Analyses of combined Merkel cell carcinomas with neuroblastic components suggests that loss of T antigen expression in Merkel cell carcinoma may result in cell cycle arrest and neuroblastic transdifferentiation.

Merkel cell carcinoma (MCC) is an aggressive skin cancer frequently caused by genomic integration of the Merkel cell polyomavirus (MCPyV). MCPyV-negative cases often present as combined MCCs, which represent a distinctive subset of tumors characterized by association of an MCC with a second tumor component, mostly squamous cell carcinoma. Up to now, only exceptional cases of combined MCC with neuroblastic differentiation have been reported. Herein we describe two additional combined MCCs with neuroblastic differentiation and provide comprehensive morphologic, immunohistochemical, transcriptomic, genetic and epigenetic characterization of these tumors, which both arose in elderly men and appeared as an isolated inguinal adenopathy. Microscopic examination revealed biphasic tumors combining a poorly differentiated high-grade carcinoma with a poorly differentiated neuroblastic component lacking signs of proliferation. Immunohistochemical investigation revealed keratin 20 and MCPyV T antigen (TA) in the MCC parts, while neuroblastic differentiation was confirmed in the other component in both cases. A clonal relation of the two components can be deduced from 20 and 14 shared acquired point mutations detected by whole exome analysis in both combined tumors, respectively. Spatial transcriptomics demonstrated a lower expression of stem cell marker genes such as SOX2 and MCM2 in the neuroblastic component. Interestingly, although the neuroblastic part lacked TA expression, the same genomic MCPyV integration and the same large T-truncating mutations were observed in both tumor parts. Given that neuronal transdifferentiation upon TA repression has been reported for MCC cell lines, the most likely scenario for the two combined MCC/neuroblastic tumors is that neuroblastic transdifferentiation resulted from loss of TA expression in a subset of MCC cells. Indeed, DNA methylation profiling suggests an MCC-typical cellular origin for the combined MCC/neuroblastomas. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Wnt/ß-Catenin-Activated Nonpilomatrical Carcinoma of the Skin: A Case Series.

Among skin epithelial tumors, recurrent mutations in the APC/CTNNB1 genes resulting in activation of the Wnt/ß-catenin pathway have been reported predominantly in neoplasms with matrical differentiation. In the present study, we describe the morphologic, immunohistochemical, and genetic features of 16 primary cutaneous carcinomas harboring mutations activating the Wnt/ß-catenin pathway without evidence of matrical differentiation, as well as 4 combined tumors in which a similar Wnt/ß-catenin-activated carcinoma component was associated with Merkel cell carcinoma (MCC) or pilomatrical carcinoma. Among the pure tumor cases, 6 of 16 patients were women with a median age of 80 years (range, 58-98 years). Tumors were located on the head and neck (n = 7, 44%), upper limb (n = 4, 25%), trunk (n = 3, 18%), and leg (n = 2, 13%). Metastatic spread was observed in 4 cases resulting in death from disease in 1 patient. Microscopically, all cases were poorly differentiated neoplasms infiltrating the dermis and/or subcutaneous tissue. In 13 cases, solid "squamoid" areas were associated with a basophilic component characterized by rosette/pseudoglandular formation resulting in a biphasic appearance. Three specimens consisted only of poorly differentiated carcinoma lacking rosette formation. Immunohistochemical studies showed frequent expression of EMA (100%), BerEP4 (100%), cytokeratin 7 (94%), chromogranin A (44%), synaptophysin (82%), and cytokeratin 20 (69%). Complete loss of Rb expression was observed in all but 1 case. Nuclear ß-catenin and CDX2 expressions were detected in all cases. Recurrent pathogenic somatic mutations were observed in APC (60%), CTNNB1 (40%), and RB1 (n = 47%). Global methylation analysis confirmed that cases with rosette formation constituted a homogeneous tumor group distinct from established skin tumor entities (pilomatrical carcinoma, MCC, and squamous cell carcinoma), although the 3 other cases lacking such morphologic features did not. In addition, we identified 4 combined neoplasms in which there was a component showing a similar poorly differentiated rosette-forming carcinoma demonstrating Rb loss and ß-catenin activation associated with either MCC (n = 3) or pilomatrical carcinoma (n = 1). In conclusion, we describe a distinctive neoplasm, for which we propose the term "Wnt/ß-catenin-activated rosette-forming carcinoma," morphologically characterized by the association of rosette formation, squamous and/or neuroendocrine differentiation, diffuse CDX2 expression, Rb loss, and mutations in CTNNB1/APC genes.

