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Background: Regional nodal metastases from cutaneous squamous cell carcinoma (cSCC) is strongly associated with a poor prognosis, but these metastases are difficult to predict clinically. Sentinel node biopsy (SNB) has been used for a wide range of malignancies to assess for regional nodal metastasis, but is not widely used for cSCC., Methods: Patients presenting with high-risk cSCC of the head and neck with clinically N0 necks were offered SNB at the time of primary cSCC excision or secondary wide local excision. Patients with positive sentinel nodes were offered completion lymph node dissection, and all the patients were followed up at regular intervals for up to 5 years., Results: In this study, 105 lesions underwent SNB, and 10 sentinel nodes (9.5%) were positive. In an additional five patients, regional recurrence developed after a negative sentinel node, with a total subclinical nodal metastasis rate of 14.3%. Nodal metastases were significantly associated with reduced disease-specific survival. The significant predictors of metastasis were four or more high-risk features or tumors with a concurrent invasion deeper than 5 mm and PNI., Conclusion: For high-risk cSCC, SNB is a safe and feasible staging technique. The total number of high risk features and certain combinations of high-risk features predicted metastasis better than individual high-risk features.

Background: Extirpation of malignant tumors of the parotid results in creation of a complex facial defect often in combination with facial nerve palsy. This study presents the authors' experience using vastus lateralis muscle as a chimeric flap with anterolateral thigh flap to allow both soft-tissue reconstruction and dynamic reanimation in radical parotidectomy., Methods: A retrospective review of the medical records of cancer patients who had undergone radical parotidectomy and reconstruction using a chimeric vastus lateralis and anterolateral thigh flap between March of 2013 and May of 2017 was performed using the Sydney Head and Neck Cancer Institute database. The return of dynamic midface movement was the primary outcome investigated. Electronic, clinician-graded facial function scale grades were used to formally assess postoperative outcomes., Results: A total of 27 patients were included in the study with an average age of 72 years (range, 31 to 88 years). Thirteen patients (48 percent) had developed dynamic function by the end of the study period. Young age predicted a more rapid return to dynamic function (p = 0.018). Both being a woman and having an intact facial nerve before surgery improved dynamic midface movement (p = 0.005 and p = 0.036, respectively). On multivariable analysis, superior midface dynamic function was associated with neurotization using midface facial nerve branches as opposed to using nerve-to-masseter alone (p = 0.05)., Conclusion: The chimeric vastus lateralis and anterolateral thigh flap is a suitable option for restoring defects and dynamic function following radical parotidectomy., Clinical Question/level of Evidence: Therapeutic, IV.

Background: The outcome of patients with macroscopic stage III melanoma is poor. Neoadjuvant treatment with ipilimumab plus nivolumab at the standard dosing schedule induced pathological responses in a high proportion of patients in two small independent early-phase trials, and no patients with a pathological response have relapsed after a median follow up of 32 months. However, toxicity of the standard ipilimumab plus nivolumab dosing schedule was high, preventing its broader clinical use. The aim of the OpACIN-neo trial was to identify a dosing schedule of ipilimumab plus nivolumab that is less toxic but equally effective., Methods: OpACIN-neo is a multicentre, open-label, phase 2, randomised, controlled trial. Eligible patients were aged at least 18 years, had a WHO performance status of 0-1, had resectable stage III melanoma involving lymph nodes only, and measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1. Patients were enrolled from three medical centres in Australia, Sweden, and the Netherlands, and were randomly assigned (1:1:1), stratified by site, to one of three neoadjuvant dosing schedules: group A, two cycles of ipilimumab 3 mg/kg plus nivolumab 1 mg/kg once every 3 weeks intravenously; group B, two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg once every 3 weeks intravenously; or group C, two cycles of ipilimumab 3 mg/kg once every 3 weeks directly followed by two cycles of nivolumab 3 mg/kg once every 2 weeks intravenously. The investigators, site staff, and patients were aware of the treatment assignment during the study participation. Pathologists were masked to treatment allocation and all other data. The primary endpoints were the proportion of patients with grade 3-4 immune-related toxicity within the first 12 weeks and the proportion of patients achieving a radiological objective response and pathological response at 6 weeks. Analyses were done in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02977052, and is ongoing with an additional extension cohort and to complete survival analysis., Findings: Between Nov 24, 2016 and June 28, 2018, 105 patients were screened for eligibility, of whom 89 (85%) eligible patients were enrolled and randomly assigned to one of the three groups. Three patients were excluded after randomisation because they were found to be ineligible, and 86 received at least one dose of study drug; 30 patients in group A, 30 in group B, and 26 in group C (accrual to this group was closed early upon advice of the Data Safety Monitoring Board on June 4, 2018 because of severe adverse events). Within the first 12 weeks, grade 3-4 immune-related adverse events were observed in 12 (40%) of 30 patients in group A, six (20%) of 30 in group B, and 13 (50%) of 26 in group C. The difference in grade 3-4 toxicity between group B and A was -20% (95% CI -46 to 6; p=0·158) and between group C and group A was 10% (-20 to 40; p=0·591). The most common grade 3-4 adverse events were elevated liver enzymes in group A (six [20%)]) and colitis in group C (five [19%]); in group B, none of the grade 3-4 adverse events were seen in more than one patient. One patient (in group A) died 9·5 months after the start of treatment due to the consequences of late-onset immune-related encephalitis, which was possibly treatment-related. 19 (63% [95% CI 44-80]) of 30 patients in group A, 17 (57% [37-75]) of 30 in group B, and nine (35% [17-56]) of 26 in group C achieved a radiological objective response, while pathological responses occurred in 24 (80% [61-92]) patients in group A, 23 (77% [58-90]) in group B, and 17 (65% [44-83]) in group C., Interpretation: OpACIN-neo identified a tolerable neoadjuvant dosing schedule (group B: two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg) that induces a pathological response in a high proportion of patients and might be suitable for broader clinical use. When more mature data confirm these early observations, this schedule should be tested in randomised phase 3 studies versus adjuvant therapies, which are the current standard-of-care systemic therapy for patients with stage III melanoma., Funding: Bristol-Myers Squibb., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The American Joint Committee on Cancer (AJCC) uses the same nodal staging system for cutaneous and mucosal squamous cell carcinoma of the head and neck in its 8th edition (AJCC 8) despite differences in the etiology, risk factors, and clinical behavior of the two diseases. This study aims to evaluate the performance of the AJCC 8 nodal staging system by direct comparison of cutaneous (cSCC) versus oral squamous cell carcinoma (oSCC) patients., Methods: Patients with metastatic cSCC (N = 382) and oSCC (N = 325) were identified from a prospective database (years 1987-2016). Multivariable analysis was performed using Cox proportional hazards competing risk model. To assess staging system performance, an explained variation measure (proportion of variation explained, PVE) as well as a discrimination measure (Harrell's concordance index, C-index) were used., Results: Inclusion of extranodal extension (ENE) in AJCC 8 increased the proportion of patients in N3b category (48.7% in cSCC, 40.3% in oSCC). AJCC 8 stratified poorly with regards to risk of death from cSCC and oSCC and showed limited monotonicity of the nodal categories. Estimates of model performance revealed modest predictive capacity for overall survival (OS) and disease-specific survival (DSS) in oSCC (Harrell's C of 0.66 in both) and weak predictive capacity in cSCC (Harrell's C of 0.58 and 0.61, respectively)., Conclusions: The AJCC 8 nodal staging system performs poorly in terms of stratifying survival by N category, especially in cSCC. The data indicate that cSCC merits an independent nodal staging system from that for mucosal SCC.

