Outcomes in solid organ transplant recipients with a pretransplant diagnosis of melanoma.

Melanoma causes significant morbidity in solid organ transplant recipients (SOTRs). Melanomas diagnosed before transplantation can recur with intensive immunosuppression, but outcomes have not been well studied. We evaluated 901 non-Hispanic White SOTRs with a pretransplant melanoma identified using linked transplant and cancer registry data in the United States. Most pretransplant melanomas were invasive (60.7%), and the median time from diagnosis to transplantation was 5.1 years. After transplantation, 41 SOTRs developed a new invasive melanoma, corresponding to 9-fold increased risk compared with the general population (standardized incidence ratio, 9.2; 95% confidence interval [CI], 6.6-12). Twenty-two SOTRs died from melanoma after transplantation, corresponding to 52-fold increased risk (standardized mortality ratio, 52; 95% CI, 33-79). Risk factors for posttransplant melanoma included age at transplantation (adjusted hazard ratio [HR], 2.86; 95% CI, 1.24-6.60; for age 55+ vs <55 years) and maintenance immunosuppression with cyclosporine/azathioprine (adjusted HR, 2.53; 95% CI, 1.08-5.90). Melanoma mortality was strongly elevated after a posttransplant melanoma diagnosis (HR, 35.6; 95% CI, 14.0-90.4; adjusted for cyclosporine/azathioprine maintenance therapy and calendar year of transplantation). In conclusion, SOTRs with a pretransplant melanoma are at risk of adverse melanoma-related outcomes after transplantation. These findings support thorough dermatologic evaluation prior to transplantation and frequent posttransplant surveillance.

Atypical Spitz tumor with SQSTM1::NTRK2 fusion: Report of a case with unique spindled cell features.

A host of signature genetic alterations have been demonstrated in Spitz neoplasms, most notably fusions of kinase genes (including BRAF, ALK, ROS1, NTRK1, NTRK3, RET, MET, MAP3K8) or variants in HRAS. While there are multiple reports of rearrangements involving NTRK1 and NTRK3 in Spitz tumors, there are very few reports of NTRK2-rearranged Spitz nevi in the literature. This report presents an NTRK2-rearranged atypical Spitz tumor with spindled cell features. The patient was a 6-year-old female with a growing pigmented papule on the back. Histopathological evaluation revealed an asymmetric, biphasic, compound proliferation of melanocytes featuring an epithelioid cell population arranged as variably sized nests and single cells along the basal layer with extension down adnexa, as well as a population of spindled melanocytes with desmoplastic features and loss of Melan-A expression in the dermis. There was partial loss of p16 expression in the epidermal component and diffuse loss in the dermal component. Immunohistochemistry for PRAME, ALK, NTRK1, HRAS Q61R, p53, and BRAF V600E were negative. A SQSTM1::NTRK2 fusion was identified by RNA sequencing. No TERT promoter hotspot variants were detected. This case report expands the known histopathologic spectrum of genetic alterations in Spitz neoplasms.

Reproductive factors, hormone use, and incidence of melanoma in a cohort of US Radiologic Technologists.

