Artificial intelligence in digital pathology of cutaneous lymphomas: A review of the current state and future perspectives.

Primary cutaneous lymphomas (CLs) represent a heterogeneous group of T-cell lymphomas and B-cell lymphomas that present in the skin without evidence of extracutaneous involvement at time of diagnosis. CLs are largely distinct from their systemic counterparts in clinical presentation, histopathology, and biological behavior and, therefore, require different therapeutic management. Additional diagnostic burden is added by the fact that several benign inflammatory dermatoses mimic CL subtypes, requiring clinicopathological correlation for definitive diagnosis. Due to the heterogeneity and rarity of CL, adjunct diagnostic tools are welcomed, especially by pathologists without expertise in this field or with limited access to a centralized specialist panel. The transition into digital pathology workflows enables artificial intelligence (AI)-based analysis of patients' whole-slide pathology images (WSIs). AI can be used to automate manual processes in histopathology but, more importantly, can be applied to complex diagnostic tasks, especially suitable for rare disease like CL. To date, AI-based applications for CL have been minimally explored in literature. However, in other skin cancers and systemic lymphomas, disciplines that are recognized here as the building blocks for CLs, several studies demonstrated promising results using AI for disease diagnosis and subclassification, cancer detection, specimen triaging, and outcome prediction. Additionally, AI allows discovery of novel biomarkers or may help to quantify established biomarkers. This review summarizes and blends applications of AI in pathology of skin cancer and lymphoma and proposes how these findings can be applied to diagnostics of CL.

Genetic and epigenetic insights into cutaneous T-cell lymphoma.

Primary cutaneous T-cell lymphomas (CTCLs) constitute a heterogeneous group of non-Hodgkin T-cell lymphomas that present in the skin. In recent years, significant progress has been made in the understanding of the pathogenesis of CTCLs. Progress in CTCL classifications combined with technical advances, in particular next-generation sequencing, enabled a more detailed analysis of the genetic and epigenetic landscape and transcriptional changes in clearly defined diagnostic entities. These studies not only demonstrated extensive heterogeneity between different CTCL subtypes but also identified recurrent alterations that are highly characteristic for diagnostic subgroups of CTCLs. The identified alterations, in particular, involve epigenetic remodeling, cell cycle regulation, and the constitutive activation of targetable oncogenic pathways. In this respect, aberrant JAK-STAT signaling is a recurrent theme; however, it is not universal for all CTCLs and has seemingly different underlaying causes in different entities. A number of the mutated genes identified are potentially actionable targets for the development of novel therapeutic strategies. Moreover, these studies have produced an enormous amount of information that will be critically important for the further development of improved diagnostic and prognostic biomarkers that can assist in the clinical management of patients with CTCL. In the present review, the main findings of these studies in relation to their functional impact on the malignant transformation process are discussed for different subtypes of CTCLs.

Primary cutaneous lymphoma: recommendations for clinical trial design and staging update from the ISCL, USCLC, and EORTC.

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.

Identifying and addressing unmet clinical needs in primary cutaneous B-cell lymphoma: A consensus-based paper from an ad-hoc international panel.

Primary cutaneous B-cell lymphomas (PCBCLs) are lymphoproliferative disorders that appear on the skin without evidence of extracutaneous manifestations at the time of diagnosis. There is a lack of evidence-based guidelines for their clinical management due to the availability of very few large scale studies and controlled clinical trials. Here we present and discuss a series of major unmet clinical needs (UCNs) in the management of PCBCLs by a panel of 16 experts involved in research and clinical practice of PCBCL. The Panel produced recommendations on the appropriateness of the clinical decisions concerning the identified clinical needs and proposed research for improving the knowledge needed to solve them. Recommendations and proposals were achieved by multiple-step formalized procedures to reach a consensus after a comprehensive analysis of the scientific literature. Recommendations and proposals lay in the domain of classification uncertainties of PCBCL, optimization of diagnosis, optimization of prognosis, optimization of staging and critical issues on therapeutic strategies with particular focus on new treatments. These recommendations are intended for use not only by experts but above all by dermatologists and hematologists with limited experience in the field of PCBCLs as well as general practitioners.

Paediatric-onset lymphomatoid papulosis: results of a multicentre retrospective cohort study on behalf of the EORTC Cutaneous Lymphoma Tumours Group (CLTG).

