Avelumab in the Treatment of Advanced Merkel Cell Carcinoma: A Systematic Review.

BACKGROUND: Avelumab, a programmed death ligand-1 inhibitor, has shown success in providing durable responses for difficult-to-treat Merkel cell carcinomas (MCCs). OBJECTIVE: Evaluate the efficacy and safety of avelumab in the treatment of advanced MCC. METHODS: Studies reporting the use of avelumab as a monotherapy or in combination with other agents in the treatment of stage III or IV (advanced) MCC were included. The primary outcomes were overall response rate, overall survival (OS), and treatment-related adverse events. RESULTS: A total of 48 studies were included, involving 1,565 patients with advanced MCC. Most patients were male (1,051, 67.3%) with stage IV MCC (517, 97.0%). The overall response rate was 46.1% (partial response-25.4% and complete response-20.7%) after a mean follow-up period of 9.5 months. Kaplan-Meier survival curves for the pooled stage III and IV group demonstrated OS rates of 58% at 1 year, 47% at 2 years, and 28% at 5 years after completion of treatment with avelumab (median OS: 23.1 months). The most common treatment-related adverse events consisted of constitutional (44%), gastrointestinal (19%), and dermatologic (12%) symptoms. CONCLUSION: Avelumab monotherapy and combination therapy have shown success in the overall response rate and survival for patients with advanced MCC.

Characterization of the 2019 Micrographic Surgery and Dermatologic Oncology Standardized Letter of Recommendation.

BACKGROUND: Traditional letters of recommendation used for postgraduate medical training applications have multiple limitations, including a lack of clarity, inflated and overly flattering assessments, and low reliability between interpreting faculty. A micrographic surgery and dermatologic oncology (MSDO) standardized letter of recommendation (SLOR) was created to improve the efficiency, validity, and stratification of applicants to dermatology fellowship training programs. OBJECTIVE: To analyze the MSDO SLOR for trends in grading based on letter-writer and applicant characteristics and to evaluate its ability to demonstrate differences between applicants. METHODS: Standardized letter of recommendations received by 4 fellowship programs from the 2019 San Francisco Match application cycle were reviewed retrospectively. RESULTS: Two hundred forty-nine SLORs were analyzed from 140 applicants. Grade inflation and limited variability in scores were evident. Higher scores correlated with the length of the relationships between letter-writers and applicants and with female letter-writer gender. There was no applicant gender or ethnicity bias detected. CONCLUSION: Despite score inflation, the MSDO SLOR allows for differentiation between fellowship applicants. Future studies are needed to further evaluate the reliability of the SLOR and find ways to improve its content.

A Review of the Use of Telemedicine in Dermatologic Surgery.

BACKGROUND: Telemedicine is an emerging field with numerous applications within medicine. Previous review articles describe its use within plastic surgery and otolaryngology but none, to the authors' knowledge, within dermatologic surgery. OBJECTIVE: To provide a review of the applications of telemedicine within dermatologic surgery. MATERIALS AND METHODS: A PubMed search of articles published on teledermatology was conducted in July 2018. Articles were selected based on their relevance to dermatologic surgery and reviewed for their discussion of the applications of telemedicine in surgical and cosmetic dermatology. RESULTS: The initial search resulted in 156 articles. Eleven ultimately met inclusion criteria: 2 in referral and consultation, 5 in telepathology, 2 in intraoperative uses, and 2 in postprocedural care. CONCLUSION: For preoperative consultation, teledermatology enables the surgeon to plan ahead and increases access to care by reducing the number of clinic visits. Telepathology has the potential to allow intraoperative consultation with a dermatopathologist to achieve accurate tumor clearance without delay. Smartglasses represent a promising technology for greater care coordination and a teaching tool. Postprocedural monitoring via text messaging provides convenient access to expert advice and early detection of postoperative complications. With increasing technologic advancements, telemedicine holds great potential to augment the dermatologic surgeon's daily practice.

Merkel cell carcinoma: An update and review: Current and future therapy.

Merkel cell carcinoma (MCC) is a rare neuroendocrine tumor of the skin associated with a high risk of local recurrence and distant metastases. It most commonly occurs on sun-exposed areas of white patients >65 years of age. The Merkel cell polyomavirus (MCV) is thought to be responsible for malignant transformation in approximately 80% of cases in the northern hemisphere, while ultraviolet radiation-induced DNA damage is implicated in MCV-negative tumors. The overall incidence of MCC is low, with approximately 1600 cases diagnosed annually in the United States. The rate is much higher in patients with lymphoproliferative malignancies, solid organ transplants, and HIV infection. The low overall incidence of this tumor makes it challenging to conduct prospective clinical trials with sufficient power. As a result, most management recommendations are based on case series, retrospective reviews, and expert opinion. The pathogenesis, diagnosis, and staging of MCC was discussed in the first article in this continuing medical education series. This article focuses on current management guidelines and promising new therapies in development. Because of the complexity, aggressive nature, and individuality of each case, MCC is best treated by a multidisciplinary team.

