Invasive Primary Cutaneous Melanoma Research Articles

Lymphatic expression of the proliferation marker Ki67 is linked to sentinel node positivity, recurrence and mortality in primary cutaneous melanoma.

Lymphangiogenesis is a precursor to lymphovascular invasion, and may therefore signal a higher risk of metastasis and mortality in primary cutaneous melanoma. This retrospective longitudinal study aimed to evaluate whether emergent lymphangiogenesis, as measured through co-expression of endothelial proteins with the proliferation marker Ki67, was associated with poorer prognosis in a cohort of patients with single primary cutaneous melanoma. We screened all patients with a single locally invasive primary cutaneous melanoma who received sentinel lymph node biopsy at a tertiary dermatology centre in Brisbane, Australia between 1994 and 2007. Primary melanoma sections were stained via Opal multiplex immunofluorescence, and categorized according to the presence of Ki67 within either CD31+ or D2-40+ endothelial cells. Multivariate Cox regression modelling was used to evaluate associations between endothelial Ki67 positivity and clinical outcomes, with adjustment for age, sex, Breslow depth, ulceration, and anatomical location. Overall, 264 patients were available for analysis, with a median follow-up duration of 7.1 years. The presence of D2-40+ /Ki67+ co-expression was associated with greater melanoma-specific mortality (adjusted hazard ratio [HR]: 2.03; 95% confidence interval [CI]: 1.33-3.10; p = 0.001) and recurrence (adjusted HR: 1.70; 95% CI: 1.33-3.10; p = 0.001) relative to absence. CD31+ /Ki67+ co-expression was not prognostic in this cohort. Lymphatic proliferation, as measured through D2-40+ /Ki67+ co-expression, predicted greater melanoma-specific mortality and recurrence in this cohort of primary cutaneous melanoma.

Health Economic Consequences Associated With COVID-19–Related Delay in Melanoma Diagnosis in Europe

The COVID-19 pandemic resulted in delayed access to medical care. Restrictions to health care specialists, staff shortages, and fear of SARS-CoV-2 infection led to interruptions in routine care, such as early melanoma detection; however, premature mortality and economic burden associated with this postponement have not been studied yet. To determine the premature mortality and economic costs associated with suspended melanoma screenings during COVID-19 pandemic lockdowns by estimating the total burden of delayed melanoma diagnoses for Europe. This multicenter economic evaluation used population-based data from patients aged at least 18 years with invasive primary cutaneous melanomas stages I to IV according to the American Joint Committee on Cancer (AJCC) seventh and eighth editions, including melanomas of unknown primary (T0). Data were collected from January 2017 to December 2021 in Switzerland and from January 2019 to December 2021 in Hungary. Data were used to develop an estimation of melanoma upstaging rates in AJCC stages, which was verified with peripandemic data. Years of life lost (YLL) were calculated and were, together with cost data, used for financial estimations. The total financial burden was assessed through direct and indirect treatment costs. Models were building using data from 50 072 patients aged 18 years and older with invasive primary cutaneous melanomas stages I to IV according to the AJCC seventh and eighth edition, including melanomas of unknown primary (T0) from 2 European tertiary centers. Data from European cancer registries included patient-based direct and indirect cost data, country-level economic indicators, melanoma incidence, and population rates per country. Data were analyzed from July 2021 to September 2022. COVID-19 lockdown-related delay of melanoma detection and consecutive public health and economic burden. As lockdown restrictions varied by country, lockdown scenario was defined as elimination of routine medical examinations and severely restricted access to follow-up examinations for at least 4 weeks. Primary outcomes were the total burden of a delay in melanoma diagnosis during COVID-19 lockdown periods, measured using the direct (in US$) and indirect (calculated as YLL plus years lost due to disability [YLD] and disability-adjusted life-years [DALYs]) costs for Europe. Secondary outcomes included estimation of upstaging rate, estimated YLD, YLL, and DALY for each European country, absolute direct and indirect treatment costs per European country, proportion of the relative direct and indirect treatment costs for the countries, and European health expenditure. There were an estimated 111 464 (range, 52 454-295 051) YLL due to pandemic-associated delay in melanoma diagnosis in Europe, and estimated total additional costs were $7.65 (range, $3.60 to $20.25) billion. Indirect treatment costs were the main cost driver, accounting for 94.5% of total costs. Estimates for YLD in Europe resulted in 15 360 years for the 17% upstaging model, ranging from 7228 years (8% upstaging model) to 40 660 years (45% upstaging model). Together, YLL and YLD constitute the overall disease burden, ranging from 59 682 DALYs (8% upstaging model) to 335 711 DALYs (45% upstaging model), with 126 824 DALYs for the real-world 17% scenario. This economic analysis emphasizes the importance of continuing secondary skin cancer prevention measures during pandemics. Beyond the personal outcomes of a delayed melanoma diagnosis, the additional economic and public health consequences are underscored, emphasizing the need to include indirect economic costs in future decision-making processes. These estimates on DALYs and the associated financial losses complement previous studies highlighting the cost-effectiveness of screening for melanoma.

