A Review of Contemporary Guidelines and Evidence for Wide Local Excision in Primary Cutaneous Melanoma Management.

Surgical wide local excision (WLE) remains the current standard of care for primary cutaneous melanoma. WLE is an elective procedure that aims to achieve locoregional disease control with minimal functional and cosmetic impairment. Despite several prospective randomised trials, the optimal extent of excision margin remains controversial, and this is reflected in the persistent lack of consensus in guidelines globally. Furthermore, there is now the added difficulty of interpreting existing trial data in the context of the evolving role of surgery in the management of melanoma, with our increased understanding of clinicopathologic and genomic prognostic markers leading to the often routine use of sentinel node biopsy (SNB) as a staging procedure, in addition to the development of adjuvant systemic therapies for high-risk disease. An ongoing trial, MelMarT-II, has been designed with the aim of achieving a definitive answer to guide this fundamental surgical decision.

Risk Stratification of Sentinel Node Metastasis Disease Burden and Phenotype in Stage III Melanoma Patients.

BACKGROUND: Currently, all patients with American Joint Committee on Cancer (AJCC) pT2b-pT4b melanomas and a positive sentinel node biopsy are now considered for adjuvant systemic therapy without consideration of the burden of disease in the metastatic nodes. METHODS: This was a retrospective cohort analysis of 1377 pT1-pT4b melanoma patients treated at an academic cancer center. Standard variables regarding patient, primary tumor, and sentinel node characteristics, in addition to sentinel node metastasis maximum tumor deposit size (MTDS) in millimeters and extracapsular spread (ECS) status, were analyzed for predicting disease-specific survival (DSS). RESULTS: The incidence of SN+ was 17.3% (238/1377) and ECS was 10.5% (25/238). Increasing AJCC N stage was associated with worse DSS. There was no difference in DSS between the IIIB and IIIC groups. Subgroup analyses showed that the optimal MTDS cut-point was 0.7 mm for the pT1b-pT4a SN+ subgroups, but there was no cut-point for the pT4b SN+ subgroup. Patients with MTDS <0.7 mm and no ECS had similar survival outcomes as the N0 patients with the same T stage. Nodal risk categories were developed using the 0.7 mm MTDS cut-point and ECS status. The incidence of low-risk disease, according to the new nodal risk model, was 22.3% (53/238) in the stage III cohort, with 49% (26/53) in the pT2b-pT3a and pT3b-pT4a subgroups and none in the pT4b subgroup. Similar outcomes were observed for overall and distant metastasis-free survival. CONCLUSION: We propose a more granular classification system, based on tumor burden and ECS status in the sentinel node, that identifies low-risk patients in the AJCC IIIB and IIIC subgroups who may otherwise be observed.

Follow-up Schedule for Patients With Sentinel Node-negative Cutaneous Melanoma (The MELFO Study): An International Phase III Randomized Clinical Trial.

OBJECTIVES AND DESIGN: The MELFO (MELanoma FOllow-up) study is an international phase III randomized controlled trial comparing an experimental low-intensity schedule against current national guidelines. BACKGROUND: Evidence-based guidelines for the follow-up of sentinel node-negative melanoma patients are lacking. METHODS: Overall, 388 adult patients diagnosed with sentinel node-negative primary melanoma patients were randomized in cancer centers in the Netherlands and United Kingdom between 2006 and 2016. The conventional schedule group (control: n=196) was reviewed as per current national guidelines. The experimental schedule group (n=192) was reviewed in a reduced-frequency schedule. Quality of life was the primary outcome measurement. Detection rates and survival outcomes were recorded. Patient satisfaction rates and compliance with allocated schedules were compared. RESULTS: At 5 years, both arms expressed high satisfaction with their regimens (>97%). This study found no significant group effect on any patient-reported outcome measure scores between the follow-up protocols. In total, 75/388 (19.4%) patients recurred, with no difference in incidence found between the 2 arms (hazard ratio=0.87, 95% confidence interval: 0.54-1.39, P =0.57). Self-examination was the method of detection for 25 experimental patients and 32 control patients (75.8% vs. 76.2%; P =0.41). This study found no difference in any survival outcomes between the 2 study arms (disease-free survival: hazard ratio=1.00, 95% confidence interval: 0.49-2.07, P =0.99). CONCLUSIONS: A reduced-intensity, American Joint Committee on Cancer (AJCC) stage-adjusted follow-up schedule for sentinel node-negative melanoma patients is a safe strategy, and patient self-examination is effective for recurrence detection with no evidence of diagnostic delay. Patients' acceptance is very high.