Merkel cell carcinoma: An update and review: Pathogenesis, diagnosis, and staging.

Merkel cell carcinoma (MCC) is an uncommon primary cutaneous neuroendocrine cancer. It most commonly presents as an indurated plaque or nodule on sun-damaged skin in elderly patients and is characterized by high rates of local recurrence and nodal metastasis. Survival at 5 years is 51% for local disease and as low as 14% for distant disease, which underscores the aggressive nature of this tumor and challenges in management. Advances in immunology and molecular genetics have broadened our understanding of the pathophysiology of MCC and expanded our therapeutic arsenal. With this comprehensive review, we provide an update of MCC epidemiology, pathogenesis, clinical presentation, diagnostic evaluation and prognostic markers. The second article in this continuing medical education series explores the evolving landscape in MCC management.

Non-tuberculous mycobacterial infections following cosmetic laser procedures: a case report and review of the literature.

Skin infections are not uncommon after cosmetic laser procedures. Infection rates following ablative laser resurfacing procedures are reported to be as high as 7.6%, compared to 1.9% for fractional ablation. An infrequent yet important infectious complication of ablative laser treatment is that caused by non-tuberculous mycobacteria (NTM).

Organ transplant recipients with Merkel cell carcinoma have reduced progression-free, overall, and disease-specific survival independent of stage at presentation.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin. Immunosuppression is associated with increased incidence of MCC. OBJECTIVE: We sought to determine whether solid organ transplant recipients (SOTR) with MCC had decreased progression-free, disease-specific, and overall survival compared with immunocompetent patients. METHODS: We conducted a retrospective cohort study examining 8 SOTR with MCC and 89 immunocompetent control subjects. Cox regression models were generated for outcomes of progression, disease-specific death, and death from any cause, adjusted for patient sex, age at diagnosis, and stage at presentation. RESULTS: SOTR had a 4.1-fold increased hazard for progression (95% confidence interval 1.57-10.95, P=.004), a 10.5-fold increased hazard for all-cause mortality (95% confidence interval 3.06-35.98, P<.0001), and an 11.9-fold increased hazard for MCC-specific death (95% confidence interval 2.67-53.08, P=.001), adjusted for sex, age, and stage at presentation. SOTR had decreased 1-year overall survival, 46.8% versus 88.6%, and decreased 1-year MCC-specific survival, 56.3% versus 95.2%. LIMITATIONS: This is a single-center study from a tertiary academic care center, and may not be generalizable to all patient populations. CONCLUSIONS: SOTR have a significant reduction in overall, MCC-specific, and progression-free survival compared with immunocompetent patients. Further studies will determine whether aggressive treatment may improve outcomes in this high-risk population.

Relationships among primary tumor size, number of involved nodes, and survival for 8044 cases of Merkel cell carcinoma.

BACKGROUND: The effects of primary tumor size on nodal involvement and of number of involved nodes on survival have not, to our knowledge, been examined in a national database of Merkel cell carcinoma (MCC). OBJECTIVE: We sought to analyze a retrospective cohort of patients with MCC from the largest US national database to assess the relationships between these clinical parameters and survival. METHODS: A total of 8044 MCC cases in the National Cancer Data Base were analyzed. RESULTS: There was a 14% risk of regional nodal involvement for 0.5-cm tumors that increased to 25% for 1.7-cm (median-sized) tumors and to more than 36% for tumors 6 cm or larger. The number of involved nodes was strongly predictive of survival (0 nodes, 76% 5-year relative survival; 1 node, 50%; 2 nodes, 47%; 3-5 nodes, 42%; and ≥6 nodes, 24%; P < .0001 for trend). Younger and/or male patients were more likely to undergo pathological nodal evaluation. LIMITATIONS: The National Cancer Data Base does not capture disease-specific survival. Hence, relative survival was calculated by comparing overall survival with age- and sex-matched US population data. CONCLUSION: Pathologic nodal evaluation should be considered even for patients with small primary MCC tumors. The number of involved nodes is strongly predictive of survival and may help improve prognostic accuracy and management.

