presence of one or more of the three main driver alterations (mutated MYD88/CD79B and/or CDKN2A-loss) is promising for targeted therapies addressing these alterations and serves as a rationale for molecular-based disease monitoring, improving response evaluation and early identification and intervention of disease relapses in these poor-prognostic PCDLBCL-LT patients. ispartof: CANCERS vol:14 issue:20 ispartof: location:Switzerland status: published

The number of patients with primary cutaneous lymphoma (PCL) relative to other non-Hodgkin lymphomas (NHLs) is small and the number of subtypes large. Although clinical trial guidelines have been published for mycosis fungoides/Sézary syndrome, the most common type of PCL, none exist for the other PCLs. In addition, staging of the PCLs has been evolving based on new data on potential prognostic factors, diagnosis, and assessment methods of both skin and extracutaneous disease and a desire to align the latter with the Lugano guidelines for all NHLs. The International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous LymphomaConsortium (USCLC), and the Cutaneous Lymphoma Task Force of the European Organization for the Research and Treatment of Cancer (EORTC) now propose updated staging and guidelines for the study design, assessment, endpoints, and response criteria in clinical trials for all the PCLs in alignment with that of the Lugano guidelines. These recommendations provide standardized methodology that should facilitate planning and regulatory approval of new treatments for these lymphomas worldwide, encourage cooperative investigator-initiated trials, and help to assess the comparative efficacy of therapeutic agents tested across sites and studies.

Primary cutaneous anaplastic large cell lymphoma (pcALCL), a hematological neoplasm caused by skin-homing CD30+ malignant T cells, is part of the spectrum of primary cutaneous CD30+ lymphoproliferative disorders. To date, only a small number of molecular alterations have been described in pcALCL and, so far, no clear unifying theme that could explain the pathogenetic origin of the disease has emerged among patients. In order to clarify the pathogenetic basis of pcALCL, we performed high-resolution genetic profiling (genome/transcriptome) of this lymphoma (n=12) by using whole-genome sequencing, whole-exome sequencing and RNA sequencing. Our study, which uncovered novel genomic rearrangements, copy number alterations and small-scale mutations underlying this malignancy, revealed that the cell cycle, T-cell physiology regulation, transcription and signaling via the PI-3-K, MAPK and G-protein pathways are cellular processes commonly impacted by molecular alterations in patients with pcALCL. Recurrent events affecting cancer-associated genes included deletion of PRDM1 and TNFRSF14, gain of EZH2 and TNFRSF8, small-scale mutations in LRP1B, PDPK1 and PIK3R1 and rearrangements involving GPS2, LINC-PINT and TNK1. Consistent with the genomic data, transcriptome analysis uncovered upregulation of signal transduction routes associated with the PI-3-K, MAPK and G-protein pathways (e.g., ERK, phospholipase C, AKT). Our molecular findings suggest that inhibition of proliferation-promoting pathways altered in pcALCL (particularly PI-3-K/AKT signaling) should be explored as potential alternative therapy for patients with this lymphoma, especially, for cases that do not respond to first-line skin-directed therapies or with extracutaneous disease.

Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (pcAECyTCL) is a rare variant of cutaneous T-cell lymphoma with an aggressive clinical course and a very poor prognosis. Until now, neither a systematic characterization of genetic alterations driving pcAECyTCL has been performed, nor effective therapeutic regimes for patients have been defined. Here, we present the first highresolution genetic characterization of pcAECyTCL by using wholegenome and RNA sequencing. Our study provides a comprehensive description of genetic alterations (i.e., genomic rearrangements, copy number alterations and small-scale mutations) with pathogenic relevance in this lymphoma, including events that recurrently impact genes with important roles in the cell cycle, chromatin regulation and the JAKSTAT pathway. In particular, we show that mutually exclusive structural alterations involving JAK2 and SH2B3 predominantly underlie pcAECyTCL. In line with the genomic data, transcriptome analysis uncovered upregulation of the cell cycle, JAK2 signaling, NF-κB signaling and a high inflammatory response in this cancer. Functional studies confirmed oncogenicity of JAK2 fusions identified in pcAECyTCL and their sensitivity to JAK inhibitor treatment. Our findings strongly suggest that overactive JAK2 signaling is a central driver of pcAECyTCL, and consequently, patients with this neoplasm would likely benefit from therapy with JAK2 inhibitors such as Food and Drug Adminstration-approved ruxolitinib.

