Richard A. Scolyer

The Melanoma Institute Australia (MIA) sentinel node (SN) metastasis risk calculator provides estimates of positivity for individual patients based on 6 standard clinicopathological parameters and the full 6-parameter model has been externally validated previously using US data. However, given its geographically widespread use, further validation is required to ensure its applicability to other populations. To further externally validate the MIA SN metastasis risk calculator and increase its precision by refinement of the 95% CIs. A retrospective multicenter cohort study was carried out using data from 4 continents, including the national Danish Melanoma Database and cancer centers in the UK (n = 3), US (n = 2), New Zealand (n = 1), Sweden (n = 1), and Brazil (n = 1). All patients aged 18 years or older who had an SN biopsy performed for an invasive primary cutaneous melanoma and data available on the following parameters: SN status, patient age at diagnosis, Breslow thickness, and melanoma subtype were included (n = 15 731). Available data were also collected on ulceration status, lymphovascular invasion, and the tumor mitotic rate. Data were collected between July 2021 and December 2023, and the analysis was conducted between January 2024 and June 2024. The primary outcome was the area under the curve (AUC) of the receiver operating characteristics for the full (6-parameter) risk prediction model. Secondary outcomes were the AUCs for each country and for the limited models (3-5 parameters), the model calibration, and the recalculated 95% CIs for the models. Decision curve analysis was performed to assess the tool's clinical utility. The whole pooled cohort consisted of 15 731 patients; 4989 had all 6 parameters available. The AUC was 73.0% (95% CI, 70.6%-75.3%) in the subset with all 6 parameters available, and 70.8%, 71.5%, and 70.1% when 1, 2, or 3 optional parameters were missing, respectively. Calibration was excellent, with an intercept and calibration slope of 0.01 (95% CI, -0.02 to 0.03) and 1.03 (95% CI, 0.90-1.16), respectively. The updated 95% CI ranges were substantially tighter, with a median reduction of more than 75%. This study found that the MIA SN-positivity calculator performed best with all 6 parameters and has been significantly improved (version 2), with the same risk point estimates but much tighter 95% CIs. These results demonstrated that the calculator was robust, precise, and applicable to geographically widespread melanoma populations.

Primary cutaneous neoplasms that lack definitive histologic and immunophenotypic evidence of differentiation are a heterogeneous group of tumors with diverse prognoses and management options. These include undifferentiated and dedifferentiated melanoma (UM/DM), atypical fibroxanthoma (AFX), pleomorphic dermal sarcoma (PDS), and sarcomatoid squamous cell carcinoma. Diagnosis requires careful correlation between the clinicopathologic and molecular features, and the finding of a MAPK pathway variant commonly associated with melanoma may support the diagnosis of melanoma over other tumors in this group. To examine the frequency of typical melanoma-associated MAPK pathway-related variants (BRAF, NRAS, KIT, GNAQ, GNA11) among a cohort of primary cutaneous sarcomatoid neoplasms, we conducted a retrospective analysis of 37 cases of immunohistologically unclassifiable primary cutaneous neoplasms, submitted for targeted NGS analysis. All cases lacked a history of a prior relevant tumor, were negative for melanocytic markers (S100, SOX10, HMB45, and Melan-A), or showed <5% staining with 1 or 2 of these markers. Other lineage markers were negative. We identified typical melanoma driver variants in 7 cases (7/37, 19%), including NRAS (5/37, 14%), KIT (1/37, 3%), and GNAQ (1/37, 3%). There were no significant differences in age, sex, tumor site, or mitotic rate between patients with and without a melanoma driver variant. Melanoma cases were thicker (16.3 vs. 9.25 mm, P=0.041) and more likely to show epithelioid cell phenotype (P=0.008). In our cohort, nearly 20% of patients with immunohistologically unclassifiable cutaneous tumors could be reclassified as having primary UM/DM after molecular testing, thereby opening alternative management pathways.