Detection of wildtype Merkel cell polyomavirus genomic sequence and VP1 transcription in a subset of Merkel cell carcinoma.

AIMS: Merkel cell carcinoma (MCC) is frequently caused by the Merkel cell polyomavirus (MCPyV). Characteristic for these virus-positive (VP) MCC is MCPyV integration into the host genome and truncation of the viral oncogene Large T antigen (LT), with full-length LT expression considered as incompatible with MCC growth. Genetic analysis of a VP-MCC/trichoblastoma combined tumour demonstrated that virus-driven MCC can arise from an epithelial cell. Here we describe two further cases of VP-MCC combined with an adnexal tumour, i.e. one trichoblastoma and one poroma. METHODS AND RESULTS: Whole-genome sequencing of MCC/trichoblastoma again provided evidence of a trichoblastoma-derived MCC. Although an MCC-typical LT-truncating mutation was detected, we could not determine an integration site and we additionally detected a wildtype sequence encoding full-length LT. Similarly, Sanger sequencing of the combined MCC/poroma revealed coding sequences for both truncated and full-length LT. Moreover, in situ RNA hybridization demonstrated expression of a late region mRNA encoding the viral capsid protein VP1 in both combined as well as in a few cases of pure MCC. CONCLUSION: The data presented here suggest the presence of wildtype MCPyV genomes and VP1 transcription in a subset of MCC.

Impact of the adjunction of a short video to an original article for the recognition of newly described tumor entities in pathology: An interventional prospective study.

CONTEXT: Merkel cell carcinoma diagnosis is often based on microscopic examination by pathologists. While histopathologic diagnosis primarily hinges on conscious and analytical cognition, the pathologist's decision-making process is also influenced by a rapid "gist" or "gestalt" approach. In this study, using cases of Merkel cell carcinoma as a model, we aim to assess how pathologists' viewing short videos containing conceptual clues and visual aids, in conjunction with reading an original article as a reference, may enhance their diagnostic performance. METHOD: Sixteen pathologists were included in the present work. After participants had read the original article, their ability to distinguish Merkel cell polyomavirus (MCPyV)+ and MCPyV- Merkel cell carcinoma cases was evaluated on a first preliminary series of 20 cases. Following this test, the participants watched the video and then evaluated a second "experimental" series of 20 independent cases. RESULTS: After reading the original article, for each case, a median number of 12 participants (75%, Q1-Q3: 10-13) classified the specimen in the correct category (92 incorrect answers in the whole series). An important interobserver variability was observed in this setting (Kappa coefficient = 0.465). By contrast, following the video, all cases were correctly classified by most of the participants, with only 12 incorrect answers on the whole series and excellent interobserver reproducibility (Kappa coefficient = 0.846). CONCLUSION: Our study demonstrated that providing a short video together with an original article may enhance pathologists' performance in diagnosing Merkel cell carcinoma.

GRM1 Gene Fusions as an Alternative Molecular Driver in Blue Nevi and Related Melanomas.

Activating mutations in GNAQ, GNA11, CYSLTR2, and PLCB4 genes are regarded as the main oncogenic drivers of blue nevi (BN) and blue malignant melanocytic tumors. Here we report 4 cases of blue melanocytic neoplasms devoid of these mutations but harboring GRM1 gene fusions. In this short series, there was no gender predominance (sex ratio, 1). The mean age at diagnosis was 40 years (range, 12-72). Tumors were located on the face (n = 2), forearm (n = 1), and dorsum of the foot (n = 1). Clinically, a plaque-like pre-existing BN was found in 2 cases, including a deep location; another case presented as an Ota nevus. Two cases were diagnosed as melanoma ex-BN, one as an atypical BN, and one as a plaque-like BN. Microscopic examination revealed a dermal proliferation of dendritic melanocytes in a sclerotic stroma. A dermal cellular nodule with atypia and mitotic activity was observed in 3 cases. Genetic investigation by whole exome RNA sequencing revealed MYO10::GRM1 (n = 2) and ZEB2::GRM1 (n = 1) fusions. A GRM1 rearrangement was identified by fluorescence in situ hybridization in the remaining case. SF3B1 comutations were present in the 2 melanomas, and both had a MYO10::GRM1 fusion. Array comparative genomic hybridization was feasible for 3 cases and displayed multiple copy number alterations in the 2 melanomas and limited copy number alterations in the atypical BN, all genomic profiles compatible with those of classical blue lesions. GRM1 was overexpressed in all cases compared with a control group of blue lesions with other typical mutations. Both melanomas rapidly developed visceral metastases following diagnosis, with a fatal outcome in one case and tumor progression under palliative care in the other. These data suggest that GRM1 gene fusions could represent an additional rare oncogenic driver in the setting of BN, mutually exclusive of classical canonical mutations, especially in plaque-type or Ota subtypes.

