Description of the condition
Malignant melanoma is a lethal cancer, which caused 55,488 deaths globally in 2012 (Globocan 2012a) - and disproportionately more in high-risk countries, such as Australia and New Zealand, where there were 2019 deaths in 2012 (Globocan 2012b). The incidence of malignant melanoma in white populations has risen manyfold over recent decades (Garbe 2009). It has been proposed that this is due to an increase in risk factors, mainly exposure to ultraviolet (UV) radiation from the sun and artificial sources (Waldmann 2012). However, it has also been suggested that this rise in incidence is caused by the overdiagnosis of indolent malignant melanomas, due to increased disease awareness, as increased incidence has not always been followed by increased mortality (Norgaard 2011; Welch 2005).
The most important avoidable risk factor is exposure to UV radiation through sunlight (Gandini 2005). Intermittent sun exposure confers a higher risk, while high continuous exposure seems to be inversely associated with malignant melanoma (Gandini 2005). Exposure in childhood appears to induce a higher risk than exposure later in life (Gruber 2006). An association between artificial sources of UV radiation, such as solariums, and malignant melanoma is likely, but the evidence is limited by inherent biases in the observational studies (Lazovich 2016). Other risk factors include blonde or red hair, green or blue eyes, freckles, an inability to tan, a family history of malignant melanoma, and a large number of naevi and dysplastic naevi (Marks 2000). A randomised controlled trial showed that an effect of sunscreen was to reduce the risk of malignant melanoma, but the evidence is limited by few events in the trial (Green 2011). Educational programmes, including counselling on the avoidance of intense sun exposure and use of sunscreen, have been suggested as a way to reduce mortality of malignant melanoma through primary prevention; a Cochrane Review is currently in progress to evaluate this strategy (Langbecker 2014).
Description of the intervention
Screening for malignant melanoma can be performed through visual self-examination of the skin or visual inspection by a physician, general practitioner, dermatologist, or other health professional. This visual inspection can then be extended to include dermoscopy of identified lesions. Other methods to assist in diagnosing malignant melanomas are evolving and might also be used in screening, for example, teledermatology, mobile phone applications, and spectroscopy-based techniques (Dinnes 2015). The heightened sensitivity that these new methods might confer may increase both the major benefit (a mortality reduction) and the major harm (overdiagnosis) of the intervention. Amongst general practitioners, the sensitivity and specificity of visual inspection has been estimated to be 72% to 84% and 70% to 71%, respectively (Brochez 2001). However, most studies are testing the diagnostic accuracy of inspecting identified pigmented lesions, i.e. not the accuracy of a screening examination of adults with no suspected lesions. Furthermore, sensitivity and specificity do not take overdiagnosis into account; therefore, they are less informative in a screening context than for diagnostic tests. A suite of Cochrane Reviews are currently evaluating the accuracy of tests to assist in diagnosing malignant melanoma (Dinnes 2015).
Screening can be organised as programmes where all potential participants in a community are individually invited to screening or as campaigns where the eligible population is encouraged to participate, for example, through the mass media. Screening for malignant melanoma is not recommended in the US (USPSTF 2009), Canada (CTFPHC 2013), Australia, or New Zealand (ACNMGRWP 2008). Despite this, non-organised screening is increasingly being adopted in many Western countries: in Australia, the one-year frequency of having skin screening ranges from 10% to 50% of the adult population depending on how skin screening is defined (Balanda 1994; Borland 1995; Girgis 1991; Heywood 1994; Janda 2004), and the corresponding rate in the US is 14% to 20% (Federman 1997; Federman 2006; Ford 2004; Sarayia 2004). In Europe, a campaign involving dermatologists in over 30 countries recommends "visiting your dermatologist regularly for a skin check-up" and conducting self-examination every month (EADO 2016).
How the intervention might work
The prognosis of malignant melanoma is closely correlated to the thickness of the lesion at diagnosis, with thinner lesions having a lower risk of metastases and a better prognosis (Breslow 1970). Therefore, early detection through screening could decrease mortality and morbidity from malignant melanoma. Screening might also result in less invasive surgery and less use of adjuvant therapy if the incidence of late-stage disease is reduced, which would be an important benefit in itself (Welch 2011). However, the vast majority of the substantial increase in the incidence of malignant melanoma in countries where skin screening has been adopted represents a rise in the incidence of thin lesions (Norgaard 2011; Welch 2005).
