Classifications of cutaneous lymphomas and lymphoproliferative disorders: An update from the EORTC cutaneous lymphoma histopathology group.

The classification of primary cutaneous lymphomas and lymphoproliferative disorders (LPD) is continuously evolving by integrating novel clinical, pathological and molecular data. Recently two new classifications for haematological malignancies including entities of cutaneous lymphomas were proposed: the 5th edition of the WHO classification of haematolymphoid tumours and the International Consensus Classification (ICC) of mature lymphoid neoplasms. This article provides an overview of the changes introduced in these two classifications compared to the previous WHO classification. The main changes shared by both classifications include the downgrading of CD8+ acral T-cell lymphoma to CD8+ acral T-cell LPD, and the recognition of entities that were previously categorized as provisional and have now been designated as definite types including primary cutaneous small or medium CD4+ T-cell LPD, primary cutaneous gamma/delta T-cell lymphoma, primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma, Epstein-Barr virus-positive mucocutaneous ulcer. Both classifications consider primary cutaneous marginal zone B-cell clonal neoplasm as an indolent disease but use a different terminology: primary cutaneous marginal zone lymphoma (WHO) and primary cutaneous marginal zone LPD (ICC). The 5th WHO classification further introduces and provides essential and desirable diagnostic criteria for each disease type and includes chapters on reactive B- or T-cell rich lymphoid proliferations formerly referred as cutaneous pseudolymphomas, as well as histiocyte and CD8 T-cell rich LPD in patients with inborn error of immunity. As already emphasized in previous lymphoma classifications, the importance of integrating clinical, histological, phenotypic and molecular features remains the crucial conceptual base for defining cutaneous (and extracutaneous) lymphomas.

Genetics of adnexal tumors: An update.

Cutaneous adnexal tumors form a vast heterogeneous group that include frequent entities that are mostly benign, as well as rare tumors that are occasionally malignant. In contrast to cutaneous tumors arising from the interfollicular epidermis that develop as a result of accumulation of UV-induced DNA damage (basal cell carcinoma, squamous cell carcinoma), the oncogenesis of adnexal tumors is related to a broad spectrum of genetic mechanisms (e.g., point mutation, fusion genes, viral integration, etc.). In this setting, specific and recurrent genetic alterations have been progressively reported, and these allow better classification of these entities. For certain of them, immunohistochemical tools are now available, enabling precise integrated histological and molecular diagnosis since certain entities are linked to well-defined alterations. In this context, we aim in this review to summarize the main molecular tools currently available for the classification of adnexal tumors.

Safety and efficacy of the anti-PD1 immunotherapy with nivolumab in trichoblastic carcinomas.

Trichoblastic carcinoma is a rare malignant cutaneous adnexal tumor with a risk of local invasion and distant metastasis. As of today, there is no consensus for the treatment of locally advanced or metastatic trichoblastic carcinoma. "AcSé Nivolumab" is a multi-center Phase II basket clinical trial (NCT03012581) evaluating the safety and efficacy of nivolumab in several cohorts of rare, advanced cancers. Here we report the results of nivolumab in patients with trichoblastic carcinoma. Of the eleven patients enrolled in the study, five patients had been previously treated by sonic hedgehog inhibitors. The primary endpoint 12-week objective response rate was 9.1% (N = 1/11) with 1 partial response. Six patients who progressed under previous lines of treatment showed stable disease at 12 weeks, reflecting a good control of the disease with nivolumab. Furthermore, 54.5% of the patients (N = 6/11) had their disease under control at 6 months. The 1-year overall survival was 80%, and the median progression-free survival was 8.4 months (95%CI, 5.7 to NA). With 2 responders (2 complete responses), the best response rate to nivolumab at any time was 18.2% (95%CI, 2.3-51.8%). No new safety signals were identified, and adverse events observed herein were previously described and well known with nivolumab monotherapy. These results are promising, suggesting that nivolumab might be an option for patients with advanced trichoblastic carcinomas. Further studies on larger cohorts are necessary to confirm these results and define the role of nivolumab in the treatment of trichoblastic carcinomas.

Neutrophilic dermatoses.

