Aggressive Cutaneous Malignancy Research Articles

A Rare Case Report on Definitive Radiotherapy in Sebaceous Carcinoma of the Eyelid

Introduction: Sebaceous carcinomas are rare but potentially aggressive cutaneous malignancies. Surgical excision, albeit the primary modality of treatment, is associated with functional as well as cosmetic impairments. Radiotherapy offers an alternative treatment modality for those in whom surgical excision is not an option either due to medical reasons or patient preferences. Materials and Methods: Here we present a rare case report of an elderly Indian man with sebaceous carcinoma of the eyelid, for whom definitive radiotherapy was delivered as the primary modality of treatment. Results: There was a near complete response of the tumour to the definitive radiotherapy with acceptable toxicity. Discussion: Radiotherapy is a non-invasive alternative to surgical excision that has the advantage of better functional and cosmetic outcomes.

Epidemiology, survival, and risk of subsequent primary malignancies in patients with digital papillary adenocarcinoma: a retrospective study of 213 patients in the Surveillance, Epidemiology, and End Results (SEER) Program.

Digital papillary adenocarcinoma (DPAc) is a rare, aggressive cutaneous malignancy of sweat gland derivation. Herein, we conduct a retrospective study of 213 DPAc patients using the 17 registries of the Surveillance, Epidemiology, and End Results (SEER) program. We estimate the incidence of DPAc to be 0.11 per million persons per year, with the incidence rising over the past two decades. Our study shows DPAc to most commonly afflict White males, typically in their 40s-60s. We note a 5-year disease-specific survival of 98.3% and 5-year overall survival of 95.7%. We also show advanced age to be associated with more aggressive disease and identify tumor size as an independent risk factor impacting disease-specific survival. Our results also suggest that patients with DPAc have an elevated risk of developing subsequent primary malignancies, with males being at increased risk of developing lung/bronchial neoplasms and females being at increased risk of developing breast cancer.

Outcomes of Head and Neck Microvascular Free Tissue Transfer for Advanced Cutaneous Squamous Cell Carcinoma: A Comparison of Solid Organ Transplant Recipients to Nontransplant Patients

BackgroundPatients with solid organ transplant (SOT) are at increased risk of developing aggressive cutaneous malignancies due to their immunosuppression, particularly cutaneous squamous cell carcinoma PurposeThere is limited data regarding solid organ transplant patients with locally advanced cutaneous squamous cell carcinoma (cSCC) requiring radical surgery and microvascular free tissue transfer (MVFTT). Our objectives were to characterize outcomes in SOT patients and compare them with a non-SOT cohort. Study DesignThis is a retrospective cohort study of patients undergoing MVFTT for advanced cSCC of the head and neck between January 2016 and May 2020 at a tertiary referral center. Patients who underwent MVFTT as part of curative intent surgery for advanced cSCC during the study were considered for inclusion. Exclusion criteria included distant metastasis, palliative intent treatment, age less than 18 years, and lip primaries. PredictorThe predictor variable was SOT status. A cohort of non-SOT patients was matched to the SOT cohort based on age, smoking status, tumor stage, and defect size. Main outcome variablesThe primary reconstructive outcome was the major surgical complications and secondary outcome measures included major medical complications and minor surgical complications. The primary oncologic outcome was overall survival and the secondary outcome was disease-specific survival. The primary predictor was transplant status. CovariatesCovariates included patient comorbidities, prior treatment, tumor stage, type of reconstruction, pathologic findings, and adjuvant therapy. AnalysisContinuous and categorical variables were compared using Student’s T test and Fisher’s exact test. Survival was calculated using the Kaplan-Meier method and differences in survival between groups were calculated using the log-rank test. Statistical significance was set a priori at p ≤ 0.05 ResultsFourteen SOT and 14 matched non-SOT patients met inclusion criteria. There was not a statistically significant difference in the rate of major surgical complications (7% vs 7%, p = 0.74) between the SOT and non-SOT cohorts. Rates of minor (21% vs 43%, p = 0.26) wound complications and medical complications (0% vs 14%, p =0.24) were also similar between the SOT and non-SOT cohorts. Locoregional recurrences and distant metastasis were more common for SOT patients, though this was not statistically significant. Overall survival was significantly worse for SOT patients (21.7 vs 31.0 months, p = 0.04), though there was not a significant difference in disease-free survival (9.8 vs 31.0 months, p = 0.17). Conclusions and RelevanceMVFTT in the management of SOT patients with locally advanced head and neck cSCC demonstrates similar complication rates with non-SOT patients. While survival and oncologic outcomes are worse in the SOT cohort, aggressive surgical intervention with MVFTT can be performed with comparable complication rates to patients without a history of SOT.