Gender differences in pediatric and adolescent melanoma: A retrospective analysis of 4645 cases

There is paucity of data on how genderimpacts melanoma prognosis in pediatric and adolescent patients. This study explores gender differences in presentation and survival among pediatric and adolescent patients with melanoma. The National Cancer Database 2004-2018 was queried for cases of primary invasive cutaneous melanoma in pediatric and adolescent patients (birth to 21years) for a retrospective cohort study. Of the 4645 cases, 63.4% were female. Median Breslow depth was 1.05mm for males (interquartile range 0.50-2.31) and 0.80mm for females (interquartile range 0.40-1.67; P<.001). Trunk was the most common primary site for females (34.3%) and males (32.9%). More females than males were diagnosed with stage I disease (67.8% vs 53.6%). Males had higher rates of regional lymph node positivity (27.9% vs 18.1%; P<.001) and ulceration (17.1% vs 11.4%; P<.001). Five-year overall survival was 95.9% for females and 92.0% for males (P<.001). After adjusting for confounders, male gender independently increased mortality risk (reference: females; adjusted hazard ratio 1.57; 95% confidence interval 1.32-1.86). Retrospective study. Males exhibited more aggressive pathologic features including greater Breslow thickness and higher ulceration and lymph node positivity rates. Male gender independently increased mortality risk.

Prognostic Significance of Sentinel Lymph Node Status in Thick Primary Melanomas (> 4 mm)

BackgroundThe key prognostic factors for staging patients with primary cutaneous melanoma are Breslow thickness, ulceration, and sentinel lymph node (SLN) status. The multicenter selective lymphadenectomy trial (MSLT-I) verified SLN status as the most important prognostic factor for patients with intermediate-thickness melanoma (Breslow thickness, 1–4 mm). Although most international guidelines recommend SLN biopsy (SLNB) also for patients with thick (> 4 mm, pT4) melanomas, its prognostic role has been questioned. The primary aim of this study was to establish whether SLN status is prognostic in T4 melanoma tumors.MethodsData for all patients with a diagnosis of primary invasive cutaneous melanoma of Breslow thickness greater than 1 mm in Sweden between 2007 and 2020 were retrieved from the Swedish Melanoma Registry, a large prospective population-based registry. A multivariable Cox proportional hazard model for melanoma-specific survival (MSS) was constructed based on Breslow thickness stratified for SLN status.ResultsThe study enrolled 10,491 patients, 1943 of whom had a Breslow thickness greater than 4 mm (pT4). A positive SLN was found for 34% of these pT4 patients. The 5-year MSS was 71%, and the 10-year MSS was 62%. There was a statistically significant difference in MSS between the patients with a positive SLN and those with a negative SLN (hazard ratio of 2.4 (95% confidence interval CI 1.6–3.5) for stage T4a and 2.0 (95% CI 1.6–2.5) for satage T4b.ConclusionSentinel lymph node status gives important prognostic information also for patients with thick (> 4 mm) melanomas, and the authors thus recommend that clinical guidelines be updated to reflect this.

Increasing melanoma incidence and survival trend shifts with improved melanoma-specific survival between 1990and 2020 in Sweden.