Neutrophilic dermatoses (ND) are a group of inflammatory skin conditions characterized by a neutrophilic infiltrate on histopathology with no evidence of infection. ND are classified based upon the localization of neutrophils within the skin and clinical features. Recent findings suggest that ND are due to two main mechanisms: i) a polyclonal hereditary activation of the innate immune system (polygenic or monogenic); or ii) a clonal somatic activation of myeloid cells such as encountered in myelodysplastic syndrome or VEXAS syndrome. ND belong to internal medicine as a great number of patients with ND suffer from an underlying condition (such as hematological malignancy, inflammatory bowel disease, auto-immune and auto-inflammatory diseases). ND are diagnoses of exclusion and physicians should always consider differential diagnoses, particularly skin infections. Here, we review the pathophysiology and classification of the main ND (i.e., subcorneal pustular dermatosis (Sneddon-Wilkinson Disease) and Intercellular IgA dermatoses, aseptic pustulosis of the folds, Sweet syndrome, neutrophilic eccrine hidradenitis, pyoderma gangrenosum, erythema elevatum diutinum, neutrophilic urticarial dermatosis and neutrophilic panniculitis), their clinical and histopathological features, and we highlight the investigations that are useful to identify ND-associated diseases and to exclude the differential diagnoses.

Recent advances on cutaneous lymphoma epidemiology.

BACKGROUND: Primary cutaneous lymphomas are a group of T- (CTCL) and B-cell (CBCL) malignancies. These diseases have different clinical presentations and prognosis. Our knowledge on their epidemiology is limited. Aim of this review was to summarize recent findings on the incidence of CTCL and CBCL, how they change over time, and to describe possible causes and consequences. We found that although there are important differences in the epidemiology of cutaneous lymphomas in different countries, the relative frequency of certain, especially rare lymphomas remains stable. Several studies described growing incidences of both CTCL and CBCL. The emergence of new diagnostic criteria, a more precise definition of the entities and new biomarkers enable a better classification of cases.

Blaschko-linear lichen planus of the face: A retrospective study of 6 cases and a literature review.

INTRODUCTION AND METHODS: Different clinical and histological variants of lichen planus (LP) exist, such as lichen planopilaris, pigmentosus, linear, or atrophic LP. Recently, some cases came to our attention of hyperpigmented and atrophic linear lesions of the face with lichenoid histology, suggesting a combination of these different variants. We carried out a single-center, retrospective descriptive study of 6 similar cases selected from our database and compared them with a literature review. RESULTS: There were 4 males and 2 females of mean age 42 years. Each had linear lesions located on one side of the face. All lesions were initially itchy; they appeared hyperpigmented in all patients and atrophic in 5 cases. Biopsies indicated lichen planopilaris in 5 patients, with deep peri-eccrine involvement in 4 of them. Only 2 of the 6 patients had extra-facial lesions. DISCUSSION AND LITERATURE REVIEW: We found 24 cases in the literature having similar clinical and histological aspects. Men aged around 37 years seemed particularly affected. An atrophic course was noticed in 10 patients. Such a clinicopathological picture may suggest differential diagnoses like lichen striatus, lupus erythematosus, lichen sclerosus atrophicus, or Moulin's linear atrophoderma. Early histopathological examination could be of precious assistance in allowing the initiation of effective treatment immediately as of the initial inflammatory phase, thereby limiting the risk of cosmetic sequelae such as atrophy or residual pigmentation. CONCLUSION: We describe a form of facial lichen planus that is highly particular in terms of its follicular tropism, its blaschkoid distribution, its pigmented character, and its atrophic progression.

Treatment of Eosinophilic Annular Erythema: Retrospective multicenter study and literature review.

BACKGROUND: Eosinophilic annular erythema (EAE) is a rare eosinophil-related skin disease which typically manifests with annular erythematous plaques and severe pruritus. Besides the diagnosis, the treatment of EAE is challenging since relevant published data are sparse. METHODS: The aim of this study was to assess the underlying diseases, treatments and outcomes of patients with EAE. To this end, we conducted a retrospective multicenter study and a systematic review of the MEDLINE database. RESULTS: We included 18 patients with EAE followed in 8 centers. The MEDLINE database search yielded 37 relevant publications reporting 55 cases of EAE with 106 treatment sequences. The most common and efficient treatments included topical or systemic corticosteroids, hydroxychloroquine and dapsone. In refractory patients, a combination of systemic corticosteroids with hydroxychloroquine was associated with 88% of complete clinical response. DISCUSSION: To improve the management of EAE patients, we discuss the following treatment strategy: in topical steroid-resistant patients, hydroxychloroquine can be given as first-line systemic treatment. Dapsone, hydroxychloroquine or systemic corticosteroids are second-line options to consider. Last, monoclonal antibodies or JAK inhibitors targeting type 2 inflammation could represent promising last-resort options in refractory patients.

