Immune checkpoint inhibitor-induced sarcoidosis-like granulomas.

Immune checkpoint inhibitors targeting the cytotoxic T lymphocyte-associated antigen-4 and programmed cell death-1 receptors have transformed the treatment of melanoma and other cancers. These therapies are associated with a number of side effects, including immune-related adverse events. Sarcoidosis-like granulomas (SLGs) are important immune checkpoint inhibitor-related reactions to recognize as SLGs can mimic disease progression and accordingly impact treatment decisions. We systematically review reports of immune checkpoint inhibitor-induced SLGs in cancer patients and discuss potential underlying pathophysiological mechanisms.

Characterization of the facial microbiome in twins discordant for rosacea.

Previously, we determined that genetic and environmental factors contributed equally towards rosacea in twins. To assess an environmental factor, we characterized the malar cheek bacterial microbiome from twins discordant for rosacea. We found no significant difference in facial microbiome alpha and beta diversity between related twins discordant for rosacea. However, the relative percentage abundance of Gordonia and Geobacillus, low-abundant genera, was positively and negatively associated with rosacea severity, respectively. Our data demonstrate a significant correlation between facial microbiome and severity of rosacea in genetically matched twins and importantly that overall microbiome composition is largely unchanged.

Stage IV melanoma of unknown primary: A population-based study in the United States from 1973 to 2014.

BACKGROUND: Melanoma of unknown primary (MUP) is incompletely described on a population level. OBJECTIVE: We sought to characterize stage IV MUP in a population-based cancer registry. METHODS: We developed a novel search algorithm to identify cases of stage IV MUP in the Surveillance, Epidemiology, and End Results 18 registries from 1973 to 2014. Cases of stage IV melanoma of known primary (MKP) served as a comparison group. Age-standardized incidence rates, demographic characteristics, adjusted disease-specific survival, and Cox proportional hazard models were calculated for MUP and MKP. RESULTS: A total of 322 stage IV MUP cases and 12,796 stage IV MKP cases were identified in Surveillance, Epidemiology, and End Results 18 registries from 1973 to 2014. The incidence of stage IV MUP is increasing, particularly for patients younger than 30 years of age. In multivariate analyses, age older than 50 and a lack of surgical treatment were negative prognostic factors for stage IV MUP. Relative survival, but not 5-year adjusted disease-specific survival, was higher for stage IV MUP than for MKP. LIMITATIONS: Limitations include the retrospective study design and possible misclassification of MUP. CONCLUSIONS: The incidence of stage IV MUP is increasing, and stage IV MUP shares similar prognostic factors with stage IV MKP, including age and surgical treatment.

Primary bilateral uveal melanoma: a population-based study and systematic review.

IMPORTANCE: Primary bilateral uveal melanoma (UM) is a rare and incompletely described entity. It is not known how these patients compare to those with unilateral UM. BACKGROUND: We sought to comprehensively characterize and compare patients with primary bilateral and unilateral UM. DESIGN: Retrospective, population-based and systematic review. PARTICIPANTS: Patients with bilateral (n = 52) and unilateral UM (n = 8915). METHODS: We analysed cases of primary bilateral UM from three data sources: (i) the University Hospitals Cleveland Medical Center pathology database from 1996 to 2016 (n = 1); (ii) the Surveillance, Epidemiology and End-Results (SEER)-18 database from 1973 to 2013 (n = 5) and (iii) a systematic review of the English language literature (n = 46). Cases of unilateral UM were obtained from the SEER-18 database from 1973 to 2013 for comparison (n = 8915). MAIN OUTCOME MEASURES: Demographics, clinicopathological characteristics, treatments and survival. RESULTS: There were no differences in sex, race, mean age at diagnosis, site of uveal involvement, metastases at diagnosis, or treatment among patients with bilateral as compared to unilateral UM. Additionally, there were no clinicopathological differences between the two UMs in each patient with bilateral disease. Overall survival did not differ between unilateral and bilateral UM patients, or between bilateral UM patients who presented with, or subsequently developed, bilateral disease. CONCLUSIONS AND RELEVANCE: Bilateral and unilateral UM patients share similar demographics, clinicopathological characteristics, treatments and prognoses. Moreover, the development of bilateral disease does not portend a poorer prognosis and patients should be treated similarly to those with unilateral disease.

