Multiple primary dermatofibrosarcoma protuberans tumors in a single patient with chromosomal microarray analysis: A case report and review.

Dermatofibrosarcoma protuberans (DFSP) is a cutaneous sarcoma with a high propensity for local invasion and recurrence. Although it is a rare event, the occurrence of multiple tumors in a single patient raises a diagnostic dilemma, as metastatic disease should be differentiated from multiple primary malignant events. In more than 90% of DFSP, a pathogenic t(17;22) translocation leads to the expression of COL1A1::PDGFB fusion transcripts. Karyotype analysis, fluorescence in situ hybridization, and RT-PCR can be useful ancillary studies in detecting this characteristic rearrangement, and sequencing of the fusion transcript can be used to support a clonal origin in metastatic and multifocal disease. However, previous reports have demonstrated variable sensitivity of these assays, in part due to the high sequence variability of the COL1A1::PDGFB fusion. Here, we report a patient who developed two distinct DFSP tumors over the course of 7 years. Chromosomal microarray analysis identified distinctive genomic alterations in the two tumors, supporting the occurrence of multiple primary malignant events.

Development of a core outcome set for basal cell carcinoma.

BACKGROUND: There is variation in the outcomes reported in clinical studies of basal cell carcinoma. This can prevent effective meta-analyses from answering important clinical questions. OBJECTIVE: To identify a recommended minimum set of core outcomes for basal cell carcinoma clinical trials. METHODS: Patient and professional Delphi process to cull a long list, culminating in a consensus meeting. To be provisionally accepted, outcomes needed to be deemed important (score, 7-9, with 9 being the maximum) by 70% of each stakeholder group. RESULTS: Two hundred thirty-five candidate outcomes identified via a systematic literature review and survey of key stakeholders were reduced to 74 that were rated by 100 health care professionals and patients in 2 Delphi rounds. Twenty-seven outcomes were provisionally accepted. The final core set of 5 agreed-upon outcomes after the consensus meeting included complete response; persistent or serious adverse events; recurrence-free survival; quality of life; and patient satisfaction, including cosmetic outcome. LIMITATIONS: English-speaking patients and professionals rated outcomes extracted from English language studies. CONCLUSION: A core outcome set for basal cell carcinoma has been developed. The use of relevant measures may improve the utility of clinical research and the quality of therapeutic guidance available to clinicians.

Completion Lymph Node Dissection or Radiation Therapy for Sentinel Node Metastasis in Merkel Cell Carcinoma.

BACKGROUND: For sentinel lymph node (SLN) metastasis from Merkel cell carcinoma (MCC), the benefit of completion lymph node dissection (CLND) versus radiation therapy (RT) is unclear. This study compares outcomes for patients with SLN metastasis undergoing CLND or RT. We also evaluated positive non-SLNs as a prognostic factor. METHODS: Using a prospective database, we identified MCC patients with SLN metastasis who underwent CLND or RT. At our institution, CLND was recommended for patients with acceptable perioperative risk, while therapeutic RT was offered to those with high perioperative risk. Primary outcomes were MCC-specific survival (MCCSS), disease-free survival (DFS), nodal recurrence-free survival (NRFS), and distant recurrence-free survival (DRFS). RESULTS: From 2006 to 2017, 163 patients underwent CLND (n = 137) or RT (n = 26). Median follow-up was 1.9 years. CLND had no significant differences for MCCSS (5-year survival 71% vs. 64%, p = 1.0), DFS (52% vs. 61%, p = 0.8), NRFS (76% vs. 91%, p = 0.3), or DRFS (65% vs. 75%, p = 0.3) compared with RT. Patients with positive non-SLNs (n = 44) had significantly worse MCCSS (5-year survival 39% vs. 87%, p < 0.001), DFS (35% vs. 60%, p = 0.005), and DRFS (54% vs. 71%, p = 0.03) compared with negative non-SLNs (n = 93). Multivariate analysis showed positive non-SLNs were independently associated with MCCSS, DFS, and DRFS. CONCLUSIONS: CLND and RT may have similar outcomes for MCC patients with SLN metastasis when treatment aligns with our institutional practices. For patients undergoing CLND, positive non-SLNs is an important prognostic factor associated with poor survival and distant recurrence. This high-risk group should be considered for adjuvant systemic therapy trials.