Distinct regulations driving YAP1 expression loss in poroma, porocarcinoma and RB1-deficient skin carcinoma.

AIMS: Recently, YAP1 fusion genes have been demonstrated in eccrine poroma and porocarcinoma, and the diagnostic use of YAP1 immunohistochemistry has been highlighted in this setting. In other organs, loss of YAP1 expression can reflect YAP1 rearrangement or transcriptional repression, notably through RB1 inactivation. In this context, our objective was to re-evaluate the performance of YAP1 immunohistochemistry for the diagnosis of poroma and porocarcinoma. METHODS AND RESULTS: The expression of the C-terminal part of the YAP1 protein was evaluated by immunohistochemistry in 543 cutaneous epithelial tumours, including 27 poromas, 14 porocarcinomas and 502 other cutaneous tumours. Tumours that showed a lack of expression of YAP1 were further investigated for Rb by immunohistochemistry and for fusion transcripts by real-time PCR (YAP1::MAML2 and YAP1::NUTM1). The absence of YAP1 expression was observed in 24 cases of poroma (89%), 10 porocarcinoma (72%), 162 Merkel cell carcinoma (98%), 14 squamous cell carcinoma (SCC) (15%), one trichoblastoma and one sebaceoma. Fusions of YAP1 were detected in only 16 cases of poroma (n = 66%), 10 porocarcinoma (71%) all lacking YAP1 expression, and in one sebaceoma. The loss of Rb expression was detected in all cases except one of YAP1-deficient SCC (n = 14), such tumours showing significant morphological overlap with porocarcinoma. In-vitro experiments in HaCat cells showed that RB1 knockdown resulted in repression of YAP1 protein expression. CONCLUSION: In addition to gene fusion, we report that transcriptional repression of YAP1 can be observed in skin tumours with RB1 inactivation, including MCC and a subset of SCC.

PD-L1 in circulating exosomes of Merkel cell carcinoma.

Exosomes, as potential circulated biomarkers, have recently become a topic of interest in the field of oncology. Immune checkpoint molecule PD-L1 has recently been detected in circulating exosomes from cancer patients. The purpose of this work was to evaluate PD-L1 levels in circulating exosomes (Exo-PD-L1) isolated from patients' plasma suffering from Merkel cell carcinoma (MCC). We conducted a prospective bicentric cohort study. PD-L1 was analysed in circulating exosomes from plasma samples of patients suffering from MCC stage I to IV (according to the AJCC 8). Exosomes from 34 patients corresponding to 66 samples were analysed. PD-L1 was identified in circulating exosomes of MCC patients. Exo-PD-L1 levels of MCC patients were similar to healthy donors and lower than other cancers such as melanoma. Exo-PD-L1 levels tended to be higher in MCC patients with distant metastases. Furthermore, Exo-PD-L1 levels did not significantly vary over the course of the disease whatever the disease course or the response to treatment. This study assessed the presence of PD-L1 in circulating exosomes of MCC patients. The low levels of Exo-PD-L1 and small changes over the course of the disease may be due to the metastatic dissemination of MCC, which is mainly through the skin and lymph nodes rather than blood. PD-L1 was identified in circulating exosomes of MCC patients and tends to be higher in advanced disease. This preliminary study is a proof of concept of PD-L1 detection in circulating exosomes of MCC patients.

Avelumab expanded access program in metastatic Merkel cell carcinoma: Efficacy and safety findings from patients in Europe and the Middle East.

