Mohs micrographic surgery for the treatment of invasive melanoma: A systematic review with meta-analyses.

BACKGROUND: The use of Mohs micrographic surgery (MMS) in melanoma treatment has divided opinion and evidence-based guidelines are lacking. OBJECTIVES: This systematic review aimed to analyse clinical outcomes for patients with invasive melanomas treated with Mohs rather than wide local excision (WLE). METHODS: Embase, MEDLINE and Cochrane databases (to 30 August 2023) were searched for studies using Mohs to treat invasive melanoma. Outcomes of interest were local recurrence and death from melanoma. RESULTS: Thirty-five articles involving 41,499 patients with invasive melanoma treated with Mohs were identified. Sixteen studies compared Mohs with WLE and 19 were Mohs-only, non-comparative studies. Patients treated with Mohs differed significantly from those undergoing WLE, in particular Mohs patients were older and had thinner melanomas. Two comparative studies using the same data source reported adjusted hazard ratios for melanoma-specific death and both showed no significant difference between Mohs and WLE-treated patients; 0.87 (95% CI 0.55-1.35) and 1.20 (95% CI 0.71-20.36). There was also no statistically significant difference in local recurrence risk; the unadjusted risk ratio for patients treated with Mohs was 0.46 (95% CI 0.14-1.51 p = 0.20) with moderate heterogeneity (I2 = 62%). No studies reported multivariable analyses for risk of local recurrence. Many studies generated from relatively few and often overlapping data sets have reported the use of Mohs to treat patients with invasive melanoma. Fewer studies were comparative between Mohs and WLE and these reported substantially different baseline risks of recurrence and death from melanoma between the groups. Mohs has generally been used for thinner melanomas in older patients; therefore, comparisons based on univariable analyses are likely to have been misleading. CONCLUSIONS: On the basis of currently available data, it is not possible to reliably assess whether outcomes differ if invasive melanomas with comparable features are treated with Mohs or WLE, and randomized trial evidence will be required for reliable conclusions to be reached.

Five-year analysis of neoadjuvant dabrafenib and trametinib for stage III melanoma.

BACKGROUND: Neoadjuvant dabrafenib plus trametinib has a high pathological response rate and impressive short-term survival in patients with resectable stage III melanoma. We report 5-year outcomes from the phase II NeoCombi trial. PATIENTS AND METHODS: NeoCombi (NCT01972347) was a single-arm, open-label, single-centre, phase II trial. Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, American Joint Committee on Cancer seventh edition clinical stage IIIB-C BRAF V600E/K-mutant melanoma and Eastern Cooperative Oncology Group performance status ≤1. Patients received 52 weeks of treatment with dabrafenib 150 mg (orally twice per day) plus trametinib 2 mg (orally once per day), with complete resection of the pre-therapy tumour bed at week 12. RESULTS: Between 20 August 2014 and 19 April 2017, 35 patients were enrolled. At data cut-off (17 August 2021), the median follow-up was 60 months [95% confidence interval (CI) 56-72 months]. Overall, 21 of 35 (60%) patients recurred, including 12 (57%) with first recurrence in locoregional sites (followed by later distant recurrence in 6) and 9 (43%) with first recurrence in distant sites, including 3 in the brain. Most recurrences occurred within 2 years, with no recurrences beyond 3 years. At 5 years, recurrence-free survival (RFS) was 40% (95% CI 27% to 60%), distant metastasis-free survival (DMFS) was 57% (95% CI 42% to 76%), and overall survival was 80% (95% CI 67% to 94%). Five-year survival outcomes were stratified by pathological response: RFS was 53% with pathological complete response (pCR) versus 28% with non-pCR (P = 0.087), DMFS was 59% versus 55% (P = 0.647), and overall survival was 88% versus 71% (P = 0.205), respectively. CONCLUSIONS: Neoadjuvant dabrafenib plus trametinib has high pathological response rates in clinical stage III melanoma, but low rates of RFS, similar to those achieved with adjuvant targeted therapy alone. Patients with a pCR to dabrafenib plus trametinib still had a high risk of recurrence, unlike that seen with immunotherapy where recurrences are rare.