STUDY QUESTION: Are reproductive factors and exogenous hormone use associated with incidence of cutaneous melanoma while accounting for ultraviolet radiation (UVR) exposure across different life periods and sun sensitivity factors? SUMMARY ANSWER: Earlier age at menarche and late age at first birth, but not other estrogen-related factors were associated with an increased incidence rate of melanoma, with higher risks observed for earlier age at menarche and light hair color at age 15 years. WHAT IS KNOWN ALREADY: Although estrogens have been recognized as photosensitizing, previous studies have reported inconsistent findings for the association of melanoma with estrogen-related factors. Most have not collected detailed skin cancer risk factors and have not thoroughly investigated effect modification by ambient UVR and sun sensitivity. STUDY DESIGN, SIZE, DURATION: Participants in the US Radiologic Technologists study, an occupational cohort of 146 022 radiologic technologists (73% women), were included and followed during the four time periods (1983-1989, 1994-1998, 2003-2005 and 2012-2014). PARTICIPANTS/MATERIALS, SETTING, METHODS: Non-Hispanic white female participants who completed both the second (baseline) and third questionnaires, and did not report having cancer (except keratinocyte carcinoma) at baseline, were included and followed from their age at completion of the second (baseline) questionnaire until the earlier of first primary cancer diagnosis, including invasive melanoma of the skin, or completion of either the third or fourth questionnaire. Reproductive and exogenous hormonal factors were ascertained from the second (baseline) questionnaire, which also collected information on demographic, lifestyle factors and sun sensitivity factors. Ambient UVR was assigned by linking geocoded residential locations, based on self-reported residential history information collected from the third questionnaire to satellite-based ambient UVR data from the National Aeronautics and Space Administration's Total Ozone Mapping Spectrometer database. To examine the association of reproductive factors, exogenous hormone use, and first primary invasive melanoma of the skin, we used Poisson regression to calculate rate ratios (RRs) and 95% likelihood-based CIs, adjusting for attained age, birth cohort, lifetime average annual ambient UVR, contraceptives and menopausal hormone therapy use. To address the effect modification of ambient UVR exposure and sun sensitivities on melanoma risk, we conducted likelihood-ratio tests for multiplicative interaction. MAIN RESULTS AND THE ROLE OF CHANCE: Over a median follow-up time of 17.1 years, 0.95% of eligible participants had an incident first primary melanoma (n = 444). Higher melanoma incidence rates were observed in participants with older attained age, blue/green/gray eye color, blonde/red/auburn natural hair color at age 15, fair skin complexion, and higher UVR. We found an increased incidence rate of melanoma in women who experienced menarche at an earlier age (13, 12 and <12 years vs ≥14 years: RR = 1.48, 95% CI = 1.11-1.98; 1.19, 0.89-1.61; 1.26, 0.93-1.73), and in women with older age at first birth (25-29 and ≥30 years vs <25 years; 1.09, 0.86-1.39; 1.48, 1.12-1.95; P-value for trend = 0.006). However, no significant association was observed for other reproductive factors, and for all exogenous hormone use. The associations of melanoma incidence for most reproductive factors and exogenous hormone use were not modified by ambient UVR, eye color, natural hair color at age 15 and skin complexion. The exception was that natural hair color at age 15 modified the associations of melanoma for age at menarche (P-value for interaction = 0.004) and age at first birth among parous women (0.005). In participants with blonde/red/auburn natural hair color at age 15, we found increased risk of melanoma among women who experienced menarche at age 13, 12 and <12 years (vs ≥14 years: RR = 3.54, 95% CI = 1.98-6.90; 2.51, 1.37-4.98; 2.66, 1.41-5.36, respectively; P-value for trend = 0.10). However, the association between age at menarche and melanoma was null in participants with brown/black natural hair color at age 15. LIMITATIONS, REASONS FOR CAUTION: Information on reproductive history and exogenous hormone use was self-reported. We did not have information on specific doses or formulations of exogenous hormone medications or breastfeeding. WIDER IMPLICATIONS OF THE FINDINGS: Women residing in areas of high ambient UVR and those with blonde/red/auburn natural hair color may constitute an additional high-risk group in need of more frequent skin cancer screening. Identifying susceptible periods of exposure or factors that modify UVR susceptibility may aid in guiding more targeted guidelines for melanoma prevention. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, US Department of Health and Human Services. Authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Cutaneous melanocytic tumor with CRTC1::TRIM11 fusion and prominent epidermal involvement: A case report.

Cutaneous melanocytic tumor with CRTC1::TRIM11 fusion (CMCT) is a recently described entity with only 13 cases reported in the literature. Histopathologically, the neoplasm consists of atypical epithelioid to spindled cells that form a well-circumscribed nodule usually confined to the dermis and subcutis with cytological features including large vesicular nuclei with prominent nucleoli and abundant eosinophilic cytoplasm. Immunohistochemistry shows variable expressivity of melanocytic markers. Currently, there are limited data regarding long-term outcomes of this newly described entity. Most cases have done well, but there is one case reported with an adverse event. Hence, further studies are needed to accurately classify this tumor. Definitive diagnosis is made by laboratory evidence of CMCT. Herein, we report the first case of CMCT with epidermal involvement in the youngest patient known to be affected to date.

Histologic features of melanoma associated with germline mutations of CDKN2A, CDK4, and POT1 in melanoma-prone families from the United States, Italy, and Spain.