Incidence rates of Merkel cell carcinoma (MCC), an uncommon skin cancer with an aggressive disease course, have increased in recent decades. Limited treatment options are available for patients with metastatic MCC (mMCC). Avelumab, an anti-programmed cell death-ligand 1 monoclonal antibody, became the first approved treatment for mMCC after the results of the phase 2 JAVELIN Merkel 200 study. Prior to its regulatory approval, an expanded access program (EAP) enabled compassionate use of avelumab in patients with mMCC. Here we report findings from patients enrolled in the EAP in Europe and the Middle East. Efficacy and safety data were provided at the discretion of treating physicians. Between March 2, 2016, and December 22, 2018, 403 requests for avelumab were received from 21 countries, and avelumab was supplied to 335 patients. Most patients (96.7%) received avelumab as second-line or later treatment. In 150 patients for whom response data were available, the objective response rate was 48.0%, and in responding patients, median duration of treatment was 7.4 months (range, 1.0-41.7 months). The most common treatment-related adverse events were infusion-related reaction (2.4%) and pyrexia (2.1%), and no new safety signals were observed. Overall, results from European and Middle Eastern patients enrolled in this EAP confirm the efficacy and safety of avelumab treatment observed in previous studies in patients with mMCC.

Narrow resection margins are not associated with mortality or recurrence in patients with Merkel cell carcinoma: A retrospective study.

BACKGROUND: Wide local excision constitutes the standard of care for Merkel cell carcinoma, but the optimal margin width remains controversial. OBJECTIVES: To assess whether narrow margins (0.5-1 cm) were associated with outcome. METHODS: Patients were recruited from a retrospective French multicentric cohort and included if they had had excision of primary tumor with minimum lateral margins of 0.5 cm. Factors associated with mortality and recurrence were assessed by multivariate regression. RESULTS: Among the 214 patients included, 58 (27.1%) had undergone excision with narrow margins (0.5-1 cm) versus 156 (72.9%) with wide margins (>1 cm). During a median follow-up of 50.7 months, cancer-specific survival did not differ between groups (5-year specific survival rate 76.8% [95% confidence interval 61.7%-91.9%] and 76.2% [95% confidence interval 68.8%-83.6%], respectively). Overall survival, any recurrence-free survival, and local recurrence-free survival did not significantly differ between groups. Cancer-specific mortality was associated with age, male sex, American Joint Committee on Cancer stage III, and presence of positive margins. LIMITATIONS: Retrospective design, heterogenous baseline characteristics between groups. CONCLUSION: Excision with narrow margins was not associated with outcome in this cohort, in which most patients had clear margins and postoperative radiation therapy. Residual tumor, mostly found on deep surgical margins, was independently associated with prognosis.

Long-term Outcome of Chilblains Associated with SARS-CoV-2.

Numerous cases of chilblains have been observed in the course if the COVID-19 pandemic. The aims of this study were to provide comprehensive follow-up data for patients reporting chilblains, and to determine the risk factors for incomplete recovery. Patients referred to 5 hospitals in France between March and May 2020 for chilblains were surveyed on December 2020. A teleconsultation was offered. Among 82 patients reporting chilblains, 27 (33%) reported complete recovery, 33 (40%) had recurrences of chilblains after their hands and feet had returned to normal, and 22 (27%) developed persistent acral manifestations, mostly acrocyanosis, with or without further recurrences of chilblains. Most recurrences of chilblains occurred during the following autumn and winter. A past history of chilblains was not associated with recurrences or persistent acral manifestations. Women had a significantly higher risk of developing recurrences or persistent acral manifestations (odds ratio 1.30; 95% confidence interval 1.06-1.59). In conclusion, two-thirds of patients reporting chilblains at the start of the COVID-19 pandemic experienced persistent or recurrent acral manifestations after a 10-month follow-up.

Immunobiology of Merkel cell carcinoma.

PURPOSE OF REVIEW: Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer, which is associated in 80% of cases with the Merkel cell polyomavirus (MCPyV). Advanced stages respond to immune checkpoint inhibitors in 50% of cases. Major issues remain unanswered regarding its oncogenesis and optimal treatment. RECENT FINDINGS: MCPyV-negative and MCPyV-positive MCCs have been hypothesized to derive from distinct cells, although the cell of origin remains a matter of debate. The crucial role the MCPyV small T oncoprotein was recently confirmed by its ability to inactivate p53, together with its contribution to the metastatic progression. In advanced cases, tumoral microenvironment may adequately predict responses to immunotherapies, and several mechanisms of primary and secondary resistance have been investigated. SUMMARY: Identifying the mechanisms of oncogenesis allow experimentation of new therapeutic targets, which remain mandatory even at the era of immunotherapies. Although new insights in the mechanisms of primary and secondary resistance pave the way for development of further immunotherapy strategies, neoadjuvant strategies may challenge our whole approach of the disease.