Harold Gillies, pioneer of modern plastic surgery, and Donald Morton, pioneer of modern surgical oncology: Master problem-solvers and surgical role models.

Harold Gillies, plastic surgeon, and Donald Morton, surgical oncologist, were iconic pioneers in their respective fields. Both of them made their mark by identifying crucial practical problems and finding innovative ways of solving them. Gillies grappled with the challenge of restoring form and function to British military personnel injured in World War I, and he set up a dedicated facility for performing this work. He introduced many new reconstructive techniques that became the foundation of the modern specialty of plastic and reconstructive surgery, which he established and nurtured. Morton, in the United States, applied his problem-solving skills to the long-debated question of the best way to manage regional lymph nodes in patients with melanoma. He developed the innovative technique of sentinel lymph node biopsy and initiated large-scale international clinical trials to establish its validity and clinical value. This and other important contributions to the emerging field of surgical oncology earned Morton his reputation as a pioneer and leader of that specialty. The problems that confronted Gillies and Morton were completely different, but both demonstrated remarkable skills as master problem-solvers in their respective fields and made extraordinary contributions to the body of knowledge and welfare of patients. All surgeons must be problem-solvers because every patient who presents for surgical management represents a new problem (or set of problems) to be addressed. As surgeons, we would do well to consider individuals such as Gillies and Morton as role models for our own problem-solving activities in day-to-day clinical practice.

Representativeness of initial skin biopsies showing pure desmoplastic melanoma: implications for management.

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 to the best of our knowledge this has not been previously assessed or quantified. The aim of this study was to assess the concordance of the proportion of desmoplastic melanoma in an initial partial biopsy of PDM with the proportion in the entire tumour following complete excision, in patients with cutaneous melanoma. A secondary aim was to determine how frequently this potentially resulted in a patient not receiving a SLNB. Seventy-eight cases of cutaneous melanoma were identified from the Melanoma Institute Australia (MIA) database and 23 cases from the Memorial Sloan Kettering Cancer Centre (MSKCC), where an initial biopsy contained PDM and a subsequent wide excision had residual invasive melanoma. Clinicopathological features were analysed in all patients, including whether a SLNB was performed, the results of SLNB, and any subsequent recurrence. Ninety percent (91/101) of cases were still classified as PDM in the complete wide excision specimen while 10% (10/101) of cases were reclassified as MDM, which was a significant change in classification of final desmoplastic melanoma subtype (p<0.001). The proportion of desmoplastic melanoma was also significantly different between the initial and excisional biopsies (p=0.004). Forty-eight (48/101) patients had a SLNB, of which two (4.5%) were positive for metastatic melanoma; both cases were PDM in the excision specimen. Of the 10 cases demonstrating MDM in the excision specimen, the initial biopsy was a punch biopsy in six cases, shave biopsy in two cases and subcutaneous tissue was sampled in two patients (one punch biopsy, one incisional biopsy). Four of these 10 patients underwent SLNB which was negative in all cases. Twenty-two patients developed recurrence in the follow-up period (median 30 months, range 1-192 months), three with MDM in their excision specimen. One patient did not have a SLNB and developed regional lymph node recurrence. In this study there was a 10% risk that the percentage of desmoplastic melanoma in an initial biopsy of PDM was not representative of the entire lesion, resulting in reclassification as MDM in the excision specimen. If a SLNB is not performed in such cases, a positive SLNB may be missed (one patient in our study) which could impact treatment options for the patient. We recommend caution in not offering a SLNB in the setting of an initial biopsy of PDM if the biopsy is small compared with the overall lesion. If a SLNB is not procured at the time of wide excision in such cases, the SLNs should still be mapped by lymphoscintigraphy to facilitate careful follow up and to enable earlier detection and treatment of nodal disease.

Hypofractionated or Conventionally Fractionated Adjuvant Radiotherapy After Regional Lymph Node Dissection for High-Risk Stage III Melanoma.