Neurofilament is superior to cytokeratin 20 in supporting cutaneous origin for neuroendocrine carcinoma.

AIM: Primary cutaneous neuroendocrine carcinoma, or Merkel cell carcinoma (MCC), cannot be distinguished morphologically from small-cell neuroendocrine carcinomas (SmCC) from other sites. Immunohistochemistry is required to confirm cutaneous origin, and is also used for detection of sentinel lymph node (SLN) metastases of MCC. Cytokeratin 20 (CK20) expression is commonly used for these purposes, but is negative in some MCC cases, and has unclear specificity. We evaluated immunohistochemistry for neurofilament and CK20 in MCC compared with SmCC from other sites. METHODS AND RESULTS: We evaluated neurofilament expression in 55 MCC specimens from 39 unique patients, including nine CK20-negative MCC tumours. Neurofilament expression was observed in 42 of 55 (76.4%) MCC cases, including seven of nine (77.8%) CK20-negative MCC cases. Neurofilament was expressed in nine of 12 (75%) Merkel cell polyomavirus-positive tumours and five of 10 (50%) virus-negative tumours. Compared to a standard immunohistochemical panel (cytokeratin cocktail and CK20), neurofilament was 87.5% sensitive for detecting SLN metastases. Neurofilament and CK20 expression was also assessed in 61 extracutaneous SmCC from 60 unique patients, with primary sites including lung (27), bladder (18), cervix (3), gastrointestinal tract (3), sinonasal tract (2) and other sites (7). The specificity of neurofilament and CK20 for MCC versus non-cutaneous SmCC was 96.7% and 59.0%, respectively. CONCLUSIONS: Neurofilament has superior specificity to CK20 in distinguishing MCC from non-cutaneous SmCC. Neurofilament is frequently expressed in CK20- and virus-negative MCC tumours. Limitations of neurofilament immunohistochemistry include lower sensitivity than CK20 and subtle staining in some tumours. However, our findings indicate that neurofilament is useful for excluding non-cutaneous SmCC.

Merkel cell carcinoma arising in association with cutaneous T-cell lymphoma: A potential diagnostic pitfall.

Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine carcinoma with increased prevalence in patients with immunosuppression or B-cell neoplasms. To the best of our knowledge, an association with cutaneous T-cell lymphoma (CTCL) has not been previously described. In this report, we present two cases of MCC arising in the setting of CTCL. The first case was a female during her 70s with previously diagnosed stage IVA1 Sezary syndrome. Biopsy of a scaly patch showed two distinct abnormal cell populations. The first population consisted of hyperchromatic dermal and epidermotropic lymphocytes, expressing CD3 and CD4 with diminished CD7. The second population consisted of intraepidermal clusters of larger atypical cells that expressed synaptophysin, neurofilament, CK20, and Merkel cell polyomavirus transcript. The combination of findings was consistent with intraepidermal MCC in a background of CTCL. Excision showed residual intraepidermal MCC without dermal involvement. The second case was a male during his 50s with a longstanding history of mycosis fungoides, who presented with a new lesion on his right thigh. Biopsy and excision showed dermal MCC without secondary involvement by CTCL. Our cases show that MCC may rarely occur in the setting of T-cell lymphoma, and that intraepidermal MCC may mimic epidermotropic T-cells.

Merkel cell carcinoma: Current US incidence and projected increases based on changing demographics.

BACKGROUND: Merkel cell carcinoma (MCC) incidence rates are rising and strongly age-associated, relevant for an aging population. OBJECTIVE: Determine MCC incidence in the United States and project incident cases through the year 2025. METHODS: Registry data were obtained from the SEER-18 Database, containing 6600 MCC cases. Age- and sex-adjusted projections were generated using US census data. RESULTS: During 2000-2013, the number of reported solid cancer cases increased 15%, melanoma cases increased 57%, and MCC cases increased 95%. In 2013, the MCC incidence rate was 0.7 cases/100,000 person-years in the United States, corresponding to 2488 cases/year. MCC incidence increased exponentially with age, from 0.1 to 1.0 to 9.8 (per 100,000 person-years) among age groups 40-44 years, 60-64 years, and ≥85 years, respectively. Due to aging of the Baby Boomer generation, US MCC incident cases are predicted to climb to 2835 cases/year in 2020 and 3284 cases/year in 2025. LIMITATIONS: We assumed that the age-adjusted incidence rate would stabilize, and thus, the number of incident cases we projected might be an underestimate. CONCLUSION: An aging population is driving brisk increases in the number of new MCC cases in the United States. This growing impact combined with the rapidly evolving therapeutic landscape warrants expanded awareness of MCC diagnosis and management.

