Histologic margin status is a predictor of relapse in lentigo maligna melanoma.

BACKGROUND: Most surgical margins for lentigo maligna melanomas reported in the literature are clinical and not histologic. OBJECTIVES: We sought to determine whether histologic margin status is an independent predictor of progression. METHODS: Clinicopathologic information of 268 invasive lentigo maligna melanomas diagnosed from 1990-2019 were analyzed. Statistical analyses were performed using Cox proportional hazards model and Boruta method. RESULTS: A total of 75% of the lesions were located on the head and neck. The range of follow-up for all patients was 0 to 31.8 years (median, 10.2 years). Time to local recurrence ranges from 0 to 20 years (median, 3 years). Progression developed in 54 (20.1%) of 268 patients. Local recurrence was seen only in 36 (13.4%), both local recurrence and subsequent metastasis in 7 (2.6%), and only metastasis in 11 (4.1%) of 268 patients. Histologic margin status (positive and close/<3 mm) and tumor site (head and neck location) significantly correlated with worse progression-free survival. LIMITATIONS: Single institution and retrospective study. CONCLUSIONS: Histologic margin status is the strongest predictor of progression for lentigo maligna melanoma. Patients with positive or close/<3 mm histologic margins should consider a re-excision due to the increased risk of relapse.

Early Detection and Prognostic Assessment of Cutaneous Melanoma: Consensus on Optimal Practice and the Role of Gene Expression Profile Testing.

Importance: Therapy for advanced melanoma has transformed during the past decade, but early detection and prognostic assessment of cutaneous melanoma (CM) remain paramount goals. Best practices for screening and use of pigmented lesion evaluation tools and gene expression profile (GEP) testing in CM remain to be defined. Objective: To provide consensus recommendations on optimal screening practices and prebiopsy diagnostic, postbiopsy diagnostic, and prognostic assessment of CM. Evidence Review: Case scenarios were interrogated using a modified Delphi consensus method. Melanoma panelists (n = 60) were invited to vote on hypothetical scenarios via an emailed survey (n = 42), which was followed by a consensus conference (n = 51) that reviewed the literature and the rationale for survey answers. Panelists participated in a follow-up survey for final recommendations on the scenarios (n = 45). Findings: The panelists reached consensus (≥70% agreement) in supporting a risk-stratified approach to melanoma screening in clinical settings and public screening events, screening personnel recommendations (self/partner, primary care provider, general dermatologist, and pigmented lesion expert), screening intervals, and acceptable appointment wait times. Participants also reached consensus that visual and dermoscopic examination are sufficient for evaluation and follow-up of melanocytic skin lesions deemed innocuous. The panelists reached consensus on interpreting reflectance confocal microscopy and some but not all results from epidermal tape stripping, but they did not reach consensus on use of certain pigmented lesion evaluation tools, such as electrical impedance spectroscopy. Regarding GEP scores, the panelists reached consensus that a low-risk prognostic GEP score should not outweigh concerning histologic features when selecting patients to undergo sentinel lymph node biopsy but did not reach consensus on imaging recommendations in the setting of a high-risk prognostic GEP score and low-risk histology and/or negative nodal status. Conclusions and Relevance: For this consensus statement, panelists reached consensus on aspects of a risk-stratified approach to melanoma screening and follow-up as well as use of visual examination and dermoscopy. These findings support a practical approach to diagnosing and evaluating CM. Panelists did not reach consensus on a clearly defined role for GEP testing in clinical decision-making, citing the need for additional studies to establish the clinical use of existing GEP assays.

Guidelines of care for the management of primary cutaneous melanoma.