AIMS: Adjuvant radiotherapy can be beneficial after regional lymph node dissection for high-risk stage III melanoma, as it has been shown to reduce the risk of recurrence in the node field. However, the optimal fractionation schedule is unknown and both hypofractionated and conventionally fractionated adjuvant radiotherapy are used. The present study examined the oncological outcomes of these two approaches in patients treated in an era before effective systemic immunotherapy became available. MATERIALS AND METHODS: This retrospective cohort study involved 335 patients with stage III melanoma who received adjuvant radiotherapy after therapeutic regional lymph node dissection for metastatic melanoma between 1990 and 2011. Information on tumour characteristics, radiotherapy doses and fractionation schedules and patient outcomes was retrieved from the institution's database and patients' medical records. RESULTS: Hypofractionated radiotherapy (median dose 33 Gy in six fractions over 3 weeks) was given to 95 patients (28%) and conventionally fractionated radiotherapy (median dose 48 Gy in 20 fractions over 4 weeks) to 240 patients (72%). Five-year lymph node field control rates were 86.0% (95% confidence interval 78.4-94.4%) for the hypofractionated group and 85.5% (95% confidence interval 80.5-90.7%) for the conventional fractionation group (P = 0.87). There were no significant differences in recurrence-free survival (RFS) (41.7%, 95% confidence interval 32.5-53.5 versus 31.9%, 95% confidence interval 26.1-38.9; P = 0.18) or overall survival (41.2%, 95% confidence interval 32.1-52.8 versus 45.0%, 95% confidence interval 38.7-52.4; P = 0.77). On multivariate analysis, extranodal spread was associated with decreased RFS (P = 0.04) and the number of resected lymph nodes containing metastatic melanoma was associated with decreased RFS (P = 0.0006) and overall survival (P = 0.01). CONCLUSION: Lymph node field control rates, RFS and overall survival were similar after hypofractionated and conventionally fractionated adjuvant radiotherapy. The presence of extranodal spread and an increasing number of positive lymph nodes were predictive of an unfavourable outcome.

Predicting recurrence in patients with sentinel node-negative melanoma: validation of the EORTC nomogram using population-based data.

BACKGROUND: Identifying patients with sentinel node (SN)-negative melanoma who are at greatest risk of recurrence is important. The European Organization for Research and Treatment of Cancer (EORTC) Melanoma Group proposed a prognostic model that has not been validated in population-based data. The EORTC nomogram includes Breslow thickness, ulceration status and anatomical location as parameters. The aim of this study was to validate the EORTC model externally using a large national data set. METHODS: Adults with histologically proven, invasive cutaneous melanoma with a negative SN biopsy in the Netherlands between 2000 and 2014 were identified from the Dutch Pathology Registry, and relevant data were extracted. The EORTC nomogram was used to predict recurrence-free survival. The predictive performance of the nomogram was assessed by discrimination (C-statistic) and calibration. RESULTS: A total of 8795 patients met the eligibility criteria, of whom 14·7 per cent subsequently developed metastatic disease. Of these recurrences, 20·9 per cent occurred after the first 5 years of follow-up. Validation of the EORTC nomogram showed a C-statistic of 0·70 (95 per cent c.i. 0·68 to 0·71) for recurrence-free survival, with excellent calibration (R2 = 0·99; P = 0·999, Hosmer-Lemeshow test). CONCLUSION: This population-based validation confirmed the value of the EORTC nomogram in predicting recurrence-free survival in patients with SN-negative melanoma. The EORTC nomogram could be used in clinical practice for personalizing follow-up and selecting high-risk patients for trials of adjuvant systemic therapy.

Predicting sentinel node positivity in patients with melanoma: external validation of a risk-prediction calculator (the Melanoma Institute Australia nomogram) using a large European population-based patient cohort.