Melanoma-specific survival (MSS) is heterogenous between stages and is highly dependent on the T stage for primary localized disease. New systemic therapies for metastatic cutaneous melanoma (CM) have been introduced since 2012 in Sweden. To analyse the incidence and MSS time trends between 1990 and 2020 in Sweden. Nationwide, population-based and prospectively collected clinico-pathological data on invasive CM from the Swedish Melanoma Registry (SweMR) were analysed for survival trends between 1990 and 2020 using Kaplan-Meier curves and Cox proportional hazard ratios (HRs). In total, 77 036 primary invasive CMs were diagnosed in 70 511 patients in Sweden between 1990 and 2020. The 5-year MSS [95% confidence interval (CI)] was 88.9% (88.3-89.4) for 1990-2000, 89.2% (88.7-89.6) for 2001-2010 and 93.0% (92.7-93.9) for 2011-2020. The odds ratios for being diagnosed with nodular melanoma (vs. superficial spreading melanoma) was significantly reduced by 20% (2001-2010) and by 46% (2011-2020)vs. the reference period 1990-2000. Overall, the MSS improved over both diagnostic periods (2001-2010 and 2011-2020) vs. the reference period 1990-2000 among men and women, respectively [HRmen: 2001-2010: 0.89 (95% CI 0.82-0.96) and 2011-2020: 0.62 (95% CI 0.56-0.67); HRwomen: 2001-2010: 0.82 (95% CI 0.74-0.91) and 2011-2020: 0.62 (95% CI 0.56-0.70)]. The risk of death from CM was significantly lower in all age groups for both men and women in the most recent diagnostic period (2011-2020 vs.1990-2000). The results emphasize the improved MSS among men and women in Sweden. The MSS improvements, specifically for the period 2011-2020, may be correlated to the introduction of new systemic therapies and are here shown for the first time in detail for Sweden.

Trends and patterns of care of sentinel node biopsy in cutaneous melanoma: a population-based study in Queensland.

Sentinel node biopsy (SNB) has evolved from offering staging and prognostication to a procedure that guides therapeutic management. The aim was to evaluate the rate of SNB for patients with high-risk melanoma and assess factors that may have impacted on the procedure being performed. Data of patients with primary invasive cutaneous melanoma from 01 January 2009 to 31 December 2019 were obtained from the Queensland Oncology Repository. High-risk melanoma was defined as ≥0.8 mm thick or < 0.8 mm with ulceration present (AJCC eighth edition pT1b -pT4 ). 14 006 (33.8%) of 41 412 patients diagnosed with cutaneous invasive melanoma were in the high-risk group. 2923(20.9%) patients had SNB, with the rate increasing from 14.2% (2009) to 36.8% (2019) (P=0.002), and an increasing proportion being performed in public hospitals over the 11 year period (P=0.02). Older age (OR0.96 (0.959-0.964) (P < 0.001)), female (OR0.91 (0.830-0.998) (P=0.03)), head and neck primary (OR0.38 (0.33-0.45) (P < 0.001)), and pT1b (OR0.22 (0.19-0.25) (P < 0.001)) were factors associated with SNB not being performed. Travel out of the Hospital and Health Services of residence for SNB occurred in 26.2%. Although the travel rate decreased from 24.7% (2009) to 23.0% (2019) (P=0.04), the absolute number increased due to the increase in SNB rate. Those most likely to travel were younger, from remote areas, or from affluent backgrounds. In this first Australian population-based study, there was an increased adherence to SNB guideline, although overall SLNB rates remain low, with nearly 2/3 of eligible cases not having the procedure in 2019. Although travel rates decreased marginally, the overall number increased. This study highlights the crucial need to further improve access to SNB for melanoma surgery for the Queensland population.

Conditional survival in patients with stage IB‐IIIA melanoma undergoing sentinel node biopsy in Queensland: A longitudinal study