Clinical Outcomes and Risk Stratification of Early-Stage Melanoma Micrometastases From an International Multicenter Study: Implications for the Management of American Joint Committee on Cancer IIIA Disease.

PURPOSE: Indications for offering adjuvant systemic therapy for patients with early-stage melanomas with low disease burden sentinel node (SN) micrometastases, namely, American Joint Committee on Cancer (AJCC; eighth edition) stage IIIA disease, are presently controversial. The current study sought to identify high-risk SN-positive AJCC stage IIIA patients who are more likely to derive benefit from adjuvant systemic therapy. METHODS: Patients were recruited from an intercontinental (Australia/Europe/North America) consortium of nine high-volume cancer centers. All were adult patients with pathologic stage pT1b/pT2a primary cutaneous melanomas who underwent SN biopsy between 2005 and 2020. Patient data, primary tumor and SN characteristics, and survival outcomes were analyzed. RESULTS: Three thousand six hundred seven patients were included. The median follow-up was 34 months. Pairwise disease comparison demonstrated no significant survival difference between N1a and N2a subgroups. Survival analysis identified a SN tumor deposit maximum dimension of 0.3 mm as the optimal cut point for stratifying survival. Five-year disease-specific survival rates were 80.3% and 94.1% for patients with SN metastatic tumor deposits ≥ 0.3 mm and < 0.3 mm, respectively (hazard ratio, 1.26 [1.11 to 1.44]; P < .0001). Similar findings were seen for overall disease-free and distant metastasis-free survival. There were no survival differences between the AJCC IB patients and low-risk (< 0.3 mm) AJCC IIIA patients. The newly identified high-risk (≥ 0.3 mm) subgroup comprised 271 (66.4%) of the AJCC IIIA cohort, whereas only 142 (34.8%) patients had SN tumor deposits > 1 mm in maximum dimension. CONCLUSION: Patients with AJCC IIIA melanoma with SN tumor deposits ≥ 0.3 mm in maximum dimension are at higher risk of disease progression and may benefit from adjuvant systemic therapy or enrollment into a clinical trial. Patients with SN deposits < 0.3 mm in maximum dimension can be managed similar to their SN-negative, AJCC IB counterparts, thereby avoiding regular radiological surveillance and more intensive follow-up.

Evaluation of the Indications for Sentinel Node Biopsy in Early-Stage Melanoma with the Advent of Adjuvant Systemic Therapy: An International, Multicenter Study.

BACKGROUND: Patients presenting with early-stage melanoma (AJCC pT1b-pT2a) reportedly have a relatively low risk of a positive SNB (~5-10%). Those patients are usually found to have low-volume metastatic disease after SNB, typically reclassified to AJCC stage IIIA, with an excellent prognosis of ~90% 5-year survival. Currently, adjuvant systemic therapy is not routinely recommended for most patients with AJCC stage IIIA melanoma. The purpose was to assess the SN-positivity rate in early-stage melanoma and to identify primary tumor characteristics associated with high-risk nodal disease eligible for adjuvant systemic therapy METHODS: An international, multicenter retrospective cohort study from 7 large-volume cancer centers identified 3,610 patients with early primary cutaneous melanomas 0.8-2.0 mm in Breslow thickness (pT1b-pT2a; AJCC 8th edition). Patient demographics, primary tumor characteristics, and SNB status/details were analyzed. RESULTS: The overall SNB-positivity rate was 11.4% (412/3610). Virtually all SNB-positive patients (409/412; 99.3%) were reclassified to AJCC stage IIIA. Multivariate analysis identified age, T-stage, mitotic rate, primary site and subtype, and lymphovascular invasion as independent predictors of sentinel node status. A mitotic rate of >1/mm2 was associated with a significantly increased SN-positivity rate and was the only significant independent predictor of high-risk SNB metastases (>1 mm maximum diameter). CONCLUSIONS: The new treatment paradigm brings into question the role of SNB for patients with early-stage melanoma. The results of this large international cohort study suggest that a reevaluation of the indications for SNB for some patients with early-stage melanoma is required.