BACKGROUND: A nomogram to predict sentinel node (SN) positivity [the Melanoma Institute Australia (MIA) nomogram] was recently developed and externally validated using two large single-institution databases. However, there remains a need to further validate the nomogram's performance using population-based data. OBJECTIVES: To perform further validation of the nomogram using a European national patient cohort. METHODS: Patients with cutaneous melanoma who underwent SN biopsy in the Netherlands between 2000 and 2014 were included. Their data were obtained from the Dutch Pathology Registry. The predictive performance of the nomogram was assessed by discrimination (C-statistic) and calibration. Negative predictive values (NPVs) were calculated at various predicted probability cutoffs. RESULTS: Of the 3049 patients who met the eligibility criteria, 23% (691) were SN positive. Validation of the MIA nomogram (including the parameters Breslow thickness, ulceration, age, melanoma subtype and lymphovascular invasion) showed a good C-statistic of 0·69 (95% confidence interval 0·66-0·71) with excellent calibration (R2 = 0·985, P = 0·40). The NPV of 90·1%, found at a 10% predicted probability cutoff for having a positive SN biopsy, implied that by using the nomogram, a 16·3% reduction in the rate of performing an SN biopsy could be achieved with an error rate of 1·6%. Validation of the MIA nomogram considering mitotic rate as present or absent showed a C-statistic of 0·70 (95% confidence interval 0·68-0·74). CONCLUSIONS: This population-based validation study in European patients with melanoma confirmed the value of the MIA nomogram in predicting SN positivity. Its use will spare low-risk patients the inconvenience, cost and potential risks of SN biopsy while ensuring that high-risk patients are still identified.

Desmoplastic melanoma: a review of its pathology and clinical behaviour, and of management recommendations in published guidelines.

Desmoplastic melanomas are uncommon. Their behaviour differs from that of other melanoma subtypes; therefore, management guidelines for non-desmoplastic melanomas may not be applicable. This review sought to examine all available evidence relating to the behaviour and management of desmoplastic melanomas, based on review of all relevant English-language publications, and to critically assess the recommendations for their management in current published melanoma management guidelines. Compared with other melanoma subtypes, patients with 'pure' desmoplastic melanomas (where ≥90% of the invasive melanoma is of desmoplastic melanoma subtype) have much lower rates of sentinel node positivity and distant metastasis. Local recurrence rates are higher for desmoplastic melanomas, but resection margins wider than those recommended for non-desmoplastic melanomas have not been shown to be of benefit. Adjuvant radiotherapy reduces the risk of local recurrence when a satisfactory histological clearance (≥8 mm) cannot be achieved. Of 29 published melanoma management guidelines identified, only 11 specified management for desmoplastic melanomas, while seven simply stated that the feature should be reported. Desmoplastic melanoma is a unique melanoma subtype with biology that differs from that of other melanoma subtypes. It requires specific management strategies but few current guidelines address these.

A multicentre study of naevus-associated melanoma vs. de novo melanoma, tumour thickness and body site differences.

BACKGROUND: Whether melanoma in histological contiguity with a naevus [naevus-associated melanoma (NAM)] is distinctly different from melanoma arising de novo remains unclear. OBJECTIVES: To determine whether the characteristics of de novo melanoma differ from NAM and are not due to naevus obliteration in thicker tumours. METHODS: We conducted a multicentre retrospective study of de novo melanoma and NAM in seven referral centres in Europe, Australia and the USA between 2006 and 2015. RESULTS: In a total of 9474 localized melanomas, de novo melanoma was associated with thicker tumours and body site differences compared with NAM. In the subset of T1 melanomas (n = 5307), similar body site differences were found in multivariate analysis by body site. When compared with NAM, de novo melanoma was more likely to affect older individuals (≥ 70 years) when located on the head/neck [odds ratio (OR) 4·65, 95% confidence interval (CI) 2·55-8·46], the trunk (OR 1·82, 95% CI 1·40-2·36) or the upper extremity (OR 1·69, 95% CI 1·14-2·50), was more likely to affect female patients when located on the lower extremities (OR 1·36, 95% CI 1·03-1·80), and was more likely to be of the nodular melanoma subtype (OR 2·23, 95% CI 1·14-4·35) when located on the trunk. De novo melanoma was less likely to have regression present compared with NAM. CONCLUSIONS: Clinicopathological and body site differences between de novo melanoma and NAM support the divergent pathway model of development. These differences were also found in thin melanomas, suggesting that de novo melanomas are different from NAM and their differences are not due to the obliteration of naevus remnants in thicker tumours.

Sentinel node biopsy in patients with melanoma improves the accuracy of staging when added to clinicopathological features of the primary tumor.