BACKGROUND: Lymphomatoid papulosis (LyP) is a rare cutaneous T-cell lymphoproliferative disorder. Comprehensive data on LyP in the paediatric population are scarce. OBJECTIVES: To characterize the epidemiological, clinical, histopathological and prognostic features of paediatric LyP. METHODS: This was a retrospective multicentre international cohort study that included 87 children and adolescents with LyP diagnosed between 1998 and 2022. Patients aged ≤ 18 years at disease onset were included. LyP diagnosis was made in each centre, based on clinicopathological correlation. RESULTS: Eighty-seven patients from 12 centres were included. Mean age at disease onset was 7.0 years (range 3 months-18 years) with a male to female ratio of 2 : 1. Mean time between the onset of the first cutaneous lesions and diagnosis was 1.3 years (range 0-14). Initial misdiagnosis concerned 26% of patients. LyP was most often misdiagnosed as pityriasis lichenoides et varioliformis acuta, insect bites or mollusca contagiosa. Erythematous papules or papulonodules were the most frequent clinical presentation. Pruritus was specifically mentioned in 21% of patients. The main histological subtype was type A in 55% of cases. When analysed, monoclonal T-cell receptor rearrangement was found in 77% of skin biopsies. The overall survival rate was 100%, with follow-up at 5 years available for 33 patients and at 15 years for 8 patients. Associated haematological malignancy (HM) occurred in 10% of cases (n = 7/73), including four patients with mycosis fungoides, one with primary cutaneous anaplastic large cell lymphoma (ALCL), one with systemic ALCL and one with acute myeloid leukaemia. If we compared incidence rates of cancer with the world population aged 0-19 years from 2001 to 2010, we estimated a significantly higher risk of associated malignancy in general, occurring before the age of 19 years (incidence rate ratio 87.49, 95% confidence interval 86.01-88.99). CONCLUSIONS: We report epidemiological data from a large international cohort of children and adolescents with LyP. Overall, the disease prognosis is good, with excellent survival rates for all patients. Owing to an increased risk of associated HM, long-term follow-up should be recommended for patients with LyP.

Lymphomatoid papulosis is a very rare skin condition caused by an abnormal increase in white blood cells (called 'lymphocytes') in the skin. The condition rarely affects children, so most of the scientific data published about this disease focuses on adults. This study involved 12 academic dermatology centres in Europe, the Middle East and North America, and gathered data from about 87 children who presented with symptoms of lymphomatoid papulosis before the age of 19 years. The aim of this study was to better describe this disease in the paediatric population and discuss its treatment options and evolution. We found that the presentation of the disease in children is roughly the same as in adults. Safe and effective treatment options exist. The disease is not life threatening, but it requires investigation by a dermatologist, both to make a careful diagnosis and to monitor it as sometimes associated cancers that originate from blood cells can occur, mostly on the skin.

Mycosis Fungoides and Associated Malignancies in a Dutch Nationwide Retrospective Cohort Study.

The prognosis of patients with mycosis fungoides is variable. As the current literature is scarce and shows mixed results this study investigates the incidence of other primary malignancies in mycosis fungoides patients. A retrospective, nationwide, population- based cohort study was performed with patients with mycosis fungoides between 2000 and 2020 in The Netherlands. All histopathology reports were requested from the Nationwide Network and Registry of Histo- and Cytopathology and screened for other primary malignancies. Lifelong incidence rates were used to compare the incidence of malignancies in mycosis fungoides patients and the general population. In total 1,024 patients were included with a mean follow-up of 10 years (SD 6). A total of 294 cases of other primary malignancies were found with 29% of the mycosis fungoides patients developing at least 1 other primary malignancy. Only cutaneous (odds ratio [OR] 2.54; CI 2.0-3.2) and haematological malignancies (OR 2.62; CI 2.00-3.42) had a statistically significant higher incidence than the Dutch population overall. Mycosis fungoides patients have a significantly increased risk of developing melanomas (OR 2.76; CI 2.11-3.59) and cutaneous squamous cell carcinomas mycosis fungoides (OR 2.34; CI 1.58-3.45). This study shows no association between mycosis fungoides and other solid organ tumours; however, such patients are significantly at risk of developing other haematological and cutaneous malignancies. Clinicians should be aware of this increased risk.