For early-detection strategies to be effective, they must not only detect more cancers at an early stage, but this must also lead to a lower incidence of late-stage disease over time to result in improved prognosis (Keen 2015; Vainio 2002). If a decrease in late-stage disease does not occur, the increase in early-stage disease diagnosis may simply represent detection of lesions that are histologically malignant but would nonetheless never have caused symptoms or death if they had remained undetected, i.e. overdiagnosis (Welch 2011). Overdiagnosed melanomas differ from false positive findings in that they remain defined as malignant, even after histological examination (Welch 2011). It is not possible to know which specific individuals are overdiagnosed. The same is true for the mortality benefit, i.e. it is not possible to know which specific individuals avoid death from malignant melanoma due to screening (Welch 2011).
However, for both outcomes (i.e. overdiagnosis and mortality benefit), it is possible to estimate the rate of events in the two arms of the trials (deaths ascribed to the disease and incident cases) (Welch 2011). Because screening relies on earlier diagnosis, sufficiently long follow-up after the screening intervention has stopped is necessary to quantify overdiagnosis. It is also necessary that the control group has not been offered screening at the end of the trial. When these requirements are fulfilled, it is possible to quantify overdiagnosis by comparing the number of melanomas diagnosed in the screened versus the non-screened group (Welch 2011), because compensation will have been made for any advance of the time of diagnosis.
Overdiagnosis leads to overtreatment, which means that healthy individuals are exposed to unnecessary surgery and possibly adjuvant therapy. Overdiagnosis also constitutes unnecessary labelling of healthy individuals with a cancer diagnosis, which may result in psychological harm (Welch 2011). Rising incidence at the population level complicates the interpretation of incidence and mortality data available in national registries (Norgaard 2011; Welch 2005). In order to understand these trends, which are observed especially in Western societies, the relative contribution of increased sun exposure and possible overdiagnosis with screening needs to be studied.
As it is not possible to distinguish between benign naevi and malignant melanomas with certainty through visual inspection or dermoscopy, a number of unnecessary biopsies or local excisions of benign lesions will result from screening for malignant melanoma, i.e. false positive findings (Harris 2014; Welch 2005). This may lead to psychological stress in addition to the physical consequences of the excisions. On the other hand, malignant lesions may also be missed at screening (false negatives), which may lead to false reassurance and delayed contact with health professionals and delayed diagnosis (Goldenberg 2016). Screening for malignant melanoma may also lead to the discovery of other skin conditions, non-malignant as well as malignant, and result in treatment for these conditions. This may be either beneficial or harmful to patients. Quantifying the effects on morbidity and mortality of diagnosing such conditions is outside the scope of this Review. However, we will quantify any increase in diagnoses and treatments for such conditions, if possible.
Disease-specific mortality in cancer screening trials is an outcome prone to bias from misclassification of the cause of death (Prasad 2016), mainly due to 'sticky-diagnosis' bias and 'slippery-linkage' bias (Black 2002). Sticky-diagnosis bias refers to the risk that the cause of death is falsely attributed to the disease in question, even if this is not the case (Black 2002). Slippery-linkage bias refers to the opposite: that death is attributed to another cause, usually because some time has elapsed since diagnosis. These biases work in opposite directions, and it is not possible to know which one will dominate (Black 2002). Total mortality as an outcome is free of these and other biases and is therefore the most reliable outcome when evaluating the effect of a screening programme. Total mortality has the further advantage that it includes treatment-related mortality, which is of particular concern for screening interventions where overdiagnosis and overtreatment is suspected. It thus captures both the main benefit and the main harms of the intervention. The downside of total mortality as an outcome is that large populations are needed in the trials to reliably detect a difference (Prasad 2016).
Why it is important to do this review
Screening for malignant melanoma is currently practised in many countries, apparently without support from rigorously conducted randomised controlled trials. This is a noteworthy drawback since evidence from randomised controlled trials is considered mandatory before the introduction of screening programmes for cancer (UKNSC 2015; WHO 2008). There is evidence that screening for malignant melanoma may cause overdiagnosis of harmless malignant melanomas and consequently overtreatment (Norgaard 2011; Welch 2005); this is in addition to false positive findings, which in breast cancer screening, for example, are known to cause substantial long-lasting psychological stress (Heleno 2015).
In the light of these concerns, our aim is to assess the evidence for screening the general population to see if it can reduce morbidity and mortality due to malignant melanoma.