BACKGROUND: It has been claimed, without supporting evidence, that knowledge of sentinel node (SN) status does not provide more accurate prognostic information than basic clinicopathological features of a primary cutaneous melanoma. We sought to investigate this claim and to quantify any additional value of SN status in predicting survival outcome. PATIENTS AND METHODS: Data for a Dutch population-based cohort of melanoma patients (n = 9272) and for a validation cohort from a large Australian melanoma treatment center (n = 5644) were analyzed. Patients were adults diagnosed between 2004 and 2014 with histologically-proven, primary invasive cutaneous melanoma who underwent SN biopsy. Multivariable Cox proportional hazards analyses were carried out in the Dutch cohort to assess recurrence-free survival (RFS), melanoma-specific survival (MSS) and overall survival (OS). The findings were validated using the Australian cohort. Discrimination (Harrell's C-statistic), net benefit using decision curve analysis and net reclassification index (NRI) were calculated. RESULTS: The Dutch cohort showed an improved C-statistic from 0.74 to 0.78 for OS and from 0.74 to 0.76 for RFS when SN status was included in the model with Breslow thickness, sex, age, site, mitoses, ulceration, regression and melanoma subtype. In the Australian cohort, the C-statistic increased from 0.70 to 0.73 for OS, 0.70 to 0.74 for RFS and 0.72 to 0.76 for MSS. Decision curve analyses showed that the 3-year and 5-year risk of death or recurrence were more accurately classified with a model that included SN status. At 3 years, sensitivity increased by 12% for both OS and RFS in the development cohort, and by 10% and 6% for OS and RFS, respectively, in the validation cohort. CONCLUSIONS: Knowledge of SN status significantly improved the predictive accuracy for RFS, MSS and OS when added to a comprehensive suite of established clinicopathological prognostic factors. However, clinicians and patients must consider the magnitude of the improvement when weighing up the advantages and disadvantages of SN biopsy for melanoma.

Same-day or next-day sentinel node biopsy after lymphoscintigraphy for melanoma using 99m Tc-labelled antimony sulphide colloid.

BACKGROUND: Two recent publications have reported that a shorter interval between preoperative lymphoscintigraphy and sentinel node biopsy (SNB) is associated with improved survival of patients with primary cutaneous melanoma. The aims of this study were to analyse prospectively collected survival data for patients who had SNB on the same day as lymphoscintigraphy or the day after; and to assess tracer migration from sentinel nodes to second-tier nodes after lymphoscintigraphy on the previous day. METHODS: Outcome data were obtained for patients who had lymphoscintigraphy and SNB on the same day (time interval less than 8 h) or the next day (interval more than 16 h). In a separate prospective cohort, same-day and next-day lymphoscintigraphic images of sentinel nodes and second-tier nodes were compared. RESULTS: Following lymphoscintigraphy, 2848 patients had same-day and 3328 had next-day SNB. Survival outcomes did not differ between these groups. In a prospectively studied cohort of 30 patients, none had significant tracer migration from sentinel nodes to second-tier nodes on imaging the following day. CONCLUSION: No difference in survival after same- or next-day sentinel node biopsy is seen when 99m Tc-labelled antimony sulphide colloid is used. This may be because of less tracer migration to second-tier nodes.

