Cartilage Resection in the Surgical Management of Ear Melanoma.

Background: Melanoma of the ear accounts for approximately 1% of cutaneous melanomas. Management recommendations are based on small retrospective series and case reports. Resection of melanoma of the ear requires a delicate balance between disease clearance, preservation of function, and aesthetics.

Longitudinal Analysis Reveals Dynamic Changes in Histopathologic Features in Responders to Neoadjuvant Treatment in a Stage III BRAF-Mutant Melanoma Cohort.

Despite advances in systemic therapies, cutaneous melanoma remains a highly deadly disease. Patients with high-risk stage III melanoma have a significant likelihood of recurrence following surgery. Although adjuvant immunotherapy has been the standard of care, recent evidence demonstrates that neoadjuvant immunotherapy is more effective for higher-risk stage III patients, showing superior survival outcomes compared with adjuvant immunotherapy.

FDG-PET associations with pathological response and survival with neoadjuvant immunotherapy for melanoma.

Background: Neoadjuvant immunotherapy has become the new standard of care for stage III melanoma. This study sought to describe the metabolic changes seen with fludeoxyglucose-18-positron emission tomography (FDG-PET) following neoadjuvant immunotherapy in patients with melanoma and explore associations with pathological response and recurrence-free survival (RFS).

Methods: Data from patients with macroscopic stage III nodal melanoma treated with neoadjuvant checkpoint inhibitor therapy were pooled from five melanoma centers.

Neoadjuvant triplet immune checkpoint blockade in newly diagnosed glioblastoma.

Glioblastoma (GBM) is an aggressive primary adult brain tumor that rapidly recurs after standard-of-care treatments, including surgery, chemotherapy and radiotherapy. While immune checkpoint inhibitor therapies have transformed outcomes in many tumor types, particularly when used neoadjuvantly or as a first-line treatment, including in melanoma brain metastases, they have shown limited efficacy in patients with resected or recurrent GBM. The lack of efficacy has been attributed to the scarcity of tumor-infiltrating lymphocytes (TILs), an immunosuppressive tumor microenvironment and low tumor mutation burden typical of GBM tumors, plus exclusion of large molecules from the brain parenchyma.

Inter-rater concordance of basal cell carcinoma subtypes: influences on reporting format and opportunities for further classification modifications.

Diagnosis of basal cell carcinoma (BCC) higher risk subtypes influences management strategies because of their propensity to recur locally. Subtyping is prone to inter-observer variability, and subtyping definitions are inconsistently applied. This study sought to compare the interobserver reproducibility of individual BCC subtypes using the 4th edition World Health Organization (WHO) Classification of Skin Tumours (CoST) definitions, with classification into lower and higher risk histological subtype groups.

Molecular and clinical correlates of HER3 expression highlights its potential role as a therapeutic target in melanoma.

Overexpression of the epidermal growth factor receptor family member HER3 (erbB3) has been implicated in several types of cancer and recently drugs targeting HER3 have shown promising clinical activity. In melanoma, HER3 overexpression has been linked to both metastasis formation and resistance to drug therapy in cell culture models. Here, we sought to characterise the expression of HER3 in 187 melanoma biopsies (149 cutaneous, 38 mucosal) using immunohistochemistry, as well as to analyse the association between HER3 expression and molecular, clinical and pathological variables.

IFN-γ signature enables selection of neoadjuvant treatment in patients with stage III melanoma.

Neoadjuvant ipilimumab + nivolumab has demonstrated high pathologic response rates in stage III melanoma. Patients with low intra-tumoral interferon-γ (IFN-γ) signatures are less likely to benefit. We show that domatinostat (a class I histone deacetylase inhibitor) addition to anti-PD-1 + anti-CTLA-4 increased the IFN-γ response and reduced tumor growth in our murine melanoma model, rationalizing evaluation in patients.

In vivo reflectance confocal microscopy can detect the invasive component of lentigo maligna melanoma: Prospective analysis and case-control study.

Background: Lentigo maligna (LM), a form of melanoma in situ, has no risk of causing metastasis unless dermal invasive melanoma (LMM) supervenes. Furthermore, the detection of invasion impacts prognosis and management.

Objective: To assess the accuracy of RCM for the detection of invasion component on LM/LMM lesions.

Melanomas in children and adolescents: Clinicopathologic features and survival outcomes.

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).

Distinct pretreatment innate immune landscape and posttreatment T cell responses underlie immunotherapy-induced colitis.

Immune-related adverse events represent a major hurdle to the success of immunotherapy. The immunological mechanisms underlying their development and relation to antitumor responses are poorly understood. By examining both systemic and tissue-specific immune changes induced by combination anti-CTLA-4 and anti-PD-1 immunotherapy, we found distinct repertoire changes in patients who developed moderate-severe colitis, irrespective of their antitumor response to therapy.

Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes.

Unlabelled: Melanoma is a cancer of melanocytes, with multiple subtypes based on body site location. Cutaneous melanoma is associated with skin exposed to ultraviolet radiation; uveal melanoma occurs in the eyes; mucosal melanoma occurs in internal mucous membranes; and acral melanoma occurs on the palms, soles, and nail beds. Here, we present the largest whole-genome sequencing study of melanoma to date, with 570 tumors profiled, as well as methylation and RNA sequencing for subsets of tumors.

Unveiling the tumor immune microenvironment of organ-specific melanoma metastatic sites.

