Elsevier

Cancer Epidemiology

Volume 36, Issue 5, October 2012, Pages 421-424
Cancer Epidemiology

Increased incidence of Merkel cell carcinoma among younger statin users

https://doi.org/10.1016/j.canep.2012.05.006Get rights and content

Abstract

Background

Statins (HMG-CoA-reductase inhibitors) are suggested to act as a predisposing factor for autoimmune diseases, have immunomodulatory effects, and possibly prevent some cancer types – the sum of these effects is unknown in cancers of viral aetiology, such as Merkel cell carcinoma (MCC). Aim of our study was to find out whether statin users in Finland have an increased incidence of MCC.

Patients and methods

A cohort of 224 715 male and 230 220 female statin users during 1994–2007 was identified from the Prescription Register of the National Social Insurance Institution. This cohort was followed up through the Finnish Cancer Registry for MCC up to 2009.

Results

There were altogether 50 cases of MCCs, while the expected number of cases, calculated on the basis of the MCC incidence in comparable Finnish population, was 39.9 (SIR 1.25, 95% CI 0.93–1.65). The standardized incidence ratio (SIR) for MCC in ages <60 years was 3.16 (95% CI 0.65–9.23), in ages 60–74 years 1.94 (95% CI 1.23–2.90) and in ages ≥75 years 0.89 (95% CI 0.57–1.31). The relative risk of MCC decreased significantly, 0.79 fold (95% CI 0.67–0.92), at each 5 year step when moving towards older age groups. There was no significant variation in SIR related to years since starting the statin use, or between the genders.

Conclusions

MCC is the first neuroendocrine cancer linked to statin use. The association is statistically significant and biologically plausible through immunomodulatory effects of statins. The excess of MCCs was observed in atypically young patients, a similar phenomenon as noted earlier in patients with immunocompromising states.

Introduction

Merkel cell carcinoma (MCC) is a rare and often lethal cutaneous neuroendocrine malignancy with a tendency to early and frequent locoregional-to-systemic metastasis and relapses [1], [2]. Although rare, with annual 6–10 cases in the entire population of Finland (5.4 million), the global incidence of MCC is on the increase [3]. In one study based on the surveillance, epidemiology, and end results (SEER) program registry of the United States the incidence of MCC increased from 0.15 per 100 000 person years in 1986 to 0.44 per 100 000 in 2001, adjusted to US standard population [3]. The increase has been suspected to be caused by both advances in diagnostics, and the increase in sun exposure [3].

A new aetiological pathway leading to MCC was recognized few years ago: Merkel cell polyomavirus (MCPyV) – a small polyomavirus with double-stranded DNA – was discovered in 2008 by Feng et al. [4]. Ensuing studies have confirmed the role of viral aetiology to be global and causative with monoclonal integration and truncation of large T (LT) viral antigen in MCC cells [5]. In Finnish MCC population the proportion of MCPyV positive tumours is as high as 80% [6]. The prevalence of MCPyV is higher among immunocompromised patients, for example patients with autoimmune diseases or immunosuppressive medication [7], [8].

The consumption of statins (HMG-CoA reductase inhibitors) has been increasing, and a substantial part of the middle-aged and elderly population use them continuously [9]. Statins are one of the most used prescription drugs in Finland (95.30 defined daily dose per 1000 in 2010) [10]. Statins potently reduce blood cholesterol levels and have a well-established role in the prevention of cardio- and cerebrovascular events [11]. In addition to statins’ beneficial effects on lipid disorders, they have been reported to reduce the overall risk for cancer by up to 20% [12]. Anti-inflammatory effects mediated by the inhibition of the HMG-CoA-pharnesylation axis have been speculated to underlie this reduction [12]. According to meta-analyses, statins have a neutral effect on the overall incidence of cancer [13], [14], [15], [16]. However, in a meta-analysis by Kuoppala et al. [16] and a record-linkage study by Haukka et al. [17], the use of simvastatin and pravastatin respectively were found to lead to a predisposition for non-melanoma skin cancer.

Although statins are well tolerated by most patients, about 5% of their users suffer from toxic muscle damage, which can be concentration dependent [18]. Recent studies suggest that some effects that are not dose dependent might be mediated via autoimmune processes [19]. The use of statins could predispose patients to autoimmune diseases such as lupus erythematosus, dermatomyositis and polymyositis [19] but statins also have significant immunosuppressive effects intrinsically [20], [21]. The sum of these effects is unknown in cancers of viral aetiology, such as MCC. We hypothesized that part of the recent increase in the incidence of MCC might be due to increased use of statins.

Section snippets

Patients and methods

All residents of Finland have a unique personal identity code (PIC) since 1 January 1967. PIC is used in all main registers in Finland and allows reliable automatic record linkage. The registry linkages in this study were done using the PIC as key.

A cohort of patients with listed purchases of statins during 1994–2007 was identified from the Prescription Register of the National Social Insurance Institution. The following substances were included: simvastatin, lovastatin, pravastatin,

Results

The study cohort consisted of 224 716 (49%) men and 230 221 (51%) women. The numbers of person-years were 2 053 109 and 2 126 269 respectively (Table 1). The mean length of follow-up was 9.2 years.

There were altogether 50 cases of MCCs, while the expected number of cases, calculated on the basis of the MCC incidence in comparable Finnish population, was 39.9 (SIR 1.25, 95% CI 0.93–1.65; Table 2). Female statin users were diagnosed with 29 MCCs (SIR 1.19, 95% CI 0.80–1.71) and male patients with 21

Discussion

Herein, we found that the SIRs of MCC among statin users were elevated up to the age of 70 and decreased significantly together with increasing age. The average age at diagnosis of MCC in Finland is 76.4 years [23]. Atypically young MCC patients appear to be frequently immunocompromised [8]. Many of the cancers linked to immunosuppression or immunocompromised states have been found to have a viral aetiology, analogous to MCC. Non-Hodgkin lymphoma is associated with Epstein-Barr virus [24] and

Conflict of interest statement

No conflict of interest.

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