Melanoma subtypes demonstrate distinct PD-L1 expression profiles.

PD-L1 expression in the tumor immune microenvironment is recognized as both a prognostic and predictive biomarker in patients with cutaneous melanoma, a finding closely related to its adaptive (IFN-γ-mediated) mechanism of expression. Approximately 35% of cutaneous melanomas express PD-L1, however, the expression patterns, levels, and prevalence in rarer melanoma subtypes are not well described. We performed immunohistochemistry for PD-L1 and CD8 on 200 formalin-fixed paraffin-embedded specimens from patients with acral (n=16), mucosal (n=36), uveal (n=103), and chronic sun-damaged (CSD) (n=45) melanomas (24 lentigo maligna, 13 'mixed' desmoplastic, and 8 'pure' desmoplastic melanomas). CD8+ tumor-infiltrating lymphocyte (TIL) densities were characterized as mild, moderate, or severe, and their geographic association with PD-L1 expression was evaluated. Discrete lymphoid aggregates, the presence of a spindle cell morphology, and the relationship of these features with PD-L1 expression were assessed. PD-L1 expression was observed in 31% of acral melanomas, 44% of mucosal melanomas, 10% of uveal melanomas, and 62% of CSD melanomas (P<0.0001). Compared to our previously characterized cohort of cutaneous melanomas, the proportion of PD-L1(+) tumors was lower in uveal (P=0.0002) and higher in CSD (P=0.0073) melanomas, while PD-L1 expression in the acral and mucosal subtypes was on par. PD-L1 expression in all subtypes correlated with a moderate-severe grade of CD8+ TIL (all, P<0.003), supporting an adaptive mechanism of expression induced during the host antitumor response. The tumor microenvironments observed in CSD melanomas segregated by whether they were the pure desmoplastic subtype, which showed lower levels of PD-L1 expression when compared to other CSD melanomas (P=0.047). The presence of lymphoid aggregates was not associated with the level of PD-L1 expression, while PD-L1(+) cases with spindle cell morphology demonstrated higher levels of PD-L1 than those with a nested phenotype (P<0.0001). Our findings may underpin the reported clinical response rates for anti-PD-1 monotherapy, which vary by subtype.

Epidemiology of genitourinary melanoma in the United States: 1992 through 2012.

BACKGROUND: Primary melanoma arising in the genitourinary tract is rare and poorly characterized. OBJECTIVES: We sought to describe the epidemiology of genitourinary melanoma in the United States. METHODS: Incident case and population data were obtained for genitourinary melanoma from the Surveillance, Epidemiology, and End Results 13 Registries Database between 1992 and 2012. RESULTS: A total of 817 patients with genitourinary melanoma were identified; most cases occurred in the vulva. The incidence of genitourinary melanoma was much higher in women (1.74/1 million person-years) than men (0.17/1 million person-years). The highest rates occurred among non-Hispanic white women aged 85 years and older. Five-year melanoma-specific and overall survival were poor at 52.4% and 36.3%, respectively. Predictors of poor survival were increasing age, black race, and female sex. LIMITATIONS: The study population is small, therefore some rates reported may be unstable. In addition, cutaneous, mucosal, and other extracutaneous surfaces of the genitourinary tract cannot be reliably distinguished in Surveillance, Epidemiology, and End Results. Furthermore, melanomas may be underreported to cancer registries. CONCLUSION: From 1992 to 2012, genitourinary melanoma was 10 times more common in women than men. Survival was poor in women compared with men, which is different from cutaneous melanoma where women have a survival advantage.

Epidemiology of Anorectal Melanoma in the United States: 1992 to 2011.

