IFNγ signaling sensitizes melanoma cells to BH3 Mimetics.
Abstract Immunotherapy targeting PD-1 and/or CTLA4 leads to durable responses in a proportion of patients with melanoma. However, many patients will not respond to these immune checkpoint inhibitors, and up to 60% of responding patients will develop treatment resistance. We describe a vulnerability in melanoma driven by immune cell activity that provides a pathway towards additional treatment options. This study evaluated short-term melanoma cell lines (referred to as PD1 PROG cells) derived from melanoma metastases that progressed on PD-1 inhibitor–based therapy. We show that the cytokine IFN-γ primes melanoma cells for apoptosis by promoting changes in the accumulation and [...]
Survival update of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma in the OpACIN and OpACIN-neo trials.
Abstract Background Neoadjuvant ipilimumab plus nivolumab has yielded high response rates in patients with macroscopic stage III melanoma. These response rates translated to high short-term survival rates. However, data on long-term survival and disease recurrence are lacking. Patients and methods In OpACIN, 20 patients with macroscopic stage III melanoma were randomized to ipilimumab 3 mg/kg plus nivolumab 1 mg/kg q3w four cycles of adjuvant or split two cycles of neoadjuvant and two adjuvant. In OpACIN-neo, 86 patients with macroscopic stage III melanoma were randomized to arm A (2× ipilimumab 3 mg/kg plus nivolumab 1 mg/kg q3w; n = 30), [...]
Interobserver agreement in the histopathological classification of desmoplastic melanomas
Abstract Desmoplastic melanoma is a subtype of melanoma characterised by amelanotic fusiform melanocytes dispersed in a collagenous stroma. Cell-poor and fibrous stroma-rich ‘pure’ variants have been distinguished from ‘mixed’ variants with areas of higher cell density and/or less desmoplastic stroma. This distinction is relevant because patients whose tumours display a pure phenotype have a lower risk for regional lymph node metastasis and distant recurrence. However, little is known about interobserver agreement among pathologists in the subclassification of desmoplastic melanoma. To address this issue, we conducted a study in which eleven dermatopathologists independently evaluated whole slide scanned images of excisions [...]
Biology and genetics of acquired and congenital melanocytic naevi
Abstract Acquired and congenital melanocytic naevi are common benign neoplasms. Understanding their biology and genetics will help clinicians and pathologists correctly diagnose melanocytic tumours, and generate insights into naevus aetiology and melanomagenesis. Genomic data from published studies analysing acquired and congenital melanocytic naevi, including oncogenic driver mutations, common melanoma associated mutations, copy number aberrations, somatic mutation signature patterns, methylation profile, and single nucleotide polymorphisms, were reviewed. Correlation of genomic changes to dermoscopic features, particular anatomic sites and total body naevus counts, was also performed. This review also highlights current scientific theories and evidence concerning naevi growth arrest. Acquired and [...]
Genomic profiling of metastatic basal cell carcinoma reveals candidate drivers of disease and therapeutic targets.
Abstract Basal cell carcinomas (BCCs) are human beings’ most common malignant tumors. Most are easily managed by surgery or topical therapies, and metastasis is rare. Although BCCs can become locally advanced, metastatic BCCs are very uncommon and may be biologically distinct. We assessed the clinicopathologic characteristics of 17 patients with metastatic BCC and pursued whole-exome sequencing of tumor and germline DNA from 8 patients. Genomic profiling revealed aberrant activation of Hedgehog signaling and alterations in GLI transcriptional regulators and Notch and Hippo signaling. Matched local recurrences of primary BCCs and metastases from 3 patients provided evidence of a clonal [...]
Representativeness of initial skin biopsies showing pure desmoplastic melanoma: implications for management
Abstract Desmoplastic melanoma (DM) is an uncommon subtype of melanoma with distinct clinicopathological features. It is classified into pure desmoplastic melanoma (PDM) when the proportion of desmoplastic melanoma is ≥90% of the dermally-invasive component, and mixed desmoplastic melanoma (MDM) when the proportion of desmoplastic melanoma is <90%. Studies have reported a lower sentinel lymph node biopsy (SLNB)-positivity rate in PDM compared to MDM and non-DM. As a result, some have recommended not performing SLNB in PDM patients. When PDM is identified in a partial biopsy of a melanoma, there is a risk that sampling bias may under-recognise MDM, but [...]
Revision of the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis Classification Schema for Melanocytic Lesions: A Consensus Statement
Abstract Importance: A standardized pathology classification system for melanocytic lesions is needed to aid both pathologists and clinicians in cataloging currently existing diverse terminologies and in the diagnosis and treatment of patients. The Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) has been developed for this purpose. Objective: To revise the MPATH-Dx version 1.0 classification tool, using feedback from dermatopathologists participating in the National Institutes of Health-funded Reducing Errors in Melanocytic Interpretations (REMI) Study and from members of the International Melanoma Pathology Study Group (IMPSG). Evidence review: Practicing dermatopathologists recruited from 40 US states participated in the 2-year REMI study and [...]
Interobserver agreement in the histopathological classification of desmoplastic melanomas.
Abstract Desmoplastic melanoma is a subtype of melanoma characterised by amelanotic fusiform melanocytes dispersed in a collagenous stroma. Cell-poor and fibrous stroma-rich 'pure' variants have been distinguished from 'mixed' variants with areas of higher cell density and/or less desmoplastic stroma. This distinction is relevant because patients whose tumours display a pure phenotype have a lower risk for regional lymph node metastasis and distant recurrence. However, little is known about interobserver agreement among pathologists in the subclassification of desmoplastic melanoma. To address this issue, we conducted a study in which eleven dermatopathologists independently evaluated whole slide scanned images of excisions [...]
Biology and genetics of acquired and congenital melanocytic naevi.
Abstract Acquired and congenital melanocytic naevi are common benign neoplasms. Understanding their biology and genetics will help clinicians and pathologists correctly diagnose melanocytic tumours, and generate insights into naevus aetiology and melanomagenesis. Genomic data from published studies analysing acquired and congenital melanocytic naevi, including oncogenic driver mutations, common melanoma associated mutations, copy number aberrations, somatic mutation signature patterns, methylation profile, and single nucleotide polymorphisms, were reviewed. Correlation of genomic changes to dermoscopic features, particular anatomic sites and total body naevus counts, was also performed. This review also highlights current scientific theories and evidence concerning naevi growth arrest. Acquired and [...]
Melanomas in children and adolescents: clinicopathologic features and survival outcomes.
Abstract Background: Melanomas in the first 2 decades of life are uncommon and poorly understood. Objective: To assess clinicopathologic features and survival of children (≤11 years) and adolescents (12-19 years) diagnosed with melanoma. Methods: A pooled cohort of 514 patients was analyzed (397 Dutch, 117 Australian; 62 children, 452 adolescents). Pathology reports were reevaluated to determine melanoma subtypes. Multivariable Cox models were generated for recurrence-free survival (RFS) and overall survival (OS). Results: Melanoma subtypes were conventional melanoma (superficial spreading, nodular, desmoplastic, and acral lentiginous), spitzoid melanoma, and melanoma associated with a congenital nevus in 428, 78, and 8 patients, respectively. Ten-year RFS was [...]