Effectiveness and Safety of Anti-interleukin-17 Therapies in Elderly Patients with Psoriasis.

Anti-interleukin-17 agents have recently been developed for the treatment of psoriasis. This study evaluated the tolerance and effectiveness of anti-interleukin-17 agents for psoriasis in elderly patients in daily practice. A multicentre, retrospective study was performed, involving psoriatic patients aged ≥65 years who had received an anti-interleukin-17 agent, including secukinumab, ixekizumab or brodalumab. A total of 114 patients were included: 72 received secukinumab, 35 ixekizumab, and 7 brodalumab. Treatment was stopped in 32 patients (28.9%), because of relapses in 14 patients (41.2%), primary failures in 11 patients (32.4%), or adverse events in 7 patients (20.6%). The 3 most frequently reported adverse events were injection site reactions (n = 4), oral candidiasis (n = 3), and influenza-like illness (n = 3). Regarding effectiveness, 80 patients (70%) reached a Physician Global Assessment score of 0/1, 6 months after treatment initiation. In conclusion, anti-interleukin-17 therapy appears to be an effective and safe therapeutic option for psoriasis treatment in patients aged ≥ 65 years.

Diagnostic accuracy of a panel of immunohistochemical and molecular markers to distinguish Merkel cell carcinoma from other neuroendocrine carcinomas.

Merkel cell carcinoma is a rare neuroendocrine carcinoma of the skin mostly induced by Merkel cell polyomavirus integration. Cytokeratin 20 (CK20) positivity is currently used to distinguish Merkel cell carcinomas from other neuroendocrine carcinomas. However, this distinction may be challenging in CK20-negative cases and in cases without a primary skin tumor. The objectives of this study were first to evaluate the diagnostic accuracy of previously described markers for the diagnosis of Merkel cell carcinoma and second to validate these markers in the setting of difficult-to-diagnose Merkel cell carcinoma variants. In a preliminary set (n = 30), we assessed optimal immunohistochemical patterns (CK20, thyroid transcription factor 1 [TTF-1], atonal homolog 1 [ATOH1], neurofilament [NF], special AT-rich sequence-binding protein 2 [SATB2], paired box protein 5, terminal desoxynucleotidyl transferase, CD99, mucin 1, and Merkel cell polyomavirus-large T antigen) and Merkel cell polyomavirus load thresholds (real-time PCR). The diagnostic accuracy of each marker was then assessed in a validation set of 103 Merkel cell carcinomas (9 CK20-negative cases and 15 cases without a primary skin tumor) and 70 extracutaneous neuroendocrine carcinoma cases. The most discriminant markers for a diagnosis of Merkel cell carcinoma were SATB2, NF expression, and Merkel cell polyomavirus DNA detection (positive likelihood ratios: 36.6, 44.4, and 28.2, respectively). Regarding Merkel cell carcinoma variants, cases without a primary skin tumor retained a similar immunohistochemical  profile and CK20-negative tumors displayed a different profile (decrease frequency of NF and SATB2 expression), but Merkel cell polyomavirus DNA remained detected (78% of cases by qPCR). Moreover, 8/9 (89%) CK20-negative Merkel cell carcinoma cases but only 3/61 (5%) CK20-negative extracutaneous neuroendocrine cases were positive for at least one of these markers. In conclusion, detection of SATB2 and NF expression and Merkel cell polyomavirus DNA helps distinguish between Merkel cell carcinoma classical and variant cases and extracutaneous neuroendocrine carcinomas.

Morphologic and immunophenotypical features distinguishing Merkel cell polyomavirus-positive and negative Merkel cell carcinoma.