The incidence of primary cutaneous melanoma continues to increase each year. Melanoma accounts for the majority of skin cancer-related deaths, but treatment is usually curative following early detection of disease. In this American Academy of Dermatology clinical practice guideline, updated treatment recommendations are provided for patients with primary cutaneous melanoma (American Joint Committee on Cancer stages 0-IIC and pathologic stage III by virtue of a positive sentinel lymph node biopsy). Biopsy techniques for a lesion that is clinically suggestive of melanoma are reviewed, as are recommendations for the histopathologic interpretation of cutaneous melanoma. The use of laboratory, molecular, and imaging tests is examined in the initial work-up of patients with newly diagnosed melanoma and for follow-up of asymptomatic patients. With regard to treatment of primary cutaneous melanoma, recommendations for surgical margins and the concepts of staged excision (including Mohs micrographic surgery) and nonsurgical treatments for melanoma in situ, lentigo maligna type (including topical imiquimod and radiation therapy), are updated. The role of sentinel lymph node biopsy as a staging technique for cutaneous melanoma is described, with recommendations for its use in clinical practice. Finally, current data regarding pregnancy and melanoma, genetic testing for familial melanoma, and management of dermatologic toxicities related to novel targeted agents and immunotherapies for patients with advanced disease are summarized.

Clinical spectrum of cutaneous melanoma morphology.

BACKGROUND: Melanoma can mimic other cutaneous lesions, but the full spectrum and prevalence of these morphologic variants remain largely unknown. OBJECTIVE: To classify nonacral cutaneous melanomas into distinct morphologic clusters and characterize clusters' clinicopathologic features. METHODS: All pathologic melanoma diagnoses (occurring during 2011-2016) were reviewed for routine prebiopsy digital photographs (n = 400). Six dermatologists independently assigned lesions into 1 of 14 diagnostic classes on the basis of morphology. Image consensus clusters were generated by K-means; clinicopathologic features were compared with analysis of variance and χ2. RESULTS: Five morphologic clusters were identified: typical (n = 136), nevus-like (n = 81), amelanotic/nonmelanoma skin cancer (NMSC)-like (n = 70), seborrheic keratosis (SK)-like (n = 68), and lentigo/lentigo maligna (LM)-like (n = 45) melanomas. Nevus-like melanomas were found in younger patients. Nevus-like and lentigo/LM-like melanomas tended to be thinner and more likely identified on routine dermatologic examinations. NMSC-like melanomas were tender, thicker, more mitotically active, and associated with prior NMSC. Typical and SK-like melanomas had similar clinicopathologic features. LIMITATIONS: Cluster subdivision yielded diminished sample sizes. Visual assignment was performed without clinical context. CONCLUSION: When primary cutaneous melanomas were assigned into diagnostic groups and subjected to novel consensus clustering, recurrent morphologic patterns emerged. The spectrum of these morphologies was unexpectedly diverse, which might have implications for visual training and possibly clinical diagnosis.

Contrasting features of childhood and adolescent melanomas.

BACKGROUND/OBJECTIVES: Melanoma in children and adolescents is uncommon, and there are limited data on pediatric outcomes. Several studies have shown comparable survival rates in children and adults, but other research demonstrates that prepubescent children have more favorable outcomes. This study aims to compare childhood and adolescent melanoma. METHODS: Retrospective cohort study of children who received a melanoma diagnosis at the Massachusetts General Hospital between January 1, 1995, and December 21, 2016. Childhood melanoma is defined as disease occurring in patients younger than 11 years old, and adolescent melanoma is defined as disease occurring in patients 11 to 19 years old. Patients diagnosed with ocular melanoma and borderline tumors of uncertain malignant potential were excluded. This analysis compares clinical, histopathologic, and outcome characteristics of childhood and adolescent melanoma. RESULTS: Thirty-two children with melanoma were identified (12 children, 20 adolescents). The spitzoid melanoma subtype was significantly more common in children (6/12) than adolescents (2/20) (P = .01). Four adolescents and no children with melanoma died from melanoma, and survival was significantly different between the age groups (P = .04). Median follow-up time for survivors was 3.6 years. CONCLUSIONS: These results suggest that children and adolescents present with different melanoma subtypes and that adolescents have a more aggressive disease course than children.