Background Cutaneous peripheral T-cell lymphoma, not otherwise specified (PTL NOS) is an aggressive, but poorly characterized neoplasm. Objectives The European Organization for Research and Treatment of Cancer cutaneous lymphoma taskforce (EORTC CLTF) investigated 33 biopsies of 30 patients with primary cutaneous PTL NOS to analyse their clinical, histological, immunophenotypic features and outcome. Methods Retrospective analysis of clinical data and histopathological features by an expert panel. Results Cutaneous PTL NOS manifested clinically either with solitary or disseminated rapidly grown ulcerated tumours or disseminated papulo-nodular lesions. Histologically, a mostly diffuse or nodular infiltrate in the dermis and often extending into the subcutis was found. Epidermotropism was rarely present and only mild and focal. Unusual phenotypes were frequent, e.g. CD3+ /CD4- /CD8- and CD3+ /CD4+ /CD8+ . Moreover, 18% of the cases exhibited an aberrant expression of the B-cell marker CD20 by the tumour cells. All solitary tumours were located on the limbs and presented a high expression of GATA-3 but this did not correlate with outcome and therefore could not serve as a prognostic factor. The prognosis was shown to be generally poor with 10 of 30 patients (33%) dying of lymphoma within the follow-up of 36 months (mean value; range 3-144). The survival rates were 61% after 3 years (CI, 43-85%) and 54% after 5 years (CI, 36-81%). Small to medium-sized morphology of tumour cells was associated with a better outcome than medium to large or large tumour cells. Age, gender, clinical stage, CD4/CD8 phenotype and GATA-3 expression were not associated with prognosis. Chemotherapy was the most common treatment modality, but surgical excision and/or radiotherapy may represent an appropriate first-line treatment for solitary lesions. Conclusions Cutaneous PTL NOS shows an aggressive course in most patients independent of initial presentation, age and phenotype. Cytomorphology was identified as a prognostic factor. The data indicate a need for more effective treatment modalities in PTL NOS.

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Background Lymphomatoid papulosis (LyP) can be associated with other haematological malignancies (HM), but reported percentages vary from 20% to over 50%. Objective To evaluate the frequency and prognostic significance of associated HM and non‐HM in LyP patients. Methods In this multicentre cohort study, the complete Dutch LyP population was included from the Dutch Cutaneous Lymphoma Registry between 1985 and 2018. Clinical and histopathological information was retrieved from every individual patient. Results After a median follow‐up of 120 months (range, 6–585), an associated HM was observed in 78/504 (15.5%) patients. Most common associated HM were mycosis fungoides (MF; n = 31) and anaplastic large‐cell lymphoma (ALCL; n = 29), while 19 patients had another HM of B‐cell (n = 14) or myeloid origin (n = 5). Even after a 25‐year follow‐up period, percentages of associated HM did not exceed 20%. Thirty‐nine of 465 patients (8.4%) without a prior or concurrent associated HM developed an associated HM during follow‐up, after a median of 68 months (range of 3–286 months). Nine of 78 patients died of associated HM, including 6/22 patients developing extracutaneous ALCL, while all patients with associated MF or skin‐limited ALCL had an excellent prognosis. Compared with the general population, LyP patients showed an increased risk (relative risk, 2.8; 95% confidence intervals, 2.4–3.3) for non‐HM, in particular cutaneous squamous cell carcinoma, melanoma and intestinal/lung/bladder cancer. Conclusions An associated HM was reported in 15.5% of the LyP patients, particularly MF and ALCL. Although the frequency of associated HM is lower than suggested and the prognosis of most patients with associated HM is excellent, a small subgroup will develop aggressive disease, in particular extracutaneous ALCL. Furthermore, LyP patients have a higher risk of developing other malignancies. Clinicians should be aware of these risks, and LyP patients require close monitoring., Linked article: F. Rongioletti. J Eur Acad Dermatol Venereol 2020; 34: 216–217. https://doi.org/10.1111/jdv.16157.

