3. Early detection of keratinocyte cancers
‘Early detection’ is a broad term that covers a number of discrete activities including:
- screening – the systematic, population-wide evaluation of asymptomatic patients to identify those with (or likely to have) skin cancer
- surveillance – the ongoing follow-up of people after a previous diagnosis of keratinocyte cancer (KC) or those at pre-determined high risk of skin cancer (e.g. based on history or clinical phenotype)
- case-finding – opportunistic examination of patients who have presented for clinical care
- skin self-examination.
Keratinocyte cancer (KC) comprising basal cell cancer (BCC) and cutaneous squamous cell carcinoma (cSCC), causes enormous morbidity and small but important mortality in Australia. Early detection is one arm of the overall skin cancer control strategy (along with primary prevention and optimal treatment) intended to reduce the burden of these cancers. Unresolved questions remain about the balance of harms and benefits arising from early detection, and hence the cost-effectiveness of this strategy when considered for the whole population.
Early detection of KCs through clinical inspection of the skin offers the potential to reduce morbidity. However, it is unlikely that a mortality benefit would ever be observed at the population level, because the age of onset is typically late and international data suggest that relative survival rates for patients with BCC (approximately 100%) and cSCC (approximately 95%) are very high under existing models of care No Australian data are available to estimate relative survival for BCC or cSCC.
In the absence of data for assessing survival benefit, evidence of benefit must be assessed using other endpoints, including morbidity, quality of life, cosmesis and cost.
Given the uniquely high incidence and burden of KCs in Australia, the high levels of public awareness, and the fact that most such cancers are treated in primary care settings, these guidelines have sought evidence primarily from studies conducted in Australia, supplemented with findings from other populations where relevant.
A particular challenge when reviewing the literature is that all studies exploring the benefits and hazards of early detection of skin cancer have been designed with melanoma as the primary endpoint. Data on the incidence and burden of KCs following early detection activities has been captured as a secondary endpoint, if at all. In Australia, it is impossible to formally evaluate early detection programs for KCs independently of early detection for melanomas for several reasons:
- The principal mode of detection is the same (i.e. visual inspection of the skin surface, with or without dermoscopy or other technological aids).
- The populations of patients at risk of melanoma overlap with those at risk of KCs.
- All suspicious lesions arising from a clinical examination of the skin require a clinical decision to excise or not.
Overview of evidence (non-systematic literature review)
What are the benefits versus hazards of early detection?
The principal intended benefit of early detection of KCs is to diagnose and excise the primary tumour when it is small in size, and before extension into the deeper dermis and subcutis or metastasis occur. Early excision restores skin health and should reduce the extent of surgical intervention or obviate it, thereby reducing patient discomfort and adverse events, achieving better cosmetic results, and lowering costs. While lower mortality is a theoretical benefit of early detection, in practice mortality rates from keratinocyte cancer are so low that improvements through early detection are not considered feasible (with the possible exception of patients undergoing solid organ transplants).
The principal hazard of early detection is overtreatment (i.e. medical or surgical intervention for lesions that are not malignant, or would never have led to morbidity or mortality had they been left untreated). The sequelae of overtreatment include unnecessary interventions, increased likelihood of adverse events and increased costs to patients and society.
A recent systematic review by the US Preventive Services Taskforce examined the evidence for the effect of visual skin cancer screening in the general population on morbidity and mortality (specific and all-cause). That review found no trials that reported on mortality but did report one ecologic study judged to be of ‘fair quality’ (the German SCREEN Study). This skin cancer screening study reported that 4.4% of screened patients (n=360,288) underwent at least one excision following a visual inspection of the skin, of whom 18.2% had a confirmed malignant diagnosis and 74.3% had confirmed benign diagnoses. Thus, the majority of skin excisions in that screened population were for benign lesions. However, these findings cannot be generalised to the Australian population given the far lower incidence of KCs in Germany than Australia and the differences in training and service provision of clinicians.
Is early detection of keratinocyte cancer accurate?
A key determinant of the performance of early detection is the diagnostic accuracy of the examining clinician. Accuracy is a function of sensitivity (the proportion of histopathologically confirmed skin cancers among those diagnosed clinically as ‘skin cancer’) and specificity (the proportion of truly benign lesions among all those lesions diagnosed clinically as ‘benign’). Globally, data informing these parameters from well-designed studies are scarce.
(Note: the definitions of sensitivity and specificity given above are pragmatic, and based on the necessity to establish the true diagnosis using the gold-standard test of histopathological examination of excised lesions. This restriction means that one can never know the ‘true’ sensitivity or specificity, since the size of the pools of ‘population true negative lesions’ and ‘population false negative lesions' are unknown).