Integrating Skin Cancer-Related Technologies into Clinical Practice.

Early diagnosis and treatment of melanoma improve survival. New technologies are emerging that may augment the diagnosis, assessment, and management of melanoma but penetrance into everyday practice is low. In the current health care climate, greater emphasis will be placed on the incorporation of technology for clinically suspicious pigmented lesions to facilitate better, more cost-effective management.

Skin cancer screening: recommendations for data-driven screening guidelines and a review of the US Preventive Services Task Force controversy.

Melanoma is usually apparent on the skin and readily detected by trained medical providers using a routine total body skin examination, yet this malignancy is responsible for the majority of skin cancer-related deaths. Currently, there is no national consensus on skin cancer screening in the USA, but dermatologists and primary care providers are routinely confronted with making the decision about when to recommend total body skin examinations and at what interval. The objectives of this paper are: to propose rational, risk-based, data-driven guidelines commensurate with the US Preventive Services Task Force screening guidelines for other disorders; to compare our proposed guidelines to recommendations made by other national and international organizations; and to review the US Preventive Services Task Force's 2016 Draft Recommendation Statement on skin cancer screening.

Contribution of health care factors to the burden of skin disease in the United States.

The American Academy of Dermatology has developed an up-to-date national Burden of Skin Disease Report on the impact of skin disease on patients and on the US population. In this second of 3 manuscripts, data are presented on specific health care dimensions that contribute to the overall burden of skin disease. Through the use of data derived from medical claims in 2013 for 24 skin disease categories, these results indicate that skin disease health care is delivered most frequently to the aging US population, who are afflicted with more skin diseases than other age groups. Furthermore, the overall cost of skin disease is highest within the commercially insured population, and skin disease treatment primarily occurs in the outpatient setting. Dermatologists provided approximately 30% of office visit care and performed nearly 50% of cutaneous surgeries. These findings serve as a critical foundation for future discussions on the clinical importance of skin disease and the value of dermatologic care across the population.

Association of nevus count with prevention attitudes and behaviors before melanoma diagnosis.

Although melanoma risk factors are commonly known to healthcare professionals, the extent to which the at-risk public is either aware of these factors or perceives their risk accordingly has rarely been studied. We sought to investigate whether the presence of known melanoma risk factors, such as high total nevus and atypical nevus counts, was associated with increased prevention attitudes and behaviors, such as skin self-examinations and physician skin examinations. This was a retrospective study of 566 individuals recently diagnosed with melanoma in two large academic centers. Most prevention attitudes and behaviors did not vary on the basis of total nevi or atypical nevi counts. However, younger patients (<60 years) with many total nevi (>50) were more likely than those with fewer nevi (<20) to believe that they were at-risk for melanoma (42 vs. 23%; P<0.05), and more likely to state that they had been instructed on the signs of melanoma (36 vs. 21%; P<0.05). Patient and health provider recognition of the impact of nevus count on melanoma risk presents a unique and mostly untapped opportunity for earlier detection.

Adjuvant Radiation Therapy and Chemotherapy in Merkel Cell Carcinoma: Survival Analyses of 6908 Cases From the National Cancer Data Base.

