Shifts in Cutaneous Melanocytic Tumor Diagnostic Terminology: Melanocytoma, MPATH-Dx V2.0 and the WHO Skin5
Abstract In this Special Issue of the Journal of Cutaneous Pathology in memory of Dr. Martin C. Mihm, Jr, we highlight his many contributions over more than 50 years to the catalog of specific melanocytic tumor terminology. Dr. Mihm was an active participant in the International Melanoma Pathology Study Group (IMPSG). Discussions led to proposed recommendations for changes in the terminology of melanocytic tumors and their standardized diagnostic reporting. Histopathological reports of melanocytic tumors provide critical information that guides patient counseling and therapy. Importantly the pathology report must relay whether the melanocytic tumor is benign, intermediate, or malignant, and [...]
Tumor miRNA Signatures Associate with Outcomes of Patients with Stage II/III Melanoma
Abstract Purpose: Patients with stage II and resected stage III melanomas have variable clinical outcomes, providing evidence of underlying biological differences in tumors and/or the patients themselves, beyond stage. The approval of adjuvant immunotherapy for stage IIB/C and resected stage III/IV disease (and adjuvant targeted therapy for resected stage III disease) has created a pressing need to develop biomarkers to accurately distinguish patients at low risk versus high risk for recurrence and death from melanoma. miRNAs are promising biomarkers because of their stability in tissues and fluids and their demonstrated functional and prognostic roles in melanoma. We hypothesized that miRNA [...]
Characterization of the treatment-naive immune microenvironment in melanoma with BRAF mutation
Abstract Background: Patients with BRAF-mutant and wild-type melanoma have different response rates to immune checkpoint blockade therapy. However, the reasons for this remain unknown. To address this issue, we investigated the precise immune composition resulting from BRAF mutation in treatment-naive melanoma to determine whether this may be a driver for different response to immunotherapy. Methods: In this study, we characterized the treatment-naive immune context in patients with BRAF-mutant and BRAF wild-type (BRAF-wt) melanoma using data from single-cell RNA sequencing, bulk RNA sequencing, flow cytometry and immunohistochemistry (IHC). Results: In single-cell data, BRAF-mutant melanoma displayed a significantly reduced infiltration of CD8+ T cells and macrophages but also increased B cells, natural [...]
DNA Methylation Classes of Stage II and III Primary Melanomas and Their Clinical and Prognostic Significance
Abstract Purpose: Patients with stage II and III cutaneous primary melanoma vary considerably in their risk of melanoma-related death. We explore the ability of methylation profiling to distinguish primary melanoma methylation classes and their associations with clinicopathologic characteristics and survival. Materials and methods: InterMEL is a retrospective case-control study that assembled primary cutaneous melanomas from American Joint Committee on Cancer (AJCC) 8th edition stage II and III patients diagnosed between 1998 and 2015 in the United States and Australia. Cases are patients who died of melanoma within 5 years from original diagnosis. Controls survived longer than 5 years without evidence of [...]
Updated pan-tumor guidelines for neoadjuvant scoring of pathologic response: a joint SITC and INMC effort
Abstract Background: Practice-changing clinical trials for novel therapeutic regimens administered in the neoadjuvant setting have been reported for multiple cancer types, bringing this treatment strategy to the forefront for patients with high-risk surgically resectable disease. Previously, tumor-type- or therapy-type-specific scoring systems were used for pathologic response assessment. The goal of this effort is to update, harmonize, and standardize the emerging system(s) for pathologic response assessment and data capture. Materials and methods: Leaders in pathology, oncology, and surgery, including those from the Society for Immunotherapy of Cancer's Pan-tumor Harmonization of Pathologic Response Assessment (PATHdata) efforts and the International Neoadjuvant Melanoma Consortium (INMC), [...]
Pathological response calculation assessment remains accurate with reduced tumor bed examination following neoadjuvant immunotherapy in clinically detectable stage III melanoma
Abstract Background: Neoadjuvant immunotherapy produces event-free survival advantage over adjuvant therapy for patients with surgically resectable macroscopic stage IIIB/C/D melanoma. Pathological response, determined as percentage residual viable tumor (% RVT), provides critical prognostic information and informs management decisions. Here, we assessed accuracy of %RVT calculation when reduced tumor bed (TB) was examined and leverage these results proposing streamlined protocols for pathological examination. Patients and methods: Comprehensive histopathological examination was carried out on 134 patient specimens after neoadjuvant immunotherapy with ipilimumab and nivolumab. Impact on %RVT when evaluating less TB than recommended by the initial International Neoadjuvant Melanoma Consortium (INMC) protocol was [...]
A dynamic recurrence risk prediction tool for adjuvant therapy in stage III melanoma
Abstract Background: Prognosis for AJCC stage III melanoma varies significantly. Adjuvant therapies, including pembrolizumab, nivolumab, and dabrafenib/trametinib, have markedly reduced recurrence risk, as shown in pivotal trials (Keynote-054, CheckMate-238, and Combi-AD). Despite these advancements, clinicians lack tools to dynamically assess recurrence risk across the patient journey. Patients and methods: Using pooled individual patient data (IPD) from Kaplan-Meier curves of these trials, we developed a tool to dynamically estimate relapse-free survival (RFS) and distant metastasis-free survival (DMFS) over time. Conditional survival analyses incorporated AJCC-8 substages, treatment regimens, and recurrence data. Results: The analysis included 2206 patients (IIIA: 174, IIIB: 768, IIIC: 1169, IIID: [...]
Sites of metastases before systemic treatment influence progression patterns and survival in stage IV melanoma patients
Abstract Background: Metastatic sites influence response rates to immune checkpoint inhibitors (ICI) and survival, suggesting anatomical locations impact treatment outcomes. This study examines how baseline metastatic sites affect progression patterns and survival in melanoma patients receiving first-line ICI or BRAF/MEK inhibitors (BRAF/MEKi). Methods: Metastatic site presence and lesion counts at baseline and progression were captured chronologically for 347 ICI-treated and 210 BRAF/MEKi-treated patients using a novel graph representation. This novel approach enabled systematic comparison of progression patterns post-therapy failure across patients by providing a standardized representation of patterns of progression in patients with distinct clinical histories. Associations of baseline metastatic sites [...]
The Development and Evaluation of a Convolutional Neural Network for Cutaneous Melanoma Detection in Whole Slide Images
Abstract Context: The current melanoma staging system does not account for 26% of the variance seen in melanoma-specific survival, therefore our ability to predict patient outcome is not fully elucidated. Morphology may be of greater significance than in other solid tumors, with Breslow thickness remaining the strongest prognostic indicator despite being subject to high levels of interobserver variation. The application of convolutional neural networks to whole slide images affords objective morphologic metrics, which may reveal new insights into patient prognosis. Objective: To develop and evaluate a convolutional neural network for invasive cutaneous melanoma detection in whole slide images for [...]