BACKGROUND: Anorectal melanoma is a rare type of malignant melanoma and thus the epidemiology of patients with this tumor has been poorly defined. OBJECTIVE: To describe the epidemiology of anorectal melanoma in the United States. METHODS AND MATERIALS: We obtained case and population data from the Surveillance, Epidemiology, and End Results 13 Registries Database (SEER 13) between 1992 and 2011 using rectal diagnostic codes C20.9 to 21.8 and ICD-O-3 melanoma codes 8720 to 8721 and 8742 to 8746. RESULTS: There were 260 primary anorectal melanomas in SEER 13 from 1992 to 2011, occurring mostly in the rectum. The incidence of anorectal melanoma was higher among women than men with the highest rates occurring among white Hispanics ages 65 to 74 years. During this time period, the age-adjusted incidence rates rose significantly (p < .05) for both women and men with estimated annual percentage changes of 3.02% and 5.08%, respectively. Overall and melanoma-specific survival was poor irrespective of gender or ethnicity. CONCLUSION: Anorectal melanoma in the United States is increasing in both men and women, with the highest rates in elderly Hispanic white women. Hispanic whites were more likely to develop anorectal melanoma than non-Hispanic whites, suggesting that this population may be targeted for screening interventions. These results warrant further investigation to better understand the gender, racial, ethnic, and geographic variations for anorectal melanomas.

A systematic review and meta-analysis of animal-type melanoma.

BACKGROUND: Animal-type melanoma is a rare subtype of melanoma with heavily pigmented dermal epithelioid and spindled melanocytes. Its classification as a subtype of melanoma versus a borderline melanocytic tumor is debated. OBJECTIVES: Our primary objective was to characterize the demographics, clinical presentation, histopathology, management, and outcomes of patients with animal-type melanoma. METHODS: We performed a systematic review and meta-analysis of the English-language literature on animal-type melanoma. RESULTS: We identified 190 cases of animal-type melanoma. They occurred equally in men and women, with Caucasians (53.7%) most commonly affected. The median Breslow depth was 3.8 mm; ulceration was reported present in 15.8%; and dermal mitoses greater than or equal to 1/mm(2) was reported in 27.4%. The most common initial management was wide local excision with sentinel lymph node biopsy (55.7%). In all, 78 patients underwent sentinel lymph node biopsy with 41.0% positivity rate. A total of 32 patients underwent completion lymph node dissection with 34.4% positivity rate. Locoregional recurrence was reported in 15 patients, recurrence with distant metastases in 6 patients, and death in 5 patients. LIMITATIONS: Data were obtained from small studies with limited follow-up. There is no universally accepted definition of animal-type melanoma. CONCLUSION: Prospective studies with complete staging information and molecular profiling may allow further characterization of this tumor.

Update on primary mucosal melanoma.

Mucosal melanomas are aggressive cancers of mucosal surfaces with clinical and pathologic characteristics distinct from cutaneous melanomas, warranting different staging systems and treatment approaches. Surgical resection is performed frequently for the primary tumor, although the utility of lymph node surgery and radiation therapy is not established. Therapies targeted against C-KIT activating mutations, identified in many mucosal melanomas, are emerging as promising treatments.

InterMEL: An international biorepository and clinical database to uncover predictors of survival in early-stage melanoma.

INTRODUCTION: We are conducting a multicenter study to identify classifiers predictive of disease-specific survival in patients with primary melanomas. Here we delineate the unique aspects, challenges, and best practices for optimizing a study of generally small-sized pigmented tumor samples including primary melanomas of at least 1.05mm from AJTCC TNM stage IIA-IIID patients. We also evaluated tissue-derived predictors of extracted nucleic acids' quality and success in downstream testing. This ongoing study will target 1,000 melanomas within the international InterMEL consortium. METHODS: Following a pre-established protocol, participating centers ship formalin-fixed paraffin embedded (FFPE) tissue sections to Memorial Sloan Kettering Cancer Center for the centralized handling, dermatopathology review and histology-guided coextraction of RNA and DNA. Samples are distributed for evaluation of somatic mutations using next gen sequencing (NGS) with the MSK-IMPACTTM assay, methylation-profiling (Infinium MethylationEPIC arrays), and miRNA expression (Nanostring nCounter Human v3 miRNA Expression Assay). RESULTS: Sufficient material was obtained for screening of miRNA expression in 683/685 (99%) eligible melanomas, methylation in 467 (68%), and somatic mutations in 560 (82%). In 446/685 (65%) cases, aliquots of RNA/DNA were sufficient for testing with all three platforms. Among samples evaluated by the time of this analysis, the mean NGS coverage was 249x, 59 (18.6%) samples had coverage below 100x, and 41/414 (10%) failed methylation QC due to low intensity probes or insufficient Meta-Mixed Interquartile (BMIQ)- and single sample (ss)- Noob normalizations. Six of 683 RNAs (1%) failed Nanostring QC due to the low proportion of probes above the minimum threshold. Age of the FFPE tissue blocks (p<0.001) and time elapsed from sectioning to co-extraction (p = 0.002) were associated with methylation screening failures. Melanin reduced the ability to amplify fragments of 200bp or greater (absent/lightly pigmented vs heavily pigmented, p<0.003). Conversely, heavily pigmented tumors rendered greater amounts of RNA (p<0.001), and of RNA above 200 nucleotides (p<0.001). CONCLUSION: Our experience with many archival tissues demonstrates that with careful management of tissue processing and quality control it is possible to conduct multi-omic studies in a complex multi-institutional setting for investigations involving minute quantities of FFPE tumors, as in studies of early-stage melanoma. The study describes, for the first time, the optimal strategy for obtaining archival and limited tumor tissue, the characteristics of the nucleic acids co-extracted from a unique cell lysate, and success rate in downstream applications. In addition, our findings provide an estimate of the anticipated attrition that will guide other large multicenter research and consortia.

