Increasing time trends of thin melanomas in The Netherlands: What are the explanations of recent accelerations?

BACKGROUND: A disproportional increase in in situ or thin melanomas may point at underlying causes such as increased melanoma awareness, as well as 'overdiagnosis' of melanoma in diagnostically equivocal small lesions. OBJECTIVES: The purposes of this study were to estimate trends in melanoma incidence by sex, Breslow thickness (thin melanomas subdivided into four subgroups: <0.25 mm, 0.25-0.49 mm, 0.50-0.74 mm, and 0.75-1.0 mm), age and location, and to compare these with trends in subgroups of thicker melanomas. METHODS: Data on all histologically confirmed in situ and invasive melanomas diagnosed between 1994 and 2010 were retrieved from the Netherlands Cancer Registry. Trends in European standardised rates (ESRs) were assessed using joinpoint analysis, and expressed as estimated annual percentage change (EAPC). RESULTS: Between 1994 and 2010, 34,156 persons were diagnosed with an in situ or thin melanoma. The ESR of in situ melanomas doubled for males and females with a recent steeper rise in incidence (EAPC 12% (95% confidence interval [CI]: 8.1-16) and 13% (95% CI: 5.9-20), respectively). ESR for thin melanomas amongst males approximately doubled with a steep, but non-significant acceleration compared to other thickness categories since 2006 for <0.25 mm melanomas (EAPC 26% (95% CI: 2.1-35)). For female patients with thin melanomas the ESRs increased almost two-fold, except for <0.25 mm melanomas. CONCLUSIONS: The incidence rates of in situ, thin and thick melanomas increased similarly between 1994 and 2010. Recently steep increases were found for in situ melanomas and thin melanomas in men. Explanations are 'overdiagnosis' in conjunction with increased ultraviolet exposure (natural and artificial) and therefore a 'true' increase, increased awareness, early detection, diagnostic drift and changed market forces in the Dutch health care system.

Surveillance of second-degree relatives from melanoma families with a CDKN2A germline mutation.

BACKGROUND: Lifetime melanoma risk of mutation carriers from families with a germline mutation in the CDKN2A gene is estimated to be 67%. The necessity to include family members in a melanoma surveillance program is widely endorsed, but there is no consensus on which family members should be invited. METHODS: In a retrospective follow-up study, we investigated the yield of surveillance of first- and second-degree relatives of melanoma and pancreatic cancer patients from 21 families with the "p16-Leiden" CDKN2A mutation. Melanoma incidence rates were compared with the general population. RESULTS: Three-hundred and fifty-four first-degree relatives and 391 second-degree relatives were included. Forty-five first-degree relatives and 11 second-degree relatives were diagnosed with melanoma. Most (72%) of second-degree relatives diagnosed with melanoma had become a first-degree relative before diagnosis, due to the occurrence of a melanoma in a parent or sibling. Overall, melanoma incidence rate was 2.1 per 1,000 person years [95% confidence interval (CI), 1.2-3.8] in family members still being second-degree relatives at diagnosis, compared with 9.9 per 1,000 person years (95% CI, 7.4-13.3) in first-degree relatives. The standardized morbidity ratio for melanoma of second-degree relatives compared with the general population was 12.9 (95% CI, 7.2-23.4). CONCLUSION: Second-degree relatives from families with the p16-Leiden mutation in CDKN2A have a considerably increased melanoma risk compared with the general population. IMPACT: This study provides justification for the surveillance of second-degree relatives from families with a CDKN2A germline mutation.

Melanocortin 1 receptor (MC1R) variants in high melanoma risk patients are associated with specific dermoscopic ABCD features.

Individuals with two red hair colour (RHC)-MC1R genetic variants have light skin and blond/reddish hair and, in comparison with those without such alleles, are at an increased risk of developing melanoma. Our study investigated the association of RHC variants and the Total Dermo-scopy Score (TDS), and the items that make up the TDS, in those with atypical naevi and melanomas from high risk melanoma patients. Eight hundred and seventy-six atypical naevi and 21 melanomas were scored according to the TDS system and MC1R polymorphisms were determined. Analyses revealed that several TDS items including pigment network, dark-brown colour and streaks were more frequently observed in atypical naevi from individuals without RHC variants, while structureless areas were more often observed in individuals with two RHC variants. Finally, no significant difference in TDS was detected in atypical naevi from individuals with two RHC variants compared to those without RHC. Clinicians should be aware of a different dermoscopic naevus pheno-type in patients with light blond or RHC MC1R variants.

[A man with blisters on hand and feet]. / Een man met blaren op handen en voeten.