Subungual atypical lentiginous melanocytic proliferations in children and adolescents: A clinicopathologic study.

BACKGROUND: Most subungual melanocytic lesions in children are benign, but some are difficult to classify due to prominent lentiginous growth and high-grade cytologic atypia. OBJECTIVE: To characterize the clinicopathologic features of these rare lesions. METHODS: Subungual atypical lentiginous melanocytic proliferations from patients <20 years of age were collected for clinical and histopathologic review. Fluorescence in situ hybridization (FISH) was performed when possible. RESULTS: Eleven patients aged 2-19 years had expanding or darkening longitudinal pigmented streak(s) with or without Hutchinson sign. Microscopically, all revealed predominantly single-cell growth, pagetoid scatter, and poor circumscription. Eight (73%) cases showed focal or poor nesting, and 3 (27%) demonstrated confluence. Nuclear enlargement, hyperchromasia, and angulation were present in 8 (73%) cases, 7 (64%) cases, and 6 (55%) cases, respectively. One of 4 cases tested by FISH was positive. Three lesions recurred locally without other adverse outcome. LIMITATIONS: Small sample size and short clinical follow-up. Two cases were examined in partial biopsies only. CONCLUSION: Some subungual melanocytic lesions in children and adolescents are histologically indistinguishable from adult subungual melanoma in situ. While the biologic potential remains elusive, FISH might aid in risk stratification. Awareness of this rare group of lesions is crucial for facilitating future investigation into its biologic behavior.

The natural history of thin melanoma and the utility of sentinel lymph node biopsy.

BACKGROUND AND OBJECTIVES: Current literature may overestimate the risk of nodal metastasis from thin melanoma due to reporting of data only from lesions treated with SLNB. Our objective was to define the natural history of thin melanoma, assessing the likelihood of nodal disease, in order to guide selection for SLNB. METHODS: Retrospective review. The primary outcome was the rate of nodal disease. Clinicopathologic factors were evaluated to find associations with nodal disease. RESULTS: Five hundred and twelve lesions, follow up available for 488 (median: 48 months). Lesions treated with WLE/SLNB compared to WLE alone were more likely to have high-risk features. The rate of nodal disease was higher in the WLE/SLNB group (24 positive SLNB, five false-negative SLNB with nodal recurrence: 10.2%) compared to WLE alone (four nodal recurrences: 2.0%). Univariate analysis showed age ≤45, Breslow depth ≥0.85 mm, mitotic rate >1 mm2 , and ulceration were associated with nodal disease. Multivariate analysis confirmed the association of age ≤45 and ulceration. CONCLUSIONS: SLNB for melanoma 0.75-0.99 mm should be considered in patients age ≤45, Breslow depth ≥0.85 mm, mitotic rate >1 mm2 , and/or with ulceration. Thin melanoma <0.85 mm without high-risk features may be treated with WLE alone.

Analysis of Prognostic Factors from 9387 Merkel Cell Carcinoma Cases Forms the Basis for the New 8th Edition AJCC Staging System.

BACKGROUND: The first consensus Merkel cell carcinoma (MCC) staging system was published in 2010. New information on the clinical course prompts review of MCC staging. METHODS: A total of 9387 MCC cases from the National Cancer Data Base Participant User File with follow-up and staging data (1998-2012) were analyzed. Prognostic differences based on clinical and pathological staging were evaluated. Survival estimates were compared by disease extent. RESULTS: Sixty-five percent of cases presented with local disease, whereas 26 and 8 % presented with nodal and distant disease. Disease extent at presentation was predictive of 5-year overall survival (OS) with estimates of 51, 35, and 14 % for local, nodal, and distant disease. Tumor burden at the regional nodal basin was predictive of 5-year OS with estimates of 40 and 27 % for clinically occult and clinically detected nodal disease. For local disease, we confirm improved prognosis when the regional nodal basin was negative by pathological compared with clinical staging. We identified 336 cases with clinically detected nodal disease and unknown primary tumor and showed improved prognosis over cases presenting with concurrent primary tumor (OS estimates of 42 vs. 27 %). CONCLUSIONS: 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.