Autoantibody subclass predominance is not driven by aberrant class switching or impaired B cell development.

A subset of autoimmune diseases is characterized by predominant pathogenic IgG4 autoantibodies (IgG4-AID). Why IgG4 predominates in these disorders is unknown. We hypothesized that dysregulated B cell maturation or aberrant class switching causes overrepresentation of IgG4+ B cells and plasma cells. Therefore, we compared the B cell compartment of patients from four different IgG4-AID with two IgG1-3-AID and healthy donors, using flow cytometry. Relative subset abundance at all maturation stages was normal, except for a, possibly treatment-related, reduction in immature and naïve CD5+ cells. IgG4+ B cell and plasma cell numbers were normal in IgG4-AID patients, however they had a (sub)class-independent 8-fold increase in circulating CD20-CD138+ cells. No autoreactivity was found in this subset. These results argue against aberrant B cell development and rather suggest the autoantibody subclass predominance to be antigen-driven. The similarities between IgG4-AID suggest that, despite displaying variable clinical phenotypes, they share a similar underlying immune profile.

Improved Sézary cell detection and novel insights into immunophenotypic and molecular heterogeneity in Sézary syndrome.

Sézary syndrome (SS) is an aggressive leukemic form of cutaneous T-cell lymphoma with neoplastic CD4+ T cells present in skin, lymph nodes, and blood. Despite advances in therapy, prognosis remains poor, with a 5-year overall survival of 30%. The immunophenotype of Sézary cells is diverse, which hampers efficient diagnosis, sensitive disease monitoring, and accurate assessment of treatment response. Comprehensive immunophenotypic profiling of Sézary cells with an in-depth analysis of maturation and functional subsets has not been performed thus far. We immunophenotypically profiled 24 patients with SS using standardized and sensitive EuroFlow-based multiparameter flow cytometry. We accurately identified and quantified Sézary cells in blood and performed an in-depth assessment of their phenotypic characteristics in comparison with their normal counterparts in the blood CD4+ T-cell compartment. We observed inter- and intrapatient heterogeneity and phenotypic changes over time. Sézary cells exhibited phenotypes corresponding with classical and nonclassical T helper subsets with different maturation phenotypes. We combined multiparameter flow cytometry analyses with fluorescence-activated cell sorting and performed RNA sequencing studies on purified subsets of malignant Sézary cells and normal CD4+ T cells of the same patients. We confirmed pure monoclonality in Sézary subsets, compared transcriptomes of phenotypically distinct Sézary subsets, and identified novel downregulated genes, most remarkably THEMIS and LAIR1, which discriminate Sézary cells from normal residual CD4+ T cells. Together, these findings further unravel the heterogeneity of Sézary cell subpopulations within and between patients. These new data will support improved blood staging and more accurate disease monitoring.

Stratum corneum cytokine levels in mycosis fungoides.

Mycosis fungoides (MF) is characterised by malignant CD4+ T-cell infiltrates in the skin. The functional characteristics of the malignant T cells and their interaction with the tumor immune microenvironment is largely unknown. We performed tape stripping of the stratum corneum (SC), a non-invasive technique, to gain insight into the cytokine secretion patterns in MF skin lesions. In addition, we assessed whether the SC cytokine profile of MF lesions is distinct from that of atopic dermatitis (AD) lesions. We compared nine cytokine levels in 20 patients with MF, 10 patients with AD and 10 healthy controls. In patients with MF and AD, lesional SC levels of IL-8 and MMP9 were significantly higher than in non-lesional SC and in healthy controls. VEGFα was significantly higher in lesional MF and AD skin than in healthy controls. The SC levels of IL-1α were significantly lower in MF and AD lesions than in healthy controls. There was no specific cytokine profile or inflammation pattern that could reliably distinguish MF from AD. In conclusion, in lesional SC of MF patients, pro-inflammatory cytokines can be detected. As a diagnostic method, tape stripping of lesional SC cannot discriminate MF skin from AD skin.

Use of Pegylated Interferon Alpha-2a in Cutaneous T-cell Lymphoma: A Retrospective Case Collection.

