Elsevier

European Journal of Cancer

Volume 53, January 2016, Pages 115-124
European Journal of Cancer

Original Research
Risk factors for keratinocyte skin cancer in patients diagnosed with melanoma, a large retrospective study

https://doi.org/10.1016/j.ejca.2015.10.058Get rights and content

Highlights

  • Melanoma survivors are at increased risk of developing keratinocyte skin cancer (KSC).

  • The estimated cumulative incidence exceeds by far that of the general population.

  • Some characteristics, including melanocortin 1 receptor variants, define melanoma patients at higher risk of developing KSC.

Abstract

Background

Melanoma survivors are at an increased risk of developing other malignancies, including keratinocyte skin cancer (KSC). While it is known that many risk factors for melanoma also impact risk of KSC in the general population, no previous study has investigated risk factors for KSC development in melanoma patients.

Objective

We assessed associations of personal and clinical characteristics, including skin phenotype and variations in the melanocortin 1 receptor (MC1R) gene, with KSC risk in melanoma patients.

Patients and methods

We used prospective follow-up information on 1200 patients treated for melanoma at the Instituto Valenciano de Oncología, Spain, between 2000 and 2011. We computed hazard ratios and 95% confidence intervals (CIs) for the association of clinical, personal and genetic characteristics with risk of KSC, squamous cell carcinoma (SCC), or basal cell carcinoma (BCC) from Cox proportional hazard models. Five-year cumulative incidence based on competing risk models of SCC, BCC or KSC overall was computed using multivariate subdistribution hazard models. To assess predictive performance of the models, we computed areas under the receiver-operating characteristic curves (AUCs, discriminatory power) using cross-validation.

Results

Median follow-up was 57.2 months; a KSC was detected in 163 patients (13.6%). In multivariable Cox models, age, sex, sunburns, chronic sun exposure, past personal history of non-melanoma skin cancer or other non-cutaneous neoplasia, and the MC1R variants p.D294H and p.R163Q were significantly associated with KSC risk. A cumulative incidence model including age, sex, personal history of KSC, and of other non-cutaneous neoplasia had an AUC of 0.76 (95% CI: 0.71–0.80). When p.D294H and p.R163Q variants were added to the model, the AUC increased to 0.81 (95% CI: 0.77–0.84) (p-value for difference <0.0001).

Conclusions

In addition to age, sex, skin characteristics, and sun exposure, p.R163Q and p.D294H MC1R variants significantly increased KSC risk among melanoma patients. Our findings may help identify patients who could benefit most from preventive measures.

Introduction

Although malignant melanoma remains the major cause of death associated with skin cancers, public awareness, early detection and improved treatment strategies have markedly prolonged patient survival. Increased incidence and improved survival have led to an ever increasing number of melanoma survivors. However, like survivors of other cancers, patients who survive melanoma are also at an increased risk of developing second primary malignancies, which include second melanomas and keratinocyte skin cancers (KSCs) [1], [2], [3], [4].

Considering the morbidity caused by KSC in melanoma survivors and the added burden to healthcare systems, it is important to identify factors associated with increased risk for such malignancies for targeted prevention efforts. We hypothesised that risk factors associated with both primary melanoma and KSC also increase KSC risk in melanoma survivors. Factors associated with both risk of melanoma and risk of KSC include susceptible skin phototype with propensity to sunburn and sun exposure. Genetic variations in low-penetrant pigmentation genes that are major determinants of predisposing phenotypes like skin and hair colour are also known risk factors for both melanoma and KSC [5], [6]. Variants in the melanocortin 1 receptor (MC1R) gene are among the most important genetic determinants of high-risk phenotypes like fair skin and red hair and consequently increased risk of skin cancers in general [7], [8], [9], [10], [11], [12], [13], [14], [15].

Despite known risk of KSC in patients who survived melanoma, no prospective study to date has assessed risk factors in detail. Thus, we investigated the association of personal, clinical and genetic factors with risk of developing of KSC in melanoma patients in a cohort of 1200 melanoma patients followed for over 10 years. We also estimated cumulative incidence of KSC risk to stratify patients for increased surveillance and preventative measures.

Section snippets

Patients and methods

Patients with cutaneous melanoma in this study include individuals who had been treated at the Instituto Valenciano de Oncología between 1st January 2000 and 31th December 2011. At the end of this period, the database contained information for 1792 incident and prevalent patients. A wide range of clinical, epidemiological and histological variables evaluated by dermatologists with specialised training in melanoma management were collected, as described in detail previously [16].

In brief, all

Results

The investigated population included 1200 patients with median age at diagnosis of the first primary melanoma of 56.8 years (range 18.4–96.1 years). The characteristics of the population are detailed in Table 1 and Supplementary Table 1 (by groups defined by the development of KSC, SCC or BCC). A 50.7% of the patients were female. Most patients (61.2%) had skin phototype III–V, dark hair (73.0%) and dark eyes (59.4%); 14.0% of patients reported intense sun exposure at work (for >20 years) and

Discussion

It is well known that patients with melanoma are at an elevated risk of developing non-melanoma skin cancers;[22] however, associated factors have not been comprehensively investigated. We thus studied cumulative incidence of KSC and related risk factors in a large cohort of melanoma patients. We also estimated the role of MC1R variants in the development of KSC, particularly BCC, in patients diagnosed with cutaneous melanoma. In our population, the estimated cumulative incidence of KSC in

Conflict of interest statement

None exists.

Authors' contribution to this study

Pablo Espinosa: literature search, data collection, and writing. Ruth M. Pfeiffer: study design, figures, data analysis, data interpretation, and writing. Zaida García-Casado: data collection and writing. Celia Requena: data collection. Maria Teresa Landi: data interpretation and critical revision of the manuscript. Rajiv Kumar: data collection, data interpretation, and writing. Eduardo Nagore: literature search, conception and design of the study, data collection, data interpretation, and

Acknowledgement

We thank Orestis Panagiotou for helpful comments.

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