Abstract Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) and primary cutaneous follicle center lymphoma with a diffuse population of large cells (PCFCL-LC) are both primary cutaneous B-cell lymphomas with large-cell morphology (CLBCL) but with different clinical characteristics and behavior. In systemic diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS), gene-expression profiling (GEP) revealed two molecular subgroups based on their cell-of-origin (COO) with prognostic significance: the germinal center B-cell-like (GCB) subtype and the activated B-cell-like (ABC) subtype. This study investigated whether COO classification is a useful tool for classification of CLBCL. For this retrospective study, 51 patients with PCDLBCL-LT and 15 patients with PCFCL-LC were analyzed for their COO according to the immunohistochemistry-based Hans algorithm and the NanoString GEP-based Lymph2Cx algorithm. In PCFCL-LC, all cases (100%) classified as GCB by both Hans and Lymph2Cx. In contrast, COO classification in PCDLBCL-LT was heterogeneous. Using Hans, 75% of the PCDLBCL-LT patients classified as non-GCB and 25% as GCB, while Lymph2Cx classified only 18% as ABC, 43% as unclassified/intermediate, and 39% as GCB. These COO subgroups did not differ in the expression of BCL2 and IgM, mutations in MYD88 and/or CD79B, loss of CDKN2A, or survival. In conclusion, PCFCL-LC uniformly classified as GCB, while PCDLBCL-LT classified along the COO spectrum of DLBCL-NOS using the Hans and Lymph2Cx algorithms. In contrast to DLBCL-NOS, the clinical relevance of COO classification in CLBCL using these algorithms has limitations and cannot be used as an alternative for the current multiparameter approach in differentiation of PCDLBCL-LT and PCFCL-LC.

The differential diagnosis of atypical dermal nonepidermotropic CD8To assess the clinical, histological and immunophenotypic features; outcomes of; and differences between dermal CD8Retrospective analysis of a series of 46 patients and biopsies by the international EORTC Cutaneous Lymphoma Group.The dermal CD8A constellation of distinct clinical, histopathological and phenotypic features allows discrimination and assignment of dermal CD8

Cutaneous T-cell Lymphoma's (CTCL) are a rare, heterogeneous group of T-cell lymphomas that primarily manifest in the skin. Mycosis fungoides (MF) and Sézary syndrome (SS) are considered the classic types of CTCL. The diverse manifestation of CTCL results in a wide range of symptoms with a possible mild to severe impact on Quality of Life (QoL) depending on the disease stage. Previous studies on QoL in CTCL patients report diverse patient populations and use many different QoL instruments. In the current literature, a clear overview on the influence of the different stages of disease (early MF, late-stage MF/SS or total group) on the QoL is lacking. Therefore, a systematic search of the literature was conducted using the PubMed, Embase, PsycINFO and Web of Science databases. Studies were included if they described QoL in patients with MF and SS retrieved by standardized instruments or qualitative interviews. In total, 24 studies were included using 18 different questionnaires to report on dermatology-specific, cancer-specific and generic QoL. The effect on QoL was found to be greater in patients with late-stage disease as compared to early stage disease, with significant impairments on functional, emotional and physical domains. Nonetheless, even in patients with limited disease, QoL was mildly to moderately affected. Overall, pruritus was the most frequent reported and most bothersome symptom. Significant influence of the disease on daily life activities were found, not only in patients but also on caregivers and family. This broad, structured overview on QoL in MF and SS patients underlines the influence of disease stage on QoL, and therefore, recommends future studies to distinguish between disease stages when reporting results. Furthermore, this overview can inform clinicians in clinical practice by creating awareness of QoL deficits according to disease stage.