Mycosis fungoides with CD20 expression: report of two cases and review of the literature.

CD20 expression is exceedingly rare in T-cell lymphomas. Most published cases have been diagnosed as peripheral T-cell lymphomas, not otherwise specified. Only 18 cases of CD20-positive mycosis fungoides (MF) have been previously reported. Here, we describe two cases of CD20-positive MF. Patient 1 was an 84-year-old woman who presented with a 5-year history of multiple pruritic erythematous papules coalescing into thin plaques over 80% of her body surface area. She expired after developing tumors and large cell transformation. Patient 2 was a 67-year-old woman with a long-standing history of tumor stage MF with large cell transformation. She developed a nodular plaque while receiving topical and systemic therapy. In both cases, the neoplastic T-cells demonstrated a CD4-positive immunophenotype with loss of pan-T-cell markers and a monoclonal T-cell receptor gamma gene rearrangement. CD20 was expressed by a significant population of the neoplastic T-cells, but these T-cells lacked expression of other B-cell markers, including CD79a, CD19 and PAX5. This report adds to and summarizes the small body of literature describing CD20-positive MF, and discusses diagnostic and clinical implications.

Verrucous Carcinoma of the Foot: A Retrospective Study of 19 Cases and Analysis of Prognostic Factors Influencing Recurrence.

This study sought to evaluate a cohort of patients with verrucous carcinoma of the foot with special focus on 5 cases of locally recurrent tumors despite negative margins. Nineteen cases of verrucous carcinoma of the foot were identified through the University of Michigan (Ann Arbor, Michigan) pathology database from 1995 to 2019 and were included in demographic and clinical presentation analyses. Sixteen cases were treated at the University of Michigan and are included in the treatment analyses. A review of medical records was conducted to characterize clinical, surgical, and pathologic features. Recurrent cases were found to have a predilection for nonglabrous skin of the foot and great toe. Otherwise, there was little to differentiate outcomes between recurrent and nonrecurrent groups based on demographic, clinical, surgical, or histopathologic data. Recurrent tumors regrew locally and were not associated with histologic progression to conventional squamous cell carcinoma. Verrucous carcinoma of the nonglabrous surface of the foot should have a higher suspicion for possible local recurrence. Recurrence occurs within months of treatment, deserves early biopsy, and warrants aggressive re-treatment. Future directions should include greater examination of pathologic features and genetic markers to improve management of verrucous carcinoma of the foot.

Virus-positive Merkel Cell Carcinoma Is an Independent Prognostic Group with Distinct Predictive Biomarkers.

PURPOSE: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma that can be divided into two classes: virus-positive (VP) MCC, associated with oncogenic Merkel cell polyomavirus (MCPyV); and virus-negative (VN) MCC, associated with photodamage. EXPERIMENTAL DESIGN: We classified 346 MCC tumors from 300 patients for MCPyV using a combination of IHC, ISH, and qPCR assays. In a subset of tumors, we profiled mutation status and expression of cancer-relevant genes. MCPyV and molecular profiling results were correlated with disease-specific outcomes. Potential prognostic biomarkers were further validated by IHC. RESULTS: A total of 177 tumors were classified as VP-MCC, 151 tumors were VN-MCC, and 17 tumors were indeterminate. MCPyV positivity in primary tumors was associated with longer disease-specific and recurrence-free survival in univariate analysis, and in multivariate analysis incorporating age, sex, immune status, and stage at presentation. Prioritized oncogene or tumor suppressor mutations were frequent in VN-MCC but rare in VP-MCC. TP53 mutation developed with recurrence in one VP-MCC case. Importantly, for the first time we find that VP-MCC and VN-MCC display distinct sets of prognostic molecular biomarkers. For VP-MCC, shorter survival was associated with decreased expression of immune markers including granzyme and IDO1. For VN-MCC, shorter survival correlated with high expression of several genes including UBE2C. CONCLUSIONS: MCPyV status is an independent prognostic factor for MCC. Features of the tumor genome, transcriptome, and microenvironment may modify prognosis in a manner specific to viral status. MCPyV status has clinicopathologic significance and allows for identification of additional prognostic subgroups.