Type I interferon response and vascular alteration in chilblain-like lesions during the COVID-19 outbreak.

BACKGROUND: The outbreak of chilblain-like lesions (CLL) during the COVID-19 pandemic has been reported extensively, potentially related to SARS-CoV-2 infection, yet its underlying pathophysiology is unclear. OBJECTIVES: To study skin and blood endothelial and immune system activation in CLL in comparison with healthy controls and seasonal chilblains (SC), defined as cold-induced sporadic chilblains occurring during 2015 and 2019 with exclusion of chilblain lupus. METHODS: This observational study was conducted during 9-16 April 2020 at Saint-Louis Hospital, Paris, France. All patients referred with CLL seen during this period of the COVID-19 pandemic were included in this study. We excluded patients with a history of chilblains or chilblain lupus. Fifty patients were included. RESULTS: Histological patterns were similar and transcriptomic signatures overlapped in both the CLL and SC groups, with type I interferon polarization and a cytotoxic-natural killer gene signature. CLL were characterized by higher IgA tissue deposition and more significant transcriptomic activation of complement and angiogenesis factors compared with SC. We observed in CLL a systemic immune response associated with IgA antineutrophil cytoplasmic antibodies in 73% of patients, and elevated type I interferon blood signature in comparison with healthy controls. Finally, using blood biomarkers related to endothelial dysfunction and activation, and to angiogenesis or endothelial progenitor cell mobilization, we confirmed endothelial dysfunction in CLL. CONCLUSIONS: Our findings support an activation loop in the skin in CLL associated with endothelial alteration and immune infiltration of cytotoxic and type I IFN-polarized cells leading to clinical manifestations.

Clinicopathologic analysis of trichoblastoma and comparison with nodular basal cell carcinoma.

BACKGROUND: Trichoblastoma (TB) is an uncommon benign follicular tumour for which clinical data is limited since most reports originate from pathology studies. OBJECTIVE: To describe the clinical aspects of TB. METHODS: This is an ancillary study of a prospective multicentre cohort of 2710 clinically suspected basal cell carcinoma (BCC), including 935 nodular BCCs. Sixty-two cases were TB: they were analysed and compared to 935 nodular BCCs. RESULTS: TB mostly occurred in females (61% vs. 43% for BCC, P<0.01) of mean age 63 years. They were located on the head and neck, mainly on the nose and forehead, in 87% of cases. The mean size was 8.1mm, 77% were<10mm (55% of BCCs, P<0.001), 8% were ulcerated (vs. 21% of BCCs, P<0.02), and 47% persisted for more than 1 year (34% of BCCs, P<0.05). Most cases had a clinical presentation similar to nodular BCC, except for 5 small, flat, white papules and 1 anfractuous plaque. LIMITATIONS: Cases originated from a series of tumours clinically suspected as BCCs. DISCUSSION: Some 2.6% of tumours clinically diagnosed as BCC are in fact TB. TB occurs on the head, are more frequent in women, and are smaller and of longer duration than BCC. In most cases, clinical diagnosis on clinical grounds is difficult.

Lymphomatoid papulosis types D and E: a multicentre series of the French Cutaneous Lymphomas Study Group.

BACKGROUND: Lymphomatoid papulosis (LyP) type D (LyP D) and type E (LyP E) have recently been described in small series of cases or isolated case reports. AIM: To further describe the clinical and histological features of LyP D and E based on a retrospective multicentre study. METHODS: The clinical and histopathological features of 29 patients with an initial diagnosis of LyP D or LyP E were retrospectively assessed using standardized forms. RESULTS: After exclusion of 5 cases, 24 patients (14 LyP D, 10 LyP E) were enrolled in the study. The median follow-up was 2.5 years (range 1 month to 13 years). LyP D was characterized by multiple recurrent self-regressing small papules that developed central erosion or necrosis, whereas LyP E presented as papulonodular lesions that rapidly evolved into necrotic eschar-like lesions > 10 mm in size. Epidermal changes were more frequent in LyP D, whereas dermal infiltrates were deeper in LyP E. Anaplastic cytology was rare and the DUSP22 rearrangement was never observed. Two patients (8%) had an associated cutaneous lymphoma. CONCLUSION: LyP D and E have distinct clinical findings and may be associated with other cutaneous lymphomas.