Tumour characteristics such as thickness and ulceration, along with sentinel lymph node (SLN) status, have been essential in predicting survival in patients with locally invasive melanomas at the time of diagnosis. It is unclear if these prognostic factors are relevant 1, 2 or 5 years after diagnosis. The key aim of this project was to analyse conditional survival in a cohort of Queensland patients with stage IB to IIIA melanomas (American Joint Committee on Cancer's staging system, 8th version) and to test the relevance of clinicopathological prognostic factors for melanoma outcome after varying intervals of survival time. Patients with primary invasive cutaneous melanoma who were referred to a tertiary melanoma clinic and underwent SLN biopsy between 1994 and 2011 were ascertained. The effect of patient and tumour characteristics on melanoma survival were calculated using multivariate Cox proportional hazard models at diagnosis and at variable times after diagnosis. The final analysis included 651 patients (average age 49 years, 55.5% male) with stage IB to IIIA melanoma. At diagnosis, and after 1 and 2 years survived, SLN positivity, thickness and ulceration were predictive of 10-year survival since diagnosis. However, once patients survived 5 years, only SLN status was predictive. Overall conditional melanoma survival improved with increasing time survived. Five years after diagnosis, 10-year conditional melanoma survival (MSS) was 91% (95% CI 86%-95%) compared with 85% (82%-88%) predicted at diagnosis. The improvement in MSS was observed mainly for Stage II melanoma patients and not for those with a positive SLN biopsy. This study confirms the improvement of prognosis according to time survived since diagnosis suggesting that after 5 years survival the classic prognostic indicators may not have the same influence.

Association of metformin use and survival in patients with cutaneous melanoma and diabetes.

Metformin use has been associated with improved survival in patients with different types of cancer, but research regarding the effect of metformin on cutaneous melanoma (CM) survival is sparse and inconclusive. To investigate the association between metformin use and survival among patients with CM and diabetes. All adult patients with a primary invasive CM between 2007 and 2014 were identified in the Swedish Melanoma Registry and followed until death, or end of follow-up on 31 December 2017 in this population-based cohort study. Patients with both CM and type 2 diabetes mellitus were assessed further. Overall survival (OS) and melanoma-specific survival (MSS) were the primary endpoints. Cox proportional hazard models estimating crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were used comparing peridiagnostic use vs. nonuse of metformin. Dose response was evaluated based on defined daily doses. Among a total of 23 507 patients, 1162 patients with CM and type 2 diabetes mellitus were included in the final cohort, with a median follow-up time of 4.1 years (interquartile range 2.4-6.1). Peridiagnostic metformin use was associated with a significantly decreased risk of death by any cause (HR 0.68, 95% CI 0.57-0.81). Cumulative pre- and postdiagnostic metformin use was also associated with improved OS: the HR for prediagnostic use was 0.90 (95% CI 0.86-0.95) for every 6 months of use and the HR for postdiagnostic use ranged from 0.98 (95% CI 0.97-0.98) for 0-6 months to 0.59 (0.49-0.70) for 24-30 months of use. No association was found for metformin use and MSS. Metformin use was associated with improved OS in patients with CM and diabetes regardless of timing (pre-, post- or peridiagnostic use) and followed a dose-response pattern. However, further research regarding the underlying mechanisms is warranted.

Prognostic Utility of CpG Island Hypermethylated Phenotype in Early-Stage Invasive Primary Melanomas

In their article in the Journal of Investigative Dermatology, Conway etal. (2021) show the significance of the CpG island methylator phenotype (CIMP) subclass in early-stage invasive primary melanomas, particularly in the lentigo maligna melanoma histological subtype. CIMP melanomas had reduced melanoma-specific survival compared with intermediate and low methylation subtypes. This study emphasizes the importance of epigenomic changes in early-stage primary tumors that are associated with poor prognosis.

Stage-specific trends in incidence and survival of cutaneous melanoma in the Netherlands (2003–2018): A nationwide population-based study

ObjectiveTo examine stage-specific trends in the incidence and survival of cutaneous melanoma in the Netherlands between 2003 and 2018, as well as the uptake of the sentinel lymph node biopsy (SLNB) and novel drugs during that period. MethodsData were obtained from the nationwide population-based Netherlands Cancer Registry for all patients diagnosed with invasive primary cutaneous melanoma (n = 60,267). We presented age-standardized incidence rates, the proportion of patients with an SLNB, the proportion of patients who received a novel drug (for their primary diagnosis) and one- and five-year relative survival rates. ResultsBetween 2003 and 2018, the incidence rate increased from 10.9 to 23.9 for men and from 15.6 to 27.3 for women. This increase reflected the increasing incidence rate of patients with stage I and III. The proportion of patients with an SLNB increased from 23% to 64%. A reasonable increase was observed in the proportion of patients with a positive outcome (from 2% to 11%). For patients with stage IV, there was a shift from chemotherapy towards novel drugs as from 2013. The five-year relative survival rate increased from 81% to 92% for men and from 88% to 96% for women. This increase reflected the increasing five-year relative survival rate of patients with stage II, III, and IV. ConclusionWe observed an increase in incidence for patients with stage I and III and an improvement in survival for patients with stage II, III and IV. These trends can be partly explained by the introduction of the SLNB and the novel drugs.