Basal cell carcinoma and anthropometric factors in the U.S. radiologic technologists cohort study.

Basal cell carcinoma (BCC) is the most common cancer in Caucasian populations. Although several risk factors are well-established, including ultraviolet radiation (UVR) sensitivity and exposure, few studies have examined anthropometric measures and BCC. Using Cox proportional hazards regression analysis, we prospectively investigated the relationship between height, weight and body mass index (BMI) and BCC in 58,213 Caucasian participants (11,631 men and 46,582 women) from the United States Radiological Technologists cohort. This analysis was limited to participants who were cancer-free at baseline. The baseline questionnaire provided self-reported anthropometric factors and the subsequent questionnaire collected skin cancer susceptibility factors, lifetime UVR exposure derived from residential and personal UVR exposure (time outdoors) and health outcomes. During 509,465 person-years of follow-up, we identified 2,291 BCC cases (486 men; 1,805 women). BCC risk increased with increasing height, and decreased with increasing weight and BMI in both sexes, even after adjusting for UVR susceptibility factors and exposures. For BMI categories: <25 (reference); 25-<30; 30-<35 and ≥ 35 kg m(-2) , multivariate hazard ratios (HR) in women were: 1.00; 0.74 (95% CI = 0.66-0.83); 0.67 (0.56-0.81) and 0.57 (0.44-0.74), respectively, p-trend ≤ 0.0001. Risks were similar in men. The inverse association between BMI and BCC was unaffected by controlling for sun-related exposures. Nevertheless, it may at least partly reflect residual UVR confounding. Further research with more detailed sun exposure data, including clothing patterns, would help clarify the relationship between BMI and BCC.

Pompholyx and eczematous reactions associated with intravenous immunoglobulin therapy.

INTRODUCTION: Intravenous immunoglobulin (IVIG) is used to treat many inflammatory and autoimmune disorders and although generally well tolerated, cutaneous side effects occur. OBJECTIVE: We reviewed reports of pompholyx and eczematous reactions associated with IVIG. METHODS: A literature search was performed using the PubMed and MEDLINE databases with the search terms "intravenous immunoglobulin pompholyx," "intravenous immunoglobulin eczema," "intravenous immunoglobulin cutaneous adverse effects," "intravenous immunoglobulin cutaneous effects," "intravenous immunoglobulin skin effects," and "intravenous immunoglobulin adverse effects." Relevant English-language articles or articles in other languages cited in English-language articles were included. RESULTS: We identified 64 cases of eczematous reactions associated with IVIG therapy, including a patient treated on our inpatient consult service. In reported cases, the majority of patients (62.5%) had pompholyx alone or a combination of pompholyx on the hands or feet and two or fewer additional body surfaces involved. The majority of reported cases (75%) experienced the eczematous reaction after their first IVIG treatment. Neurologic conditions were the most common (85.9%) diseases for which IVIG was used. Most patients responded well to topical steroids or did not require treatment. LIMITATIONS: Some reported cases had insufficient descriptions to be included in this review. A literature review may underestimate the frequency of eczematous reactions to IVIG because these reactions are often limited and may not be reported. CONCLUSIONS: With the use of IVIG increasing, it is important for dermatologists to recognize this cutaneous side effect of IVIG.

