Prognosis in stage II melanoma of the head and neck depends on the histological subtype.

BACKGROUND AND OBJECTIVES: The melanoma guideline is mainly based on the AJCC stage. There is no difference according to histological subtypes such as superficial spreading melanoma (SSM), lentigo maligna melanoma (LMM) or nodular malignant melanoma (NM). We aimed to evaluate whether patients with LMM have a different clinical course from patients with SSM/NM. This is particularly important as adjuvant anti-PD-1 therapy is approved for stage IIB and IIC melanoma. PATIENTS AND METHODS: Data were extracted from the Central Registry of Malignant Melanoma. Only patients with LMM, SSM, and NM of the head and neck with primary diagnosis between 01/01/2000 and 12/31/2019 were included. Progression-free survival (PFS), melanoma-specific survival (MSS), and pattern of metastases were analyzed for the LMM group compared to SSM/NM. RESULTS: The LMM cohort (n = 902) had significantly better MSS than the SSM/NM cohort (n = 604). There was no difference in PFS. The 5-year MSS of the stage II LMM cohort was 88.5% (95% CI 81.4-95.6) compared to 79.7% (95% CI 72.8-86.6) in the stage II SSM/NM cohort. CONCLUSION: It does not appear appropriate to use adjuvant therapy in stage II LMM patients to the same extent as in patients with SSM/NM.

Real-world Treatment Patterns and Outcomes with Systemic Therapies in Unresectable Locally Advanced and Metastatic Cutaneous Squamous Cell Carcinoma in Germany.

Advanced cutaneous squamous cell carcinoma is a challenge to treat. Conventional systemic treatment options include chemotherapy and epidermal growth factor receptor-inhibitors. The aim of this study was to assess clinical outcomes with systemic treatments in advanced cutaneous squamous cell carcinoma. Patients receiving systemic treatment at the Tübingen Dermato-Oncology centre between 2007 and 2017 were identified (n = 59). Median age was 76 years (interquartile range (IQR) 71-80 years), 83.1% of patients were male, 72.9% had metastatic cutaneous squamous cell carcinoma, and 27.1% had unresectable locally advanced cutaneous squamous cell carcinoma. During median follow-up of 52 weeks (IQR 27-97 weeks), overall response rate was 14.3%, and disease control rate was 53.6%. Median progression-free survival was 15 weeks (IQR 8-42 weeks), and median overall survival was 52 weeks (IQR 27-97 weeks). Patients receiving chemoradiation vs chemotherapy alone showed better overall survival (hazard ratio 0.41, p = 0.014,) and progression-free survival (hazard ratio 0.42, p = 0.009); no differences were observed for metastatic cutaneous squamous cell carcinoma vs locally advanced cutaneous squamous cell carcinoma patients. Although chemotherapy and/or cetuximab showed limited outcomes in advanced cutaneous squamous cell carcinoma, such therapy may still be an option when anti-PD-1 treatment is contraindicated.

Epidemiology of Skin Cancer: Update 2019.

Melanoma and keratinocyte skin cancer (KSC) are the most common types of cancer in White-skinned populations. Both tumor entities showed increasing incidence rates worldwide but stable or decreasing mortality rates. Rising incidence rates of cutaneous melanoma (CM) and KSC are largely attributed to increasing exposure to ultraviolet (UV) radiation, the main causal risk factor for skin cancer.Incidence rates of KSC, comprising of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), are much higher than that of melanoma. BCC development is mainly the cause of an intensive UV exposure in childhood and adolescence, while SCC development is related to chronic, cumulative UV exposure over decades. Although mortality is relatively low, KSC is an increasing problem for health care services causing significant morbidity.Cutaneous melanoma is rapidly increasing in White populations, with an estimated annual increase of around 3-7% over the past decades. In contrast to SCC, melanoma risk is associated with intermittent and chronic exposure to sunlight. The frequency of its occurrence is closely associated with the constitutive color of the skin and the geographical zone. Changes in outdoor activities and exposure to sunlight during the past 70 years are an important factor for the increasing incidence of melanoma. Mortality rates of melanoma show stabilization in the USA, Australia, and in European countries. In the USA even dropping numbers of death cases were recently reported, probably reflecting efficacy of the new systemic treatments.Among younger cohorts in some populations (e.g., Australia and New Zealand,), stabilizing or declining incidence rates of CM are observed, potentially caused by primary prevention campaigns aimed at reducing UV exposure. In contrast, incidence rates of CM are still rising in most European countries and in the USA. Ongoing trends towards thinner melanoma are largely ascribed to earlier detection.