BACKGROUND: Merkel cell carcinoma (MCC) has a high risk of recurrence after initial surgical therapy. Adjuvant radiation therapy (RT) and chemotherapy may be used to reduce the risk of locoregional and systemic recurrence, respectively, but there are conflicting data regarding their impact on survival. We performed a retrospective analysis of MCC cases from the National Cancer Data Base (NCDB) to assess whether adjuvant therapy was associated with differences in survival. METHODS: Six thousand nine hundred and eight MCC patients with staging, treatment, and survival data were included. Multivariable analyses were conducted for overall survival (OS) with various treatment modalities while adjusting for prognostic variables including age, sex, comorbidities (Charlson/Deyo score), margin status, primary tumor site and size, and lymph node status. All statistical tests were two-sided. RESULTS: For localized MCC (stage I: n = 3369, stage II: n = 1474 ), surgery plus adjuvant RT was associated with statistically significantly better OS than with surgery alone in multivariable analyses (stage I: hazard ratio [HR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.80, P < .001; stage II: HR = 0.77, 95% CI = 0.66 to 0.89, P < .001). In patients with regional nodal metastases (stage III: n = 2065 ), neither adjuvant RT nor chemotherapy was associated with statistically significantly improved or worsened OS. CONCLUSIONS: In this study of the largest MCC cohort reported to date, adjuvant RT was associated with improved OS in stages I-II MCC. Neither adjuvant RT nor chemotherapy was associated with improved OS in stage III MCC. These results, with the limitations of retrospective analyses, are consistent with earlier studies suggesting benefit with adjuvant RT but do not support the routine use of adjuvant chemotherapy in MCC.

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.

Total Nevi, Atypical Nevi, and Melanoma Thickness: An Analysis of 566 Patients at 2 US Centers.

IMPORTANCE: Nevi are among the strongest risk factors for melanoma. However, little is known about the association of many total nevi (TN) or atypical nevi (AN) with tumor thickness. OBJECTIVES: To examine the association between age and the number of TN and AN and to explore whether there was a relationship between TN or AN and tumor thickness, controlling for multiple variables. DESIGN, SETTING, AND PARTICIPANTS: Survey of patients with melanoma at 2 academic sites and an affiliated Veteran Affairs medical center. Participants included 566 patients surveyed within 3 months of diagnosis. Patients were surveyed in the melanoma clinics from May 17, 2006, through March 31, 2009, within 3 months of diagnostic biopsy. The dates of the analysis were April 1, 2015, to August 1, 2015. MAIN OUTCOMES AND MEASURES: Counts of TN and AN were performed at the first visit after diagnosis and were categorized as 0 to 20, 20 to 50, or more than 50 for TN and as 0, 1 to 5, or more than 5 for AN. Tumor thickness was categorized as 2.00 mm or less or as 2.01 mm or greater. All analyses were stratified by patient age (<60 or ≥60 years). Logistic regression was used to test associations, controlling for age, sex, anatomic location of melanoma, institution, histologic subtype, marital status, performance of skin self-examination, number of health care visits in the past year, mode of melanoma discovery, and receipt of skin examination by a physician. RESULTS: The study population included 566 patients. Their mean (SD) age was 56.7 (15.9) years, and 39.0% (n = 221) were female. Of 566 patients, the number of TN was classified as 0 to 20 (66.4% [n = 376]), 20 to 50 (20.5% [n = 116]), or more than 50 (13.1% [n = 74]). Atypical nevus counts were 0 (73.3% [n = 415]), 1 to 5 (14.5% [n = 82]), or more than 5 (12.2% [n = 69]). For those younger than 60 years, the presence of more than 50 TN was associated with a sharply reduced risk of thick melanoma (odds ratio, 0.32; 95% CI, 0.12-0.81), and the presence of more than 5 AN compared with no AN was associated with thicker melanoma (odds ratio, 2.43; 95% CI, 1.02-5.75). CONCLUSIONS AND RELEVANCE: Most patients with melanoma had few nevi and no AN. In younger patients (<60 years), thick melanomas were commonly found in those with fewer TN but more AN, suggesting that physicians and patients should not rely on the total nevus count as a sole reason to perform skin examinations or to determine a patient's at-risk status. Younger patients should be educated on the increased risk of thicker melanomas that is associated with having more AN.

Early detection of melanoma: reviewing the ABCDEs.

Over the course of their nearly 30-year history, the ABCD(E) criteria have been used globally in medical education and in the lay press to provide simple parameters for assessment of pigmented lesions that need to be further evaluated by a dermatologist. In this article, the efficacy and limitations of the ABCDE criteria as both a clinical tool and a public message will be reviewed.