In 2008, Feng et al. identified Merkel cell polyomavirus integration as the primary oncogenic event in ~80% of Merkel cell carcinoma cases. The remaining virus-negative Merkel cell carcinoma cases associated with a high mutational load are most likely caused by UV radiation. The current study aimed to compare the morphological and immunohistochemical features of 80 virus-positive and 21 virus-negative Merkel cell carcinoma cases. Microscopic evaluation revealed that elongated nuclei-similar to the spindle-shape variant of small cell lung cancer-were less frequent in Merkel cell polyomavirus-positive Merkel cell carcinoma compared to the virus-negative subset (p = 0.005). Moreover, virus-negative cases more frequently displayed a "large-cell neuroendocrine carcinoma" phenotype with larger cell size (p = 0.0026), abundant cytoplasm (p = 4×10-7) and prominent nucleoli (p = 0.002). Analysis of immunohistochemical data revealed frequent positivity for thyroid transcription factor 1 and cytokeratin 7, either absence or overexpression of p53, as well as frequent lack of neurofilament expression in virus-negative cases. By contrast, cytokeratin 8, 18 and 20 and a CD99 with a dot pattern as well as high EMA expression were identified as characteristic features of virus-positive Merkel cell carcinoma. In particular, the CD99 dot-like expression pattern was strongly associated with presence of the Merkel cell polyomavirus in Merkel cell carcinoma (sensitivity = 81%, specificity = 90%, positive likelihood ratio = 8.08). To conclude, virus-positive and -negative Merkel cell carcinoma are characterized by distinct morphological and immunohistochemical features, which implies a significant difference in tumor biology and behavior. Importantly, we identified the CD99 staining pattern as a marker indicating the virus status of this skin cancer.

Viral and tumor antigen-specific CD8 T-cell responses in Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous cancer, which is immunogenic, regardless of the presence of MCPyV (80% of cases). The identification of MCC-specific epitopes recognized by CD8 T cells is crucial to expand the arsenal of immunotherapeutic treatments. Until now, most efforts focused on the identification of virus-specific epitopes, whereas immune responses directed against shared cellular tumor-specific antigens have not been evidenced. In this study, we measured T-cell responses against viral (n = 3) and tumor antigens (n = 47) from TILs derived from 21 MCC tumors. Virus-specific CD8 T-cell responses dominated MCC-specific immune responses, and we identified two new HLA-peptide complexes derived from the LT antigen, located in a region encompassing 3 previously identified epitopes. Finally, we show that MAGE-A3 antigen, frequently expressed by MCC tumors, was recognized by CD8 TILs from a virus-negative MCC tumor and thus could be a target for immunotherapy in this setting.

Effect of Diet in Chronic Spontaneous Urticaria: A Systematic Review.

Strategies for diets in chronic spontaneous urticaria (CSU) are controversial. This systematic review assessed the interest in diet for managing CSU. We searched for original reports in MEDLINE, EMBASE, CENTRAL and LILACS. Among the 278 reports screened, 20 were included, involving 1,734 patients. Reports described 3 types of systematic diet: pseudoallergen-free diet (n = 1,555 patients), low-histamine diet (n = 223) and diet without fish products (n = 47), which induced complete remission in 4.8%, 11.7% and 10.6% of patients, respectively, and partial remission in 37.0%, 43.9% and 4.3%. Eight reports described personalized exclusion diets (66 patients) adapted to symptoms/allergological test results and led to complete remission in 74.6% of patients, although the diagnosis of CSU was doubtful. No comparative randomized studies of diets were available. The only randomized studies were based on oral provocation tests with the suspected responsible diet. Population and outcomes were heterogeneous. In conclusion, there is evidence for the benefit of diets in CSU only in individual patients with clinical symptoms. However, the level of evidence is low for the benefit of systematic diets in CSU because systematic double-blind controlled trials of diet are lacking.

Non-antistreptococcal interventions for acute guttate psoriasis or an acute guttate flare of chronic psoriasis.