Mycosis fungoides and Sézary syndrome are rare and largely incurable types of cutaneous T-cell lymphoma with limited therapeutic options. In 1984 Bunn et al. reported that interferon alpha is an efficient monotherapy in cutaneous T-cell lymphoma and 14 years later it was shown in a prospective, randomized trial that a combination of interferon alpha and psoralen plus ultraviolet A therapy (PUVA) is most efficient in the treatment of cutaneous T-cell lymphoma. Since then interferon alpha as single agent or, most often, in combination with phototherapy and/or retinoids has been integrated as standard of care in cutaneous T-cell lymphoma guidelines worldwide. However, production of interferon alpha was discontinued recently worldwide and pegylated interferon alpha-2a (PEG-IFNα) has been used as an alternative therapy. In contrast to numerous interferon alpha studies, only a few studies focusing on PEG-IFNα are available. Therefore, the aim of this study was to conduct a retrospective data collection to report on the efficacy, adverse events and therapy regimens of PEG-IFNα in cutaneous T-cell lymphoma. In 28 patients with cutaneous T-cell lymphoma treated in Germany and in the Netherlands, 36% of patients achieved complete remission, 36% partial remission and 29% stable disease. Eighteen percent of patients developed adverse events during therapy, which led to the discontinuation of PEG-IFNα therapy in 2 patients. The most common concomittant therapies were oral PUVA phototherapy and local radiotherapy. In conclusion, PEG-IFNα, especially in combination with skin-directed therapies, is an effective treatment option for cutaneous T-cell lymphoma in clinical practice.

Identifying unmet needs and challenges in the definition of a plaque in mycosis fungoides: An EORTC-CLTG/ISCL survey.

BACKGROUND: Consensus about the definition and classification of 'plaque' in mycosis fungoides is lacking. OBJECTIVES: To delineate a comprehensive view on how the 'plaque' entity is defined and managed in clinical practice; to evaluate whether the current positioning of plaques in the TNMB classification is adequate. METHODS: A 12-item survey was circulated within a selected panel of 22 experts (pathologists, dermatologists, haematologists and oncologists), members of the EORTC and International Society for Cutaneous Lymphoma. The questionnaire discussed clinical and histopathological definitions of plaques and its relationship with staging and treatment. RESULTS: Total consensus and very high agreement rates were reached in 33.3% of questions, as all panellists regularly check for the presence of plaques, agree to evaluate the presence of plaques as a potential separate T class, and concur on the important distinction between plaque and patch for the management of early-stage MF. High agreement was reached in 41.7% of questions, since more than 50% of the responders use Olsen's definition of plaque, recommend the distinction between thin/thick plaques, and agree on performing a biopsy on the most infiltrated/indurated lesion. High divergence rates (25%) were reported regarding the possibility of a clinically based distinction between thin and thick plaques and the role of histopathology to plaque definition. CONCLUSIONS: The definition of 'plaque' is commonly perceived as a clinical entity and its integration with histopathological features is generally reserved to specific cases. To date, no consensus is achieved as for the exact definition of thin and thick plaques and current positioning of plaques within the TNMB system is considered clinically inadequate. Prospective studies evaluating the role of histopathological parameters and other biomarkers, as well as promising diagnostic tools, such as US/RM imaging and high-throughput blood sequencing, are much needed to fully integrate current clinical definitions with more objective parameters.

Deregulation of JAK2 signaling underlies primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma.

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.

Whole-genome profiling of primary cutaneous anaplastic large cell lymphoma.

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.

Flow cytometry for the assessment of blood tumour burden in cutaneous T-cell lymphoma: towards a standardized approach.

Mycosis fungoides (MF) and Sézary syndrome (SS) are the best-studied subtypes of cutaneous T-cell lymphoma, a rare non-Hodgkin lymphoma that primarily presents in the skin but can also involve blood, lymph nodes and viscera. The role of blood involvement in the assessment and staging of MF and SS has evolved in recent years from being classed as simply 'present' or 'absent', with no impact on staging, to full analysis of abnormal peripheral blood T cells using flow cytometry (FC) to detect and quantify aberrant T-cell phenotypes and polymerase chain reaction (PCR) to characterize T-cell receptor gene rearrangements. These sensitive peripheral blood assessments are replacing manual Sézary cell counts and have become an important part of clinical workup in MF and SS, providing the potential for more accurate prognosis and appropriate management. However, although international recommendations now include guidelines for FC analysis of peripheral blood markers for staging purposes, many clinics only perform these analyses in patients with advanced-stage lymphoma, if at all, and there is still a need for standardized use of validated markers. Standardization of a single effective multiparameter FC panel would allow for accurate identification and quantification of blood tumour burden for diagnosis, staging, assessment of therapeutic response, and monitoring of disease progression at all stages of disease. Once defined, validation of an MF/SS biomarker FC panel will enable uptake into clinical settings along with associated standardization of protocols and reagents. This review discusses the evolution of the role of FC in evaluating blood involvement in MF and SS, considers recently published international guidelines and identifies evidence gaps for future research that will allow for standardization of FC in MF and SS.

