The incidence of primary cutaneous melanoma continues to increase each year. Melanoma accounts for the majority of skin cancererelated deaths, but treatment is usually curative following early detection of disease. In this American Academy of Dermatology clinical practice guideline, updated treatment

Background The management of Merkel cell carcinoma (MCC) has been complicated by a lack of detailed prognostic data and by the presence of conflicting staging systems. Objective To determine the prognostic significance of tumor size, clinical vs pathologic nodal evaluation, and extent of disease at presentation and thereby derive the first consensus staging/prognostic system for MCC. Methods 5,823 prospectively enrolled MCC cases from the National Cancer Data Base (NCDB) had follow-up data (median 64 months) and were used for prognostic analyses. Results At 5 years, overall survival was 40% and relative survival (compared to age- and sex-matched population data) was 54%. Among all MCC cases, 66% presented with local, 27% with nodal and 7% with distant metastatic disease. For cases presenting with local disease only, smaller tumor size was associated with better survival (stage I: ≤2cm: 66% relative survival at five years; stage II: >2cm: 51%; p<0.0001). Patients with clinically local-only disease and pathologically proven negative nodes had better outcome (76% at five years) than those who only underwent clinical nodal evaluation (59%, p<0.0001). Limitations The NCDB does not capture disease-specific survival. Overall survival for MCC patients was therefore used to calculate relative survival based on matched population data. Conclusion Although the majority (68%) of MCC patients in this nationwide cohort did not undergo pathologic nodal evaluation, this procedure may be indicated in many cases as it improves prognostic accuracy and has important treatment implications for those found to have microscopic nodal involvement.

Analysis of a national dataset of MCC cases validates the predictive value of disease extent at presentation. Separation of clinical and pathological stage groups and regrouping of unknown primary tumors are supported by the analysis. The revised staging system provides more accurate prognostication and has been formally accepted by the AJCC staging committee for inclusion in the 8th edition.

Primary cilia are present on most mammalian cells and are implicated in transducing Hedgehog (Hh) signals during development; however, the prevalence of cilia on human tumors remains unclear, and the role of cilia in cancer has not been examined. Here we show that human basal cell carcinomas (BCCs) are frequently ciliated, and we test the role of cilia in BCC by conditionally deleting Kif3a (encoding kinesin family member 3A) or Ift88 (encoding intraflagellar transport protein 88), genes required for ciliogenesis, in two Hh pathway-dependent mouse tumor models. Ciliary ablation strongly inhibited BCC-like tumors induced by an activated form of Smoothened. In contrast, removal of cilia accelerated tumors induced by activated Gli2, a transcriptional effector of Hh signaling. These seemingly paradoxical effects are consistent with a dual role for cilia in mediating both the activation and the repression of the Hh signaling pathway. Our findings demonstrate that cilia function as unique signaling organelles that can either mediate or suppress tumorigenesis depending on the nature of the oncogenic initiating event.Elevated Hh pathway activity is associated with diverse tumors, including basal cell carcinoma, the most commonly diagnosed cancer in North America 1,2 . Hh signaling is normally restrained by the tumor suppressor Patched (Ptch1), which inhibits the function of the protooncogene Smoothened (Smo), a central activator of the pathway 3 . Binding of Hh ligand to Ptch1 relieves its inhibition of Smo, allowing Smo to induce downstream Gli activators and inhibit the formation of Gli repressors. In BCCs, loss of function mutations in PTCH1, gain of function mutations in SMO, and upregulation of GLI1 and GLI2 are frequently observed, suggesting that dysregulated Hh signaling is the underlying cause of this disease [4][5][6][7][8] .Recent studies have shown that the primary cilium has a prominent role in modulating mammalian Hh signaling 9 . Ptch1 suppresses the Hh pathway, at least in part, by preventing the trafficking of Smo into the primary cilium 10 In addition to its essential role in transducing Hh signals, the cilium also negatively regulates the pathway. Genetic analyses have shown that the cilium is required for the proteolytic processing of Gli3 into a form that represses the Hh transcriptional program (Gli3-R) [12][13][14][15] . Cilium-dependent formation of Gli3-R occurs in the absence of Hh and is suppressed upon Smo movement to the cilium. Thus, the cilium exerts both positive and negative control over the Hh pathway.Although cilia are present on many vertebrate cells, their involvement in cancer has not been explored. Early ultrastructural studies have indicated that individual cells from human BCCs can be ciliated 16 ; however, the prevalence of these ciliated cells has remained unclear. To determine whether cancer cells frequently possess cilia, we examined clinical biopsies from eight human BCCs. We observed that five BCCs contained numerous ciliated cells ( Fig. 1a and Supplementary Fig. ...

Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous neuroendocrine tumor. Merkel cell polyomavirus (MCPyV) may contribute to tumorigenesis in a subset of tumors via inhibition of tumor suppressors such as retinoblastoma (RB1) by mutated viral T-antigens, but the molecular pathogenesis of MCPyV-negative MCC is largely unexplored. Through our MI-ONCOSEQ precision oncology study we performed integrative sequencing on two cases of MCPyV-negative MCC, as well as a validation cohort of 14 additional MCC cases (n=16). In addition to previously identified mutations in TP53, RB1, and PIK3CA, we discovered activating mutations of oncogenes including HRAS and loss-of-function mutations in PRUNE2 and NOTCH family genes in MCPyV-negative MCC. MCPyV-negative tumors also displayed high overall mutation burden (10.09 +/− 2.32 mutations per Mb) and were characterized by a prominent UV-signature pattern with C > T transitions comprising 85% of mutations. In contrast, mutation burden was low in MCPyV-positive tumors (0.40 +/− 0.09 mutations per Mb) and lacked a UV signature. These findings suggest a potential ontologic dichotomy in MCC, characterized by either viral-dependent or UV-dependent tumorigenic pathways.

In a 12.5 cM genome-wide scan for psoriasis susceptibility loci, recombination-based tests revealed linkage to the HLA region (Zmax = 3.52), as well as suggestive linkage to two novel regions: chromosome 16q (60-83.1 cM from pter, Zmax = 2.50), and chromosome 20p (7.5-25 cM from pter, Zmax = 2.62). All three regions yielded P values < or = 0.01 by non-parametric analysis. Recombination-based and allele sharing methods also confirmed a previous report of a dominant susceptibility locus on distal chromosome 17q (108.2 cM from pter, Zmax = 2.09, GENEHUNTER P = 0.0056). We could not confirm a previously reported locus on distal chromosome 4q; however, a broad region of unclear significance was identified proximal to this proposed locus (153.6-178.4 cM from pter, Zmax = 1.01). Taken together with our recent results demonstrating linkage to HLA-B and -C, this genome-wide scan identifies a psoriasis susceptibility locus at HLA, confirms linkage to 17q, and recommends two novel genomic regions for further scrutiny. One of these regions (16q) overlaps with a recently-identified susceptibility locus for Crohn's disease. Psoriasis is much more common in patients with Crohn's disease than in controls, suggesting that an immunomodulatory locus capable of influencing both diseases may reside in this region.

This selection from the NCCN Guidelines for Merkel Cell Carcinoma (MCC) focuses on areas impacted by recently emerging data, including sections describing MCC risk factors, diagnosis, workup, follow-up, and management of advanced disease with radiation and systemic therapy. Included in these sections are discussion of the new recommendations for use of Merkel cell polyomavirus as a biomarker and new recommendations for use of checkpoint immunotherapies to treat metastatic or unresectable disease. The next update of the complete version of the NCCN Guidelines for MCC will include more detailed information about elements of pathology and addresses additional aspects of management of MCC, including surgical management of the primary tumor and draining nodal basin, radiation therapy as primary treatment, and management of recurrence.

Merkel cell carcinoma (MCC) is a relatively rare cutaneous malignancy that occurs predominantly in the older white population. The incidence of MCC appears to have tripled during the past 20 years; an increase that is likely to continue because of the growing number of older Americans. The pathogenesis of MCC remains largely unknown. However, ultraviolet radiation and immunosuppression are likely to play a significant pathogenetic role. Many questions currently remain unanswered regarding the biologic behavior and optimal treatment of MCC. Large, prospective, randomized studies are not available and are unlikely to be performed because of the rarity of the disease. The objective of this review was to provide a comprehensive reference for MCC based on a critical evaluation of the current data. The authors investigated the importance of sentinel lymph node biopsy as a staging tool for MCC to assess the status of the regional lymph node basin and to determine the need for additional therapy to the lymph node basin. In an attempt to standardize prospective data collection with the intention to define prognostic indicators, the authors also present histopathologic profiles for primary MCC and sentinel lymph nodes. The controversies regarding the appropriate surgical approach to primary MCC, the use of adjuvant radiation therapy, and the effective- A n increasing number of patients presenting with Merkel cell carcinoma (MCC) during the past 2 decades has focused attention on this cutaneous malignancy, which is seen primarily in older individuals. Based on the projection that, by 2030, 1 in 5 Americans will be aged !65 years, the increasing trend in MCC incidence is likely to continue.1 Currently, information regarding the biologic behavior and optimal treatment of MCC is limited given the paucity of high-level evidence and the absence of prospective, randomized trials. The objective of this review was to create a current reference for those involved in the care of patients with MCC or the investigation of this potentially aggressive malignancy. This review was based on a critical evaluation of the available data using an extensive PubMed search combined with our experience in the University of Michigan Comprehensive Cancer Center Multidisciplinary MCC program. EpidemiologyThe incidence of MCC is low compared with the incidence of other cutaneous malignancies. However, the trend is toward an increasing