BACKGROUND: CDKN2A, CDK4, and POT1 are well-established melanoma-susceptibility genes. OBJECTIVE: We evaluated melanoma histopathology for individuals with germline mutations of CDKN2A, CDK4, and POT1. METHODS: We assessed histopathology for melanomas diagnosed in melanoma-prone families (≥2 individuals with melanoma) from the United States, Italy, and Spain. Comparisons between mutation carriers and noncarriers (no mutation) were adjusted for age, sex, Breslow depth, and correlations among individuals within the same family. RESULTS: Histologic slides were evaluated for 290 melanomas (139 from 132 noncarriers, 122 from 68 CDKN2A carriers, 10 from 6 CDK4 carriers, and 19 from 16 POT1 carriers). Superficial spreading was the predominant subtype for all groups. Spitzoid morphology (>25% of tumor) was observed in 10 of 15 invasive melanomas (67%) from POT1 carriers (P < .0001 vs noncarriers). This finding was independently confirmed by 3 expert melanoma dermatopathologists in 9 of 15 invasive melanomas (60%). In situ and invasive melanomas from CDKN2A and CDK4 carriers were histologically similar to melanomas from noncarriers. LIMITATIONS: Limited sample sizes for rare melanoma-susceptibility syndromes (CDK4, POT1). CONCLUSION: Spitzoid morphology was associated with POT1 mutations suggesting that telomere dysfunction (POT1 mutations) may contribute to spitzoid differentiation in melanocytic tumors.

Diagnostic accuracy of whole slide imaging for cutaneous, soft tissue, and melanoma sentinel lymph node biopsies with and without immunohistochemistry.

BACKGROUND: Diagnostic accuracy with whole slide imaging (WSI) for complex inpatient and outpatient dermatopathology cases with immunohistochemistry (IHC) is unknown. METHODS: WSI (Leica Aperio AT2 Digital Pathology scanner, N = 151 cases) was performed for Emory inpatient and outpatient skin (N = 105), soft tissue (N = 30), and melanoma sentinel lymph node biopsies (N = 16) collected between 2000 and 2016. Resultant images were uploaded to an online cloud storage system for review by 2 board-certified dermatopathologists (reviewers 1 and 2) with greater than 5 years of dermatopathology experience and 1 dermatopathology fellow (reviewer 3). RESULTS: Reviewers 1 (diagnostic accuracy = 97%) and 2 (diagnostic accuracy = 95%) demonstrated high diagnostic accuracy with WSI. Diagnostic accuracy was greater than 90% for inpatient biopsies, melanocytic lesions, melanoma sentinel lymph node biopsies, and cases with immunohistochemistry, but was slightly lower for soft tissue cases (reviewer 1 = 89%; reviewer 2 = 89%). The dermatopathology fellow (reviewer 3) demonstrated lower diagnostic accuracy (84%). CONCLUSIONS: Diagnostic accuracy with WSI for skin, soft tissue, and melanoma sentinel lymph node biopsies with and without immunohistochemistry was greater than 95% for 2 reviewers with greater than 5 years of dermatopathology experience. Professional experience signing out dermatopathology cases may impact diagnostic accuracy with WSI.

Future growth of physicians and non-physician providers within the U.S. Dermatology workforce.

Trends in the training, supply, availability, career decisions, and retirement of US dermatology physicians are not well delineated. The current study evaluates whether growth in the dermatology workforce will keep pace with population expansion in the United States. A dermatologist supply model was projected to 2030 drawing on data from the American Academy of Dermatology, American Medical Association, Bureau of Labor Statistics, American Association of Medical Colleges, and other associations. The clinically active dermatologist workforce in 2015 was 36 per capita (1,000,000); entry following postgraduate training was age 30 with career separation at age 65 on average. Added to the provider model are physician assistants and nurse practitioners in dermatology practices. A linear regression micro simulation model based on age cohorts produced a per capita supply of dermatology providers of 61 (±3) per 1,000,000 by 2030, up from 47 in 2016. The dermatology workforce is growing faster than population expansion. Workforce estimates could be affected by changing trends in retirement and training of dermatology providers. Investments in training of nurse practitioners and physician assistants, in addition to training more doctors, may be an effective strategy for increasing access to care in populations with low dermatologist density.

Effective local anesthesia for onabotulinumtoxin A injections to treat hyperhidrosis associated with traumatic amputation.

BACKGROUND: Botulinum toxin type A (BTX-A) injections are an effective treatment for controlling hyperhidrosis at sites of amputation. Hyperesthesia associated with amputated limbs is a major barrier to performing this procedure under local anesthesia. OBJECTIVE: To present a novel method for improving local anesthesia with BTX-A injections. Methods & RESULTS: A 29-year-old military veteran with a below-the-knee amputation of his right leg was suffering from amputation site hyperhidrosis, which was impeding his ability to comfortably wear a prosthesis. Prior to presenting to our clinic, the patient received one treatment of BTX-A injections to his amputation stump while under general anesthesia for surgical repair of trauma-related injuries. In our dermatology clinic, we repeated the procedure using topical lidocaine-prilocaine (30 gm total) for local anesthesia. This provided effective relief of hyperhidrosis for 6 months, but the procedure was very painful (9/10 intensity). We repeated the same procedure 6 months later, using ice in addition to topical lidocaine-prilocaine (30 gm) for local anesthesia; this resulted in reduced pain (3/10 intensity) for the patient. CONCLUSIONS: We suggest using ice in combination with a topical anesthetic as an effective method for pain control that avoids general anesthesia in treating amputation-associated hyperhidrosis.