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. All patients underwent baseline and preoperative FDG-PET and CT assessments, and all had surgery. Pathological response was determined using the International Neoadjuvant Melanoma Consortium criteria, radiological response using Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and FDG-PET response using European Organization for Research and Treatment of Cancer (EORTC) criteria. The primary endpoint was to explore the associations of metabolic and radiological responses with pathological response; secondary endpoints were RFS outcomes stratified by each response category. Results: 115 patients were included, 69% male, median age 59 years (27-92), 43% BRAF mutant, and median follow-up was 22.2 months (95% CI 13.7 to 26.4). 40 patients received anti-PD-1 monotherapy, 20 patients received pembrolizumab combined with lenvatinib, and 55 patients received ipilimumab and nivolumab. The major pathological response (MPR) rate was 62%, and the pathological complete response rate was 51%. RECIST response underestimated pathological response; patients achieving RECIST stable disease (38%) had a 50% chance of achieving MPR. The FDG-PET metabolic response rate was 73%, with most achieving an MPR (80%), especially in patients with a complete metabolic response (CMR, 96% MPR). A small proportion of patients (10%) had stable metabolic disease on FDG-PET, and all these patients were non-MPR. Patients with progressive metabolic disease were also in the majority non-MPR (79%). Patients with MPR, complete response/partial response on CT, and CMR/partial metabolic response on FDG-PET had a favorable 24-month RFS (95.6%, 97.3%, and 93.7%, respectively), with FDG-PET able to identify a greater proportion of patients with favorable progression-free survival (PFS) than pathology or CT (73%, 62%, and 43%, respectively). Conclusions: Neoadjuvant immunotherapy has high FDG-PET response rates in melanoma. FDG-PET response associates with pathological response and confers impressive RFS, suggesting this could be an important clinical tool.

Objective: This study examines whether wide local excision (WLE) after complete diagnostic excision improves recurrence-free survival (RFS) in clinical stage I/II primary cutaneous melanoma. Background: Since the 1950s, melanoma treatment has included a two-step surgical approach, involving diagnostic excision followed by WLE. WLE aims to achieve locoregional disease control by eliminating potential microsatellites and, thus, minimising the risk of locoregional recurrence and melanoma-related death. However, its impact on RFS is unclear, while it adds morbidity and costs. Methods: This retrospective nationwide cohort study analysed pathology reports of a Dutch population-based cohort of newly diagnosed invasive cutaneous melanoma patients who underwent a complete diagnostic excision between January 1st, 2012, and December 31st, 2013. Data were obtained from the Dutch Nationwide Pathology Database (PALGA). Patients with completely excised superficial spreading and nodular melanoma located on the trunk and upper and lower extremities were included. Cox regression showed no significant RFS benefit from WLE. Results: A total of 6189 eligible patients were included. WLE was not performed in 271 patients (4.4 %). Of those undergoing WLE (n = 5918), residual dermal invasive tumour cells were identified in 0.7 % (n = 44/5918). The overall recurrence rate was 7.7 % (n = 477/6189). Recurrence rates were 7.6 % for WLE cases (local: 2.5 %, nodal: 4.0 %, distant: 1.2 %) and 10.3 % when WLE was omitted. Cox regression showed no significant RFS benefit from WLE. Conclusions: WLE does not significantly improve RFS in patients with completely excised cutaneous superficial spreading and nodular melanoma on the trunk or extremities.

Background: A diagnosis of melanoma in situ presents negligible risk to a person's lifespan or physical well-being, but existing terminology makes it difficult for patients to distinguish these from higher risk invasive melanomas. This study aims to explore whether using an alternative label for melanoma in situ may influence patients' management choices and anxiety levels. Methods: This study is a between-subjects randomised online experiment, using hypothetical scenarios. Following consent, eligible participants will be randomised 1:1:1 to three labels: 'melanoma in situ' (control), 'low-risk melanocytic neoplasm' (intervention 1) and 'low-risk melanocytic neoplasm, in situ' (intervention 2). The required sample size is 1668 people. The co-primary outcomes are (1) choice between no further surgery or further surgery to ensure clear histological margins greater than 5 mm and (2) choice between patient-initiated clinical follow-up when needed (patient-led surveillance) and regular routinely scheduled clinical follow-up (clinician-led surveillance). Secondary outcomes include diagnosis anxiety, perceived risk of invasive melanoma and of dying from melanoma and management choice anxiety (after surgery choice and follow-up choice). We will make pairwise comparisons across the three diagnostic label groups using regression models (univariable and multivariable). Background: The study has been registered with the Australian New Zealand Clinical Trials Registry (ACTRN12624000740594). Ethics approval has been received from The University of Sydney Human Research Ethics Committee (2024/HE000019). The results of the study will be published in a peer-reviewed medical journal, and a plain language summary of the findings will be shared on the Wiser Healthcare publication page (https://www.wiserhealthcare.org.au/category/publications/). Background: Australian New Zealand Clinical Trials Registry (ID 386943).

Molecular Profiling and Matched Targeted Therapy for Patients With Metastatic Melanoma