Human Papillary and Reticular Fibroblasts Show Distinct Functions on Tumor Behavior in 3D-Organotypic Cultures Mimicking Melanoma and HNSCC.

Human dermis can be morphologically divided into the upper papillary and lower reticular dermis. Previously, we demonstrated that papillary (PFs) and reticular (RFs) fibroblasts show distinct morphology and gene expression profiles. Moreover, they differently affect tumor invasion and epithelial-to-mesenchymal transition (EMT) in in vitro 3D-organotypic cultures of cutaneous squamous cell carcinoma (cSCC). In this study, we examined if these distinct effects of PFs and RFs can be extrapolated in other epithelial/non-epithelial tumors such as melanoma and head and neck squamous cell carcinoma (HNSCC). To this end, 3D-Full-Thickness Models (FTMs) were established from melanoma (AN and M14) or HNSCC cell lines (UM-SCC19 and UM-SCC47) together with either PFs or RFs in the dermis. The interplay between tumor cells and different fibroblasts was investigated. We observed that all the tested tumor cell lines showed significantly stronger invasion in RF-FTMs compared to PF-FTMs. In addition, RF-FTMs demonstrated more tumor cell proliferation, EMT induction and basement membrane disruption. Interestingly, RFs started to express the cancer-associated fibroblast (CAF) biomarker α-SMA, indicating reciprocal interactions eventuating in the transition of RFs to CAFs. Collectively, in the melanoma and HNSCC FTMs, interaction of RFs with tumor cells promoted EMT and invasion, which was accompanied by differentiation of RFs to CAFs.

Whole-genome analysis uncovers recurrent IKZF1 inactivation and aberrant cell adhesion in blastic plasmacytoid dendritic cell neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive hematological malignancy with a poorly understood pathobiology and no effective therapeutic options. Despite a few recurrent genetic defects (eg, single nucleotide changes, indels, large chromosomal aberrations) have been identified in BPDCN, none are disease-specific, and more importantly, none explain its genesis or clinical behavior. In this study, we performed the first high resolution whole-genome analysis of BPDCN with a special focus on structural genomic alterations by using whole-genome sequencing and RNA sequencing. Our study, the first to characterize the landscape of genomic rearrangements and copy number alterations of BPDCN at nucleotide-level resolution, revealed that IKZF1, a gene encoding a transcription factor required for the differentiation of plasmacytoid dendritic cell precursors, is focally inactivated through recurrent structural alterations in this neoplasm. In concordance with the genomic data, transcriptome analysis revealed that conserved IKZF1 target genes display a loss-of-IKZF1 expression pattern. Furthermore, up-regulation of cellular processes responsible for cell-cell and cell-ECM interactions, which is a hallmark of IKZF1 deficiency, was prominent in BPDCN. Our findings suggest that IKZF1 inactivation plays a central role in the pathobiology of the disease, and consequently, therapeutic approaches directed at reestablishing the function of this gene might be beneficial for patients.

Plaque stage folliculotropic mycosis fungoides: histopathologic features and prognostic factors in a series of 40 patients.

BACKGROUND: Folliculotropic mycosis fungoides (FMF) is a distinct variant of mycosis fungoides. Recent studies recognized indolent and aggressive subgroups of FMF, but there is controversy how patients presenting with plaques should be classified. The present study describes the histopathologic features of 40 FMF plaques. The aim of the study was to identify risk factors for disease progression and poor outcome in this group. METHODS: Clinical, histopathological, and immunophenotypical data from 40 patients with plaque stage FMF were reviewed and analysed for risk factors for disease progression and survival. RESULTS: After a median follow-up of 80 months, disease progression occurred in 20 of 40 patients. Percentage of atypical cells, cell size, percentage of Ki-67+ cells, and co-existent interfollicular epidermotropism, but not the extent of perifollicular infiltrates, were associated with disease progression and reduced survival, while extensive follicular mucinosis was associated with increased survival. CONCLUSIONS: This study underlines that FMF patients presenting with plaques represent a heterogeneous group and that a subgroup of these patients may have an indolent clinical course. It further shows that histological examination is a valuable tool to differentiate between indolent and aggressive disease.