Identification of hub anoikis-associated genes and risk signature in cutaneous melanoma.

As one of the most lethal and aggressive cutaneous malignancies, cutaneous melanoma (CM) greatly threatens human health and has long challenged clinicians because of its poor therapeutic response. Anoikis is a newly discovered form of apoptosis that was originally identified in the extracellular matrix (ECM). Recent studies have reported that anoikis is central to cancer metastasis. The aim of this study is to explore the role of anoikis-associated genes in CM. We identified hub anoikis-associated genes in CM and constructed a risk signature for patients with CM. Gene expression from The Cancer Genome Atlas (TCGA) database was used to screen hub anoikis-associated genes connected with CM, and the Gene Expression Omnibus (GEO) dataset was applied to externally validate the identified genes. Weighted gene co-expression network analysis (WGCNA), differential expression, univariate Cox regression, and least absolute shrinkage and selection operator (LASSO) analyses were used to identify hub genes. Immune cell infiltration in CM was also evaluated to explore the association between hub genes and immune heterogeneity. Finally, an anoikis-associated prognostic model was constructed. Following complex analysis, FASLG, SOD2, BST2, PIK3R2, IKZF3, CDK2, and RAC3 were identified as hub anoikis-associated genes. Indeed, Kaplan-Meier and receiver operating characteristic analyses suggested that the expression patterns of hub genes can be used as prognostic factors for CM survival. The expression and survival trends of hub genes were verified in the validation cohort. Immune cell infiltration analysis showed that the number of immune cells varied among patients with CM and identified seven genes. Furthermore, functional analyses indicated that the constructed risk signature was significantly associated with patient survival, age, and tumor growth and could also serve as an independent prognostic factor for patients with CM. We suggest that the hub genes FASLG, SOD2, BST2, PIK3R2, IKZF3, CDK2, and RAC3 are involved in the anoikis-associated signature. The pattern of hub anoikis-associated genes may have a prognostic potential for CM progression and overall patient survival.

Epidemiology and Mortality Risk Factors of Sebaceous Carcinoma: A SEER – Based Population Study

Background:
 Sebaceous carcinoma is a rare and potentially aggressive cutaneous malignancy. It is derived from the adnexal epithelium of sebaceous glands and tends to hold a diverse clinical presentation. Although it is often reported in the periocular region, it can manifest from any sebaceous unit in the skin. Due to the rarity of this condition, prognostic and demographic factors are largely indeterminate. Hence, we sought to assess the prognostic impact of demographic and socioeconomic factors on the outcome of patients with sebaceous carcinoma.
 
 Methods:
 A retrospective analysis was performed utilizing data from the Surveillance, Epidemiology, and End Results (SEER) database. From the registries, cases of sebaceous carcinoma from the years 2000 to 2018 were analyzed. Univariate and multivariate cox regression analyses were used to analyze the significance of socioeconomic and demographic factors on the survival of sebaceous carcinoma. Tumor grade and extent were included in the multivariate cox regression to minimize confounding.
 
 Results:
 A total of 4154 cases of sebaceous carcinoma were analyzed within this study. Socioeconomic and demographic factors analyzed includes age, sex, race, and income. On multivariate analysis including tumor grade, tumor extent, age, sex, race and income, African American race was a significant risk indicator for survival (hazard ratio [HR], 1.9; P=.007). Increased age of 70+ were also identified as a significant risk indicator for survival (HR, 5.86; P<0.001). Female sex was identified as a protective indicator for survival (HR, 0.82; P=0.03). Income status did not significantly influence the survival outcome of sebaceous carcinoma.
 