PGC-1α induced mitochondrial biogenesis in stromal cells underpins mitochondrial transfer to melanoma.

INTRODUCTION: Progress in the knowledge of metabolic interactions between cancer and its microenvironment is ongoing and may lead to novel therapeutic approaches. Until recently, melanoma was considered a glycolytic tumour due to mutations in mitochondrial-DNA, however, these malignant cells can regain OXPHOS capacity via the transfer of mitochondrial-DNA, a process that supports their proliferation in-vitro and in-vivo. Here we study how melanoma cells acquire mitochondria and how this process is facilitated from the tumour microenvironment. METHODS: Primary melanoma cells, and MSCs derived from patients were obtained. Genes' expression and DNA quantification was analysed using Real-time PCR. MSC migration, melanoma proliferation and tumour volume, in a xenograft subcutaneous mouse model, were monitored through bioluminescent live animal imaging. RESULTS: Human melanoma cells attract bone marrow-derived stromal cells (MSCs) to the primary tumour site where they stimulate mitochondrial biogenesis in the MSCs through upregulation of PGC1a. Mitochondria are transferred to the melanoma cells via direct contact with the MSCs. Moreover, inhibition of MSC-derived PGC1a was able to prevent mitochondrial transfer and improve NSG melanoma mouse tumour burden. CONCLUSION: MSC mitochondrial biogenesis stimulated by melanoma cells is prerequisite for mitochondrial transfer and subsequent tumour growth, where targeting this pathway may provide an effective novel therapeutic approach in melanoma.

Machine-learning algorithm to predict multidisciplinary team treatment recommendations in the management of basal cell carcinoma.

BACKGROUND: Basal cell carcinoma (BCC) is the most common human cancer. Facial BCCs most commonly occur on the nose and the management of these lesions is particularly complex, given the functional and complex implications of treatment. Multidisciplinary team (MDT) meetings are routinely held to integrate expertise from dermatologists, surgeons, oncologists, radiologists, pathologists and allied health professionals. The aim of this research was to develop a supervised machine-learning algorithm to predict MDT recommendations for nasal BCC to potentially reduce MDT caseload, provide automatic decision support and permit data audit in a health service context. METHODS: The study population included all consecutive patients who were discussed at skin cancer-specialised MDT (SSMDT) with a diagnosis of nasal BCC between January 1, 2015 and December 31, 2015. We conducted analyses for gender, age, anatomical location, histological subtype, tumour size, tumour recurrence, anticoagulation, pacemaker, immunosuppressants and therapeutic modalities (Mohs surgery, conventional excision or radiotherapy). We used S-statistic computing language to develop a supervised machine-learning algorithm. RESULTS: We found that 37.5% of patients could be reliably predicted to be triaged to Mohs micrographic surgery (MMS), based on tumour location and age. Similarly, the choice of conventional treatment (surgical excision or radiotherapy) by the MDT could be reliably predicted based on the patient's age, tumour phenotype and lesion size. Accordingly, the algorithm reliably predicted the MDT decision outcome of 45.1% of nasal BCCs. CONCLUSIONS: Our study suggests that the machine-learning approach is a potentially useful tool for predicting MDT decisions for MMS vs conventional surgery or radiotherapy for a significant group of patients. We suggest that utilising this algorithm gives the MDT more time to consider more complex patients, where multiple factors, including recurrence, financial costs and cosmetic outcome, contribute to the final decision, but cannot be reliably predicted to determine that outcome. This approach has the potential to reduce the burden and improve the efficiency of the specialist skin MDT and, in turn, improve patient care, reduce waiting times and reduce the financial burden. Such an algorithm would need to be updated regularly to take into account any changes in patient referral patterns, treatment options or local clinical expertise. CLINICAL TRIAL REGISTRATION: lPLAS_20-21_A08.

