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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.

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.

Spitz nevi are indolent melanocytic tumors arising preferentially during and after childhood. Over the last decades, recurrent oncogenic drivers, sparsely detected in melanoma, were identified in Spitz melanocytic proliferations. Therefore, the detection of such drivers appears as a relevant diagnostic tool to distinguish both entities. Interestingly, morphologic features might correlate with the oncogenic drivers. Thus, the goal of this study was to assess the performances of previously identified morphological criteria to predict the presence of specific drivers. In total, 352 Spitz melanocytic proliferations either with a genetically identified oncogenic driver or investigated for ALK, ROS1, and NTRK1 overexpression by immunohistochemistry were enrolled in the present study. The microscopic features of the cases were assessed blindly with regards to the molecular status and, performances of previously described morphological criteria to predict the molecular status were assessed applying the likelihood-ratio test (LHR). Overall, an oncogenic driver was identified in 76% of the cases (n = 268/352). No microscopic features allowed the reliable prediction of ROS1- and NTRK1-overexpressing cases. By contrast, a plexiform pattern can contribute to the recognition of ALK-overexpressing cases (LHR(+) = 6.14). Importantly, the pseudo-schwannoma variant was highly suggestive of NTRK3-rearranged cases (LHR(+) = 43). Moreover, atypical/malignant tumor (LHR(+) = 5.18), severe cellular atypia (LHR(+) = 5.07), and p16 loss (LHR(+) = 14) contribute to the recognition of MAP3K8-rearranged cases, while the presence of a sheet-like architecture (LHR(+) = 5.39) and a marked fibrosis of the stroma (LHR(+)=5.06) were predictive of BRAF-fused tumors. To conclude, our study confirms ALK-overexpressing, NTRK3-, MAP3K8-, and BRAF-rearranged cases harbored distinct morphologic features allowing their microscopic recognition.

Antibody–drug conjugates (ADCs) are an emerging class of therapeutics, with twelve FDA- and EMA-approved drugs for hematological and solid cancers. Such drugs consist in a monoclonal antibody linked to a cytotoxic agent, allowing a specific cytotoxicity to tumor cells. In recent years, tremendous progress has been observed in therapeutic approaches for advanced skin cancer patients. In this regard, targeted therapies (e.g., kinase inhibitors) or immune checkpoint-blocking antibodies outperformed conventional chemotherapy, with proven benefit to survival. Nevertheless, primary and acquired resistances as well as adverse events remain limitations of these therapies. Therefore, ADCs appear as an emerging therapeutic option in oncodermatology. After providing an overview of ADC design and development, the goal of this article is to review the potential ADC indications in the field of oncodermatology.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin. The main etiological agent is Merkel cell polyomavirus (MCPyV), detected in 80% of cases. About 5% of cases, called combined MCC, feature an admixture of neuroendocrine and non-neuroendocrine tumor cells. Reports of the presence or absence of MCPyV in combined MCC are conflicting, most favoring the absence, which suggests that combined MCC might have independent etiological factors and pathogenesis. These discrepancies might occur with the use of different virus identification assays, with different sensitivities. In this study, we aimed to determine the viral status of combined MCC by a multimodal approach. We histologically reviewed 128 cases of MCC and sub-classified them as “combined” or “conventional.” Both groups were compared by clinical data (age, sex, site, American Joint Committee on Cancer [AJCC] stage, immunosuppression, risk of recurrence, and death during follow-up) and immunochemical features (cytokeratin 20 and 7, thyroid transcription factor 1 [TTF1], p53, large T antigen [CM2B4], CD8 infiltrates). After a first calibration step with 12 conventional MCCs and 12 cutaneous squamous cell carcinomas as controls, all eight cases of combined MCC were investigated for MCPyV viral status by combining two independent molecular procedures. Furthermore, on multiplex genotyping assay, the samples were examined for the presence of other polyoma- and papillomaviruses. Combined MCC differed from conventional MCC in earlier AJCC stage, increased risk of recurrence and death, decreased CD8 infiltrates, more frequent TTF1 positivity (5/8), abnormal p53 expression (8/8), and frequent lack of large T antigen expression (7/8). With the molecular procedure, half of the combined MCC cases were positive for MCPyV in the neuroendocrine component. Beta papillomaviruses were detected in 5/8 combined MCC cases and 9/12 conventional MCC cases. In conclusion, the detection of MCPyV DNA in half of the combined MCC cases suggests similar routes of carcinogenesis for combined and conventional MCC.

BackgroundMetastases are the leading cause of mortality in many cancer types and lungs are one of the most common sites of metastasis alongside the liver, brain, and bones. In melanoma, 85% of late-stage patients harbor lung metastases. A local administration could enhance the targeting of metastases while limiting the systemic cytotoxicity. Therefore, intranasal administration of immunotherapeutic agents seems to be a promising approach to preferentially target lung metastases and decrease their burden on cancer mortality. From observations that certain microorganisms induce an acute infection of the tumor microenvironment leading to a local reactivating immune response, microbial-mediated immunotherapy is a next-generation field of investigation in which immunotherapies are engineered to overcome immune surveillance and escape from microenvironmental cancer defenses.MethodsThe goal of our study is to evaluate the potential of the intranasal administration of Neospora caninum in a syngeneic C57BL6 mouse model of B16F10 melanoma lung metastases. It also compares the antitumoral properties of a wild-type N. caninum versus N. caninum secreting human interleukin (IL)-15 fused to the sushi domain of the IL-15 receptor α chain, a potent activator of cellular immune responses.ResultsThe treatment of murine lung metastases by intranasal administration of an N. caninum engineered to secrete human IL-15 impairs lung metastases from further progression with only 0,08% of lung surface harboring metastases versus 4,4% in wild-type N. caninum treated mice and 36% in untreated mice. The control of tumor development is associated with a strong increase in numbers, within the lung, of natural killer cells, CD8+ T cells and macrophages, up to twofold, fivefold and sixfold, respectively. Analysis of expression levels of CD86 and CD206 on macrophages surface revealed a polarization of these macrophages towards an antitumoral M1 phenotype.ConclusionAdministration of IL-15/IL-15Rα-secreting N. caninum through intranasal administration, a non-invasive route, lend further support to N. caninum-demonstrated clear potential as an effective and safe immunotherapeutic approach for the treatment of metastatic solid cancers, whose existing therapeutic options are scarce. Combination of this armed protozoa with an intranasal route could reinforce the existing therapeutic arsenal against cancer and narrow the spectrum of incurable cancers.