Aim Recent studies suggested a role for IL31 in the pathogenesis of pruritus and disease severity in patients with cutaneous T cell lymphomas (CTCL). However, discrepant results were reported for IL31 serum levels, transcriptional expression levels or immunohistochemistry studies and its relation to pruritus intensity and/or disease severity in CTCL. Most studies did not distinguish between different CTCL variants. We investigated IL31 serum levels in different subtypes of CTCL, including Mycosis Fungoides (MF) (typically not pruritic), Folliculotropic Mycosis Fungoides (FMF) and Sézary syndrome (SS) (both often pruritic). Methods From 54 CTCL patients (17 SS, 21 FMF and 16 classic MF) serum samples were analyzed with a high sensitivity V-PLEX immunoassay for IL31. The study group included 35/54 (65%) patients with complaints of pruritus. Thirty-five patients had advanced stage disease (≥stage IIB). A visual analog scale score (VAS score) for pruritus was available in 29 CTCL patients (7 SS, 9 FMF and 13 classic MF) and in other cases complaints of pruritus were retrieved from medical records. qPCR analyses for IL31 expression were performed in lesional skin biopsies from 8 CTCL patients. Serum samples from 4 healthy individuals without pruritus and from 5 atopic dermatitis (AD) patients with severe pruritus were included as controls. Results In 11/54 (20%) of CTCL patients low serum levels of IL31 were detected (mean 0.48 pg/mL, range 0.20–1.39 pg/mL) including 6/17 (35%) SS patients (mean 0.57 pg/mL) and 5/21 (24%) FMF patients (mean 0.33 pg/mL). All 11 patients with detectable levels of IL31 reported complaints of moderate to severe pruritus and 9/11 patients presented with advanced stage disease (≥IIB). qPCR analyses resulted in lowly expressed IL31 expression levels in 4 of 8 patients; these patients all suffered from pruritus and advanced stage disease. Conclusions Translational and transcriptional expression levels of IL31 were very low or undetectable in CTCL patients. Detectable low IL31 serum levels were exclusively observed in SS and FMF patients and not in patients with classic MF. However, these marginal IL31 levels in a small proportion of CTCL patients do not support an essential role for IL31 in CTCL patients., Highlights • Interleukin 31 (IL31) is suggested to play a key role in pruritus. • Cutaneous T cell lymphoma (CTCL) patients may suffer from severe pruritus. • Previous reports show variable results regarding the role of IL31 in CTCL patients. • Minimal to undetectable IL31 serum levels were found in 54 CTCL patients. • These observations do not support a prominent role for IL31 in CTCL.

Primary cutaneous lymphomas are a heterogeneous group of T- and B-cell lymphomas that present in the skin with no evidence of extracutaneous disease at the time of diagnosis. The 2005 World Health Organization–European Organization for Research and Treatment of Cancer (WHO-EORTC) consensus classification has served as a golden standard for the diagnosis and classification of these conditions. In September 2018, an updated version of the WHO-EORTC was published in the fourth edition of the WHO Classification of Skin Tumours Blue Book. In this classification, primary cutaneous acral CD8+ T-cell lymphoma and Epstein-Barr virus positive (EBV+) mucocutaneous ulcer are included as new provisional entities, and a new section on cutaneous forms of chronic active EBV disease has been added. The term “primary cutaneous CD4+ small/medium T-cell lymphoma” was modified to “primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder” because of its indolent clinical behavior and uncertain malignant potential. Modifications have also been made in the sections on lymphomatoid papulosis, increasing the spectrum of histologic and genetic types, and primary cutaneous marginal zone lymphomas recognizing 2 different subtypes. Herein, the characteristic features of these new and modified entities as well as the results of recent molecular studies with diagnostic, prognostic, and/or therapeutic significance for the different types of primary cutaneous lymphomas are reviewed. An update of the frequency and survival of the different types of primary cutaneous lymphomas is provided.