MelRisk: Using neutrophil-to-lymphocyte ratio to improve risk prediction models for metastatic cutaneous melanoma in the sentinel lymph node.

BACKGROUND: Identifying metastatic melanoma in the sentinel lymph node (SLN) is important because 80% of SLN biopsies are negative and 11% of patients develop complications. The neutrophil-to-lymphocyte ratio (NLR), a biomarker of micrometastatic disease, could improve prediction models for SLN status. We externally validated existing models and developed 'MelRisk' prognostic score to better predict SLN metastasis. METHODS: The models were externally validated using data from a multicenter cohort study of 1,251 adults. Additionally, we developed and internally validated a new prognostic score `MelRisk', using candidate predictors derived from the extant literature. RESULTS: The Karakousis model had a C-statistic of 0.58 (95% CI, 0.54-0.62). The Sondak model had a C-statistic of 0.57 (95% CI 0.53-0.61). The MIA model had a C-statistic of 0.60 (95% CI. 0.56-0.64). Our 'MelRisk' model (which used Breslow thickness, ulceration, age, anatomical site, and the NLR) showed an adjusted C-statistic of 0.63 (95% CI, 0.56-0.64). CONCLUSION: Our prediction tool is freely available in the Google Play Store and Apple App Store, and we invite colleagues to externally validate its performance .

Mitochondrial oxidative phosphorylation in cutaneous melanoma.

The Warburg effect in tumour cells is associated with the upregulation of glycolysis to generate ATP, even under normoxic conditions and the presence of fully functioning mitochondria. However, scientific advances made over the past 15 years have reformed this perspective, demonstrating the importance of oxidative phosphorylation (OXPHOS) as well as glycolysis in malignant cells. The metabolic phenotypes in melanoma display heterogeneic dynamism (metabolic plasticity) between glycolysis and OXPHOS, conferring a survival advantage to adapt to harsh conditions and pathways of chemoresistance. Furthermore, the simultaneous upregulation of both OXPHOS and glycolysis (metabolic symbiosis) has been shown to be vital for melanoma progression. The tumour microenvironment (TME) has an essential supporting role in promoting progression, invasion and metastasis of melanoma. Mesenchymal stromal cells (MSCs) in the TME show a symbiotic relationship with melanoma, protecting tumour cells from apoptosis and conferring chemoresistance. With the significant role of OXPHOS in metabolic plasticity and symbiosis, our review outlines how mitochondrial transfer from MSCs to melanoma tumour cells plays a key role in melanoma progression and is the mechanism by which melanoma cells regain OXPHOS capacity even in the presence of mitochondrial mutations. The studies outlined in this review indicate that targeting mitochondrial trafficking is a potential novel therapeutic approach for this highly refractory disease.

The MelFo Study UK: Effects of a Reduced-Frequency, Stage-Adjusted Follow-Up Schedule for Cutaneous Melanoma 1B to 2C Patients After 3-Years.

