Pathology: the next chapter.
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BRAF mutation testing for patients diagnosed with stage III or stage IV melanoma: practical guidance for the Australian setting
Abstract Targeted therapy (BRAF inhibitor plus MEK inhibitor) is now among the possible treatment options for patients with BRAF mutation-positive stage III or stage IV melanoma. This makes prompt BRAF mutation testing an important step in the management of patients diagnosed with stage III or IV melanoma; one that can help better ensure that the optimal choice of systemic treatment is initiated with minimal delay. This article offers guidance about when and how BRAF mutation testing should be conducted when patients are diagnosed with melanoma in Australia. Notably, it recommends that pathologists reflexively order BRAF mutation testing whenever a [...]
Multiomic profiling of checkpoint inhibitor-treated melanoma: Identifying predictors of response and resistance, and markers of biological discordance.
Abstract We concurrently examine the whole genome, transcriptome, methylome, and immune cell infiltrates in baseline tumors from 77 patients with advanced cutaneous melanoma treated with anti-PD-1 with or without anti-CTLA-4. We show that high tumor mutation burden (TMB), neoantigen load, expression of IFNγ-related genes, programmed death ligand expression, low PSMB8 methylation (therefore high expression), and T cells in the tumor microenvironment are associated with response to immunotherapy. No specific mutation correlates with therapy response. A multivariable model combining the TMB and IFNγ-related gene expression robustly predicts response (89% sensitivity, 53% specificity, area under the curve [AUC], 0.84); tumors with [...]
BRAF mutation testing for patients diagnosed with stage III or stage IV melanoma: practical guidance for the Australian setting.
Abstract Targeted therapy (BRAF inhibitor plus MEK inhibitor) is now among the possible treatment options for patients with BRAF mutation-positive stage III or stage IV melanoma. This makes prompt BRAF mutation testing an important step in the management of patients diagnosed with stage III or IV melanoma; one that can help better ensure that the optimal choice of systemic treatment is initiated with minimal delay. This article offers guidance about when and how BRAF mutation testing should be conducted when patients are diagnosed with melanoma in Australia. Notably, it recommends that pathologists reflexively order BRAF mutation testing whenever a [...]
Impact of Next-generation Sequencing on Interobserver Agreement and Diagnosis of Spitzoid Neoplasms.
Abstract Atypical Spitzoid melanocytic tumors are diagnostically challenging. Many studies have suggested various genomic markers to improve classification and prognostication. We aimed to assess whether next-generation sequencing studies using the Tempus xO assay assessing mutations in 1711 cancer-related genes and performing whole transcriptome mRNA sequencing for structural alterations could improve diagnostic agreement and accuracy in assessing neoplasms with Spitzoid histologic features. Twenty expert pathologists were asked to review 70 consultation level cases with Spitzoid features, once with limited clinical information and again with additional genomic information. There was an improvement in overall agreement with additional genomic information. Most significantly, [...]
Assessing the Potential for Patient-led Surveillance After Treatment of Localized Melanoma (MEL-SELF): A Pilot Randomized Clinical Trial.
Abstract Importance: Patient-led surveillance is a promising new model of follow-up care following excision of localized melanoma. Objective: To determine whether patient-led surveillance in patients with prior localized primary cutaneous melanoma is as safe, feasible, and acceptable as clinician-led surveillance. Design, setting, and participants: This was a pilot for a randomized clinical trial at 2 specialist-led clinics in metropolitan Sydney, Australia, and a primary care skin cancer clinic managed by general practitioners in metropolitan Newcastle, Australia. The participants were 100 patients who had been treated for localized melanoma, owned a smartphone, had a partner to assist with skin self-examination (SSE), and had [...]
Multi-trait genetic analysis identifies auto-immune loci associated with cutaneous melanoma.
Abstract Genome-wide association studies (GWAS) have identified a number of risk loci for cutaneous melanoma. Cutaneous melanoma shares overlapping genetic risk (genetic correlation) with a number of other traits, including its risk factors such as sunburn propensity. This genetic correlation can be exploited to identify additional cutaneous melanoma risk loci by multitrait analysis of GWAS (MTAG). We used bivariate linkage disequilibrium-score regression score regression to identify traits that are genetically correlated with clinically confirmed cutaneous melanoma and then used publicly available GWAS for these traits in a multitrait analysis of GWAS. Multitrait analysis of GWAS allows GWAS to be [...]
Case report of a challenging medium-sized congenital melanocytic nevus (CMN): Highlighting a role for reflectance confocal microscopy (RCM) for evaluating changing CMN in children.
Abstract A 3.5-month-old boy presented with a changing medium-sized congenital melanocytic nevus on his leg. Due to atypical features on dermoscopy and reflectance confocal microscopy (RCM), an excision of the area of concern was performed. Histopathology showed many of the pathological features usually associated with a diagnosis of melanoma in situ in older patients, but due to the young age of the patient, absence of mitoses, and the degree of atypia, a diagnosis of a dysplastic compound nevus arising in a congenital compound (predominantly dermal) nevus was favored. In our case, RCM corresponded to histopathology helped target the area [...]
Association Between Melanoma Detected During Routine Skin Checks and Mortality.
Abstract Importance: Early melanoma diagnosis is associated with better health outcomes, but there is insufficient evidence that screening, such as having routine skin checks, reduces mortality. Objective: To assess melanoma-specific and all-cause mortality associated with melanomas detected through routine skin checks, incidentally or patient detected. A secondary aim was to examine patient, sociodemographic, and clinicopathologic factors associated with different modes of melanoma detection. Design, setting, and participants: This prospective, population-based, cohort study included patients in New South Wales, Australia, who were diagnosed with melanoma over 1 year from October 23, 2006, to October 22, 2007, in the Melanoma Patterns of Care Study [...]
High-Dimensional Single-Cell Transcriptomics in Melanoma and Cancer Immunotherapy
Abstract Recent advances in single-cell transcriptomics have greatly improved knowledge of complex transcriptional programs, rapidly expanding our knowledge of cellular phenotypes and functions within the tumour microenvironment and immune system. Several new single-cell technologies have been developed over recent years that have enabled expanded understanding of the mechanistic cells and biological pathways targeted by immunotherapies such as immune checkpoint inhibitors, which are now routinely used in patient management with high-risk early-stage or advanced melanoma. These technologies have method-specific strengths, weaknesses and capabilities which need to be considered when utilising them to answer translational research questions. Here, we provide guidance [...]