A genomic survey of sarcomas on sun-exposed skin reveals distinctive candidate drivers and potentially targetable mutations.

Sarcomas on photodamaged skin vary in prognosis and management, but can display overlapping microscopic and immunophenotypic features. Improved understanding of molecular alterations in these tumors may provide diagnostic and therapeutic insights. We characterized 111 cutaneous sarcomatoid malignancies and their counterparts, including primary cutaneous angiosarcoma (n = 7), atypical fibroxanthoma (AFX) (n = 21), pleomorphic dermal sarcoma (PDS) (n = 17), extracutaneous undifferentiated pleomorphic sarcoma (n = 8), cutaneous leiomyosarcoma (LMS) (n = 5), extracutaneous LMS (n = 9), sarcomatoid squamous cell carcinoma (spindle cell squamous cell carcinoma) (S-SCC) (n = 24), and conventional cutaneous squamous cell carcinoma (SCC) (n = 20), by next-generation sequencing (NGS) using the StrataNGS panel for copy number variations, mutations, and/or fusions in more than 60 cancer-related genes. TP53 mutations were highly recurrent in most groups. Angiosarcoma displayed previously reported MYC amplifications, as well as CCND1 gains. RB1 mutations were relatively restricted to cutaneous LMS. As previously reported, PIK3CA mutations occurred in AFX, whereas RAS activation was more frequent in PDS. CDKN2A mutations were recurrent in AFX and S-SCC, whereas PDS displayed frequent CDKN2A deletion. S-SCC displayed mutational similarity to conventional SCC. BRCA1/2 mutations were specific to tumors with disease progression. In a subset, we detected potential driver events novel to these tumor types: activating mutations in IDH2 (PDS), MAP2K1 (angiosarcoma, PDS), and JAK1 (S-SCC) and copy gains in FGFR1 (angiosarcoma, S-SCC), KIT (AFX), MET (PDS), and PDGFRA (PDS). Our findings confirm and expand the spectrum of known genomic aberrations, including potential targetable drivers, in cutaneous sarcomatoid malignancies. In addition, certain events are relatively specific to particular tumors within this differential diagnosis and hence might be diagnostically informative.

The biology and treatment of Merkel cell carcinoma: current understanding and research priorities.

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer associated with advanced age and immunosuppression. Over the past decade, an association has been discovered between MCC and either integration of the Merkel cell polyomavirus, which likely drives tumorigenesis, or somatic mutations owing to ultraviolet-induced DNA damage. Both virus-positive and virus-negative MCCs are immunogenic, and inhibition of the programmed cell death protein 1 (PD-1)-programmed cell death 1 ligand 1 (PD-L1) immune checkpoint has proved to be highly effective in treating patients with metastatic MCC; however, not all patients have a durable response to immunotherapy. Despite these rapid advances in the understanding and management of patients with MCC, many basic, translational and clinical research questions remain unanswered. In March 2018, an International Workshop on Merkel Cell Carcinoma Research was held at the US National Cancer Institute, at which academic, government and industry experts met to identify the highest-priority research questions. Here, we review the biology and treatment of MCC and report the consensus-based recommendations agreed upon during the workshop.

Increased expression of EZH2 in Merkel cell carcinoma is associated with disease progression and poorer prognosis.

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that affects tumorigenesis by epigenetic gene silencing. Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine carcinoma that has a high risk of disease progression with nodal and distant metastases. Here, we evaluated EZH2 expression by immunohistochemistry in a cohort of 85 MCC tumors (29 primary tumors, 41 lymph node metastases, 13 in-transit metastases, and 2 distant metastases) with clinical follow-up. We show strong/moderate EZH2 expression in 54% of tumors. Importantly, weak expression of EZH2 in the primary tumor, but not nodal metastases, correlated with improved prognosis compared to moderate/strong EZH2 expression (5-year MCC-specific survival of 68% versus 22%, respectively, P=.024). In addition, EZH2 was expressed at higher levels in nodal metastases compared to primary tumors (P=.005). Our data demonstrate that EZH2 has prognostic value and may play an oncogenic role in MCC.

