Melanomas and nevi displaying regression features can be difficult to differentiate. To describe reflectance confocal microscopy features in benign and malignant pigmented skin lesions characterized by regression features in dermoscopy. Methods: Observational retrospective study. Inclusion criteria were presence of dermoscopic features of regression; availability of clinical, dermoscopic and RCM imaging; definite histopathologic diagnosis. The study sample comprised 217 lesions; 108 (49.8%) melanomas and 109 were benign lesions, of which 102 (47.0%) nevi and 7 (3.2%) lichen planus like keratosis (lplk). Patients with melanoma were significantly older than those with benign lesions (61.9±15.4 vs. 46.1±14.8; p<0.001) and a higher proportion of melanomas displayed dermoscopic regression structures in more than 50% of lesion surface (n=83/108; 76.9%; p<0.001). On RCM examination, pagetoid cells were significantly more reported in melanoma group, than in benign lesions (86.1% vs. 59.6%; p<0.001) and were more frequently widespread distributed (65.6% vs. 20.0%; p<0.001) and both dendritic and roundish (36.6% vs. 15.4%; p<0.001) in shape. Aspecific architecture at the dermo-epidermal junction (DEJ) was more commonly seen among melanomas than benign lesions (23.1% vs. 11.9%; p=0.002) with higher presence of dendritic and both dendritic and roundish atypical cells at the DEJ (28.7% vs. 18.3% and 19.4% vs. 3.7%; p<0.001, respectively). Focal pagetoid infiltration and ringed or clod patterns were more commonly seen in benign lesion. In conclusion, the correct interpretation of regressing lesions remains a challenge, assessing carefully the extent and characteristics of architectural and cytologic atypia on RCM is an additional piece of the complex puzzle of melanoma diagnosis. This article is protected by copyright. All rights reserved.

Dysplastic nevi (DN) are benign lesions with atypical features intermediate between that of common melanocytic nevi (CMN) and malignant melanoma (MM). Debate remains over whether DN represent progressive lesions from CMN. Through gene expression profiling and analysis of molecular gene signatures, our study revealed progressive increases in immune activation and regulation, along with pathways implicated in melanomagenesis, from CMN to DN to MM. Using criteria of 1.5 fold change and false discovery rate ≤ 0.05, we found differential expression of 7,186 probes (6,370 unique genes) with the largest difference detected between DN and MM from the standpoint of genomic melanoma progression. Despite progressive increases in the T-helper type 1 (Th1) inducing gene (IL-12), RT-PCR indicated impaired Th1 or cytotoxic T-cell response (decreased IFN-γ) in MM. Concordantly, our results indicated progressive increases in molecular markers associated with regulatory T-cells, exhausted T-cells, and tolerogenic dendritic cells, including detection of increased expression of suppressor of cytokine signaling 3 (SOCS3) in dendritic cells associated with MM. All together, our findings suggest that the increased immunosuppressive microenvironment of melanoma may contribute to unhampered proliferation of neoplastic cells. In addition, the detection of increased markers associated with tolerogenic dendritic cells in MM suggest that targeting these suppressive immune cell types may represent an alternative avenue for future immunotherapy. This article is protected by copyright. All rights reserved.

Ipilimumab is an immune-modulating drug that is being used today for various cancers including metastatic malignant melanoma. Owing to its mechanism of action, several adverse events have been reported, including some affecting skin. In this work, we report a novel display of multiple ipilimumab-associated halo lichenoid reactions surrounding benign nevi during treatment of metastatic melanoma. A patient underwent treatment with ipilimumab for treatment of stage IIIC melanoma at our center and was monitored for progress and adverse events throughout treatment. During treatment with ipilimumab, the patient clinically developed multiple halo lichenoid reactions surrounding previously present nevi, which histopathologically showed a lichenoid interface dermatitis associated with the mildly atypical nevi and ill-formed granulomata within the infiltrate. Therefore, ipilimumab may be associated with halo lichenoid reactions surrounding benign nevi and this adverse effect should be added to the various dermatologic reactions that patients can develop while being treated with this agent.

As cancer remains an increasing problem in industrial countries, the incidence of melanoma has risen rapidly in many populations during the last decades and still continues to rise. Current strategies aiming to control the disease have largely focused on improving the understanding of the interplay of causal factors for this cancer.

Spindle or epithelioid melanocytic (Spitz) nevi usually affect children or adolescents and growth in the face or the lower extremities. Histologically, they may show cytoarchitectural atypia and mitotic figures that could represent diagnostic pitfalls with malignant melanoma. Atypical spitzoid tumors (AST) indicate lesions that microscopically show intermediate characteristics between benign nevi and malignant melanoma. Nestin expression has been evaluated in benign nevi and malignant melanoma, but no studies on its role in Spitz lesion have been elaborated so far. Our results indicate that Nestin could allow to discriminate between AST and malignant spiztoid melanoma; the typical dermoscopic pattern is also associated with benign nevi in contrast to the atypical pattern that accumunates AST and malignant spitzoid melanoma.

Patients with multiple atypical nevi are at higher risk of developing melanoma. Among different techniques, sequential digital dermatoscopic imaging (SDDI) is a state-of-the art method to enhance diagnostic accuracy in evaluating pigmented skin lesions. It relies on analyzing digital dermatoscopic images of a lesion over time to find specific dynamic criteria inferring biologic behavior. SDDI can reduce the number of necessary excisions and finds melanomas in an early-and potentially curable-stage, but precautions in selecting patients and lesions have to be met to reach those goals.

Significant progress in the molecular pathology of melanocytic tumors have revealed that benign neoplasms, so-called nevi, are initiated by gain-of-function mutations in one of several primary oncogenes, such as BRAF in acquired melanocytic nevi, NRAS in congenital nevi or GNAQ/GNA11 in blue nevi, with consequent MAPK and PI3K/AKT/mTOR activation. Secondary genetic alterations overcome tumor suppressive mechanisms and allow the progression to intermediate lesions characterized by TERT-p mutation or to invasive melanomas displaying disruption of tumor suppressor genes. Currently, melanoma is molecularly regarded as four different diseases, namely BRAF, NRAS, NF1 and the "triple wild type" subtypes, which are associated with particular clinicopathological features. Melanocytic Spitzoid lesions include benign Spitz nevus, atypical Spitz tumor (AST) and Spitzoid melanoma. This is a challenging diagnostic group, particularly with regard to the distinction between AST and Spitzoid melanoma on clinical and histological grounds. Molecular analysis has identified the presence of HRAS mutation, BAP1 loss (often accompanying by BRAF mutations) or several kinase fusions in distinct categories of Spitz tumors. These aberrations account for the rapid growth characteristic of Spitz nevi. Subsequent growth is halted by various tumor suppressive mechanisms abrogation of which allow the development of AST, now better classified as low-grade melanocytic tumor. Although at present ancillary genetic techniques have not been very helpful in the prediction of biological behavior of AST, they have defined distinct tumor subsets differing with regard to biology and histology. Finally, we discuss how novel molecular markers may assist the differential diagnosis of melanoma, particularly from malignant peripheral nerve sheath tumor (MPNST). It is anticipated that the significant progress in the field of molecular pathology regarding the various types of melanocytic tumors, will eventually contribute to a more accurate histologic categorization, prediction of biologic behavior and personalized treatment.