Dermatofluoroscopy diagnostics in different pigmented skin lesions: Strengths and weaknesses.

BACKGROUND: The melanin fluorescence of skin lesions is measurable with two-photon excitation, a process termed dermatofluoroscopy, which has shown a shift from the green spectra in benign melanocytic lesions to the red spectra in melanoma. This study addressed the question as to which kind of pigmented lesions can be correctly diagnosed as melanin-bearing malignant tumors. METHODS: 476 pigmented lesions including 101 cutaneous melanomas were analyzed with dermatofluoroscopy, measuring the melanin fluorescence in a grid-like fashion with a separation of measurement points of 0.2 mm. The results of the dermatofluoroscopy are presented as a diagnostic score with a cut-off score of ≥ 28 for the diagnosis of melanin-bearing malignant tumors, and were compared to the gold standard of histopathology. RESULTS: A highly significant difference (p < 0.0001) between the diagnostic scores of different skin tumors was found. Dermatofluoroscopy scores showed the highest sensitivity for melanomas (92.1 %). Interestingly, most pigmented basal cell carcinomas (BCCs, 88.9 %) were diagnosed as melanin-bearing malignant tumors. A higher sensitivity for the correct diagnosis was observed in older patients (≥ 53 years, p = 0.003), in patients with skin tanning (p = 0.025), and in patients with freckles during childhood (p = 0.046). CONCLUSIONS: Two-photon fluorescence is an innovative technique for the diagnosis of pigmented skin lesions, and shows a high sensitivity for detection of melanomas and pigmented BCCs.

Age as key factor for pattern, timing, and extent of distant metastasis in patients with cutaneous melanoma: A study of the German Central Malignant Melanoma Registry.

BACKGROUND: Melanoma incidence rates rise as people age, but the impact of aging on distant metastasis is unclear. OBJECTIVE: To investigate how timing, pattern, and extent of distant metastasis is influenced by age. METHODS: Analysis of a single-center cohort of 1457 patients of the German Central Malignant Melanoma Registry with prospectively documented follow-up. Findings were compared with those for 1682 patients from 5 different institutions. All patients presented initially with stage IA to IIC and developed distant metastasis in their further disease course. RESULTS: The number of metastatic sites decreased with increasing age at melanoma diagnosis (P < .001). The rate of stage M1d disease decreased from 50.2% in patients aged 50 years or younger to 30.1% in patients older than 70 years, and the rate of stage M1b disease increased from 5.8% to 21.5%. The rate of lung metastases remained stable in all investigated age groups (P = .54). Distant metastases occurred earlier and were more synchronized in patients older than 70 years than in patients aged 50 years or younger. An age-dependent decrease in metastatic sites and stable rate of lung metastasis were found and confirmed by data on the multi-institutional cohort. LIMITATIONS: The study was not population based. CONCLUSION: Pattern, timing, and extent of distant metastasis change as people age. These findings may be considered when treating patients with melanoma of different ages.

Impact of 18F-FDG-PET/CT on surgical management in patients with advanced melanoma: an outcome based analysis.

PURPOSE: To evaluate the influence of 18F-FDG-PET/CT on clinical decision making and outcome in advanced melanoma patients planned for radical metastasectomy. METHODS AND MATERIALS: A cohort of 333 patients with mainly stage III/IV melanoma having a PET/CT for clinical reasons was prospectively enrolled in our oncologic PET/CT registry between 2013 and 2015. Referring physicians completed questionnaires regarding their intended management for each patient before and after PET/CT. Management changes after PET/CT were classified as major and minor changes. A subgroup of 107 patients (stage I, N = 5; stage II, N = 3; stage III, N = 42; stage IV, N = 57) was planned for complete metastasectomy initially, based on conventional imaging. Management changes and outcome were evaluated by linkage with the information obtained from patients' medical records. RESULTS: In 28 of 107 patients (26%), the surgical treatment plan remained unchanged after PET/CT. In 24 patients (22%), minor changes were performed, such as enlargement or reduction of the surgical field. In 55 patients (51%, 95% CI 42%-61%) major changes of the intended treatment plan occurred; of those, 20 patients (19%) were classified to be tumor-free with PET/CT, 32 patients (30%) were found to have multiple previously unrecognized metastases and had to be treated by systemic therapy, three patients (3%) had to be changed to palliative radiotherapy or isolated extremity perfusion. The 1-year and 2-year overall survival (OS) in patients with complete metastasectomy (N = 52) was 90% and 79%, respectively. Systemically treated patients (N = 32) resulted in 1-year OS of 72% and 2-year OS of 61%. Eleven of 32 patients (34%) with systemic therapy experienced a complete response. Until December 2016, all 20 patients classified as tumor-free by PET/CT were alive. CONCLUSION: The study confirms the high impact of PET/CT on clinical management in patients with advanced melanoma planned for radical metastasectomy. PET/CT resulted in frequent management changes, preventing futile surgery in half of the patients.

Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial.

BACKGROUND: Complete lymph node dissection is recommended in patients with positive sentinel lymph node biopsy results. To date, the effect of complete lymph node dissection on prognosis is controversial. In the DeCOG-SLT trial, we assessed whether complete lymph node dissection resulted in increased survival compared with observation. METHODS: In this multicentre, randomised, phase 3 trial, we enrolled patients with cutaneous melanoma of the torso, arms, or legs from 41 German skin cancer centres. Patients with positive sentinel lymph node biopsy results were eligible. Patients were randomly assigned (1:1) to undergo complete lymph node dissection or observation with permuted blocks of variable size and stratified by primary tumour thickness, ulceration of primary tumour, and intended adjuvant interferon therapy. Treatment assignment was not masked. The primary endpoint was distant metastasis-free survival and analysed by intention to treat. All patients in the intention-to-treat population of the complete lymph node dissection group were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02434107. Follow-up is ongoing, but the trial no longer recruiting patients. FINDINGS: Between Jan 1, 2006, and Dec 1, 2014, 5547 patients were screened with sentinel lymph node biopsy and 1269 (23%) patients were positive for micrometastasis. Of these, 483 (39%) agreed to randomisation into the clinical trial; due to difficulties enrolling and a low event rate the trial closed early on Dec 1, 2014. 241 patients were randomly assigned to the observation group and 242 to the complete lymph node dissection group. Ten patients did not meet the inclusion criteria, so 233 patients were analysed in the observation group and 240 patients were analysed in the complete lymph node dissection group, as the intention-to-treat population. 311 (66%) patients (158 in the observation group and 153 in the dissection group) had sentinel lymph node metastases of 1 mm or less. Median follow-up was 35 months (IQR 20-54). Distant metastasis-free survival at 3 years was 77·0% (90% CI 71·9-82·1; 55 events) in the observation group and 74·9% (69·5-80·3; 54 events) in the complete lymph node dissection group. In the complete lymph node dissection group, grade 3 and 4 events occurred in 15 patients (6%) and 19 patients (8%) patients, respectively. Adverse events included lymph oedema (grade 3 in seven patients, grade 4 in 13 patients), lymph fistula (grade 3 in one patient, grade 4 in two patients), seroma (grade 3 in three patients, no grade 4), infection (grade 3 in three patients, no grade 4), and delayed wound healing (grade 3 in one patient, grade 4 in four patients); no serious adverse events were reported. INTERPRETATION: Although we did not achieve the required number of events, leading to the trial being underpowered, our results showed no difference in survival in patients treated with complete lymph node dissection compared with observation only. Consequently, complete lymph node dissection should not be recommended in patients with melanoma with lymph node micrometastases of at least a diameter of 1 mm or smaller. FUNDING: German Cancer Aid.

Sentinel Lymph Node Dissection in Head and Neck Melanoma has Prognostic Impact on Disease-Free and Overall Survival.