Merkel cell polyomavirus (MCPyV) is the first polyomavirus clearly associated with a human cancer, i.e. the Merkel cell carcinoma (MCC). Polyomaviruses are small naked DNA viruses that induce a robust polyclonal antibody response against the major capsid protein (VP1). However, the polyomavirus VP1 capsid protein epitopes have not been identified to date. The aim of this study was to identify the neutralizing epitopes of the MCPyV capsid. For this goal, four VP1 mutants were generated by insertional mutagenesis in the BC, DE, EF and HI loops between amino acids 88-89, 150-151, 189-190, and 296-297, respectively. The reactivity of these mutants and wild-type VLPs was then investigated with anti-VP1 monoclonal antibodies and anti-MCPyV positive human sera. The findings together suggest that immunodominant conformational neutralizing epitopes are present at the surface of the MCPyV VLPs and are clustered within BC and EF loops.

Merkel cell carcinoma (MCC) is a rare high-grade neuroendocrine tumour of the skin. It has been speculated that MCCs express somatostatin receptors (SSTRs), but this has never been assessed in a large series of MCCs. The main aim of this study was to assess the expression of SSTR2A and SSTR5 in MCC tumours. The secondary aims were to assess whether expression of SSTR was associated with the Ki67 proliferative index, Merkel cell polyomavirus (MCPyV) status, clinical characteristics and outcome.Clinical data and tumours were collected from an ongoing cohort of French patients with MCC. Immunohistochemistry was performed with anti-SSTR2A and anti-SSTR5 monoclonal antibodies, and tumours were classified into 3 groups: 'no expression', 'low expression' and 'moderate expression' using an SSTR staining score.SSTR expression was assessed for 105 MCC tissue samples from 98 patients, and clinical characteristics were available for 87 of them. SSTR expression was consistent between the primary skin tumour and the corresponding metastases for SSTR2A and SSTR5 in 3/7 and 6/7 cases, respectively. SSTR2A and SSTR5 were expressed in 58 cases (59.2%) and in 44 cases (44.9%), respectively. Overall, at least one SSTR was expressed in 75 tumours (76.5%). SSTR expression was not associated with clinical characteristics, Ki67 proliferative index, recurrence-free survival or MCC-specific survival. Expression of SSTR2A was associated with MCPyV status in MCC tumours but not SSTR5.SSTRs were expressed in a high proportion of MCCs, although expression was heterogeneous between tumours and was not associated with disease severity

Oral lichen planus (OLP) is a chronic inflammatory disease whose pathogenesis involves a T-cell mediated, epithelium-directed inflammation in response to unknown antigen(s). The disease evolves by intermittent flares and displays polymorphous clinical features (reticular, erosive, atrophic, plaque, papular, bullous, etc.). When present, symptoms vary depending on the clinical form and range from discomfort to severe pain. Topical superpotent corticosteroids constitute the first-line treatment of symptomatic flares, whereas a wide range of second/third-line treatments are available among topical calcineurin inhibitors, systemic corticosteroids, systemic retinoids, topical/systemic immunomodulators, etc. Follow-up of patients is necessary to detect transformation into squamous cell carcinoma, occurring in approximately 1% of patients.

Among the 100 initial priority topics for comparative effectiveness research, three concern topical drugs in the following dermatologic diseases: psoriasis, chronic lower-extremity wounds (CLEWs), and acne vulgaris (AV). Our objective was to explore the geometry of the corresponding networks of randomized controlled trials (RCTs). We performed a review of RCTs on topical drugs in psoriasis, CLEWs, and AV. We searched MEDLINE, Embase, and CENTRAL for published trials from 2007 to 2012 and ClinicalTrials.gov for unpublished trials registered since 2011. RCTs comparing at least one topical treatment with any active or inactive comparator, regardless of RCT design and outcomes, were eligible. We produced network graphs (each node representing a treatment and links between nodes representing trials) and tested for co-occurrence (preference or avoidance of specific comparisons). We included 60 RCTs on psoriasis (14,255 patients) and 19 registered RCTs, 50 of CLEWs (5,916 patients) and 7 registered RCTs, and 90 of AV (22,984 patients) and 21 registered RCTs. Head-to-head comparisons were made in 78%, 32%, and 57% of published RCTs of these conditions, respectively. The co-occurrence test suggested that no specific head-to-head comparison was significantly preferred or avoided (P-value=0.53, 0.20, and 0.57, respectively). This study has limitations, the main being that the search period was restricted to 5 years. In conclusion, more comparative effectiveness trials are needed for CLEWs, for which head-to-head comparisons are fewer than those for psoriasis and AV.