Landscape of mutations in early stage primary cutaneous melanoma: An InterMEL study.

It is unclear why some melanomas aggressively metastasize while others remain indolent. Available studies employing multi-omic profiling of melanomas are based on large primary or metastatic tumors. We examine the genomic landscape of early-stage melanomas diagnosed prior to the modern era of immunological treatments. Untreated cases with Stage II/III cutaneous melanoma were identified from institutions throughout the United States, Australia and Spain. FFPE tumor sections were profiled for mutation, methylation and microRNAs. Preliminary results from mutation profiling and clinical pathologic correlates show the distribution of four driver mutation sub-types: 31% BRAF; 18% NRAS; 21% NF1; 26% Triple Wild Type. BRAF mutant tumors had younger age at diagnosis, more associated nevi, more tumor infiltrating lymphocytes, and fewer thick tumors although at generally more advanced stage. NF1 mutant tumors were frequent on the head/neck in older patients with severe solar elastosis, thicker tumors but in earlier stages. Triple Wild Type tumors were predominantly male, frequently on the leg, with more perineural invasion. Mutations in TERT, TP53, CDKN2A and ARID2 were observed often, with TP53 mutations occurring particularly frequently in the NF1 sub-type. The InterMEL study will provide the most extensive multi-omic profiling of early-stage melanoma to date. Initial results demonstrate a nuanced understanding of the mutational and clinicopathological landscape of these early-stage tumors.

Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours.

Activation of the Hedgehog (Hh) signalling pathway by sporadic mutations or in familial conditions such as Gorlin's syndrome is associated with tumorigenesis in skin, the cerebellum and skeletal muscle. Here we show that a wide range of digestive tract tumours, including most of those originating in the oesophagus, stomach, biliary tract and pancreas, but not in the colon, display increased Hh pathway activity, which is suppressible by cyclopamine, a Hh pathway antagonist. Cyclopamine also suppresses cell growth in vitro and causes durable regression of xenograft tumours in vivo. Unlike in Gorlin's syndrome tumours, pathway activity and cell growth in these digestive tract tumours are driven by endogenous expression of Hh ligands, as indicated by the presence of Sonic hedgehog and Indian hedgehog transcripts, by the pathway- and growth-inhibitory activity of a Hh-neutralizing antibody, and by the dramatic growth-stimulatory activity of exogenously added Hh ligand. Our results identify a group of common lethal malignancies in which Hh pathway activity, essential for tumour growth, is activated not by mutation but by ligand expression.

Necrolytic acral erythema as a cutaneous marker of hepatitis C: report of two cases and review.

Necrolytic acral erythema (NAE) is a member of the necrolytic erythemas, which include necrolytic migratory erythema (NME), acrodermatitis enteropathica, and various dermopathies secondary to nutritional deficiencies. NAE is distinct from the other necrolytic erythemas by virtue of its consistent association with hepatitis C (HCV) together with the acral distribution of its lesions, in particular, dorsal hands and feet. Although its etiology is unknown, NAE has been reported to respond to zinc replacement, suggesting a causal relationship. Two patients with HCV infection presented with scaly acral plaques and histopathologic features consistent with NAE while also demonstrating atypical palmoplantar accentuation of lesions. Both patients were found to have zinc deficiency, and their lesions responded to zinc supplementation. Awareness of NAE as a unique cutaneous marker for HCV infection is important not only for accurate dermatologic diagnosis but also for appropriate management of associated morbidity and prompt detection of potentially undiagnosed underlying HCV.

Bullous lupus: an unusual initial presentation of systemic lupus erythematosus in an adolescent girl.

Bullous systemic lupus erythematosus is a subepidermal blistering disease that occurs only rarely in a subset of patients with systemic lupus erythematosus and even less commonly in pediatric patients. Autoimmunity in bullous systemic lupus erythematosus is characterized by the presence of circulating anti-type VII collagen antibodies. We report here a case of a child whose initial systemic lupus erythematosus presentation was a diffuse bullous eruption.