Volume tumor impact on melanoma survival assessed using Breslow density

Volume tumor impact on melanoma survival assessed using Breslow density

Clinicopathological, Genetic and Survival Advantages of Naevus-associated Melanomas: A Cohort Study.

Several studies have suggested that naevus-associated melanomas differ from de novo melanomas, being thinner and with less ulceration; however, the prognostic implication is unclear. The objective of this study was to describe clinicopathological, genetic and survival characteristics of de novo and naevus-associated melanomas in a cohort of primary invasive cutaneous melanomas over a 20-year period. Of the 2,227 patients included in the study, 509 (22.86%) had naevus-associated melanomas. Compared with patients with de novo melanoma, they were younger, with a fairer phototype and a higher naevus count, tumours were predominantly the superficial spreading subtype, American Joint Committee on Cancer stage I, located on the trunk, and there were fewer signs of invasiveness (thinner Breslow index, less ulceration, lower mitotic index and less satellitosis). Germline mutational status did not show any significant association. As determined through univariate analysis, overall survival was significantly better in patients with naevus-associated melanoma (hazard ratio 0.64; 95% confidence interval 0.51–0.80, p < 0.001), but multivariate analysis did not support this prognostic indication (hazard ratio 0.94; 95% confidence interval 0.75–1.18, p < 0.606). Despite this, we conclude that naevus-associated and de novo melanomas should be considered as different subtypes of melanoma.

Early detection of melanoma in specialised primary care practice in Australia

BackgroundPrimary care skin cancer clinics facilitate early treatment of melanoma in Australia. We investigated the clinical and histopathological features of melanomas diagnosed and treated in an established clinic in Brisbane. MethodsRetrospective audit of medical records of patients diagnosed with in situ or invasive primary cutaneous melanoma in a primary care clinic specializing in skin cancer, 2000−2017. Demographic and clinical data were standardly extracted by a medically-trained investigator. We used descriptive analyses to assess characteristics of patients and melanomas, and examine surgical management according to tumour thickness. ResultsOf 380 patients (median age 57 years; 57 % male) newly diagnosed with 497 histologically-confirmed primary cutaneous melanomas, 369 were in situ and 128 invasive. Of the 369 in situ melanomas, 143 (39 %) were on the trunk and 87 (24 %) on the head and neck; 247 (67 %) were diagnosed by shave biopsy; and 141 (38 %) referred for wide local excision (WLE). Of the 128 invasive melanomas, only 21 (16 %) had thickness ≥ 0.8 mm and these occurred more often on head and neck than thin invasive melanomas (p = 0.02). The majority of invasive melanomas were diagnosed by excision biopsy, and WLE was carried out in a median of 3 days (melanomas ≥ 0.8 mm) and 2 days (<0.8 mm). The doctor detected the majority of in situ (83 %) and thin invasive (73 %) melanomas during surveillance, compared with 48 % of thicker invasive melanomas ≥ 0.8 mm (p < 0.001). ConclusionIn Australia, specialised primary care practice plays a major role in detection and treatment of early primary melanoma.

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

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. 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. 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. 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.

18509 Nodular primary cutaneous melanoma is associated with PD-L1 expression

In previous studies, stage III patients with melanomas expressing PD-L1 in more than 5% of their cells had improved recurrence-free survival with anti-PD1 adjuvant therapy. In this context, we examined PD-L1 expression in primary cutaneous melanomas in the vertical growth phase to identify a possible biomarker. This was a retrospective study including 66 patients with invasive primary cutaneous melanomas. We assessed patient clinical and histopathologic data and performed immunohistochemical assays with melanoma specimens from the patients to evaluate PD-L1, PD-1, CD3, CD8 and FoxP3 expression.

Nodular primary cutaneous melanoma is associated with PD-L1 expression.