Merkel cell carcinoma: current status of targeted and future potential for immunotherapies.

Merkel cell carcinoma is an aggressive neuroendocrine tumor with a high incidence of local recurrence, regional nodal and distant metastasis, and a high mortality rate. It has been linked to a polyomavirus in addition to immune suppression. Traditionally, treatment options have been limited to surgery and radiation therapy. Better understanding of the molecular pathways of infection and carcinogenesis has provided potential molecular targets and potential immunotherapies which are discussed in this review.

Circulating Tumor DNA Assay Detects Merkel Cell Carcinoma Recurrence, Disease Progression, and Minimal Residual Disease: Surveillance and Prognostic Implications.

PURPOSE: Merkel cell carcinoma (MCC) is an aggressive skin cancer with a 40% recurrence rate, lacking effective prognostic biomarkers and surveillance methods. This prospective, multicenter, observational study aimed to evaluate circulating tumor DNA (ctDNA) as a biomarker for detecting MCC recurrence. METHODS: Plasma samples, clinical data, and imaging results were collected from 319 patients. A tumor-informed ctDNA assay was used for analysis. Patients were divided into discovery (167 patients) and validation (152 patients) cohorts. Diagnostic performance, including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), was assessed. RESULTS: ctDNA showed high sensitivity, 95% (discovery; 95% CI, 87 to 99) and 94% (validation; 95% CI, 85 to 98), for detecting disease at enrollment, with corresponding specificities of 90% (95% CI, 82 to 95) and 86% (95% CI, 77 to 93). A positive ctDNA during surveillance indicated increased recurrence risk, with hazard ratios (HRs) of 6.8 (discovery; 95% CI, 2.9 to 16) and 20 (validation; 95% CI, 8.3 to 50). The PPV for clinical recurrence at 1 year after a positive ctDNA test was 69% (discovery; 95% CI, 32 to 91) and 94% (validation; 95% CI, 71 to 100), respectively. The NPV at 135 days after a negative ctDNA test was 94% (discovery; 95% CI, 90 to 97) and 93% (validation; 95% CI, 89 to 97), respectively. Patients positive for ctDNA within 4 months after treatment had higher rates of recurrence, with 1-year rates of 74% versus 21% (adjusted HR, 7.4 [95% CI, 2.7 to 20]). CONCLUSION: ctDNA testing exhibited high prognostic accuracy in detecting MCC recurrence, suggesting its potential to reduce frequent surveillance imaging. ctDNA also identifies high-risk patients who need more frequent imaging and may be best suited for adjuvant therapy trials.

Tobacco smoking and dermatologic surgery.

BACKGROUND: Cigarette smoking is the leading cause of preventable death and a major public health concern. Numerous clinical and experimental studies have examined the effect of nicotine on wound healing and surgical procedures, but there are limited published reports in the dermatologic surgery literature. OBJECTIVE: This article seeks to develop evidence-based recommendations regarding the effect of tobacco use in patients undergoing dermatologic surgery procedures. METHODS: This article reviews the existing published English-language literature pertaining to the effects of tobacco on wound healing and surgical complications. RESULTS: Tobacco use is associated with a higher incidence of postoperative complications including wound dehiscence, flap or graft necrosis, prolonged healing time, and infections. LIMITATIONS: This review article only summarizes past reports and studies. CONCLUSION: Recommendations for smoking cessation before dermatologic surgery are provided based on the available data.

18F-fluorodeoxyglucose positron emission tomography-computed tomography imaging in the management of Merkel cell carcinoma: a single-institution retrospective study.

BACKGROUND: Merkel cell carcinoma (MCC) is among the deadliest of cutaneous malignancies. A lack of consensus evaluation and treatment guidelines has hindered management of this disease. The utility of simultaneous positron emission tomography and computed tomography (PET/CT) has been demonstrated for a variety of tumors yet remains underinvestigated for MCC. OBJECTIVES: To report the value of fluorodeoxyglucose PET/CT imaging in the initial staging and ongoing management of individuals with MCC and to determine whether any patient or tumor characteristics may predict when PET/CT is more likely to have greater influence on medical decision-making. MATERIALS AND METHODS: A single-institution retrospective chart review was conducted of all patients diagnosed with MCC who underwent FDG-PET/CT scanning from 2007 to 2010. The outcome of each of these studies was evaluated as to the influence on patient staging and management. Patient clinical information and information on gross and microscopic tumor characteristics were collected and analyzed. RESULTS: Twenty patients underwent 39 PET/CT scans. Results of PET/CT imaging revealed previously unknown information related to MCC in four (20%) patients, leading to changes in management in three of these four cases. Three previously unknown neoplasms were detected. CONCLUSION: Fluorodeoxyglucose-positron emission tomography and computed tomography is a valuable tool for initial staging and to assess response to therapy of patients diagnosed with MCC. Larger prospective studies would be required to establish the optimal timing for this imaging modality.