Risk Factors for Keratinocyte Carcinoma in Recipients of Allogeneic Hematopoietic Cell Transplants.

Importance: Allogeneic hematopoietic cell transplant (alloHCT) is known to increase the risk for keratinocyte carcinoma. The extent to which host characteristics, including pigmentary phenotype and UV radiation exposure, contribute is unknown. Objective: To identify and validate independent risk factors for keratinocyte carcinoma after alloHCT, including those associated with the transplant and the host. Design, Setting, and Participants: This retrospective cohort study analyzed a consecutive sample of alloHCT recipients from January 1, 2000, to December 31, 2014, at the Mayo Clinic, Rochester, Minnesota (n = 872) and University Hospitals Cleveland Medical Center, Cleveland, Ohio (n = 147). Participants from the Mayo Clinic were randomly allocated (2:1) into discovery (n = 581) and validation (n = 291) cohorts. Time to first keratinocyte carcinoma and information about transplant- and host-associated risk factors were extracted. A multivariate keratinocyte carcinoma risk model was created using a stepwise Cox proportional hazards regression model with P ≤ .05 for entry that incorporated all covariates that were individually statistically significant at α = 0.05 in the discovery cohort. The risk model was first internally validated using the Mayo Clinic validation cohort and then externally validated using the independent cohort of alloHCT recipients at University Hospitals Cleveland Medical Center. Data were analyzed from March 13, 2018, to June 12, 2019. Exposures: Allogeneic hematopoietic cell transplant. Main Outcomes and Measures: The primary outcome was time to development of the first cutaneous keratinocyte carcinoma after alloHCT; secondary outcome, time to development of the first individual basal and/or squamous cell carcinoma after alloHCT. Results: Of the 872 alloHCT recipients identified in the Mayo Clinic cohort (520 men [59.6%]; mean [SD] age, 48.3 [12.6] years), 95 (10.9%) developed keratinocyte carcinoma after alloHCT during 5349 person-years of follow-up. Of the 147 alloHCT recipients in the exernal validation cohort (86 men [58.5%]; mean [SD] age, 47.9 [17.5] years), 18 (12.2%) developed keratinocyte carcinoma after alloHCT in 880 person-years of follow up. Risk factors independently associated with keratinocyte carcinoma after alloHCT included age (hazard ratio [HR] per 10 years, 1.72; 95% CI, 1.21-2.42), chronic lymphocytic leukemia (HR, 2.47; 95% CI, 1.20-5.09), clinically photodamaged skin (HR, 3.47; 95% CI, 1.87-6.41), and history of cutaneous squamous cell carcinoma (HR, 2.60; 95% CI, 1.41-5.91). Harrell concordance statistics were 0.81 (95% CI, 0.72-0.90) and 0.86 (95% CI, 0.74-0.98) for internal and external validation of the keratinocyte carcinoma risk model, respectively. Conclusions and Relevance: This study found validated independent risk factors for keratinocyte carcinoma after alloHCT that are enriched with host- compared with transplant-associated risk factors. These findings highlight the importance of assessing host-associated risk factors for keratinocyte carcinoma in patients eligible for alloHCT. Future studies should examine whether keratinocyte carcinoma risk stratification before alloHCT may inform long-term surveillance strategies.

Nucleotide diversity and population differentiation of the melanocortin 1 receptor gene, MC1R.

BACKGROUND: The melanocortin 1 receptor gene (MC1R) is responsible for normal pigment variation in humans and is highly polymorphic with numerous population-specific alleles. Some MC1R variants have been associated with skin cancer risk. RESULTS: Allele frequency data were compiled on 55 single nucleotide polymorphisms from seven geographically distinct human populations (n = 2306 individuals). MC1R nucleotide diversity, pi, was much higher (10.1 x 10-4) than in other genes for all subjects. A large degree of population differentiation, determined by FST, was also present, particularly between Asia and all other populations, due to the p.R163Q (c.488 G>A) polymorphism. The least amount of differentiation was between the United States, Northern Europe, and Southern Europe. Tajima's D statistic suggested the presence of positive selection in individuals from Europe. CONCLUSION: This study further quantifies the degree of population-specific genetic variation and suggests that positive selection may be present in European populations in MC1R.