BACKGROUND: Sentinel lymph node biopsy (SLNB) plays an important role in the prognostic classification of melanoma and is now a standard staging procedure. However, due to the complex drainage pattern and the risk of site associated morbidity, the potential survival benefit of SLNB is controversial in head and neck (H&N) melanoma. METHODS: Patients with primary H&N melanoma with a tumor thickness ≥1.00 mm diagnosed in the Department of Dermatology, University of Tuebingen, Germany between 1991 and 2010 were included in this study. Regarding patterns of metastases, disease-free, and overall-survival, 259 patients with SLNB were compared retrospectively to 218 patients without SLNB. RESULTS: The detection of micrometastasis in SLN proved to be a significant prognostic factor in H&N patients [hazard ratio (HR) 3.69, p < 0.0001]. A significant improvement of recurrence-free survival (RFS, p = 0.011), regional lymph node metastasis-free survival (LFS, p = 0.007), and distant metastasis-free survival (DMSF, p = 0.015) was observed for patients with SLNB versus non-SLNB. Furthermore, a trend towards better overall survival (OS) was found (p = 0.053) for the SLNB group. CONCLUSIONS: SLNB improved prognostic outcome in H&N melanoma in terms of disease-free and distant metastases survival, reduced subsequent regional lymph node metastases, and showed a trend towards a better OS.

Epidemiology of Keratinocyte Skin Cancer with a Focus on Cutaneous Squamous Cell Carcinoma.

Keratinocyte skin cancer, consisting of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), is by far the most common cancer in white-skinned populations, with rapid increases over the last 50 years. While the age-standardized incidence rates increase worldwide, the age-standardized mortality rates are variable. The incidence rates of keratinocyte skin cancer are much higher compared to those of melanoma, and are largely attributed to the raising exposure to ultraviolet (UV) radiation, the most important causal risk factor for skin cancer. Whereas the development of BCC is mainly due to intense UV exposure during childhood and adolescence, the development of SCC is related to chronic, cumulative UV exposure over decades. Although mortality rates are relatively low, SCC is an increasing problem for healthcare services, significantly causing morbidity, especially in older age groups. This review reports on the epidemiology of keratinocyte skin cancer, with a focus on SCC, in Australia, the United States, and the north of Europe, with an outlook on further challenges health systems will be confronted with in the next 20 years.

Incidence, mortality and trends of cutaneous squamous cell carcinoma in Germany, the Netherlands, and Scotland.

AIM OF THE STUDY: Cutaneous squamous cell carcinoma (cSCC) incidences are increasing but scarcely available separated. We analysed incidence rates of cSCC over three decades with an extrapolation to 2040. METHODS: Cancer registries from the Netherlands, Scotland and two federal states of Germany (Saarland/Schleswig-Holstein) were sourced for separate cSCC incidence data. Incidence and mortality trends between 1989/90 and 2020 were assessed using Joinpoint regression models. Modified age-period-cohort models were applied to predict incidence rates up to 2044. Rates were age-standardised using the new European standard population (2013). RESULTS: Age-standardised incidence rates (ASIR, per 100,000 persons per year) increased in all populations. The annual percent increase ranged between 2.4% and 5.7%. The highest increase occurred in the age groups ≥60 years, especially in men aged ≥80 years, with a three to 5-fold increase. Extrapolations up to 2044 showed an unrestrained increase in incidence rates in all countries investigated. Age-standardised mortality rates (ASMR) showed slight increases between 1.4 and 3.2% per year in Saarland and Schleswig-Holstein for both sexes and for men in Scotland. For the Netherlands, ASMRs remained stable for women but declined for men. CONCLUSION: There was a continuous increase of cSCC incidence over three decades with no tendency for levelling-off, especially in the older populations as males ≥80 years. Extrapolations point to a further increasing number of cSCC up to 2044, especially among ≥60 years. This will have a significant impact on the current and future burden on dermatologic health care which will be faced with major challenges.

Identification of stage I/II melanoma patients at high risk for recurrence using a model combining clinicopathologic factors with gene expression profiling (CP-GEP).

PURPOSE: Patients with cutaneous melanoma stage I/IIA disease are currently not eligible for adjuvant therapy, despite their risk for relapses and death. This study validates the ability of a model combining clinicopathologic factors with gene expression profiling (CP-GEP) to identify patients at high risk for disease recurrence in stage I/II and subgroup stage I/IIA. PATIENTS AND METHODS: 543 patients with stage I/II primary cutaneous melanoma from the University of Tuebingen diagnosed between 2000 and 2017 were analysed. All patients received sentinel lymph node biopsy (SLNB). Analysis was conducted for a separate group of 80 patients who did not undergo SLNB. RESULTS: CP-GEP stratified 424 stage I/IIA patients (78% of the cohort) according to their risk for recurrence, with five-year relapse-free survival (RFS) rates of 77.8% and 93% for CP-GEP high risk (195 patients) and low risk (229 patients), respectively, and hazard ratio of 3.53 (p-value <0.001). In patients who did not receive SLNB biopsy, CP-GEP captured 6 out of 7 relapses. CONCLUSION: CP-GEP can be used to identify primary cutaneous melanoma patients with a high risk for disease recurrence - especially for stage I/IIA, who are considered low risk by AJCC 8th. These patients may benefit from adjuvant therapy. Also, in the future, when SLNB may become irrelevant, CP-GEP may serve as a risk stratification tool.