Histologic features of melanoma associated with CDKN2A genotype.

BACKGROUND: Inherited susceptibility genes have been associated with histopathologic characteristics of tumors. OBJECTIVE: We sought to identify associations between histology of melanomas and CDKN2A genotype. METHODS: This was a case-control study design comparing 28 histopathologic tumor features among individuals with sporadic melanomas (N = 81) and cases from melanoma families with (N = 123) and without (N = 120) CDKN2A germline mutations. RESULTS: Compared with CDKN2A(-) cases, mutation carriers tended to have histologic features of superficial spreading melanoma subtype including higher pigmentation (Ptrend = .02) and increased pagetoid scatter (Ptrend = .07) after adjusting for age at diagnosis, sex, and American Joint Committee on Cancer thickness category. Similar associations were observed when comparing mutation carriers with a combined group of CDKN2A(-) (wild type) and sporadic melanomas. The presence of spindle cell morphology in the vertical growth phase was also an important predictor of genotype. Of the 15 cases with this phenotype, none were observed to harbor a CDKN2A mutation. LIMITATIONS: Our study examined rare mutations and may have been underpowered to detect small, but biologically significant associations between histology and genotype. CONCLUSION: Familial melanomas with CDKN2A mutations preferentially express a histologic phenotype of dense pigmentation, high pagetoid scatter, and a non-spindle cell morphology in the vertical growth phase.

Ambient ultraviolet radiation and ocular melanoma incidence in the United States, 2000-2019.

BACKGROUND/OBJECTIVES: Ocular melanoma is a rare, but deadly cancer. This large cancer registry study examines the associations between solar ultraviolet radiation (UVR) and incidence of different anatomical sites of ocular melanoma by sex, age, laterality, and race and ethnicity. METHODS: Incidence data were derived from 21 cancer registries in the US for the years 2000-2019. Satellite-based UVR estimates were linked to county of residence at diagnosis. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated for UVR quartiles using Poisson models. RESULTS: UVR was not associated with total ocular melanoma (N = 18,089) comparing Q4 versus Q1 (IRR = 0.98; 95%CI:0.94,1.03; p-trend = 0.07) or conjunctival melanoma (IRR = 0.99; 95%CI:0.82,1.19; p-trend = 0.81). However, in analyses of continuous UVR (per 10 mW/m2), risks were reduced for total ocular melanoma (IRR = 0.97; 95% CI: 0.96, 0.99). Incidence was increased for ciliary body/iris melanoma in the highest UVR quartile (IRR = 1.63; 95%CI:1.43,1.87; p-trend < 0.0001) and remained increased in non-Hispanic White individuals only. Incidence was reduced for choroidal melanoma in the highest UVR quartile (IRR = 0.86; 95%CI:0.82,0.91; p-trend < 0.0001). CONCLUSIONS: UVR may be associated with increased risk of ciliary body/iris melanoma. Reduced risk of choroidal melanoma may be due to higher diffuse UVR exposure to posterior ocular sites in locations at higher latitudes. Our results support and expand previous findings of associations of UVR using various surrogates on ocular melanoma risk and serve as a starting point for understanding the differences in the relationship between UVR and specific anatomical sites.

Treatment outcomes following partial shave biopsy of atypical and malignant melanocytic tumors in pediatric patients.