 Conclusion:
 Although income status did not show any significant influence on the survival outcome of sebaceous carcinoma, sex, race, and age characteristics did. The etiology behind these prognostic factors is unclear but may be related to access to medical care or lack of social support.

Wide Local Excision for Eccrine Porocarcinoma of the Forearm.

Eccrine porocarcinoma is a rare and aggressive cutaneous malignancy that develops in the seventh and eight decades of life. We present a 76-year-old male with eccrine porocarcinoma developing from a long standing previously benign lesion who underwent successful treatment with wide local excision. It can also develop de novo, presenting most commonly as a mass or nodule. Tissue biopsy with histopathology is required to confirm the diagnosis. Wide local excision is recommended for local disease. Radiation and chemotherapy can be used as adjuncts in advanced and metastatic disease. Given its rarity, there are no guidelines to direct therapy for locally advance or metastatic disease and for follow-up. Further studies are needed to better understand and guide management of this entity.

Surgical management of dermatofibrosarcoma protuberans.

Dermatofibrosarcoma protuberans (DFSP) is an uncommon, locally aggressive cutaneous malignancy. Complete resection is the primary treatment but there is debate over the optimal method. Wide local excision was traditionally the standard of care; however, National Comprehensive Cancer Network guidelines now recommend Mohs micrographic surgery as the preferred approach. Medical therapy with imatinib can be used in advanced or unresectable disease. This review will discuss the current management of DFSP, focusing on optimal surgical approach.

A novel Cuprotosis-related signature predicts the prognosis and selects personal treatments for melanoma based on bioinformatics analysis.

Melanoma is a common and aggressive cutaneous malignancy characterized by poor prognosis and a high fatality rate. Recently, due to the application of Immune-checkpoint inhibitors (ICI) in melanoma treatment, melanoma patients' prognosis has been tremendously improved. However, the treatment effect varies quite differently from patient to patient. In this study, we aim to construct and validate a Cuproptosis-related risk model to improve outcome prediction of ICIs in melanoma and divide patients into subtypes with different Cuproptosis-related genes. Here, according to differentially expressed genes from four melanoma datasets in GEO (Gene Expression Omnibus), and one in TCGA (The Cancer Genome Atlas) database, a novel signature was developed through LASSO and Cox regression analysis. We used 781 melanoma samples to examine the molecular subtypes associated with Cuproptosis-related genes and studied the related gene mutation and TME cell infiltration. Patients with melanoma can be divided into at least three subtypes based on gene expression profile. Survival pan-cancer analysis was also conducted for melanoma patients. The Cuproptosis risk score can predict tumor immunity, subtype, survival, and drug sensitivity for melanoma. And Cuproptosis-associated subtypes can help predict therapeutic outcomes. Cuproptosis risk score is a promising potential biomarker in cancer diagnosis, molecular subtypes determination, TME cell infiltration characteristics, and therapy response prediction in melanoma patients.

LBA42 Combined nivolumab and ipilimumab with or without stereotactic body radiation therapy for advanced Merkel cell carcinoma