In previous studies, patients with Stage III melanomas expressing PD-L1 in more than 5% of their neoplastic cells had improved recurrence-free survival with anti-PD1 adjuvant therapy. We examined PD-L1 expression as a possible biomarker of primary cutaneous melanomas in the vertical growth phase. This was a retrospective study including 66 patients with invasive primary cutaneous melanomas. We assessed patient clinical and histopathological data and performed immunohistochemical assays with melanoma specimens from the patients to evaluate PD-L1, PD-1, CD3, CD8 and FoxP3 expression. We observed PD-L1 expression in 21% (14/66) of our samples, and this expression correlated with increased melanoma thickness (p = 0.002) and nodular-type melanoma (p = 0.001). After adjusting for tumor thickness using a logistic regression test, the association of PD-L1 with nodular-type melanoma persisted. Nodular-type melanoma was 6.48 times more likely to be positive for PD-L1 than other histological types (p = 0.014; 95%CI: 1.46-28.82). As expected, PD-L1 expression correlated with the number of PD-1-expressing cells in the tumor-infiltrating lymphocyte population (p = 0.04). No correlation with PD-L1 was observed for age, sex, tumor site, skin phototype, ulceration status, sentinel lymph node status, metastasis development or survival. Regarding the immune profile of the tumor-infiltrating lymphocytes of PD-L1-positive and -negative groups, no significant differences were observed in the numbers of CD3 + , CD8 + FoxP3-, CD8-FoxP3+ and CD8 + FoxP3+ cells by immunohistochemistry. Nodular-type melanoma is associated with PD-L1 expression and may be a suitable candidate for adjuvant therapy of primary melanomas treated with immunotherapy.

Prognostic significance of tumor size for primary invasive cutaneous melanoma: A population-based study, 2004-2016.

BackgroundThis study aimed to assess the independent prognostic value of tumor size compared with other clinical and pathologic features of primary invasive cutaneous melanoma (CM).MethodsThis study included 28,593 patients with primary invasive CM in Surveillance, Epidemiology, and End Results Program database diagnosed from 2004 through 2016. Tumor size was divided into five subgroups (≤6, 7‐12, 13‐30, 31‐42, and >42 mm). The primary endpoint was melanoma‐specific survival (MSS).ResultsThe relationship between tumor size and survival was piecewise. After adjusting for age, sex, primary site, histopathologic cell type, Breslow thickness, ulceration, mitotic rate, regional metastasis, and distant metastasis, the hazard ratio (HR) of MSS increased with increasing tumor size until a peak at 31‐42 mm (HRs, 1.33, 1.59, 2.41, respectively; all P < .0001), and then decreased when tumor size was larger than 42 mm using tumor size ≤ 6 mm as the reference (HR, 2.11; 95% confidence interval [CI], 1.84 −2.42; P < .0001). This pattern mostly remained after stratification by T subcategories from T1 to T4 in localized primary CM except that tumor size >42 mm subgroup had the shortest MSS in T4. In addition, tumor size with a cutoff value of 12 mm showed stronger prognostic value for MSS (HR, 2.32; 95% CI, 1.80‐2.98; P < .0001) than Breslow thickness and mitotic rate in primary CM with T1N0M0.ConclusionsTumor size was an important independent prognostic factor for MSS in patients with primary invasive CM. Tumor size larger than 30 mm would provide additional and important prognostic information in each T subcategory of localized CM. Furthermore, tumor size with a cutoff value of 12 mm has great potential in improving the accuracy of melanoma T1 substaging.

Acral lentiginous melanoma: Clinicopathologic and survival differences according to tumour location.