ANTECEDENTES: Dos publicaciones recientes han señalado que reducir el intervalo entre la linfografía isotópica preoperatoria y la biopsia del ganglio centinela (sentinel node biopsy, SNB) se asocia con una mejor supervivencia en pacientes con melanoma maligno primario. Los objetivos de este estudio fueron los siguientes: (1) analizar los datos de supervivencia recogidos prospectivamente en pacientes en los que se realiza la SNB el mismo día o al día siguiente de la linfografía isotópica, y (2) evaluar la migración del marcador desde los ganglios centinela a los ganglios de segundo nivel a partir de la linfografía del día anterior. MÉTODOS: Se analizaron los resultados de los pacientes a los que se realizó una linfografía isotópica y la SNB el mismo día (intervalo de tiempo < 8 h) o al día siguiente (intervalo > 16 h). En una cohorte prospectiva diferente, se compararon las imágenes de los ganglios centinela y de los ganglios de segundo nivel en linfografías isotópicas realizadas el mismo día o al día siguiente. RESULTADOS: Tras la linfografía isotópica, se realizó la SNB el mismo día en 2.848 pacientes y al día siguiente en 3.328 pacientes. No hubo diferencias en la supervivencia entre ambos grupos. En una cohorte de 30 pacientes estudiada de forma prospectiva, no hubo migración significativa del trazador de los ganglios centinela a los ganglios de segundo nivel en las imágenes obtenidas al día siguiente. CONCLUSIÓN: La mejor supervivencia que se obtiene cuando se realiza la SNB poco después de la linfografía isotópica podría explicarse por una diferencia en la migración del trazador a los ganglios de segundo nivel entre los dos marcadores utilizados: nanocoloide de albúmina humana o coloide de sulfuro de antimonio, ambos marcados con 99mTc. En este estudio y con este último marcador, no se observó migración a ganglios de segundo nivel durante la noche.

The association between active tumor volume, total lesion glycolysis and levels of S-100B and LDH in stage IV melanoma patients.

INTRODUCTION: The Standardized Uptake Value (SUV) in single lesions on 18F-FDG PET/CT scans and serum S-100B concentrations are inversely associated with disease-free survival in stage IV melanoma. The aim of this study was to assess the association between biomarkers (S-100B, LDH) and the PET-derived metrics SUVmean/max, metabolic active tumor volume (MATV), and total lesion glycolysis (TLG) in stage IV melanoma in order to understand what these biomarkers reflect and their possible utility for follow-up. METHODS: In 52 stage IV patients the association between PET-derived metrics and the biomarkers S-100B and LDH was assessed and the impact on survival analyzed. RESULTS: S-100B was elevated (>0.15 µg/l) in 37 patients (71%), LDH in 11 (21%). There was a correlation between S-100B and LDH (R2 = 0.19). S-100B was correlated to both MATV (R2 = 0.375) and TLG (R2 = 0.352), but LDH was not. Higher MATV and TLG levels were found in patients with elevated S-100B (p < 0.001) and also in patients with elevated LDH (>250 U/l) (p < 0.001). There was no association between the biomarkers and SUVmean/max. Survival analysis indicated that LDH was the only predictor of melanoma-specific survival. CONCLUSION: In newly diagnosed stage IV melanoma patients S-100B correlates with 18F-FDG PET/CT derived MATV and TLG in contrast to LDH, is more often elevated than LDH (71% vs. 21%) and seems to be a better predictor of disease load and disease progression. However, elevated LDH is the only predictor for survival. The biomarkers, S-100B and LDH appear to describe different aspects of the extent of metastatic disease and of tumornecrosis.

A risk prediction model for the development of subsequent primary melanoma in a population-based cohort.

BACKGROUND: Guidelines for follow-up of patients with melanoma are based on limited evidence. OBJECTIVES: To guide skin surveillance, we developed a risk prediction model for subsequent primary melanomas, using demographic, phenotypical, histopathological, sun exposure and genomic risk factors. METHODS: Using Cox regression frailty models, we analysed data for 2613 primary melanomas from 1266 patients recruited to the population-based Genes, Environment and Melanoma study in New South Wales, Australia, with a median of 14 years' follow-up via the cancer registry. Discrimination and calibration were assessed. RESULTS: The median time to diagnosis of a subsequent primary melanoma decreased with each new primary melanoma. The final model included 12 risk factors. Harrell's C-statistic was 0·73 [95% confidence interval (CI) 0·68-0·77], 0·65 (95% CI 0·62-0·68) and 0·65 (95% CI 0·61-0·69) for predicting second, third and fourth primary melanomas, respectively. The risk of a subsequent primary melanoma was 4·75 times higher (95% CI 3·87-5·82) for the highest vs. the lowest quintile of the risk score. The mean absolute risk of a subsequent primary melanoma within 5 years was 8·0 ± SD 4.1% after the first primary melanoma, and 46·8 ± 15·0% after the second, but varied substantially by risk score. CONCLUSIONS: The risk of developing a subsequent primary melanoma varies considerably between individuals and is particularly high for those with two or more primary melanomas. The risk prediction model and its associated nomograms enable estimation of the absolute risk of subsequent primary melanoma, on the basis of on an individual's risk factors, and can be used to tailor surveillance intensity, communicate risk and provide patient education. What's already known about this topic? Current guidelines for the frequency and length of follow-up to detect new primary melanomas in patients with one or more previous primary melanomas are based on limited evidence. People with one or more primary melanomas have, on average, a higher risk of developing another primary invasive melanoma, compared with the general population, but an accurate way of estimating individual risk is needed. What does this study add? We provide a comprehensive risk prediction model for subsequent primary melanomas, using data from 1266 participants with melanoma (2613 primary melanomas), over a median 14 years' follow-up. The model includes 12 risk factors comprising demographic, phenotypical, histopathological and genomic factors, and sun exposure. It enables estimation of the absolute risk of subsequent primary melanomas, and can be used to tailor surveillance intensity, communicate individual risk and provide patient education.