We present the case of a 50-year-old patient with folliculotropic mycosis fungoides (FMF) unresponsive to retinoids and the chemotherapeutic regimens CHOP, gemcitabine, and brentuximab-vedotin. During immunosuppressive therapy, the patient developed extensive progressive molluscum contagiosum. The mollusca did not respond to topical imiquimod but showed a swift complete response to interferon-alpha 2a (IFNa). Recently, the patient started with alemtuzumab as induction therapy for an allogenic stem cell transplantation and simultaneously continued IFNa therapy. (C) 2019 The Author(s) Published by S. Karger AG, Basel

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) and primary cutaneous follicle center lymphoma (PCFCL) are cutaneous B-cell lymphomas (CBCL) with different clinical characteristics and behavior. PCDLBCL-LT is the most aggressive CBCL with a relatively poor prognosis. In nodal diffuse large B-cell lymphoma (DLBCL), rearrangements of the MYC gene, especially in combination with a second hit in BCL2 and/or BCL6, and double protein expression of MYC and BCL2 (DE) are adverse prognostic factors. As the clinical significance of these factors in CBCL is largely unknown, we studied the frequency and prognostic value of MYC rearrangements and DE in a cohort of 44 patients with PCDLBCL-LT and 17 patients with PCFCL. Compared with nodal DLBCL (9% to 14%), the PCDLBCL-LT patients had a high incidence of MYC rearrangements (32%), but only 2 patients (4%) had a second hit, both with BCL6. PCDLBCL-LT patients with a MYC rearrangement showed an inferior disease-specific survival (Log-rank, P=0.036) and disease-free survival (Log-rank, P=0.028), but no significant adverse effect on overall survival (Log-rank, P=0.157) at 5 years compared with patients without a MYC rearrangement. DE, present in 65% of the PCDLBCL-LT patients, was not associated with reduced survival. In the PCFCL group, MYC rearrangements and DE were not detected. In conclusion, this study identifies a high incidence of MYC rearrangements in PCDLBCL-LT compared to nodal DLBCL and further shows that a MYC rearrangement is an inferior prognostic marker in these patients. Therefore, our data suggest that it is useful to perform MYC-FISH in all newly diagnosed PCDLBCL-LT patients.

Background The PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study is a prospective analysis of an international database. Here we examine front-line treatments and quality of life (QoL) in patients with newly diagnosed mycosis fungoides (MF).Objectives To identify (i) differences in first-line approaches according to tumour-nodes-metastasis-blood (TNMB) staging; (ii) parameters related to a first-line systemic approach and (iii) response rates and QoL measures.Methods In total, 395 newly diagnosed patients with early-stage MF (stage IA-IIA) were recruited from 41 centres in 17 countries between 1 January 2015 and 31 December 2018 following central clinicopathological review.Results The most common first-line therapy was skin-directed therapy (SDT) (322 cases, 81 center dot 5%), while a smaller percentage (44 cases, 11 center dot 1%) received systemic therapy. Expectant observation was used in 7 center dot 3%. In univariate analysis, the use of systemic therapy was significantly associated with higher clinical stage (IA, 6%; IB, 14%; IIA, 20%; IA-IB vs. IIA, P < 0 center dot 001), presence of plaques (T1a/T2a, 5%; T1b/T2b, 17%; P < 0 center dot 001), higher modified Severity Weighted Assessment Tool (> 10, 15%

Primary cutaneous lymphomas are a heterogeneous group of non-Hodgkin lymphomas that present in the skin with no evidence of extracutaneous disease at the time of diagnosis. Within this group, the majority is derived from T-cells. The different types of cutaneous lymphomas are defined by various clinical manifestations, histological patterns, and immunophenotypic markers. In contrast to the nodal non-Hodgkin lymphomas, primary cutaneous T-cell lymphomas (CTCL) usually represent an indolent disease group and therefore require mostly skin-directed therapies. However, at later stages, certain subtypes run a more aggressive course.