Image-guided lymph node core-needle biopsy predicts survival in mycosis fungoides and Sézary syndrome.

BACKGROUND: The prognosis of Sézary syndrome (SS) and mycosis fungoides (MF) depends on lymph node (LN) involvement. The usefulness of LN image-guided core-needle biopsies (CNBs), instead of surgical sampling, has been poorly evaluated. OBJECTIVES: To determine the prognostic value of LN CNB in MF/SS. METHODS: A retrospective search was conducted to identify all LN biopsy specimens of MF/SS between 2008 and 2019. Biopsies were staged according to the International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer (ISCL/EORTC) criteria. We performed immunolabelling and determined the tumour clone frequency (TCF) by high-throughput sequencing of the T-cell receptor beta locus. RESULTS: We included 119 consecutive biopsies from 100 patients, 45 with MF and 55 with SS. N1, N2 and N3 stages were diagnosed in 34 (29%), 26 (22%) and 59 (49%) cases, respectively. The TCF, Ki67 index, and percentage of cells positive for thymocyte selection-associated high mobility group box protein (TOX), programmed cell death protein 1 (PD1), killer cell immunoglobulin-like receptor 3DL2 (KIR3DL2) and cluster of differentiation (CD)30 were all positively correlated with the N stage. Median overall survival (OS) for N1/N2 vs. N3 patients was 42 months (range 26-not reached) vs. 14 months (range 5-30), respectively (P < 0·001). In univariate analyses, an age > 75 years, LN short-axis diameter > 15 mm, N3 stage, presence of large-cell transformation, TOX > 60%, PD1 > 25%, Ki67 > 30%, KIR3DL2 > 15%, CD30 > 10% and TCF > 25% were identified as adverse prognostic factors. In multivariate analyses, only an age > 75 years and Ki67 index > 30% were associated with reduced OS. We developed a new prognostic index associating the N stage and the Ki67 index, which better discriminates N3 patients with poor prognosis. CONCLUSIONS: CNB allows an objective assessment of the LN involvement in MF/SS, relevant for staging and prognosis.

Treatment of early-stage mycosis fungoides: results from the PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study.

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, 81·5%), while a smaller percentage (44 cases, 11·1%) received systemic therapy. Expectant observation was used in 7·3%. 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 < 0·001), presence of plaques (T1a/T2a, 5%; T1b/T2b, 17%; P < 0·001), higher modified Severity Weighted Assessment Tool (> 10, 15%; ≤ 10, 7%; P = 0·01) and folliculotropic MF (FMF) (24% vs. 12%, P = 0·001). Multivariate analysis demonstrated significant associations with the presence of plaques (T1b/T2b vs. T1a/T2a, odds ratio 3·07) and FMF (odds ratio 2·83). The overall response rate (ORR) to first-line SDT was 73%, while the ORR to first-line systemic treatments was lower (57%) (P = 0·027). Health-related QoL improved significantly both in patients with responsive disease and in those with stable disease. CONCLUSIONS: Disease characteristics such as presence of plaques and FMF influence physician treatment choices, and SDT was superior to systemic therapy even in patients with such disease characteristics. Consequently, future treatment guidelines for early-stage MF need to address these issues.

Clinical factors predictive for histological aggressiveness of basal cell carcinoma: A prospective study of 2274 cases.

INTRODUCTION: Since surgery is the first-line treatment for basal cell carcinomas (BCC), the histological aggressiveness of the disease must be clinically predicted in order to apply optimal safety margins that ensure a high rate of complete resection while minimising the risk of recurrence. OBJECTIVES: To evaluate clinical predictive factors of histological aggressiveness of BCC, we conducted a national prospective multi-centre study. METHODS: All consecutive patients presenting for BCC surgery were included, and standardised clinical data collected, and slides were submitted for review. Trabecular, micronodular and morpheaform BCCs were classified as aggressive. RESULTS: Of the 2710 cases included, 2274 were histologically confirmed. Clinical subtyping was correct in 49.9% of superficial BCCs, 86.2% of nodular BCCs and only 22% of aggressive BCCs. By multivariate analysis, aggressive BCCs were more frequently ulcerated (45%), indurated (70%), showed adherence (8.6%), and were associated with high-risk anatomical zones (50.3%, P<0.0001). These predictive clinical features may be helpful for decision making.