Merkel Cell Carcinoma is an aggressive cutaneous malignancy associated with Merkel cell polyomavirus or UV exposure. In recent years, anti-PD1/PDL1 therapy has dramatically improved the treatment landscape, but outcome remains poor among patients who progress on this therapy. In this multicenter phase 2 randomized study, patients with unresectable, recurrent or metastatic Merkel cell carcinoma patients received NIVO 240mg IV q2 wks plus IPI 1mg/kg IV q6 wks (Arm A) or NIVO 240mg IV q2 wks plus IPI 1mg/kg IV q6 wks plus stereotactic body radiation therapy (SBRT) to 24Gy in 3 fractions at week 2 (Arm B). Patients were required to have at least two measurable sites of disease to ensure that at least one non-irradiated site could be followed for treatment response. Both arms were experimental and randomized in a 1:1 ratio based on a Bayesian pick-the-winner design with each arm using a Simon’s Mini-Max two-stage design. Patients were stratified by prior treatment with immune checkpoint inhibitor (ICI). The primary endpoint was objective response rate (ORR). Tumor status was assessed every 12 weeks and evaluated by immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). 50 patients (24 ICI-naïve, 26 with prior ICI) received ≥1 dose of NIVO plus IPI and 24 received SBRT (median follow-up 14.6 months). ORR in ICI-naïve patients was 100% [95%CI, 82%-100%], 41% with complete response. ORR in prior ICI patients was 31% [95%CI, 15%-52%], 15% with complete response. No significant differences in ORR were observed between Arms A and B (72% vs. 52%, p=0.26). Median duration of response was not reached [95%CI, 33.9 months-NE] in the ICI-naïve cohort and was 10.8 months [95% CI, 4.9 months-NE] in the prior ICI cohort. Treatment was well tolerated with a toxicity profile similar to that previously observed. In this study, first-line therapy with NIVO plus IPI in patients with advanced MCC demonstrated an exceptionally high ORR of 100%, with durable responses and a manageable safety profile. NIVO plus IPI also exhibited clinical activity in patients who progressed on prior anti-PD1/PDL1 monotherapy. Addition of SBRT did not alter the efficacy of NIVO plus IPI in this study.

A Primary Extracutaneous Presentation of Merkel Cell Carcinoma

Merkel cell carcinoma (MCC) is a rare aggressive cutaneous neuroendocrine malignancy with a mortality rate of around 33%. The presence of advanced disease at the time of diagnosis is associated with poor prognosis. Twofold etiologies have been described in the pathogenesis of Merkel cell carcinoma: chronic exposure to ultraviolet (UV) light and Merkel cell polyomavirus (MCPvY). MCC usually affects sun-exposed skin areas, and the presence of cutaneous nodules is the hallmark of the disease. However, there have been case reports in the literature where the diagnosis of MCC was made in the absence of any cutaneous findings. We present a case report of Merkel cell carcinoma that is unique in its presentation because of the presence of pulmonary and hepatic nodules and the absence of cutaneous lesions.

Merkel cell carcinoma: a case report

Merkel cell carcinoma is a rare and aggressive cutaneous neuroendocrine malignancy that presents as a persistent red-purplish, asymptomatic and rapidly growing nodule. It typically affects sun-exposed skin of white elderly individuals. In addition, risk factors for Merkel cell carcinoma include immunosuppression, as well as the presence of multiple myeloma or a history of chronic lymphocytic leukemia.
 To diagnose Merkel cell carcinoma, five criteria of the AEIOU algorithm proposed in 2008 by a group of scientists at the University of Washington are used.
 From the methods of laboratory diagnostics a detailed analysis of blood is used, also a histological and immunohistochemical study is carried out . Among the methods of instrumental diagnostics, ultrasound examination of the primary tumor and groups of lymph nodes of the appropriate localization, abdominal and pelvic organs; chest X-ray and skeletal bone scintigraphy; positron emission tomography combined with X-ray computed tomography are mandatory. A sentinel node biopsy followed by histological and immunohistochemical examination is recommended in the absence of metastatic lymph node lesions.
 We herein contribute by reporting a case of Merkel cell carcinoma affecting the forearm of a 51-year-old female. This clinical case confirms the aggressiveness of this type of the skin cancer as well as high possibility of misdiagnosis due to the scarce occurrence of Merkel cell carcinoma and lack of professional knowledge.
 Therefore, it is important for the practitioners involved in the care of skin lesions to be aware of this condition and the need for a multidisciplinary treatment approach.

Merkel cell carcinoma of unknown primary: Clinical presentation and outcomes.

Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy that usually occurs in the head/neck or extremities. However, there are reports of MCC developing in the lymph nodes or parotid gland without evidence of a primary cutaneous lesion. We reviewed 415 patients with biopsy-proven MCC. Patients with MCC of unknown primary (n = 37, 9%, MCCUP) made up the study cohort. The primary endpoints of the study were rate of recurrence, disease-free survival, and overall survival. Patients with MCCUP presented with tumors in lymph nodes (n = 34) or parotid gland (n = 3). Nodal disease was most commonly detected in the inguinal/external iliac (n = 15) or axillary (n = 14) regions. The mean age at diagnosis was 70 years and 24% were female. Patients presented with distant metastases in 24.3% of cases. Patients with stage IIIA disease treated with regional lymph node dissection (RLND) had a lower risk of disease recurrence (hazard ratio 0.26, p = 0.046). Recurrence-free survival was 59.3% at 5 years. Disease-specific survival was 63.3% at 5 years. Patients with MCCUP have a high risk of recurrence and mortality. The optimal treatment for MCCUP has yet to be elucidated, although therapeutic RLND appears beneficial for these patients.

Oncologic outcomes of patients with lymph node–positive Merkel cell carcinoma with unknown primary: A retrospective cohort study

To the Editor: Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine malignancy that has been increasing in incidence.1 Four percent to 5% of patients present with unknown primary tumors, which has been observed to be associated with improved overall survival (OS) over those with known primaries.2 To determine the effect of T and M stage on OS, we conducted a retrospective analysis of the National Cancer Database containing patients with lymph node (LN)–positive MCC diagnosed from 2004 to 2016 (Supplementary Fig 1, available via Mendeley at https://doi.org/10.17632/x854j5thxd.2).

PET-CT in Clinical Adult Oncology-VI. Primary Cutaneous Cancer, Sarcomas and Neuroendocrine Tumors.

Simple SummaryPositron emission tomography (PET), typically combined with computed tomography (CT), has become a critical advanced imaging technique in oncology. With PET-CT, a radioactive molecule (radiotracer) is injected into the bloodstream and localizes to tumor sites because of specific cellular features of the tumor that accumulate the targeting radiotracer. The CT scan is performed at the same time, facilitating better visualization of radioactivity from deep or dense structures and providing detailed anatomic information. PET-CT has a variety of applications in oncology, including staging, therapeutic response assessment, restaging and surveillance. This series of six articles provides an overview of the value, applications, imaging and interpretive strategies of PET-CT in the more common adult malignancies. In the current and sixth report in this series, the application of PET-CT is reviewed for more aggressive skin cancers, sarcomas and neuroendocrine tumors.PET-CT is an advanced imaging modality with many oncologic applications, including staging, therapeutic assessment, restaging and surveillance for recurrence. The goal of this series of six review articles is to provide practical information to providers and imaging professionals regarding the best use of PET-CT for specific oncologic indications, the potential pitfalls and nuances that characterize these applications, and guidelines for image interpretation. Tumor-specific clinical information and representative PET-CT images are provided. The current, sixth article in this series addresses PET-CT in an evaluation of aggressive cutaneous malignancies, sarcomas and neuroendocrine tumors. A discussion of the role of FDG PET for all types of tumors in these categories is beyond the scope of this review. Rather, this article focuses on the most common malignancies in adult patients encountered in clinical practice. It also focuses on Food and Drug Agency (FDA)-approved and clinically available radiopharmaceuticals rather than research tracers or those requiring a local cyclotron. This information will serve as a guide to primary providers for the appropriate role of PET-CT in managing patients with cutaneous malignancies, sarcomas and neuroendocrine tumors. The nuances of PET-CT interpretation as a practical guide for imaging providers, including radiologists, nuclear medicine physicians and their trainees, are also addressed.