Botulinum toxin type A in the treatment of Raynaud's phenomenon.

Raynaud's phenomenon is a vasospastic disorder clinically characterized by cold or stress-induced discoloration of the skin, pain and ulcers of the fingers or toes. Although this phenomenon might be self-limiting, there is a subgroup of patients requiring a therapeutic approach. The majority of patients do well on conservative measures; however, there is also a subgroup requiring systemic treatment. The efficacy of these systemic treatments is currently not thoroughly investigated. Furthermore, no uniform guidelines exist regarding the choice for a treatment option. In the past several years, several reports have shown the benefits of botulinum toxin for the treatment of Raynaud's phenomenon. In this case series, we report our experience with botulinum toxin type A in the treatment of Raynaud's phenomenon.

IPH4102, a first-in-class anti-KIR3DL2 monoclonal antibody, in patients with relapsed or refractory cutaneous T-cell lymphoma: an international, first-in-human, open-label, phase 1 trial.

BACKGROUND: IPH4102 is a first-in-class monoclonal antibody targeting KIR3DL2, a cell surface protein that is expressed in cutaneous T-cell lymphoma, and predominantly in its leukaemic form, Sézary syndrome. We aimed to assess the safety and activity of IPH4102 in cutaneous T-cell lymphoma. METHODS: We did an international, first-in-human, open-label, phase 1 clinical trial with dose-escalation and cohort-expansion parts in five academic hospitals in the USA, France, the UK, and the Netherlands. Eligible patients had histologically confirmed relapsed or refractory primary cutaneous T-cell lymphoma, an Eastern Cooperative Oncology group performance score of 2 or less, were aged 18 years or older, and had received at least two previous systemic therapies. Ten dose levels of IPH4102, administered as an intravenous infusion, ranging from 0·0001 mg/kg to 10 mg/kg, were assessed using an accelerated 3 + 3 design. The primary endpoint was the occurrence of dose-limiting toxicities during the first 2 weeks of treatment, defined as toxicity grade 3 or worse lasting for 8 or more days, except for lymphopenia. Global overall response by cutaneous T-cell lymphoma subtype was a secondary endpoint. Safety and activity analyses were done in the per-protocol population. The study is ongoing and recruitment is complete. This trial is registered with ClinicalTrials.gov, number NCT02593045. FINDINGS: Between Nov 4, 2015, and Nov 20, 2017, 44 patients were enrolled. 35 (80%) patients had Sézary syndrome, eight (18%) had mycosis fungoides, and one (2%) had primary cutaneous T-cell lymphoma, not otherwise specified. In the dose-escalation part, no dose limiting toxicity was reported and the trial's safety committee recommended a flat dose of 750 mg for the cohort-expansion, corresponding to the maximum administered dose. The most common adverse events were peripheral oedema (12 [27%] of 44 patients) and fatigue (nine [20%]), all of which were grade 1-2. Lymphopenia was the most common grade 3 or worse adverse event (three [7%]). One patient developed possibly treatment-related fulminant hepatitis 6 weeks after IPH4102 discontinuation and subsequently died. However, the patient had evidence of human herpes virus-6B infection. Median follow-up was 14·1 months (IQR 11·3-20·5). A confirmed global overall response was achieved in 16 (36·4% [95% CI 23·8-51·1]) of 44 patients, and of those, 15 responses were observed in 35 patients with Sézary syndrome (43% [28·0-59·1]). INTERPRETATION: IPH4102 is safe and shows encouraging clinical activity in patients with relapsed or refractory cutaneous T-cell lymphoma, particularly those with Sézary syndrome. If confirmed in future trials, IPH4102 could become a novel treatment option for these patients. A multi-cohort, phase 2 trial (TELLOMAK) is underway to confirm the activity in patients with Sézary syndrome and explore the role of IPH4102 in other subtypes of T-cell lymphomas that express KIR3DL2. FUNDING: Innate Pharma.