Relationship Between Type 2 Diabetes Mellitus and Markers of Cutaneous Melanoma Aggressiveness

An Observational Multicentric Study in 443 Patients With Melanoma

E. Nagore; M.A. Martinez-Garcia; J.D. Gomez-Olivas; E. Manrique-Silva; A. Martorell; J. Bañulls; C. Carrera; P. Ortiz; J. Gardeazabal; A. Boada; E. de Eusebio; E. Chiner; C. Gonzalez; A. Pérez-Gil; D. Cullen; M. Formigón; B. de Unamuno; C. Navarro-Soriano; A. Muriel; D. Gozal

Disclosures

The British Journal of Dermatology. 2021;185(4):756-763. 

In This Article

Abstract and Introduction

Abstract

Background: Some studies have suggested a relationship between type 2 diabetes mellitus (T2DM) and increased incidence of melanoma. Efforts are under way to identify preventable and treatable factors associated with greater melanoma aggressiveness, but no studies to date have examined the relationship between T2DM and the aggressiveness of cutaneous melanoma at diagnosis.

Objectives: To explore potential associations between T2DM, glycaemic control and metformin treatment and the aggressiveness of cutaneous melanoma.

Methods: We conducted a cross-sectional multicentric study in 443 patients diagnosed with cutaneous melanoma. At diagnosis, all patients completed a standardized protocol, and a fasting blood sample was extracted to analyse their glucose levels, glycated haemoglobin concentration and markers of systemic inflammation. Melanoma characteristics and aggressiveness factors [Breslow thickness, ulceration, tumour mitotic rate (TMR), sentinel lymph node (SLN) involvement and tumour stage] were also recorded.

Results: The mean (SD) age of the patients was 55·98 (15·3) years and 50·6% were male. The median Breslow thickness was 0·85 mm. In total, 48 (10·8%) patients were diagnosed with T2DM and this finding was associated with a Breslow thickness > 2 mm [odds ratio (OR) 2·6, 95% confidence interval (CI) 1·4–4·9; P = 0·004)] and > 4 mm (OR 3·6, 95% CI 1·7–7·9; P = 0·001), TMR > 5 per mm2 (OR 4·5, 95% CI 1·4–13·7; P = 0·009), SLN involvement (OR 2·3, 95% CI 1–5·7; P = 0·038) and tumour stages III–IV (vs. I–II) (OR 3·4, 95% CI 1·6–7·4; P = 0·002), after adjusting for age, sex, obesity, alcohol intake and smoking habits. No significant associations emerged between glycated haemoglobin levels, metformin treatment and melanoma aggressiveness.

Conclusions: T2DM, rather than glycaemic control and metformin treatment, is associated with increased cutaneous melanoma aggressiveness at diagnosis.

Introduction

Exposure to ultraviolet radiation is the major known environmental risk factor for the development of cutaneous melanoma. Other factors, such as obesity (among men), decreased physical activity, cigarette smoking and alcohol consumption might also contribute to its increasing incidence.[1–5] Although the current clinical, molecular and histopathological markers provide insight into cutaneous melanoma outcomes, it is still an unpredictable disease.[6]

Type 2 diabetes mellitus (T2DM) accounts for 90–95% of all diagnosed cases of diabetes and, in parallel with the worldwide escalation in the prevalence of obesity, T2DM is becoming increasingly common on a global scale.[7] Patients with T2DM increasingly present several types of solid tumours, although there have also been reports of a paradoxical reduction in the incidence of prostate cancer.[8–12]

However, the relationship between T2DM and cutaneous melanoma has scarcely been studied. A recent meta-analysis has suggested that T2DM represents a risk factor for melanoma, although the findings of each study included in the meta-analysis were inconsistent.[13] Insulin resistance has recently been found to be associated with cutaneous melanoma,[14] and hyperinsulinaemia, hyperglycaemia and fat-induced chronic inflammation have been suggested as plausible links between T2DM and cancer.[15] Adipose tissue may play a role here, as supported by the positive correlation between obesity and cutaneous melanoma risk, at least in men.[16]

However, the potential contributions of T2DM and the effect of confounders such as age, obesity, alcohol intake, smoking habits, environmental factors, glycaemic control and diabetes treatment (especially metformin, given its putative antitumoral activity)[17] on the aggressiveness of cutaneous melanoma at the time of its detection and diagnosis have not been studied prospectively.

Therefore, we formulated a working hypothesis, whereby T2DM would be associated with greater cutaneous melanoma aggressiveness, based on the existing evidence that insulin resistance and secondary chronic hyperinsulinaemia and hyperleptinaemia (both key antecedents of T2DM), may stimulate faster tumour growth and promote metastases.[18–20]

The objective of this study was to analyse potential associations between, on the one hand, T2DM, glycaemic control and diabetes treatment with metformin and, on the other, parameters influencing the aggressiveness of cutaneous malignant melanoma.

processing....