Features and Long-Term Outcomes of Stage IV Melanoma Patients Achieving Complete Response Under Anti-PD-1-Based Immunotherapy.

BACKGROUND: Immune checkpoint inhibition (ICI) has changed the melanoma treatment spectrum. Few studies have examined the characteristics and long-term outcomes of patients achieving complete response (CR) under ICI. MATERIALS AND METHODS: We evaluated patients with unresectable stage IV melanoma treated with first-line ICI. The characteristics of those achieving CR were compared with those not achieving CR. Progression-free survival (PFS) and overall survival (OS) were assessed. Late-onset toxicities, response to second-line treatment, the prognostic value of clinicopathologic features, and blood markers were examined. RESULTS: A total of 265 patients were included; 41 (15.5%) achieved CR, while 224 (84.5%) had progressive disease, stable disease, or partial response. At the therapy start, those who had CR were more likely to be older than 65 years of age (p = 0.013), have a platelet-to-lymphocyte ratio below 213 (p = 0.036), and have lower lactate dehydrogenase levels (p = 0.008) than those not achieving a CR. For those who discontinued therapy after CR, the median follow-up time after CR was 56 months (interquartile range [IQR] 52-58) and the median time from CR to therapy end was 10 months (IQR 1-17). Five-year PFS after CR was 79% and 5-year OS was 83%. Most complete responders had a normalization of S100 at the time of CR (p < 0.001). In simple Cox regression analysis, age below 77 years at CR (p = 0.04) was associated with better prognosis after CR. Eight patients received second-line ICI; disease control was seen in 63%. Late immune-related toxicities occurred in 25% of patients, most being cutaneous immune-related toxicities. CONCLUSIONS: Response, according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, is, until now, the most important prognostic factor, and CR is a valid surrogate marker for long-term survival in patients treated with ICI. Our results highlight the importance of investigating the optimal therapy duration in complete responders.

Deep learning-based scoring of tumour-infiltrating lymphocytes is prognostic in primary melanoma and predictive to PD-1 checkpoint inhibition in melanoma metastases.

BACKGROUND: Recent advances in digital pathology have enabled accurate and standardised enumeration of tumour-infiltrating lymphocytes (TILs). Here, we aim to evaluate TILs as a percentage electronic TIL score (eTILs) and investigate its prognostic and predictive relevance in cutaneous melanoma. METHODS: We included stage I to IV cutaneous melanoma patients and used hematoxylin-eosin-stained slides for TIL analysis. We assessed eTILs as a continuous and categorical variable using the published cut-off of 16.6% and applied Cox regression models to evaluate associations of eTILs with relapse-free, distant metastasis-free, and overall survival. We compared eTILs of the primaries with matched metastasis. Moreover, we assessed the predictive relevance of eTILs in therapy-naïve metastases according to the first-line therapy. FINDINGS: We analysed 321 primary cutaneous melanomas and 191 metastatic samples. In simple Cox regression, tumour thickness (p < 0.0001), presence of ulceration (p = 0.0001) and eTILs ≤16.6% (p = 0.0012) were found to be significant unfavourable prognostic factors for RFS. In multiple Cox regression, eTILs ≤16.6% (p = 0.0161) remained significant and downgraded the current staging. Lower eTILs in the primary tissue was associated with unfavourable relapse-free (p = 0.0014) and distant metastasis-free survival (p = 0.0056). In multiple Cox regression adjusted for tumour thickness and ulceration, eTILs as continuous remained significant (p = 0.019). When comparing TILs in primary tissue and corresponding metastasis of the same patient, eTILs in metastases was lower than in primary melanomas (p < 0.0001). In therapy-naïve metastases, an eTILs >12.2% was associated with longer progression-free survival (p = 0.037) and melanoma-specific survival (p = 0.0038) in patients treated with anti-PD-1-based immunotherapy. In multiple Cox regression, lactate dehydrogenase (p < 0.0001) and eTILs ≤12.2% (p = 0.0130) were significantly associated with unfavourable melanoma-specific survival. INTERPRETATION: Assessment of TILs is prognostic in primary melanoma samples, and the eTILs complements staging. In therapy-naïve metastases, eTILs ≤12.2% is predictive of unfavourable survival outcomes in patients receiving anti-PD-1-based therapy. FUNDING: See a detailed list of funding bodies in the Acknowledgements section at the end of the manuscript.