Self-supervised artificial intelligence predicts recurrence, metastasis and disease specific death from primary cutaneous squamous cell carcinoma at diagnosis.

Primary cutaneous squamous cell carcinoma (cSCC) is responsible for ~10,000 deaths annually in the United States. Stratification of risk of poor outcome (PO) including recurrence, metastasis and disease specific death (DSD) at initial biopsy would significantly impact clinical decision-making during the initial post operative period where intervention has been shown to be most effective. In this multi-institutional study, we developed a state-of-the-art self-supervised deep-learning approach with interpretability power and demonstrated its ability to predict poor outcomes of cSCCs at the time of initial biopsy. By highlighting histomorphological phenotypes, our approach demonstrates that poor differentiation and deep invasion correlate with poor prognosis. Our approach is particularly efficient at defining poor outcome risk in Brigham and Women's Hospital (BWH) T2a and American Joint Committee on Cancer (AJCC) T2 cSCCs. This bridges a significant gap in our ability to assess risk among T2a/T2 cSCCs and may be useful in defining patients at highest risk of poor outcome at the time of diagnosis. Early identification of highest-risk patients could signal implementation of more stringent surveillance, rigorous diagnostic work up and identify patients who might best respond to early postoperative adjunctive treatment.

Immunohistochemical prognostication of Merkel cell carcinoma: p63 expression but not polyomavirus status correlates with outcome.

Merkel cell carcinoma (MCC) represents a cutaneous malignancy with high associated mortality. Numerous studies have attempted to define characteristics to more accurately predict outcome. Two recent studies have demonstrated that Merkel cell polyomavirus (MCPyV) seropositivity correlated with a better prognosis, while a third study revealed no difference. Expression of p63 by tumor cell nuclei has been shown to be associated with a worse prognosis in a European cohort. To better understand the relationship between prognosis and MCPyV or p63 status, we used immunohistochemistry to evaluate both attributes in 36 US patients with MCC. Our results show that when considered as a binary variable, p63 expression represents a strong risk factor (p < 0.0001, hazards ratio (HR) = ∞) for shortened survival. In addition, our results show that MCPyV status does not correlate with survival (p = 0.6067, HR = 1.27). Our study corroborates the European observation that p63 immunoexpression is useful as a prognostic tool. Larger studies will need to be performed in order to determine whether p63 status should be included in MCC staging, since our study is limited by its relative small size.

Skin Color Match in Head and Neck Reconstructive Surgery.

OBJECTIVES/HYPOTHESIS: To quantify the degree of color match achieved during microvascular facial reconstruction, and to describe a novel technique for improving reconstructive skin color match. We hypothesize that split-thickness skin grafts (STSG) placed atop de-epithelialized free tissue produces better facial skin color match than free tissue with intact epithelium. STUDY DESIGN: Cross sectional photographic study of reconstructed facial skin color match. METHODS: Sixty-eight adults, who underwent head and neck reconstructive surgery, were divided into six categories based on cutaneous reconstructive technique: cervicofacial flap, radial forearm free flap (RFFF), fibula free flap, anterolateral thigh free flap (ALT), STSG over adiopofascial flap (STAFF), and STSG over myogenous flap (STMF). Averaged color samplings of the reconstructed defect and adjacent normal skin were taken from digital photographs. The color difference was calculated using the delta-E calculation. Blinded expert observers also rated the degree of color match. Nonparametric cohort contrast and correlation statistical analyses were performed. RESULTS: The mean delta-E's and 10-point Likert ratings for the ALT, fibula, RFFF, STAFF, STMF, and cervicofacial flaps were 11.6, 10.0, 7.7, 6.3, 8.8, and 4.7, and 5.1, 6.4, 2.4, 3.2, 2.7, and 1.1, respectively. Likert scale inter-rater correlation was strong, with coefficient = 0.80. CONCLUSIONS: On average, STSG over de-epithelialized myogenous and adipofascial free tissue transfers produced a better color match than the skin paddles of donor sites, with the exception of the radial forearm donor site. Delta-E values obtained from photos correlated well with expert ratings of color match. This reliable technique for quantifying color match may be used in future studies. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:1753-1759, 2022.