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Primary cutaneous lymphomas are a heterogeneous group of cutaneous T-cell lymphomas (CTCL) and cutaneous B-cell lymphomas (CBCL) that present in the skin with no evidence of extracutaneous disease at the time of diagnosis. In the last decade the 2005 WHO-EORTC consensus classification has served as a golden standard for the diagnosis and classification of these conditions. Recently, an updated version of the WHO-EORTC was published. This classification contains several new entities, including primary cutaneous acral CD8+ T-cell lymphoma and EBV-positive mucocutaneous ulcer, while other conditions were slightly modified. Herein, the characteristic features of the different types of CTCL and CBCL are presented, differences with previous classification schemes discussed and the results of more recent molecular studies with clinical implications for these conditions reviewed. In addition, an update of the frequency and survival of the different types of primary cutaneous lymphomas is provided.

Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (pcAECyTCL) is a rare variant of cutaneous T-cell lymphoma with an aggressive clinical course and a very poor prognosis. Until now, neither a systematic characterization of genetic alterations driving pcAECyTCL has been performed, nor effective therapeutic regimes for patients have been defined. Here, we present the first highresolution genetic characterization of pcAECyTCL by using wholegenome and RNA sequencing. Our study provides a comprehensive description of genetic alterations (i.e., genomic rearrangements, copy number alterations and small-scale mutations) with pathogenic relevance in this lymphoma, including events that recurrently impact genes with important roles in the cell cycle, chromatin regulation and the JAKSTAT pathway. In particular, we show that mutually exclusive structural alterations involving JAK2 and SH2B3 predominantly underlie pcAECyTCL. In line with the genomic data, transcriptome analysis uncovered upregulation of the cell cycle, JAK2 signaling, NF-κB signaling and a high inflammatory response in this cancer. Functional studies confirmed oncogenicity of JAK2 fusions identified in pcAECyTCL and their sensitivity to JAK inhibitor treatment. Our findings strongly suggest that overactive JAK2 signaling is a central driver of pcAECyTCL, and consequently, patients with this neoplasm would likely benefit from therapy with JAK2 inhibitors such as Food and Drug Adminstration-approved ruxolitinib.

Unlike systemic anaplastic large cell lymphoma, the vast majority of primary cutaneous anaplastic large cell lymphomas (C-ALCL) do not carry translocations involving the ALK gene and do not express ALK. Expression of ALK protein therefore strongly suggests secondary cutaneous involvement of a systemic anaplastic large cell lymphoma. Recent studies described a small subgroup of ALK-positive C-ALCL, but information on frequency, prognosis, and translocation partners is virtually lacking. A total of 6/309 (2%) C-ALCL patients included in the Dutch registry for cutaneous lymphomas between 1993 and 2019 showed immunohistochemical ALK expression. Clinical and histopathologic characteristics, immunophenotype and disease course were evaluated. Underlying ALK translocations were analyzed with anchored multiplex polymerase chain reaction-based targeted next-generation sequencing. Median age at diagnosis was 39 years (range: 16 to 53 y). All patients presented with a solitary lesion. Treatment with radiotherapy (n=5) or anthracycline-based chemotherapy (n=1) resulted in complete responses in all 6 patients. Three patients developed a relapse, of whom 2 extracutaneous. After a median follow-up of 41 months, 5 patients were alive without disease and 1 patient died of lymphoma. Immunohistochemically, 3 cases (50%) showed combined nuclear and cytoplasmic ALK expression with underlying NPM1-ALK fusions, while 3 cases (50%) showed solely cytoplasmic ALK expression with variant ALK fusion partners (TRAF1, ATIC, TPM3). ALK-positive C-ALCL is extremely uncommon, has a comparable favorable prognosis to ALK-negative C-ALCL, and should be treated in the same way with radiotherapy as first-line treatment.

Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (pcAECyTCL) is a rare provisionally categorized cutaneous lymphoma characterized by an aggressive course. Its pathogenesis and molecular mechanisms are still unknown, and only two individual cases have so far been molecularly characterized. The aim of this study was to define the pattern of numerical chromosomal alterations in tumor samples taken from 20 patients with pcAECyTCL at the time of diagnosis by means of array-comparative genomic hybridization (a-CGH). a-CGH detected numerous genomic aberrations in all the patients and, putting these together as a whole, they affected all the chromosomes. However, no specific profile of recurrent copy number alterations (CNAs) was found. Most of the gains involved regions previously described in other aggressive cutaneous lymphomas such as 7q, 8q24.3, and 17q, whereas the most significant CNA was the loss of 9p21.3 (CDKN2A-CDKN2B), which has already been found in a variety of malignant tumors and is associated with aggressive cutaneous T-cell lymphomas. In brief, CGH analysis revealed a large number of CNAs with only few recurring regions that probably do not represent driving events. The genomic instability found in this aggressive variant of cutaneous lymphoma may therefore be a secondary event but, at the time of the diagnosis of pcAECyTCL, the genomic integrity of tumor cells is already compromised.

This pathology PILOT study aims to define the role and feasibility of centralized pathology review in a cohort of 75 patients from different centers in the United States and Europe using digital slide scanning. The pathologic material from 75 patients who had been diagnosed with mycosis fungoides/Sézary syndrome and were clinically staged as IIb or above was retrieved from 11 participating centers. Each pathology reviewer was provided with the pathologic diagnosis (by the referring pathologist), and the following list of histopathologic criteria (presence or absence) from the initial report: epidermotropism, folliculotropism (FT), large cell transformation, syringotropism, and granulomas. Patients with advance stage were selected for this study as this is a population where there is significant variability in the diagnosis of pathologic prognostic and predictive biomarkers. The slides were digitally scanned with an Aperio scanner and consensus review of cases occurred when major or minor discrepancies between the referral diagnosis and central pathology review occurred. Among the 75 cases, 70 (93.3%) had a final consensus diagnosis between the 3 central review pathologists. The overall agreement between the consensus review and the referring pathologist was 60%. The overall agreement was also higher between the reviewers and consensus review, compared with the referring pathologist and consensus. 65.3% of cases had some type of discrepancy (major or minor) between the outside and consensus review. Major discrepancies were seen in 34 of 73 cases (46.6%; 73 cases indicated a yes or no response). Minor discrepancies were seen in 32 of 75 (42.7%) of cases. Most of the major discrepancies were accounted by a difference in interpretation in the presence or absence of large cell transformation or FT. Most minor discrepancies were explained by a different interpretation in the expression of CD30. We found digital slide scanning to be a beneficial, reliable, and practical for a methodical approach to perform central pathology review in the context of a large clinical prospective study.

BackgroundThere is no consensus on the treatment of multifocal primary cutaneous anaplastic large cell lymphoma (C-ALCL). Radiotherapy (RT) and methotrexate (MTX) are the current treatment options, but their efficacy is unknown. Recently, targeted therapies showed promising results in C-ALCL, and may therefore be an attractive first choice of treatment.ObjectivesTo assess the efficacy of conventional treatment strategies for patients with multifocal C-ALCL, and to define which patients may require novel targeted therapies.MethodsIn this multicentre study, treatment was evaluated in patients initially presenting (n = 24) or relapsing with multifocal C-ALCL (n = 17; 23 relapses). Distinction was made between patients with five or less lesions (n = 36) and more than five lesions (n = 11).ResultsTreatments most commonly used were RT (n = 21), systemic chemotherapy (n = 9) and low-dose MTX (n = 7) with complete response rates of 100%, 78% and 43%, respectively, and an overall response rate of 100%, 100% and 57%, respectively. Four patients showed complete spontaneous regression. In total, 16 of 24 patients (67%) first presenting with multifocal C-ALCL relapsed, including all five patients initially treated with CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone). Compared with patients presenting with two to five skin lesions, patients presenting with more than five lesions had a higher chance of developing extracutaneous relapse (56% vs. 20%) and more often died of lymphoma (44% vs. 7%).ConclusionsPatients with five or less lesions should be treated with low-dose RT (2 x 4 Gy). Maintenance low-dose MTX (20 mg weekly) is a suitable option in patients with more than five lesions. Targeted therapies may be considered in rare patients who are refractory to MTX or patients developing extracutaneous disease.What's already known about this topic?There is no consensus on the treatment of multifocal primary cutaneous anaplastic large cell lymphoma (C-ALCL). New targeted therapies are evaluated without knowledge of the efficacy of conventional therapies.What does this study add?This study evaluated the efficacy of conventional therapies for multifocal C-ALCL. Radiotherapy and low-dose methotrexate are suitable options in patients with five or less and more than five lesions, respectively. Targeted therapies may be considered in rare patients who are refractory to methotrexate or developing extracutaneous disease.Linked Comment:Kempf. Br J Dermatol 2018; 179:565-566. Respond to this article