Reporting of melanoma cell densities in the sentinel node refines outcome prediction.

INTRODUCTION: Sentinel node biopsy is a key procedure to predict prognosis in melanoma. In a prospective study we compare reporting on melanoma cell densities in cytospin preparations with semiquantitative histopathology for predicting outcome. PATIENTS AND METHODS: Sentinel nodes from 900 melanoma patients were bisected. One half of each node was disaggregated mechanically. The melanoma cell density (number of HMB45 positive cells per million lymphocytes with at least one cell showing morphological features of a melanoma cell) was recorded after examining two cytospins. For the second half the maximum diameter of metastasis was determined after haematoxylin and eosin (H&E) and immunohistological staining of three slides. RESULTS: Cytospins were positive for melanoma in 218 of 900 patients (24%). Routine pathology was positive in 111 of 900 (12%) patients. A more extensive pathological workup in cytospin-only positive patients led to a revised diagnosis (from negative to positive) in 23 of 101 patients (22.7%). We found a moderate but significant correlation between melanoma cell densities (determined in cytospins) and the maximum diameter of metastasis (determined by pathology) (rho = 0.6284, p < 0.001). At a median follow-up of 37 months (IQR 25-53 months) melanoma cell density (cytospins) (p < 0.001), thickness of melanoma (p = 0.008) and ulceration status (p = 0.026) were significant predictors for melanoma specific survival by multivariable testing and were all confirmed as key predictive factors by the random forest model. Maximum diameter of metastases, age and sex were not significant by multivariable testing (all p > 0.05). CONCLUSION: Recording melanoma cell densities by examining two cytospins accurately predicts melanoma outcome and outperforms semiquantitative histopathology.

Prognosis of Patients With Primary Melanoma Stage I and II According to American Joint Committee on Cancer Version 8 Validated in Two Independent Cohorts: Implications for Adjuvant Treatment.

PURPOSE: The first randomized trial of adjuvant treatment with checkpoint inhibitor in stage II melanoma reported a significant reduction in risk of tumor recurrence. This study evaluates two independent data sets to further document survival probabilities for patients with primary stage I and II melanoma. PATIENTS AND METHODS: The Central Malignant Melanoma Registry (CMMR) in Germany evaluated 17,544 patients with a primary diagnosis of stage I and II melanoma from 2000 to 2015. The exploratory cohort consisted of 6,725 patients from the Center for Dermato-Oncology at the University of Tübingen, and the confirmatory cohort consisted of 10,819 patients from 11 other German centers. Survival outcomes were compared with published American Joint Committee on Cancer version 8 (AJCCv8) stage I and II survival data. RESULTS: For the two CMMR cohorts in stage IA compared with the AJCCv8 cohort, melanoma-specific survival rates at 10 years were 95.1%-95.6% versus 98%; 89.7%-90.9% versus 94% in stage IB; 80.7%-83.1% versus 88% in stage IIA; 72.0%-79.9% versus 82% in stage IIB; and 57.6%-64.7% versus 75% in stage IIC, respectively. Recurrence rates were approximately twice as high as melanoma-specific mortality rates in stages IA-IIA. CONCLUSION: The melanoma-specific survival rates in the two CMMR cohorts across stages I and II are less favorable than published in AJCCv8. This has important implications for the consideration of adjuvant treatment in this population.

Epidemiology of cutaneous melanoma and keratinocyte cancer in white populations 1943-2036.