Age and Gender Associations of Virus Positivity in Merkel Cell Carcinoma Characterized Using a Novel RNA In Situ Hybridization Assay.

Purpose: Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine tumor of the skin. Merkel cell polyomavirus (MCPyV) plays an oncogenic role in the majority of MCCs. Detection of MCPyV in MCCs has diagnostic utility and prognostic potential. We investigated whether RNAscope, an RNA in situ hybridization (ISH) assay for detection of RNA transcripts in tissues, is useful for MCPyV detection.Experimental Design: We applied an RNAscope probe targeting MCPyV T antigen transcripts on tissue microarrays (TMA) and whole-tissue sections encompassing 87 MCCs from 75 patients, 14 carcinomas of other types, and benign tissues. For comparison, qPCR was performed on 57 cases of MCC from 52 patients.Results: RNA-ISH demonstrated the presence of MCPyV in 37 of 75 cases (49.3%). Notably, tumors from younger patients (<73 years) had a significantly higher virus positivity than those from elderly patients (≥73 years; 64.9% vs. 34.2%, P = 0.011). Female patients had a higher positive rate of MCPyV than male patients (66.7% vs. 39.6%, P = 0.032). Data from both RNA-ISH and qPCR were available for 57 samples. Considering MCPyV qPCR as the gold standard for determining MCPyV status, RNAscope had 100% sensitivity and 100% specificity. There was a strong correlation between qPCR copy number and RNA-ISH product score (Spearman correlation coefficient R2 = 0.932, P < 0.0001).Conclusions: RNA-ISH is comparably sensitive to qPCR for detection of MCPyV and allows for correlation with tissue morphology. This study also reveals a significant association between age, gender, and MCPyV positivity. Clin Cancer Res; 23(18); 5622-30. ©2017 AACR.

Molecular Profiling of Multiple Primary Merkel Cell Carcinoma to Distinguish Genetically Distinct Tumors From Clonally Related Metastases.

Importance: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma. In rare cases, the development of an additional cutaneous MCC tumor is clinically consistent with a second primary MCC tumor rather than a cutaneous metastasis, which has important treatment and prognostic implications. Objective: To evaluate genetic relatedness in 4 cases with the clinical diagnosis of multiple primary MCCs. Design, Setting, and Participants: In this case series, 7 cases of clinically designated multiple primary MCC were identified; 4 cases met inclusion criteria for next-generation sequencing (NGS) analysis. Mutations, copy number alterations, and Merkel cell polyomavirus (MCPyV) sequence were analyzed and compared between clinically designated multiple primary tumors to characterize genetic relatedness and hence assess clonality. Patients with clinically designated multiple primary MCC were identified from the multidisciplinary MCC Program at the University of Michigan, a tertiary care center. Main Outcomes and Measures: Four cases of clinically designated multiple primary MCC were characterized by tumor sequencing and targeted MCPyV sequencing to distinguish independent primary tumors from related metastases. Results: Overall, 4 patients in their 70s or 80s were included and analyzed. Cases 1 and 4 were verified as genetically distinct primary tumors and did not harbor similar copy number alterations or demonstrate significant mutational overlap. Cases 2 and 3 were designated as clonally related based on overlapping copy number alterations. In clonally related tumors, chromosomal copy number changes were more reliable than mutations for demonstrating clonality. Regardless of clonality, we found that MCPyV status was concordant for all tumor pairs and MCPyV positive tumors harbored predominatly subclonal mutations. Conclusions and Relevance: Our findings suggest that patients with MCC may develop a second genetically distinct primary tumor; in this case, the subsequent tumor is likely to develop through similar mechanisms of pathogenesis, either MCPyV-mediated or ultraviolet light-mediated. Next-generation sequencing analysis of chromosomal copy number changes and mutations is useful in distinguishing multiple primary MCCs from progression of MCC clinically resembling multiple primaries, allowing appropriate staging of the patient.