BACKGROUND: Guttate psoriasis displays distinctive epidemiological and clinical features, making it a separate entity within the heterogeneous group of cutaneous psoriasis types. It is associated with genetic, immune, and environmental factors (such as stress and infections) and usually arises in younger age groups (including children, teenagers, and young adults). There is currently no cure for psoriasis, but various treatments can help to relieve the symptoms and signs. The objectives of treatment when managing an acute flare of guttate psoriasis are to reduce time to clearance and induction of long-term remission after resolution. This is an update of a Cochrane Review first published in 2000; since then, new treatments have expanded the therapeutic spectrum of systemic treatments used for psoriasis. OBJECTIVES: To assess the effects of non-antistreptococcal interventions for acute guttate psoriasis or an acute guttate flare of chronic psoriasis. SEARCH METHODS: We searched the following databases up to June 2018: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We searched five trials registers and checked the reference lists of included studies for further references to relevant randomised controlled trials. We checked the proceedings of key dermatology conferences from 2004 to 2018, and also searched for trials in the US Food and Drug Administration (FDA) database for drug registration. SELECTION CRITERIA: All randomised controlled trials assessing the effects of treatments for acute guttate psoriasis or an acute guttate flare of chronic psoriasis clinically diagnosed in children and adults. This included all topical and systemic drugs, biological therapy, phototherapy (all forms: topical and systemic), and complementary and alternative therapies. We compared these treatments against placebo or against another treatment. We did not include studies on drugs that aim to eradicate streptococcal infection. We did not include studies when separate results for guttate psoriasis participants were not available. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility and methodological quality and extracted data. We used standard methodological procedures expected by Cochrane. Our primary outcomes were 'percentage of participants clear or almost clear (i.e. obtaining Psoriasis Area Severity Index (PASI) 100/90 and/or Physician's Global Assessment (PGA) of 0 or 1)' and 'percentage of participants with adverse effects and severe adverse effects'. Our secondary outcomes were 'number of relapses of guttate psoriasis or flares within a period of six months after the treatment has finished', 'percentage of participants achieving a PASI 75 or PGA of 1 or 2', and 'improvement in participant satisfaction measures and quality of life assessment measures'. We used GRADE to assess the quality of the evidence for each outcome. MAIN RESULTS: This review included only one trial (21 participants), which compared fish oil-derived (n-3) fatty acid-based lipid emulsion (50 mL per infusion (1.05 g eicosapentaenoic and 10.5 g docosahexaenoic acid)) (10 participants) to soya oil-derived (n-6) fatty acid-based lipid emulsion (50 mL per infusion (1.05 g eicosapentaenoic and 10.5 g docosahexaenoic acid)) (11 participants) administered intravenously twice daily for 10 days, with a total follow-up of 40 days. The study was conducted in a single centre in Germany in 18 men and three women, aged between 21 and 65 years, who were in hospital with acute guttate psoriasis and had mean total body surface involvement of 25.7% ± 20.4% (range 10 to 90). The study was funded by a company that produces the oil emulsions. We found no other evidence regarding non-antistreptococcal interventions used in clinical practice for guttate psoriasis, such as topical treatments (corticosteroids, vitamin D3 analogues), systemic drugs, biological therapy, and phototherapy.The primary outcomes of the review were not measured, and only one of our secondary outcomes was measured: improvement in participant satisfaction measures and quality of life assessment measures. However, the study authors did report that there was rare skin irritation at the site of peripheral intravenous route, but the number of affected participants was not provided.Improvement between baseline and day 10, using a non-validated score assessed by participants themselves daily based on five items (appearance of lesions, impairment of daily life, pruritus, burning, and pain), was greater in the group that received the fish oil-derived (n-3) fatty acid-based lipid emulsion (75%) than in the group receiving the soya oil-derived (n-6) fatty acid-based lipid emulsion (18%) (one trial, 21 participants). However, these results are uncertain as they are based on very low-quality evidence. AUTHORS' CONCLUSIONS: There is no evidence regarding topical and systemic drugs, biotherapy, or phototherapy in guttate psoriasis (we did not consider drugs that aimed to eradicate streptococcal infection because these are assessed in another Cochrane Review). We are uncertain of the effect of intravenously administered lipid emulsion on guttate psoriasis because the quality of the evidence is very low, due to risk of bias (unclear risk of bias for all domains), indirectness (the trial only included adults, and the follow-up from baseline was only 10 days), and imprecision (small number of participants).This review highlights the need for trials assessing the efficacy and safety of phototherapy and topical and systemic drugs for guttate psoriasis. There is also a need for studies that clearly distinguish the specific population with guttate psoriasis from the larger group of people with chronic plaque psoriasis, and children and young adults should be assessed as a distinct group.

Merkel cell carcinoma and cellular cytotoxicity: sensitivity to cellular lysis and screening for potential target antigens suitable for antibody-dependent cellular cytotoxicity.