OBJECTIVES: Cutaneous melanoma (CM) and keratinocyte cancer (KC) cause considerable morbidity and mortality. We analysed long-term trends of CM and KC in different white populations. MATERIAL AND METHODS: Age-standardised (European Standard Population 2013) incidence and mortality rates (ASIR, ASMR) of CM were extracted from cancer registries in Denmark, New Zealand and the US SEER-Database. ASIRs of KC were sourced from registries of the German federal states Saarland and Schleswig-Holstein, and from Scotland. Age-period-cohort models were used to project melanoma incidence trends. RESULTS: In Denmark between 1943 and 2016, melanoma ASIR increased from 1.1 to 46.5 in males, and from 1.0 to 48.5 in females, estimated to reach 60.0 and 73.1 in males and females by 2036. Melanoma mortality in Denmark (1951-2016) increased from 1.4 to 6.7 (males) and 1.2 to 3.7 (females). In New Zealand between 1948 and 2016, ASIR increased from 2.7 to 81.0 (males) and from 3.8 to 54.7 (females), slight declines are estimated by 2036 for both genders. Melanoma mortality increased six-fold in New Zealand males between 1950 and 2016; smaller increases were observed in females. We observed three- to four-fold increases in melanoma incidence in US whites, predicted to rise to 56.1 and 36.2 in males and females until 2036. Melanoma mortality also increased among US whites between 1970 and 2017, female melanoma mortality remained stable. Similar trends are shown for KC. CONCLUSIONS: In white populations, incidence of CM and KC significantly increased. CM incidence continues to rise in the short term but is predicted to decline in future.

Diffuse PRAME Expression Is Highly Specific for Thin Melanomas in the Distinction from Severely Dysplastic Nevi but Does Not Distinguish Metastasizing from Non-Metastasizing Thin Melanomas.

BACKGROUND: PReferentially expressed Antigen in MElanoma (PRAME) immunohistochemistry is increasingly used as diagnostic adjunct in the evaluation of melanocytic tumors. The expression and prognostic significance of PRAME in melanomas ≤1.0 mm and its diagnostic utility in the distinction from severely dysplastic compound nevi (SDN) have not been studied. METHODS: We investigated and compared the immunohistochemical PRAME expression in 70 matched thin metastasizing and non-metastasizing melanomas and 45 nevi from patients with long-term follow-up (35 SDN and 10 unequivocally benign compound nevi). RESULTS: Diffuse PRAME staining in >75% of lesional epidermal and dermal melanocytes identified 58.6% of thin melanomas but did not distinguish metastasizing from non-metastasizing melanomas (p = 0.81). A superficial atypical melanocytic proliferation of uncertain significance, in which the final diagnostic interpretation favored a SDN was the only nevus with diffuse PRAME expression (1/45). Melanomas and SDN with PRAME immunoreactivity exhibited different staining patterns. Most melanomas (67.6%) showed uniform PRAME expression in the in situ and invasive component, whereas most SDN (81.0%) showed a decreasing gradient with depth. CONCLUSION: Diffuse intraepidermal and dermal PRAME staining is highly specific for melanomas in the distinction from SDN. PRAME expression is not a prognostic biomarker in melanomas ≤1.0 mm.

Cutaneous melanoma attributable to UVR exposure in Denmark and Germany.

BACKGROUND: Increasing incidence rates of cutaneous melanoma (CM) observed during the last five decades in white populations are largely attributed to increased exposure to solar ultraviolet radiation (UVR), often expressed as population attributable fraction (PAF). Thus, many CMs could be prevented by reducing UVR exposure. The aim of this study was to estimate the PAF of CM attributable to UVR exposure and demographic changes in Denmark and Saarland/Germany for the period 1943 to 2036. MATERIAL AND METHODS: CM incidence data (ICD-10, C43) for Denmark (1943-2016) and the German Federal State of Saarland (1972-2016) were retrieved from the NORDCAN database and from the Saarland Cancer Registry. The number of CMs attributable to UVR exposure was calculated by comparing contemporary or predicted CM incidence rates with CM rates in Denmark during the years 1943-1946. RESULTS: In Denmark, the proportion of CM cases attributable to UVR exposure increased from around 20% in 1947-1951 to 96% in 2012-2016; in the Federal State of Saarland, it increased from 50% in 1972-1976 to 90% in 2012-2016. Until 2032-2036, the PAF is expected to rise in Denmark to 97% and in the Saarland to 92%. The demographic influence, on the other hand, is rather small. CONCLUSIONS: More than 90% of all CM in Germany and Denmark are attributable to UVR exposure, and in principle, preventable. These findings underline the need for primary prevention strategies, aiming to increase the awareness of melanoma and its risk factors and to promote behavioural changes that decrease sun exposure.