Outcome of patients with de novo versus nevus-associated melanoma.

BACKGROUND: Prior reports indicate a wide range of melanomas in histopathologic contiguity with a nevus, and an associated nevus has unclear prognostic implications in melanoma. OBJECTIVE: We sought to investigate the relationship among nevus-associated melanomas, sentinel lymph node status, and overall survival. METHODS: We conducted a retrospective analysis of 850 patients with cutaneous melanoma and sentinel lymph node removed at Massachusetts General Hospital from 1998 through 2008 and meta-analysis of the literature. RESULTS: Nevus-associated melanomas represented 28% (235/850) of cases and were significantly correlated with younger age (P = .03), truncal site (P = .0005), superficial spreading type (P < .0001), and absent ulceration (P = .005). There was no association with sentinel lymph node status (P = .94) and no survival difference between nevus-associated versus de novo melanoma (P = .41). Meta-analysis of over 4000 cases revealed a similar percentage of associated nevi (32%). LIMITATIONS: This was a retrospective study. CONCLUSIONS: Approximately 30% of melanomas are associated with a nevus. The presence of a nevus associated with a melanoma has no prognostic implication in sentinel lymph node status or overall survival.

Melanoma epidemic: an analysis of six decades of data from the Connecticut Tumor Registry.

PURPOSE: Melanoma is the most commonly fatal form of skin cancer, with nearly 50,000 annual deaths worldwide. We sought to assess long-term trends in the incidence and mortality of melanoma in a state with complete and consistent registration. METHODS: We used data from the Connecticut Tumor Registry, the original National Cancer Institute SEER site, to determine trends in invasive melanoma (1950-2007), in situ melanoma (1973-2007), tumor thickness (1993-2007), mortality (1950-2007), and mortality to incidence (1950-2007) among the 19,973 and 3,635 Connecticut residents diagnosed with invasive melanoma (1950-2007) and who died as a result of melanoma (1950-2007), respectively. Main outcome measures included trends in incidence and mortality by age, sex, and birth cohort. RESULTS: In the initial period (1950-1954), a diagnosis of invasive melanoma was rare, with 1.9 patient cases per 100,000 for men and 2.6 patient cases per 100,000 for women. Between 1950 and 2007, overall incidence rates rose more than 17-fold in men (1.9 to 33.5 per 100,000) and more than nine-fold in women (2.6 to 25.3 per 100,000). During these six decades, mortality rates more than tripled in men (1.6 to 4.9 per 100,000) and doubled in women (1.3 to 2.6 per 100,000). Mortality rates were generally stable or decreasing in men and women through age 54 years. CONCLUSION: Unremitting increases in incidence and mortality of melanoma call for a nationally coordinated effort to encourage and promote innovative prevention and early-detection efforts.

Sentinel lymph node metastasis is not predictive of poor outcome in patients with problematic spitzoid melanocytic tumors.

The diagnosis and clinical management of spitzoid melanocytic tumors with atypical features remain problematic and controversial. In the past decade, sentinel lymph node mapping has been advocated as a diagnostic test in this setting to discriminate melanoma from benign tumors. Recent studies, however, consistently show that despite the presence of lymph node metastases these patients almost always fare well. We investigated the outcome of patients with atypical Spitz tumors and spitzoid melanoma who received sentinel lymph node mapping to clarify current recommendations in managing patients with these diagnostically challenging tumors. A search of the electronic files of the Massachusetts General Hospital Pathology Service identified 41 patients treated with sentinel lymph node biopsy for atypical Spitz tumor or spitzoid melanoma from 1998 to 2008. These patients included 23 patients with atypical Spitz tumors and 17 patients with spitzoid melanoma. Sentinel lymph nodes were positive in 26% of patients with atypical Spitz tumors (6/23) and 35% with spitzoid melanomas (6/17). One patient with spitzoid melanoma developed in-transit metastasis; 0 of 40 patients developed metastases beyond the regional lymph node basin with a mean follow-up of 57 months. Sentinel lymph node biopsy may not be a reliable prognostic discriminatory test in patients with atypical Spitz tumors. Patients with spitzoid melanomas and positive sentinel lymph nodes have a more indolent course than those with bona fide conventional melanoma and positive sentinel nodes.