Patient- and County-Level Factors Associated with Late-Stage Merkel Cell Carcinoma at Diagnosis

Merkel cell carcinoma (MCC) is a rare, yet aggressive cutaneous malignancy that typically presents in the elderly population ( Coggshall et al., 2018 Coggshall K. Tello T.L. North J.P. Yu S.S. Merkel cell carcinoma: an update and review: pathogenesis, diagnosis, and staging. J Am Acad Dermatol. 2018; 78: 433-442 Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar ). MCC incidence rates have risen by >95% since the year 2000 ( Paulson et al., 2018 Paulson K.G. Park S.Y. Vandeven N.A. Lachance K. Thomas H. Chapuis A.G. et al. Merkel cell carcinoma: current US incidence and projected increases based on changing demographics. J Am Acad Dermatol. 2018; 78: 457-463.e2 Abstract Full Text Full Text PDF PubMed Scopus (253) Google Scholar ), and the 5-year survival of late-stage disease is only 14% (compared with 51% for early stage) ( Coggshall et al., 2018 Coggshall K. Tello T.L. North J.P. Yu S.S. Merkel cell carcinoma: an update and review: pathogenesis, diagnosis, and staging. J Am Acad Dermatol. 2018; 78: 433-442 Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar ). Despite the promising efficacy of immunotherapy for late-stage MCC, the treatment carries risks of toxicity and financial burden, underscoring the importance of early diagnosis ( Tello et al., 2018 Tello T.L. Coggshall K. Yom S.S. Yu S.S. Merkel cell carcinoma: an update and review: current and future therapy. J Am Acad Dermatol. 2018; 78: 445-454 Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar ).

Recurrence of metastatic Merkel carcinoma after cessation of avelumab in a patient previously with a complete response

AbstractBackgroundMerkel cell carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine malignancy. Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for patients with metastatic MCC (mMCC). In mMCC, the response duration after cessation of ICIs treatment for complete response (CR) is unknown.ObservationWe report a case of a woman in her 70s with metastatic MCC treated in first‐line with avelumab. The treatment was stopped after 2 years of CR. The patient relapsed after 11 months of cessation of treatment and rechallenge with avelumab at the same dosing regimen was decided. The first tumour assessment at 3 months after reintroduction revealed a CR.DiscussionIn contrast with observations made for patients who have discontinued ICIs in the metastatic melanoma setting, disease progression is observed after ICIs cessation in mMCC including for patients with low tumour burden and who achieve a CR.ConclusionThe case of our patient underlines this risk of relapse and suggests great caution before stopping ICIs in patients treated for mMCC, even when they are in CR.

Concurrence of Merkel Cell Carcinoma and Squamous Cell Carcinoma in A Patient with Generalized Actinic Keratosis: A Case Report

Abstract Introduction: Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy, and its pathogenesis might relate to ultraviolet light and Merkel cell polyomavirus infection. MCC in the Chinese population is uncommon. Here, we present a case of MCC that occurred based on widespread actinic keratosis (AK) in a Chinese female. Case report: An 82-year-old woman presented with two rapidly enlarging and rupture lesions on the face for 1 year. Biopsy was suggestive of squamous cell carcinoma (SCC) on the forehead and MCC on the left cheek. The patient had a history of generalized AK for 3years. The lesion on the left cheek was also revealed as an AK by histopathological examination 1 year ago. Complete surgical resection was performed to remove the two malignancies. Discussion: The co-occurrence of AK, SCC, and MCC in a Chinese woman is unusual. Immunohistopathological examination is vital for correct diagnosis. The three tumors, in this case, may originate from two different precursor cells and are affected by the same carcinogen. Alternatively, they may come from the same pluripotent epidermal stem cells, and chronic exposure to ultraviolet light and Merkel cell polyomavirus lead to the formation of different types of tumors. The coexist of MCC with other cutaneous tumors provided a train of thought for exploring the origin of MCC. Conclusion: We reported a rare co-existence phenomenon of MCC associated with AK and SCC. Hence, long-term follow-up and early treatment are imperative for patients with premalignant lesions, such as widespread AK.

Primary Cutaneous Gamma-Delta T Cell Lymphomas: A Case Series and Overview of the Literature.