BACKGROUND: Evidence-based guidelines for follow-up treatment of American Joint Committee on Cancer (AJCC) stages 1B to 2C melanoma patients are lacking. The MELanoma FOllow-up study is an international phase 3 randomized trial, and the 3-year interim data were recently reported from the Netherlands. The study was undertaken concurrently with a British cohort for comparison and validation of the Dutch study. METHODS: The study enrolled and stratified 207 patients by AJCC stage. The conventional schedule group (CSG; n = 103) cohort was reviewed as per UK guidelines. The experimental schedule group (ESG; n = 104) cohort was reviewed in a reduced-frequency nurse-led, consultant-supervised clinic. Quality of life (QoL) was measured at baseline (T1), a 1 year (T2), and at 3 years (T3) using the State-Trait Anxiety Inventory, the Cancer Worry Scale, the Impact-of-Event Scale, and the Mental and Physical Component scales (PCS/MCS) of the RAND-36. RESULTS: Of the 207 QoL questionnaires, 170 (82.1%) were completed at T3. Both cohorts expressed high satisfaction (> 93%) with their regimens. At T3, no significant group effect was found on any patient-reported outcome measures scores, indicating no QoL difference between the follow-up protocols. Recurrence had developed in 33 patients Conventional follow-up (CFU), 16 [15.5%]; Experimental follow-up (EFU), 17 [16.3%]. Self-examination was the method of detection for 12 ESG patients (70.6%) and 11 CSG patients (68.8%). The melanoma-specific survival was identical. CONCLUSION: The UK 3-year data were consistent with the previous Dutch report. The reduced follow-up strategy was shown to be safe, with significant resource usage benefits for national cancer services. Patient anxiety levels were not increased by a less-intensive follow-up regimen, and acceptance was high. The study data indicate that patient self-examination is very effective for recurrence detection.

Improved Perioperative Seroma and Complication Rates Following the Application of a 2-Layer Negative Pressure Wound Therapy System After Inguinal Lymphadenectomy for Metastatic Cutaneous Melanoma.

BACKGROUND: Perioperative complications following inguinal lymphadenectomy, including seroma formation, are frequent. We have employed a 2-layer negative pressure wound therapy (2-LNPWT) as a method to reduce seroma rate and perioperative complications. We present the outcome of our initial experience with 2-LNPWT and compare the outcomes of its use with traditional closed suction drains (CSDs). MATERIALS AND METHODS: A non-randomised retrospective case-control series was analysed. Surgeons performing inguinal lymphadenectomy for metastatic cutaneous melanoma utilised either the 2-LNPWT therapy or traditional CSDs according to their practice preference. RESULTS: The study included 111 patients. The cohorts were well matched for gender, disease burden, body mass index and comorbidities. The 2-LNPWT technique was associated with significantly better postoperative outcomes than CSD, in terms of incidence of seroma formation (26.9% vs 49.4%; p < 0.03), period of drainage (15 days vs 20 days; p = 0.005) and return to theatre rate (0% vs 15.3%; p = 0.03). The overall seroma rate was 44.1%. The only significant association with seroma initiation was the type of drainage system used (2-LNPWT 31.2% vs CSD 58.3%; p < 0.03; OR 3.0). The method of drainage did not alter the course of an established seroma. There was no significant difference in overall or disease-specific survival detected between the 2 groups. CONCLUSION: This retrospective non-randomised case control study has demonstrated the safe use of a novel application of negative pressure wound therapy that significantly reduced the incidence of seroma formation and postoperative complication rate for inguinal lymphadenectomy for melanoma.

The neutrophil-lymphocyte ratio and locoregional melanoma: a multicentre cohort study.

OBJECTIVES: The neutrophil-lymphocyte ratio (NLR) is an inflammatory biomarker which is useful in cancer prognostication. We aimed to investigate the differences in baseline NLR between patients with localised and metastatic cutaneous melanoma and how this biomarker changed over time with the recurrence of disease. METHODS: This multicentre cohort study describes patients treated for Stage I-III cutaneous melanoma over 10 years. The baseline NLR was measured immediately prior to surgery and again at the time of discharge or disease recurrence. The odds ratios (OR) for sentinel node involvement are estimated using mixed-effects logistic regression. The risk of recurrence is estimated using multivariable Cox regression. RESULTS: Overall 1489 individuals were included. The mean baseline NLR was higher in patients with palpable nodal disease compared to those with microscopic nodal or localised disease (2.8 versus 2.4 and 2.3, respectively; p < 0.001). A baseline NLR ≥ 2.3 was associated with 30% higher odds of microscopic metastatic melanoma in the sentinel lymph node [adjusted OR 1.3 (95% CI 1.3, 1.3)]. Following surgery, 253 patients (18.7%) developed recurrent melanoma during surveillance although there was no statistically significant association between the baseline NLR and the risk of recurrence [adjusted HR 0.9 (0.7, 1.1)]. CONCLUSION: The NLR is associated with the volume of melanoma at presentation and may predict occult sentinel lymph metastases. Further prospective work is required to investigate how NLR may be modelled against other clinicopathological variables to predict outcomes and to understand the temporal changes in NLR following surgery for melanoma.