The distribution of microscopic melanoma metastases in sentinel lymph nodes: implications for pathology protocols.

The utility of sectioning at multiple levels in the histopathologic analysis of sentinel lymph nodes (SLNs) for melanoma and the correlation of metastasis size with risk of subsequent metastasis were investigated. Metastatic melanoma was identified in SLNs from 91 of 475 (19%) melanoma patients with SLN sampling at the Massachusetts General Hospital between 2004 and 2008. All SLNs were evaluated by a 9-slide protocol: sets of MART-1, hematoxylin and eosin, and S100 stains at 3 distinct levels separated by 80 µm. The location and size of the tumor deposits were evaluated in the context of subsequent metastasis and overall survival. Of the 91 patients with positive sentinel nodes, all 9 protocol slides were available for review in 61 (67%). Eleven of 61 patients had no tumor present in the first set of levels; 2 of these patients died of metastatic melanoma. Patients in whom 11 or more tumor cells were detected in the sentinel node had a greater chance of developing subsequent metastases when compared with patients in whom 10 or fewer tumor cells were detected (P=0.05). Of those with either metastases >2 mm in diameter or extracapsular extension, 50% developed metastases beyond the SLN basin. Eliminating 1 of the 3 levels in the SLN detection protocol would have led to a false-negative diagnosis in 18% of patients.

Prognostic factors for melanoma.

The current melanoma staging system, as defined by the American Joint Committee on Cancer (AJCC), is the standard by which melanoma prognosis is determined. This article focuses on the components of the AJCC melanoma staging system regarding patient prognosis. In addition, this article summarizes the other commonly researched clinical and histologic melanoma prognostic factors and reviews the recent advancements in genetic biomarkers associated with prognosis.

Histologically challenging melanocytic tumors referred to a tertiary care pigmented lesion clinic.

BACKGROUND: The histopathologic diagnosis of some melanocytic tumors is extraordinarily difficult. With this in mind, melanocytic tumors from patients referred to the Massachusetts General Hospital (MGH) Pigmented Lesion Clinic (PLC) are routinely reviewed in the MGH Dermatopathology Unit. OBJECTIVE: We sought to determine the frequency of diagnostically challenging cases from patients treated at the MGH PLC, as measured by a change in the diagnosis upon review of the referral materials. METHODS: We retrospectively reviewed the MGH and referral pathology reports for 478 consecutive cutaneous melanocytic tumors: 126 from 1996-1997 and 352 from 2010-2011. Differences in diagnosis and in therapeutic impact were evaluated. RESULTS: Changes in diagnosis occurred in 168 of 478 cases (35%), more frequently when the original diagnostician was a general pathologist (P = .003). A similar fraction of diagnoses were changed from malignant to benign or vice versa, in both historic and contemporary cohorts. In 64 patients (13%), changes in diagnosis led to a change in therapy. Changes in stage or grading led to the most changes in therapy (78%; 50/64) versus changes from benign to malignant or vice versa (22%; 14/64). LIMITATIONS: This is a retrospective study with the bias of a tertiary-care referral center. CONCLUSIONS: These findings demonstrate the diagnostic difficulty of a subset of melanocytic tumors and highlight the utility of review by more than one pathologist; patient treatment is affected in more than 10% of cases. Identification of melanoma prognostic factors and melanocytic nevus grading led to clinically significant changes in diagnosis leading to a change in patient management.