Inguinal and Ilio-inguinal Lymphadenectomy in Management of Palpable Melanoma Lymph Node Metastasis: A Long-Term Prospective Evaluation of Morbidity and Quality of Life.

PURPOSE: Prospective data are lacking on long-term morbidity of inguinal lymphadenectomy including the influence of extent of surgery, use of radiotherapy, and patient factors. The aim of this study is to evaluate the effects of these factors on patient outcome, quality of life (QOL), regional symptoms, and limb volumes after inguinal or ilio-inguinal lymphadenectomy for melanoma. METHODS: Analysis of the subgroup of patients with inguinal lymph node field relapse of melanoma, treated by inguinal or ilio-inguinal lymphadenectomy in the ANZMTG/TROG randomized trial of adjuvant radiotherapy versus observation. RESULTS: Sixty-nine patients, 46 having undergone inguinal and 23 ilio-inguinal lymphadenectomy, with median follow-up of 73 months were analyzed. Mean limb volume increased rapidly after surgery (7% by 3 months) and continued to increase for at least another 18 months. Patients with body mass index (BMI) ≥ 25 kg/m2 had greater limb volume increase than normal-weight patients (13.3% versus 6.9%, P = 0.030). QOL improved over the first 18 months, but despite initial improvement, regional symptoms persisted long term. Type of surgery (inguinal or ilio-inguinal lymphadenectomy) had no demonstrably significant effect on limb volume (9.9% versus 13.4%, P = 0.35), QOL (P = 0.68), or regional symptoms (P = 0.65). There was no difference in overall survival between inguinal and ilio-inguinal lymphadenectomy [hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.40-1.40, P = 0.43]. CONCLUSIONS: Inguinal lymphadenectomy for melanoma is a potentially morbid procedure with significant increases in limb volume. Patients report reasonable QOL but may have ongoing regional symptoms. Overweight/obesity is associated with poorer QOL, increased limb volume, and regional symptoms.

External validation of a prognostic model to predict survival of patients with sentinel node-negative melanoma.

BACKGROUND: Identifying patients with sentinel node-negative melanoma at high risk of recurrence or death is important. The European Organisation for Research and Treatment of Cancer (EORTC) recently developed a prognostic model including Breslow thickness, ulceration and site of the primary tumour. The aims of the present study were to validate this prognostic model externally and to assess whether it could be improved by adding other prognostic factors. METHODS: Patients with sentinel node-negative cutaneous melanoma were included in this retrospective single-institution study. The ß values of the EORTC prognostic model were used to predict recurrence-free survival and melanoma-specific survival. The predictive performance was assessed by discrimination (c-index) and calibration. Seeking to improve the performance of the model, additional variables were added to a Cox proportional hazards model. RESULTS: Some 4235 patients with sentinel node-negative cutaneous melanoma were included. The median follow-up time was 50 (i.q.r. 18·5-81·5) months. Recurrences and deaths from melanoma numbered 793 (18·7 per cent) and 456 (10·8 per cent) respectively. Validation of the EORTC model showed good calibration for both outcomes, and a c-index of 0·69. The c-index was only marginally improved to 0·71 when other significant prognostic factors (sex, age, tumour type, mitotic rate) were added. CONCLUSION: This study validated the EORTC prognostic model for recurrence-free and melanoma-specific survival of patients with negative sentinel nodes. The addition of other prognostic factors only improved the model marginally. The validated EORTC model could be used for personalizing follow-up and selecting high-risk patients for trials of adjuvant systemic therapy.

