Keratinocyte carcinoma in Iceland: Epidemiology and risk in association with medication

Abstract

Vitað er að mikil aukning hefur verið á grunnfrumu og flöguþekjumeinum í húð síðustu ár í vestrænum löndum en ekki er alveg skýrt hvers vegna svo er. Helstu áhættuþættir þessara meina eru ljós húð og útfjólublá geislun, og einnig hafa sum lyf verið bendluð við aukina áhættu með því að valda ónæmisbælingu eða auknu næmi fyrir útfjólublárri geislun í húð. Ekki er mikið til af rannsóknum sem skoða faraldsfræði og áhættuþætti þessara húðmeina, og það er óljóst hvort sum þessara lyfja sem auka þessa áhættu myndu gera það á Íslandi þar sem er lítil útfjólublá geislun miðað við flest önnur lönd. Helstu markmið þessarar rannsóknarar var að athuga sérstaklega tíðni þessara meina á Íslandi og einnig skoða hvaða áhrif ákveðin lyf gætu verið að hafa á áhættu íslendinga að fá þessi mein. Við skoðuðum sérstaklega hydrochlorothiazide (HCTZ), TNF-alpha hindra og statín, sem hafa í sumum rannsóknum verið bendluð við aukna áhættu á húðmeinum. Einnig þá skoðuðum við hugsanleg tengsl metformin við húðmein, en metformin hefur sýnt að lækki áhættu á krabbameinum í sumum rannsóknum. Gagnagrunnur hjá krabbameinsskrá var notaður til þess að reikna tíðnitölur, og var lyfjagrunnur landlæknisembættis notaður til þess að skoða tengsl við lyf. Niðurstöður okkar sýndu að þrátt fyrir það að útfjólublá geislun á Íslandi sé lág hefur tíðni grunn- og flöguþekjumeina aukist til muna, og Ísland er eina landið þar sem að tíðni grunnfrumumeins og grunns flöguþekjumeins er hærra í konum heldur en körlum. Þetta kann að skýrast af því konur virðast vera líklegri til þess að nota ljósabekki og stunda sólböð þegar þær eru erlendis heldur en karlmenn. Karlmenn vinna oftar úti heldur en konur en erlendis þá eru þeir því í hárri áhættu að fá húðkrabbamein vegna mikillrar geislunar. Á Íslandi er þessi geislun heldur minni. Einnig sáum við að þessi aukning á húðmeinum er mest á búk og fótleggjum kvenna, sem bendir enn frekar til ljósabekkja eða sólarlandafera sem orsök. Varðandi lyf, þá var HCTZ tengt við aukna áhættu á bæði grunn- og flöguþekjuæxlum. HCTZ eykur næmi fyrir útfjólubláum geislum og því var ekki endilega viðbúist að lyfið auki áhættu í landi með svo litla bakgrunns geislun. TNF-alpha hindrar og statín voru bæði tengt við aukna áhættu á flöguþekjumeinum, en ekki grunnfrumukrabbameini. Læknar sem skrifa út þessi lyf þurfa að vera meðvitaðir um þessa tengingu. Metformín var tengt við lægri áhættu á grunnfrumukrabbameini en ekki flöguþekjukrabbameini, en þörf er á frekari rannsóknum til þess að staðfesta þessa tengingu.

An epidemic of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) has led to a significant healthcare burden in white populations. The incidence of both cancers is on the rise, the reasons for which are unclear. While the principal risk factors for these cancers are fair skin and ultraviolet radiation (UVR) exposure, certain medications have also been implicated in increased skin cancer risk through immunosuppression, immunomodulation, or UVR sensitization. Whole population studies assessing the epidemiology of and risk factors for BCC and SCC are lacking, and it is unclear whether medications significantly increase the risk of BCC and SCC development in the low UV radiation environment that Iceland provides. The primary objective of this study was to establish incidence rates and tumor burden in an unselected, geographically isolated population that is exposed to low levels of UVR. The secondary objective was to delineate the relationship between SCC/BCC and hydrochlorothiazide (HCTZ), TNF-alpha inhibitors (TNFi), and statins. These medications have, in some studies, been associated with increased risk of BCC and SCC development through UV sensitization, immunosuppression, and immunomodulation, respectively. Lastly, the relationship between metformin, which has been shown in some studies to decrease cancer risk, and BCC and SCC development was investigated. To accomplish our goals, we undertook a whole-population study based on the Icelandic cancer registry. We assessed incidence according to age, residence, and multiplicity and assessed trends using joinpoint analysis. Age-standardized (World) and age-specific incidence rates were calculated along with cumulative and lifetime risks. To assess the relationship between medication and skin cancer, we used a population-based case-control study design. The group of cases consisted of all individuals diagnosed for the first time with SCCis, invasive SCC, and BCC of the skin. For each case, ten unaffected population controls, matched by year of birth and sex, were randomly selected from the National Register of Iceland. We employed conditional logistic regression analysis to calculate multivariate odds ratios (ORs). During the study period, the incidence for all subtypes of KC increased, despite Iceland’s low background UVR. This increase was most prominent in women on sites not generally exposed to UV radiation in Iceland: the trunk and legs. Joinpoint analysis showed the fastest increase in SCCis incidence to be in women. Women with SCCis also had a higher likelihood of developing new lesions than men, with a multiplicity of 1.71. Men are more likely than women to develop invasive SCCs, which occur almost exclusively in the head and neck. Lip SCCs were much more likely to be invasive than in situ. HCTZ was associated with all subtypes of KC. TNFis and statins were associated with SCC but not BCC. Cutaneous KC is becoming a significant public health problem worldwide. Iceland is the only reported population, to our knowledge, in which the incidence of BCC and SCCis is significantly higher in women than in men. While in most countries, men have a higher incidence of BCC and SCC, Iceland's low UV radiation environment might protect men, as women may be more likely to engage in high-risk tanning behaviors. Despite the low background UV radiation in Iceland, high cumulative exposure to the UV sensitizing medication HCTZ was associated with the development of BCC, SCCis, and invasive SCC, suggesting that sun-protective behaviors alone may not eliminate the carcinogenic potential of HCTZ in high UV countries. TNFis and statins increased individual risk for SCC, but not BCC, a phenomenon also seen in organ transplant recipients and patients on immunosuppressive medications such as cyclosporine. These associations require further study. Public health efforts (focusing on the potentially harmful effects of UVR) and physician education will be essential to counteract the increasing skin cancer incidence in Iceland as its population ages. Since metformin use was associated with decreased BCC development, it is possible that metformin might be a reasonable option for patients at high risk for developing BCC, or used to slow the rate of BCC development in patients with multiple skin cancers. This requires further study using prospective design models.