Background: The liver is a known site of resistance to immunotherapy and the presence of liver metastases is associated with shorter progression-free and overall survival (OS) in melanoma, while lung metastases have been associated with a more favorable outcome. There are limited data available regarding the immune microenvironment at different anatomical sites of melanoma metastases. This study sought to characterize and compare the tumor immune microenvironment of liver, brain, lung, subcutaneous (subcut) as well as lymph node (LN) melanoma metastases.

Diagnostic utility of PRAME, p53 and 5-hmC immunostaining for distinguishing melanomas from naevi, neurofibromas, scars and other histological mimics.

High expression of PRAME (PReferentially expressed Antigen in MElanoma) and p53 (a proposed marker of desmoplastic melanoma) and low expression of 5-hydroxymethylcytosine (5-hmC) have each been reported in melanoma. However, their combined diagnostic utility for distinguishing melanomas, including uncommon variants, from histological mimics is unknown. This study sought to determine the utility of PRAME, p53 and 5-hmC immunostains for diagnosing melanocytic tumours.

Personalized response-directed surgery and adjuvant therapy after neoadjuvant ipilimumab and nivolumab in high-risk stage III melanoma: the PRADO trial.

Neoadjuvant ipilimumab and nivolumab induces high pathologic response rates (pRRs) in clinical stage III nodal melanoma, and pathologic response is strongly associated with prolonged relapse-free survival (RFS). The PRADO extension cohort of the OpACIN-neo trial ( NCT02977052 ) addressed the feasibility and effect on clinical outcome of using pathologic response after neoadjuvant ipilimumab and nivolumab as a criterion for further treatment personalization. In total, 99 patients with clinical stage IIIb-d nodal melanoma were included and treated with 6 weeks of neoadjuvant ipilimumab 1 mg kg and nivolumab 3 mg kg.

Comprehensive Clinical, Histopathologic, and Molecular Analysis and Long-term Follow-up of Patients With Nodal Blue Nevi.

Blue nevi are benign, melanocytic neoplasms that show a range of clinical and morphologic patterns and include common/dendritic, cellular, and atypical cellular subtypes. Like other nevi, they most commonly occur in skin but can occasionally involve lymph nodes where they may be misinterpreted as representing metastatic melanoma. Moreover, whether benign blue nevi can metastasize to lymph nodes and their natural history and prognostic significance has been the subject of great controversy.

Pathologist initiated reflex BRAF mutation testing in metastatic melanoma: experience at a specialist melanoma treatment centre.

Testing for BRAF mutations in metastatic melanoma is pivotal to identifying patients suitable for targeted therapy and influences treatment decisions regarding single agent versus combination immunotherapy. Knowledge of BRAF V600E immunohistochemistry (IHC) results can streamline decisions during initial oncology consultations, prior to DNA-based test results. In the absence of formal guidelines that require pathologist initiated ('reflex') BRAF mutation testing, our institution developed a local protocol to perform BRAF V600E IHC on specimens from all stage III/IV melanoma patients when the status is otherwise unknown.

Representativeness of the Index Lymph Node for Total Nodal Basin in Pathologic Response Assessment After Neoadjuvant Checkpoint Inhibitor Therapy in Patients With Stage III Melanoma.

Importance: Neoadjuvant checkpoint inhibition in patients with high-risk stage III melanoma shows high pathologic response rates associated with a durable relapse-free survival. Whether a therapeutic lymph node dissection (TLND) can be safely omitted when a major pathologic response in the largest lymph node metastasis at baseline (index lymph node; ILN) is obtained is currently being investigated. A previous small pilot study (n = 12) showed that the response in the ILN may be representative of the pathologic response in the entire TLND specimen.

The progressive relationship between increasing Breslow thickness and decreasing survival is lost in patients with ultrathick melanomas (≥15 mm in thickness).

Background: Survival tends to decrease as the Breslow thickness of a primary melanoma increases. However, little is known about the prognostic value of Breslow thickness in patients with very thick melanomas.

Objective: We sought to assess survival in patients with melanomas ≥4.

BRAF mutation testing for patients diagnosed with stage III or stage IV melanoma: practical guidance for the Australian setting.

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.

Road to Metastasis: The TWEAK Pathway as a Discriminant between Metastasizing and Non-Metastasizing Thick Melanomas.

Cutaneous melanoma (CM) is the most aggressive form of skin cancer, and its worldwide incidence is rapidly increasing. Early stages can be successfully treated by surgery, but once metastasis has occurred, the prognosis is poor. However, some 5-10% of thick (≥2 mm) melanomas do not follow this scenario and run an unpredictable course.

Melanoma with osseous or chondroid differentiation: a report of eight cases including SATB2 expression and mutation analysis.

Melanoma can present with osteocartilaginous differentiation, however few reports exist on this rare subtype. We present eight cases of melanoma with osteocartilaginous differentiation to highlight its clinical, pathological and molecular features. The cases showed no association with gender (5 males and 3 females) or age (range 23-84 years).

Mucosal Melanoma: A Review Emphasizing the Molecular Landscape and Implications for Diagnosis and Management.

Mucosal melanomas are rare, often aggressive tumors that can arise at any mucosal site but most frequently occur in the head and neck, vulvovaginal, and anorectal regions. They have distinct biological, clinical, and histopathologic features, which have important management implications. Recent whole-genome sequencing studies have led to a greater understanding of the molecular landscape of mucosal melanomas and uncovered oncogenic drivers that could potentially be susceptible to therapeutic manipulation.