ANTECEDENTES: Es importante identificar a los pacientes con melanoma y ganglio centinela negativo con alto riesgo de recidiva o muerte. Con este fin, la European Organisation for Research and Treatment of Cancer (EORTC) ha desarrollado recientemente un modelo pronóstico que incluye el índice de Breslow, la presencia de úlcera y la localización del tumor primario. Los objetivos del presente estudio fueron efectuar la validación externa de este modelo pronóstico y evaluar si pudiera mejorarse agregando otros factores pronósticos. MÉTODOS: Estudio retrospectivo de una sola institución, en el que se incluyeron 4.235 pacientes con melanoma cutáneo y ganglio centinela negativo. La mediana de seguimiento fue de 50 meses (rango intercuartílico 18,5-81,5). Para predecir la supervivencia sin recidiva y la supervivencia específica para el melanoma se utilizaron los valores beta del modelo de pronóstico de la EORTC. La capacidad predictiva se evaluó mediante los índices de discriminación (índice c) y de calibración. Para mejorar el rendimiento de este modelo, se agregaron más variables utilizando un modelo de riesgos proporcionales de Cox. RESULTADOS: Las recidivas y muertes por melanoma fueron 793 (19%) y 456 (11%), respectivamente. La validación del modelo EORTC mostró una buena calibración para ambos resultados y un índice c de 0,69. El índice c sólo mejoró marginalmente a 0,71 cuando se agregaron otros factores pronósticos significativos (género, edad, tipo de tumor, índice mitótico). CONCLUSIÓN: La validación externa del modelo de pronóstico EORTC para la supervivencia sin recidiva y específica en pacientes con melanoma y ganglio centinela negativo fue satisfactoria. La adición de otros factores pronósticos solo mejoró marginalmente el modelo. El modelo validado de la EORTC podría utilizarse para personalizar las estrategias de seguimiento y seleccionar a pacientes de alto riesgo para ensayos con terapia sistémica adyuvante.

Pre-operative ctDNA predicts survival in high-risk stage III cutaneous melanoma patients.

BACKGROUND: The outcomes of patients with stage III cutaneous melanoma who undergo complete surgical resection can be highly variable, and estimation of individual risk of disease recurrence and mortality remains imprecise. With recent demonstrations of effective adjuvant targeted and immune checkpoint inhibitor therapy, more precise stratification of patients for costly and potentially toxic adjuvant therapy is needed. We report the utility of pre-operative circulating tumour DNA (ctDNA) in patients with high-risk stage III melanoma. PATIENTS AND METHODS: ctDNA was analysed in blood specimens that were collected pre-operatively from 174 patients with stage III melanoma undergoing complete lymph node (LN) dissection. Cox regression analyses were used to evaluate the prognostic significance of ctDNA for distant metastasis recurrence-free survival and melanoma-specific survival (MSS). RESULTS: The detection of ctDNA in the discovery and validation cohort was 34% and 33%, respectively, and was associated with larger nodal melanoma deposit, higher number of melanoma involved LNs, more advanced stage and high lactate dehydrogenase (LDH) levels. Detectable ctDNA was significantly associated with worse MSS in the discovery [hazard ratio (HR) 2.11 P < 0.01] and validation cohort (HR 2.29, P = 0.04) and remained significant in a multivariable analysis (HR 1.85, P = 0.04). ctDNA further sub-stratified patients with AJCC stage III substage, with increasing significance observed in more advanced stage melanoma. CONCLUSION: Pre-operative ctDNA predicts MSS in high-risk stage III melanoma patients undergoing complete LN dissection, independent of stage III substage. This biomarker may have an important role in determining prognosis and stratifying patients for adjuvant treatment.