A new American Joint Committee on Cancer staging system for cutaneous squamous cell carcinoma: creation and rationale for inclusion of tumor (T) characteristics.

BACKGROUND: The incidence of cutaneous squamous cell carcinoma (cSCC) is increasing. Although most patients achieve complete remission with surgical treatment, those with advanced disease have a poor prognosis. The American Joint Committee on Cancer (AJCC) is responsible for the staging criteria for all cancers. For the past 20 years, the AJCC cancer staging manual has grouped all nonmelanoma skin cancers, including cSCC, together for the purposes of staging. However, based on new evidence, the AJCC has determined that cSCC should have a separate staging system in the 7th edition AJCC staging manual. OBJECTIVE: We sought to present the rationale for and characteristics of the new AJCC staging system specific to cSCC tumor characteristics (T). METHODS: The Nonmelanoma Skin Cancer Task Force of AJCC reviewed relevant data and reached expert consensus in creating the 7th edition AJCC staging system for cSCC. Emphasis was placed on prospectively accumulated data and multivariate analyses. Concordance with head and neck cancer staging system was also achieved. RESULTS: A new AJCC cSCC T classification is presented. The T classification is determined by tumor diameter, invasion into cranial bone, and high-risk features, including anatomic location, tumor thickness and level, differentiation, and perineural invasion. LIMITATIONS: The data available for analysis are still suboptimal, with limited prospective outcomes trials and few multivariate analyses. CONCLUSIONS: The new AJCC staging system for cSCC incorporates tumor-specific (T) staging features and will encourage coordinated, consistent collection of data that will be the basis of improved prognostic systems in the future.

An isolated Merkel cell carcinoma metastasis at a distant cutaneous site presenting as a second 'primary' tumor.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin. Disease progression usually occurs via lymphatic spread to regional lymphatic draining basins, followed by distant metastasis. We report the clinical course, histopathology and genetic analysis of a 69-year-old woman with likely hematogenous spread of cutaneous neuroendocrine carcinoma manifesting as a single metastatic lesion to a distant cutaneous site. Although the possibility of two cutaneous primary MCCs was considered, array comparative genomic hybridization (aCGH) identified identical distal amplification of a region of chromosome 12p, and synchronous loss of chromosomes 8p and 17p, effectively ruling out the possibility of independent primaries. We propose that this represents a primary cheek MCC with rapid, isolated cutaneous metastasis to the contralateral ankle via hematogenous spread. The distinction between a second primary MCC and a distant cutaneous metastasis clearly has important implications with regard to staging, treatment and prognosis. To our knowledge, this represents the first report of the use of aCGH to clarify the relationship of multiple synchronous cutaneous MCCs and the first report of a single distant cutaneous focus of hematogenous spread. Our data calls into question prior reports alleging multiple cutaneous primaries of this very rare tumor.

Should Sentinel Lymph Node Biopsy Status Guide Adjuvant Radiation Therapy in Patients With Merkel Cell Carcinoma?

PURPOSE: Radiation of the draining lymph node basin remains controversial for Merkel cell carcinoma, particularly in the era of sentinel lymph node biopsy (SLNB). METHODS AND MATERIALS: Based on a 20-year experience using SLNB-guided adjuvant radiation therapy (RT), we conducted a retrospective review of clinically node-negative patients testing 2 hypotheses: (1) whether nodal RT could be safely omitted in SLNB-negative Merkel cell carcinoma and (2) whether the excised primary site should always be radiated. Clinically node-positive patients were excluded. RESULTS: Among 57 clinically node-negative patients who underwent SLNB and wide local excision (WLE), 42 (74%) had a negative SLNB, and 15 (26%) had a positive SLNB. At a median follow-up of 43 months (range, 5-182), SLNB-negative patients irradiated to the primary site had improved 4-year disease-specific survival (100% vs 65%, P = .008), local recurrence-free survival (100% vs 76%, P = .009), and distant recurrence-free survival (100% vs 75%, P = .008), but not overall survival (87.5% vs 57.7%, P = .164) compared with SLNB-positive patients receiving comprehensive RT. Among SLNB-negative patients treated with WLE only, 67% (6/9) had a disease relapse, half of which were local relapses (33%). CONCLUSIONS: In this single-institution retrospective review, after negative SLNB and WLE, RT given only to the primary site provided 100% disease control without a need for nodal RT. Among SLNB-negative patients who had WLE, omission of postoperative primary-site RT was associated with 67% cancer relapse, of which half was local.