Primary cutaneous gamma-delta T cell lymphomas (PCGDTCLs) are rare and aggressive cutaneous malignancies that have been diagnostically challenging for dermopathologists and clinicians since their first published descriptions in 1991. Since then, the availability of immunostaining for T cell receptors γ and δ in formalin-fixed paraffin-embedded samples has greatly increased our knowledge of the gamma-delta phenotype by showing that it may also be present in the context of indolent entities, such as mycosis fungoides (MFs) and lymphomatoid papulosis, and this has raised questions concerning its diagnostic and prognostic implications. We here describe the histological and clinical differences between the dermo-epidermal and subcutaneous sub-groups of PCGDTCL observed in a cohort of 20 patients attending a single experienced centre, with particular focus on cases with an MF-like presentation, which are still less well defined than those of classic MF.

Mutational Landscape of Virus- and UV-Associated Merkel Cell Carcinoma Cell Lines Is Comparable to Tumor Tissue.

Simple SummaryMerkel cell carcinoma (MCC) is an aggressive, rare skin cancer which is caused either by a virus or chronic UV exposure. For both forms, distinct genetic alterations have been described; however, these observations were mostly made in tumor tissue. Since cancer cell lines are frequently used as preclinical models to investigate biological function, we considered it necessary to establish the genomic landscape of MCC cell lines by whole-exome sequencing. We confirmed the presence of UV-induced DNA damage, a high number of mutations and several coding mutations in virus-negative cell lines which were absent in virus-positive cell lines; these, however, harbored characteristic copy number variations, suggesting some virally caused genetic instability. Knowing the genomic features of MCC cell lines validates previous, and facilitates upcoming, experimental studies to discover their biological and translational relevance.Merkel cell carcinoma (MCC) is a rare, highly aggressive cutaneous malignancy that is either associated with the integration of the Merkel cell polyomavirus or chronic UV exposure. These two types of carcinogenesis are reflected in characteristic mutational features present in MCC tumor lesions. However, the genomic characteristics of MCC cell lines used as preclinical models are not well established. Thus, we analyzed the exomes of three virus-negative and six virus-positive MCC cell lines, all showing a classical neuroendocrine growth pattern. Virus-negative cell lines are characterized by a high tumor mutational burden (TMB), UV-light-induced DNA damage, functionally relevant coding mutations, e.g., in RB1 and TP53, and large amounts of copy number variations (CNVs). In contrast, virus-positive cell lines have a low TMB with few coding mutations and lack prominent mutational signatures, but harbor characteristic CNVs. One of the virus-negative cell lines has a local MYC amplification associated with high MYC mRNA expression. In conclusion, virus-positive and -negative MCC cell lines with a neuroendocrine growth pattern resemble mutational features observed in MCC tissue samples, which strengthens their utility for functional studies.

Molecular Profiling of Merkel Cell Polyomavirus-Associated Merkel Cell Carcinoma and Cutaneous Melanoma.

Merkel cell carcinoma (MCC) is a rare, high-grade, aggressive cutaneous neuroendocrine malignancy most commonly associated with sun-exposed areas of older individuals. A relatively newly identified human virus, the Merkel cell polyomavirus (MCPyV) has been implicated in the pathogenesis of MCC. Our study aimed to examine nine MCC cases and randomly selected 60 melanoma cases to identify MCPyV status and to elucidate genetic differences between virus-positive and -negative cases. Altogether, seven MCPyV-positive MCC samples and four melanoma samples were analyzed. In MCPyV-positive MCC RB1, TP53, FBXW7, CTNNB1, and HNF1A pathogenic variants were identified, while in virus-negative cases only benign variants were found. In MCPyV-positive melanoma cases, besides BRAF mutations the following genes were also affected: PIK3CA, STK11, CDKN2A, SMAD4, and APC. In contrast to studies found in the literature, a higher tumor burden was detected in virus-associated MCC compared to MCPyV-negative cases. No association was identified between virus infection and tumor burden in melanoma samples. We concluded that analyzing the key morphologic and immunohistological features of MCC is critical to avoid confusion with other cutaneous malignancies. Molecular genetic investigations such as next-generation sequencing (NGS) enable molecular stratification, which may have future clinical impact.