Pediatric melanoma is the most common skin cancer in children and treatment relies on accurate staging. The American Academy of Dermatology recommends excisional biopsy for suspicious skin lesions, however, partial shave biopsies are often performed, the impact of which is unknown in pediatric and adolescent/young adult (AYA) patients. The aim of this retrospective case series study was to evaluate the impact of the diagnostic biopsy method on staging, treatment, and treatment-related outcomes in pediatric/AYA patients with melanoma. Among 103 pediatric/AYA patients with atypical cutaneous melanocytic lesions, the most common biopsy method was partial shave (68/103, 66.0%) followed by punch (20/103, 19.4%), excisional (14/103, 13.6%), and incisional nonshave (1/103, 1%). Over half of all biopsies yielded a positive deep margin, reflecting compromised microstaging (56/103, 55.4%), the majority occurred following partial shave (52/56, 92.9%) compared with other techniques (P < 0.001). All 11 patients with wider surgical target margins of wide local excision and 8/9 patients with sentinel lymph node biopsy performed due to positive deep margin, underwent a partial shave biopsy (P = 0.05 and 0.32, respectively). Almost half of all patients who underwent partial shave biopsy had a clinically suspected abnormal melanocytic tumor prior to biopsy (31/68, 45.6%; P = 0.03). Of 56 patients who had compromised microstaging, 17 (30.4%) had a diagnosis of melanoma (P = 0.17). Pediatric/AYA patients frequently undergo partial shave biopsy, which is associated with more invasive definitive surgical treatment due to compromised microstaging. These results may help optimize care of patients with cutaneous melanocytic tumors.

Ambient ultraviolet A, ultraviolet B and risk of melanoma in a nationwide United States cohort, 1984-2014.

BACKGROUND: Ultraviolet radiation (UVR) exposure is the primary risk factor for melanoma although the relationship is complex. Compared to radiation from UVB wavelengths, UVA makes up a majority of the surface solar UVR, penetrates the skin more deeply, is the principal range emitted by tanning beds, and is less filtered by sunscreens and window glass. Few studies have examined the relationship between ambient UVA and UVB and melanoma risk. METHODS: Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were estimated for the association between satellite-based ambient (based on residential history) UVA, UVB and melanoma in non-Hispanic White participants using data from the United States Radiologic Technologists study, a large, nationwide prospective cohort. Associations of UVA and UVB quartile (Q) were examined in mutually adjusted and stratified models, additionally adjusted for demographic and sun sensitivity characteristics. RESULTS: There were 837 incident melanoma cases among 62,785 participants. Incidence of melanoma was statistically significantly increased for the highest quartile of childhood UVA exposure after adjustment for UVB (IRR = 2.82; 95%CI:1.46,5.44), but not for higher childhood UVB after adjustment for UVA. Childhood UVA was associated with increased melanoma risk within strata of UVB. Childhood UVB was not associated with melanoma after adjustment for UVA, but there was some evidence of lower risk with increased lifetime ambient UVB after UVA adjustment. CONCLUSIONS: Melanoma risk was elevated among participants living in locations with high annual childhood and lifetime UVA after controlling for UVB. With confirmation, these findings support increased protection from solar UVA for melanoma prevention.

Multiomics Profiling Distinguishes Sebaceous Carcinoma from Benign Sebaceous Neoplasms and Provides Insight into the Genetic Evolution of Sebaceous Carcinogenesis.

PURPOSE: Sebaceous carcinoma is the third most common nonkeratinocyte skin cancer in the United States with 1,000 cases per year. The clinicopathologic features of sebaceous carcinoma and benign sebaceous neoplasms (adenomas, sebaceomas) can overlap, highlighting the need for molecular biomarkers to improve classification. This study describes the genomic and transcriptomic landscape of sebaceous neoplasms in order to understand tumor etiology and biomarkers relevant for diagnosis and treatment. EXPERIMENTAL DESIGN: We performed whole-genome sequencing (WGS) and whole-transcriptome sequencing (WTS) of sebaceous neoplasms from six academic and two federal healthcare facilities in the United States diagnosed between January 1, 1999, and December 31, 2021. RESULTS: We evaluated 98 sebaceous neoplasms: 64 tumors (32 adenomas, 2 sebaceomas, 5 atypical sebaceous neoplasms, 25 carcinomas) had sufficient material for WGS, 96 tumors (42 adenomas, 11 sebaceomas, 8 atypical sebaceous neoplasms, 35 carcinomas) had sufficient material for WTS, and 62 tumors (31 adenomas, 2 sebaceomas, 5 atypical sebaceous neoplasms, 24 carcinomas) had sufficient material for combined WGS and WTS. Overall, we found decreased cholesterol biosynthesis and increased TP53 mutations, copy number gains (chromosome 6, 8q, and/or 18), and tumor mutation burden-high (>10 mutations/MB) in carcinomas compared to adenomas. Although diminished compared to adenomas, most carcinomas still had higher cholesterol biosynthesis than nonmalignant skin. Multiomics profiling also supported a precancerous model of tumor evolution with sebaceomas and atypical sebaceous neoplasms being likely intermediate lesions. CONCLUSIONS: The study findings highlight key diagnostic biomarkers for sebaceous carcinoma and suggest that immunotherapy and modulation of cholesterol biosynthesis could be effective treatment strategies.