Cutaneous squamous cell carcinoma is the second most prevalent malignancy, most frequently occurring in the head and neck (head and neck cutaneous squamous cell carcinoma). Treatment of locally advanced or metastatic disease is associated with functional morbidity and disfigurement. Underlying genetic mechanisms are poorly understood. Targeted sequencing of 48 clinically relevant genes was performed on DNA extracted from formalin-fixed and paraffin-embedded high-risk primary head and neck cutaneous squamous cell carcinomas that remained non-metastatic at minimum follow-up of 24 months. Associations of somatic mutations with clinicopathologic characteristics were evaluated and compared with those described in the literature for metastatic disease. Alterations in 44 cancer-associated genes were identified. TP53 was mutated in 100% of cases; APC, ATM, ERBB4, GNAQ, KIT, RB1 and ABL1 were altered in 60% of cases. FGFR2 mutations (40%) were exclusively seen in patients with perineural invasion. MLH1 mutations were exclusively seen in the two younger patients (<45 years). Lower incidences of NOTCH1 mutations were observed compared with that described in metastatic head and neck cutaneous squamous cell carcinoma in the literature. Somatic mutations susceptible to EGFR inhibitors, and other small molecular targeted therapeutics were seen in 60% of cases. This study provides insights into somatic mutations in non-metastatic, high-risk head and neck cutaneous squamous cell carcinoma and identifies potential therapeutic targets. Alterations in FGFR2 and NOTCH1 may have roles in local and distant disease progression.

Programmed cell death (PD-1) and its ligand (PD-L1) inhibitors have shown clinical response in many tumours. PD-L1 data are limited in head and neck cutaneous squamous cell carcinoma (HNcSCC) and no clinical trials of PD-1/PD-L1 inhibitors are published. We performed PD-L1 immunohistochemistry on 74 cases of high risk HNcSCC with 38 matched metastases and evaluated clinicopathological associations, prognostic significance and heterogeneity in matched metastases. We observed PD-L1 expression in >5% of primary tumour cells in 29 cases (39.2%), primary tumour infiltrating lymphocytes (TILs) in 40 cases (70.2%), metastatic tumour cells in 15 cases (39.5%), and metastatic TILs in 18 cases (47.4%). PD-L1 expression in >5% of primary tumour cells was associated with an inflammatory phenotype (p = 0.04), and in primary TILs with clear margins (p = 0.05). PD-L1 expression in >5% of primary tumour cells (p = 0.01), primary TILs (p = 0.001), and metastatic TILs (p = 0.02) was associated with improved disease free survival. PD-L1 expression in >5% of tumour cells was heterogeneous between primary and metastatic tumours in 13 cases (34.2%). PD-L1 expression is common in HNcSCC supporting the rationale for a clinical trial of PD-1/PD-L1 inhibitors. PD-L1 expression in tumour cells or TILs predicts longer disease free survival and demonstrates temperospatial heterogeneity., (Copyright © 2017 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)