Survival outcomes and interval between lymphoscintigraphy and SLNB in cutaneous melanoma- findings of a large prospective cohort study.

INTRODUCTION: Sentinel lymph node biopsy (SLNB) in cutaneous melanoma (CM) is performed to identify patient at risk of regional and distant relapse. We hypothesized that timing of lymphoscintigraphy may influence the accuracy of SLNB and patient outcomes. METHODS: We reviewed prospective data on patients undergoing SLNB for CM at a large university cancer-center between 2008 and 2015, examining patient and tumor demographics and time between lymphoscintigraphy (LS) and SLNB. Kaplan-Meier survival analysis assessed disease-specific (DSS) and overall-survival (OS), stratified by timing of LS. Cox multivariate regression analysis assessed independent risk factors for survival. RESULTS: We identified 1015 patients. Median follow-up was 45 months (IQR 26-68 months). Univariate analysis showed a 6.8% absolute DSS (HR 1.6 [1.03-2.48], p = 0.04) benefit and a 10.7% absolute OS (HR 1.64 [1.13-2.38], p = 0.01) benefit for patients whose SLNB was performed < 12 h of LS (n = 363) compared to those performed >12 h (n = 652). Multivariate analysis identified timing of LS as an independent predictor of OS (p = 0.007) and DSS (p = 0.016) when competing with age, sex, Breslow thickness (BT) and SLN status. No difference in nodal relapse rates (5.2% v 4.6%; p = 0.67) was seen. Both groups were matched for age, sex, BT and SLN status. CONCLUSION: These data have significant implications for SLNB services, suggesting delaying SLNB >12 h after LS using a Tc99-labelled nanocolloid has a significant negative survival impact for patients and should be avoided. We hypothesise that temporal tracer migration is the underlying cause and advocate further trials investigating alternative, 'stable' tracer-agents.

Baseline Neutrophil-Lymphocyte and Platelet-Lymphocyte Ratios as Biomarkers of Survival in Cutaneous Melanoma: A Multicenter Cohort Study.

BACKGROUND: In the peripheral blood, the neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) change in response to malignancy. These biomarkers are associated with adverse outcomes in numerous cancers, but the evidence is limited in relation to melanoma. This study sought to investigate the association between these biomarkers and survival in Stages I-III cutaneous melanoma. METHODS: This multicenter cohort study investigated a consecutive series of patients who underwent wide excision of biopsy-proven cutaneous melanoma and sentinel lymph node biopsy during a 10-year period. The baseline NLR and PLR were calculated immediately before sentinel lymph node biopsy. Adjusted hazard ratios (HRs) for overall and melanoma-specific survival were generated. RESULTS: Overall, 1351 patients were included in the study. During surveillance, 184 of these patients died (14%), with 141 of the deaths (77%) attributable to melanoma. Worse overall survival was associated with a baseline NLR lower than 2.5 [HR 2.2; 95% confidence interval (CI) 2.0 to 2.3; p < 0.001] and a baseline PLR lower than 100 (HR 1.8; 95% CI 1.7 to 1.8; p < 0.001). Melanoma-specific survival also was worse, with a baseline NLR lower than 2.5 (HR 1.9; 95% CI 1.6 to 2.2; p < 0.001) and a baseline PLR lower than 100 (HR 1.9; 95% CI 1.7 to 2.2; p < 0.001). The 5-year survival for patients with sentinel lymph node metastases and a low NLR and PLR was approximately 50%. CONCLUSION: This study provides important new data on biomarkers in early-stage melanoma, which contrast with biomarker profiles in advanced disease. These biomarkers may represent the host inflammatory response to melanoma and therefore could help select patients for adjuvant therapy and enhanced surveillance.