Acral lentiginous melanoma (ALM) is a melanoma subtype associated with atypical locations on the hands and feet and advanced disease at diagnosis. There is a limited understanding of whether the survival is similar for nail, non-nail, lower limb and upper limb ALM patients. We therefore explored clinicopathologic characteristics and melanoma-specific survival of ALM patients according to tumour location. A prospectively collected cohort study was performed of all primary invasive cutaneous acral lentiginous melanomas with known thickness and tumour location reviewed at a tertiary referral centre over 21years. A total of 101 ALM patients were reviewed from 1994 until 2016. The majority of cases (82/101) occurred on the feet. Hand ALMs were thicker and more likely to be ulcerated than feet ALMs (P=0.05 and 0.02, respectively); however, survival was not statistically different between these two groups (univariate HR 0.48 P=0.11, 95% CI, 0.20-1.17; multivariate HR 0.67 P=0.40, 95% CI, 0.27-1.69, respectively). Non-nail ALM patients had longer survival when compared to nail ALM on univariate analysis (HR 0.40, 95% CI, 0.17 to 0.90) which was accounted for by Breslow thickness and ulceration (multivariate HR 0.56, 95% CI, 0.24 to 1.34). The reduced melanoma-specific survival in nail ALM patients was likely due to their greater thickness and ulceration. Although hand ALMs are thicker and more frequently ulcerated, this is likely due to the higher proportion of nail ALMs present in this location.

Time trends and age-period-cohort analysis of cutaneous malignant melanoma incidence rates in the Romagna Region (northern Italy), 1986-2014.

After a long-term increase, the incidence of cutaneous malignant melanoma has stabilized recently or even decreased in several populations of North-western Europe, USA, Canada, Australia and New Zealand, but not in southern Europe. The incidence trends of primary invasive cutaneous malignant melanoma (International Classification of Diseases, 10th revision, codes C43.0-C43.9) in the Romagna Region (northern Italy, 1.2 million inhabitants) for the period 1986-2014 were analysed with an age-period-cohort modelling approach. The series included 2466 men and 2481 women, a total of 4947 patients. Using the method of model building, the best-fitting models were found to be an age-drift model for men and an age-period model for women. Among men, the age-specific incidence rates increased in each successive cohort born between 1916 and 1981 with an attenuation of the trend for younger ones in the last cohorts. Among younger women, a slight decrease occurred for the cohorts born after 1961. For men, the quasi-parallel appearance of incidence curves by age group and cohort on a log scale suggested that the observed change was explained by a linear cohort effect. For women, the curves tended to overlap, suggesting an interaction between age and cohort that could be explained as a nonlinear period effect. In conclusion, the long-term upward incidence trend in the study area is stabilizing among women and an attenuation of the increasing trend is occurring among younger men in the most recent cohorts. These observations need to be confirmed with longer-term studies.

Reconstructive burden and financial implications of wider excision margins for invasive primary cutaneous melanoma

For invasive primary cutaneous melanoma, wider excision is advocated to reduce local recurrence risk and improve patient outcomes. Excision detail is controversial, especially in intermediate- and high-risk primary melanoma (AJCC pT2-pT4). Guidance varies from sizes 1 to 3cm (translating into large defects of 2-6cm). The aim of this study was to determine the reconstructive and resource burden of wider excision margins (EMs). Data analysis from our prospective database (2008-2017) included 1184 patients (563F:621M) with cutaneous melanoma (pT1b-pT4b). Procedure tariff data were sourced from our financial services department. Two hundred twenty-nine patients had a narrower EM (1cm) and 995 (80.7%) had a wider EM (2-3cm). Reconstructive requirement significantly increased with a wider EM collectively (11.3% vs 29.3%, odds ratio (OR)=3.2; p<0.0001), in the extremities (15.2% vs 42.0%; p<0.0001), and in the head and neck (H&N) (23.5% vs 64.7%; p<0.0001). Reconstruction significantly increased hospitalisation rates (26.6% vs 63.0%, OR=4.7; p<0.0001) collectively, in the H&N (26.8% vs 53.9%), and in the upper (18.9% vs 42.3%) and lower extremities (34.8% vs 77.3%). Narrower EMs significantly reduced hospitalisation rates in the upper and lower extremities (7.1% vs 28.5%; p = 0.004, 37.9% vs 58.5%; p = 0.005, respectively). Overall procedure cost significantly increased by £180 (mean, p<0.0001) and £346 (median, p = 0.0004) per patient when reconstruction was required. Our data suggest substantial impact of wider EM on patients, which more than doubled in the functionally and cosmetically sensitive extremities and the H&N region. Reconstructions add significant financial and healthcare service burden. Without randomised controlled trial (RCT) evidence demonstrating increased efficacy of wider EM, narrower EM is advocated whilst awaiting future planned RCT results specifically investigating on this.