TO THE EDITOR: Intravascular large B-cell lymphoma (IVLBCL) is a rare variant of extranodal diffuse large B-cell lymphoma (DLBCL). It is characterized by proliferation of blastic, neoplastic B cells within the lumina of small- or intermediate-sized blood vessels and capillaries.[1][1] IVLBCL may

Primary cutaneous anaplastic large cell lymphoma (C-ALCL) is an indolent cutaneous CD30-positive T-cell lymphoma with no signs of extracutaneous localizations at the time of diagnosis. C-ALCL is clinically characterized by single or localized, sometimes ulcerating tumors and histopathologically by diffuse sheets of large anaplastic cells.1 Spitzoid neoplasms are melanocytic tumors usually occurring in young individuals. They are characterized clinically by pigmented or spherical reddish lesions and histopathologically by spindle-shaped and epithelioid melanocytes.2 In a small proportion of patients, both diseases can be driven by or harbor rearrangements involving the anaplastic lymphoma kinase (ALK) gene.2,3

Introduction: Folliculotropic mycosis fungoides (FMF) is a cutaneous T cell lymphoma that is recognized as a distinct variant of mycosis fungoides (MF) due to its unique clinicopathologic features and its more aggressive disease course as compared to classic MF. Recent studies distinguished an indolent (early stage FMF) and a more aggressive (advanced stage FMF) subgroup, that require a different therapeutic approach.Areas covered: This review provides an overview of the evolving concepts and recent developments in FMF and summarizes various treatment options for early and advanced stages of FMF including skin-directed therapies, immunomodulating agents, HDAC inhibitors, targeted anti-CD30 therapy and the role of chemotherapy and haematological stem cell transplantation.Expert opinion: Recently defined prognostic subgroups show that early stage FMF patients have an indolent disease course and may benefit very well from skin-directed therapies, also used in early stage classic MF. Advanced skin lim...

Time to next treatment (TTNT), a recently established endpoint in clinical trials for primary cutaneous T-cell lymphomas (CTCL), represents a useful indication as a surrogate marker for the durtion of clinical benefit. It is a unique parameter which allows to take into consideration not only the duration of clinical activity of a specific drug regimen but also the patient compliance and tolerability of the treatment schedule. A series of data clearly support the short duration of TTNT in patients with CTCL. The present paper analyses TTNT and time to next systemic treatment (TTNsT) in the PROCLIPI cohort of patients. PROCLIPI registry was established since 2,015 and includes all the new diagnoses of mycosis fungoides/Sezary syndrome (MF/SS) patients in CTCL referral centers worldwide. Untill now, a total of 4,756 treatments were registered among which 2,647 at visit 1. According to the treatment category, 2,364 skin-directed therapies (SDT) were registered (49.7%) and 1,810 systemic (38%), while 482 patients were managed through an expectant policy. TTNT analysis was performed in 2,969 cases who received a further treatment. Median TTNT was 136 days corresponding to 4.5 months for the entire cohort (range from 1 month to 5.7 years. As to TTNsT among 1,743 cases, median values were 169 days (corresponding to 5.6 months (up to 4.3 years). This preliminary analysis confirms the short duration of TTNT and TTNsT in MF/SS patients diagnosed in treated in real life, supporting the importance of identifying clinical and biological markers with predictive value on treatment benefit as well as new treatment approaches aimed to improve disease outcome. on behalf the CLIC Alliance, CLIC Treatment Working Group, EORTC and ISCL collaborative study groups and all the PROCLIPI centers.