The recent success of checkpoint inhibitors in the treatment of Merkel cell carcinoma (MCC) confirms that MCC tumors can be immunogenic. However, no treatment directly targeting the tumor is available for use in combination with these checkpoint inhibitors to enhance their efficacity. This study was carried out to characterize MCC line sensitivity to cellular lysis and to identify cell surface antigens that could be used for direct targeting of this tumor. For five representative MCC lines, the absence or low expression of MICA, MICB, HLA-I, and ICAM-1 was associated with low level of recognition by NK cells and T lymphocytes. However, expression of HLA-I and ICAM-1 and sensitivity to cellular lysis could be restored or increased after exposure to INFγ. We tested 41 antibodies specific for 41 different antigens using a novel antibody-dependent cellular cytotoxicity (ADCC) screening system for target antigens. Anti-CD326 (EpCAM) was the only antibody capable of inducing ADCC on the five MCC lines tested. Because MCC tumors are often directly accessible, local pharmacologic manipulation to restore HLA class-I and ICAM-1 cell surface expression (and thus sensitivity to cell lysis) can potentially benefit immune therapeutic intervention. In line with this, our observation that ADCC against EpCAM can induce lysis of MCC lines and suggests that therapeutic targeting of this antigen deserves to be explored further.

Differentiating Merkel cell carcinoma of lymph nodes without a detectable primary skin tumor from other metastatic neuroendocrine carcinomas: The ELECTHIP criteria.

BACKGROUND: Merkel cell carcinoma (MCC) can present as a cutaneous tumor or a lymph node metastasis without a primary tumor. MCC presenting without a primary tumor (MCCWOPT) can be misinterpreted on histologic examination as lymph node metastasis (LNM) from another neuroendocrine carcinoma (LNMNEC). However, this distinction is crucial for therapeutic management. OBJECTIVE: To determine the discriminative criteria for the differential diagnosis of MCCWOPT, LNM from cutaneous MCC, and LNMNECs. METHODS: Clinical, morphologic, and immunohistochemical data (expression of cytokeratins AE1, AE3, 7, 19, and 20; chromogranin A, synaptophysin, thyroid transcription factor-1 [TTF-1]), as well as the presence of Merkel cell polyomavirus (by immunohistochemistry and PCR) were compared in patients with MCCWOPT (n = 17), LNM from a cutaneous MCC (n = 11), and LNMNEC (n = 20; 8 lung, 7 thyroid, 3 digestive tract, 2 other). RESULTS: MCC (including MCCWOPT and LNM from a cutaneous MCC) differed from LNMNEC by 7 discriminative criteria: 1) elderly age, 2) location of the tumor, 3) extent of the disease, 4) cytokeratin expression, 5) TTF-1 expression, 6) histologic type, and 7) Merkel cell polyomavirus detection, summarized under the acronym ELECTHIP. All MCC patients had ≥5 of the ELECTHIP criteria, whereas all patients with LNMNEC (except 1) had <3 criteria. LIMITATIONS: The discriminant ability of the ELECTHIP criteria should be validated in a second independent set. CONCLUSION: MCCWOPT can be distinguished from other LNMNEC by the ELECTHIP criteria.

Merkel cell carcinomas infiltrated with CD33+ myeloid cells and CD8+ T cells are associated with improved outcome.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare tumor of the skin that has an aggressive behavior. Immunity is the main regulator of MCC development, and many interactions between lymphocytes and tumor cells have been proven. However, the impact of tumor-infiltrating myeloid cells needs better characterization. OBJECTIVE: To characterize tumor-infiltrating myeloid cells in MCC and their association with other immune effectors and patient outcome. METHODS: MCC cases were reviewed from an ongoing prospective cohort study. In all, 103 triplicate tumor samples were included in a tissue microarray. Macrophages, neutrophils, and myeloid-derived suppressor cells were characterized by the following markers: CD68, CD33, CD163, CD15, CD33, and human leukocyte antigen-DR. Associations of these cell populations with programmed cell death ligand 1 expression, CD8 infiltrates, and vascular density were assessed. Impact on survival was analyzed by log-rank tests and a Cox multivariate model. RESULTS: The median density of macrophages was 216 cells/mm2. CD68+ and CD33+ macrophage densities were associated with CD8+ T-cell infiltrates and programmed cell death ligand 1 expression. In addition, MCC harboring CD8+ T cell infiltrates and brisk CD33+ myeloid cell infiltrates were significantly and independently associated with improved outcomes (recurrence-free and overall survival). LIMITATIONS: Sampling bias and the retrospective design were potential study limitations. CONCLUSION: Infiltration of CD33+ myeloid cells and CD8+ T lymphocytes defines a subset of MCC associated with improved outcome.