A 41-year-old man with metastases of a gastrointestinal stroma tumour was treated with an angiogenesis inhibitor. He presented with a distinct painful erythematous hyperkeratotic bullous hand-foot skin reaction. This was thought to be caused by the oral angiogenesis inhibitor and resolved after discontinuation of the therapy. This is a known adverse effect of angiogenesis inhibitors and is dose dependent.

Impact of dermoscopy on the management of high-risk patients from melanoma families: a prospective study.

Few studies have investigated the impact of dermoscopy on the management of relatives from melanoma families. The objective of this study was to assess the impact of dermoscopy on clinical diagnosis and management decisions in high-risk familial melanoma patients. In a prospective study 132 consecutive patients were recruited from the pigmented lesions clinic of a tertiary reference centre for familial melanoma. Dermatologists expert in dermoscopy identified 49 suspicious pigmented lesions and recorded pre- and post-dermoscopy diagnoses and management decisions. Dermoscopy was performed in 37% of the patients. Two melanomas were identified. Dermoscopy did not influence sensitivity (1.0), but resulted in 42% fewer excisions, increasing specificity from 0.53 to 0.74 (p = 0.031). Dermoscopy resulted in a large reduction in the number of unnecessary excisions. These results suggest that the main effect of dermoscopy in clinical practice for this high risk population is a significant increase in specificity, rather than sensitivity.

Effectiveness and causes for failure of surveillance of CDKN2A-mutated melanoma families.

BACKGROUND: For more than 25 years families with an increased susceptibility to melanoma have been under surveillance at our institution. OBJECTIVE: We sought to investigate the effectiveness of surveillance for CDKN2A-mutated families and causes for failure of the program in patients with more advanced tumors. METHODS: In a retrospective case-control study, Breslow thickness of melanomas diagnosed in relatives enrolled in the surveillance program were compared with melanomas of unscreened index patients. We investigated the influence of mode of detection and length of surveillance interval on outcome. RESULTS: Surveillance melanomas (n = 226, median thickness: 0.50 mm) had a significantly lower Breslow thickness (multiplication factor: 0.61 [95% confidence interval 0.47-0.80], P < .001) than index melanomas (n = 40, median thickness: 0.98 mm). Index melanomas were more likely diagnosed with a Breslow thickness greater than 1.0 mm (odds ratio: 3.1 [95% confidence interval 1.2-8.1], P = .022). In all, 53% of surveillance melanomas were diagnosed during regular screens, 7% during patients' first screen, 20% between regular screens, and 20% in patients who were noncompliant with the surveillance schedule. The majority of surveillance melanomas (58%) were detected within 6 months after the last screen. There was no correlation between tumor thickness and the length of the screening interval for tumors diagnosed within 24 months since the last screen. LIMITATIONS: The study is retrospective. CONCLUSIONS: Surveillance was associated with earlier detection of melanomas. Noncompliance was an important cause for failing surveillance. Shortening surveillance intervals may advance detection of tumors, but may paradoxically have little impact on prognosis.

Clinical and histologic characteristics of malignant melanoma in families with a germline mutation in CDKN2A.

BACKGROUND: About 10% of cutaneous malignant melanomas (CMM) occur in individuals with a family history of melanoma. In 20% to 40% of melanoma families germline mutations in CDKN2A are detected. Knowledge of the clinicohistologic characteristics of melanomas and patients from these families is important for optimization of management strategies, and may shed more light on the complex interplay of genetic and environmental factors in the pathogenesis of melanoma. OBJECTIVE: We sought to investigate the clinical and histologic characteristics of CMM in CDKN2A-mutated families. METHODS: Clinical and histologic characteristics of 182 patients with 429 CMM from families with a founder mutation in CDKN2A (p16-Leiden mutation) were compared with 7512 patients with 7842 CMM from a population-based cancer registry. RESULTS: Patients with p16-Leiden had their first melanoma 15.3 years younger than control patients. The 5-year cumulative incidence of second primary CMM was 23.4% for patients with p16-Leiden compared with 2.3% for control patients. The risk of a second melanoma was twice as high for patients with p16-Leiden who had their first melanoma before age 40 years, compared with older patients with p16-Leiden. Unlike control patients, there was no body site concordance of the first and second melanoma in patients with p16-Leiden and multiple primary melanomas. Patients with p16-Leiden had significantly more superficial spreading, and less nodular and lentiginous melanomas. LIMITATIONS: Ascertainment of patients with p16-Leiden was family based. The study was performed in families with a founder mutation, the p16-Leiden mutation. CONCLUSION: Our findings are consistent with a pathogenic pathway of melanoma development from nevi, starting early and ongoing throughout life, and not related to chronic sun exposure.