A large Queensland study compared the diagnostic performance of mainstream general practitioners (GPs) with those working in primary care skin cancer clinics. Of the lesions excised, about 55% were KCs; the remainder were actinic keratoses (10%), benign naevi (11%), melanomas (1.5%) and other diagnoses. Sensitivity for diagnosing KCs in both groups was very high (skin cancer clinic doctors 0.94 versus GPs 0.92), but specificity was lower (skin cancer doctors 0.71 versus GPs 0.62). Thus when taken together, the proportion of lesions that were diagnosed clinically as KCs and which were histopathologically confirmed as such (the positive predictive value) was 0.72 for skin cancer doctors and 0.71 for GPs. On average, the primary care doctors in both settings excised about two lesions for each confirmed malignancy.
Is early detection of keratinocyte cancer effective?
In its recent comprehensive review of the evidence, the US Preventive Services Task Force acknowledged the importance of the potential benefits of early detection of skin cancer, but could not determine whether there is an incremental benefit to detecting KC early through a program of regular clinical examination as compared with patient self-identification followed by clinical evaluation. The task force concluded that the evidence is insufficient to assess the balance of the benefits and harms of visual skin examination by a clinician to screen for skin cancer.
Only one randomised controlled trial (RCT) with KC as the primary endpoint has tested the effectiveness of patient-led early detection activities in Australia, although other studies have explored this issue using a variety of study designs. No studies have assessed mortality as an endpoint, and nor are they ever likely to owing to the very low case-fatality rate for KCs in the general population.
The RCT by Janda et al tested the effectiveness of a video intervention, compared with control (printed materials), to encourage skin self-examination in 930 Queensland men aged over 50 years. Both the video and printed materials were effective in increasing skin self-examination behaviours in the target group, with around 50% of men in both groups reporting having performed skin self-examination in the 6-month interval between recruitment and follow-up, compared with 10% at baseline. Rates of nonsurgical management of suspicious skin lesions during follow-up were similar in both groups, but the intervention group underwent significantly more excisions or biopsies than the control group (41% versus 27%) and had significantly more skin cancers detected (60% versus 40%, p=0.03). The corollary is that both groups had large numbers of non-malignant lesions excised.
Is early detection cost-effective?
No studies have examined cost-effectiveness of early detection solely for BCC and SCC endpoints. A health economic analysis using data arising from the Australian early detection intervention trial in men over 50 years found that early detection was more expensive than usual care (AUD$5,298 versus $4,684), and was also inferior in terms of health utility measured in quality-adjusted life years (QALY) where 1 QALY equals 1 year lived in perfect health (mean QALY 7.53 versus 7.77). In further analyses, it was found that the main driver of costs was the cost of treating benign lesions, cSCCs and BCCs detected during clinical follow-up, with essentially no impact on mortality and an adverse effect on QALYs.
Are there high-risk groups who benefit from surveillance?
Organ transplant recipients (OTRs) have rates of cSCC up to 100 times higher than the general population and malignancy is the leading cause of death for this patient group. There is no high-quality evidence that early detection programs for skin cancer lead to measurable benefits for OTRs, although there is broad international consensus across agencies and professional societies to recommend this practice. A recent systematic review identified 13 clinical practice guidelines for patients following transplantation of one or more solid organs. Of these, 10 produced guidelines on screening for skin or lip cancer, and nine recommended annual examinations either by GPs (four guidelines) or by specialist (five guidelines). The single Australian guideline identified in the review was for the care of patients following kidney transplantation. The Australian guideline, which was based on the international kidney diseases working group, suggests that 'a health care specialist with expertise in skin cancer diagnosis examine the skin and lips of kidney transplant recipients annually, especially those with previous history of skin cancers'. The guidelines assigned a D grading (very low quality of evidence) to this recommendation.
Recent Australian research shows that skin cancer follow-up for OTRs in Queensland was highly variable and that the incidence of SCC was extremely high. Several recent articles also indicate the complexity of managing skin cancers and monitoring skin cancer risk in OTRs.
Can the risk of keratinocyte cancer be predicted reliably?
Prediction algorithms have been developed which estimate a person’s future risk of KC with high discriminatory accuracy. Using such tools, people at high risk can be identified with high discrimination (area under the ROC curve 0.80, 95% confidence interval 0.79–0.81). The strongest factors contributing to future risk include past history of excision of KC, past history of ablation or destruction of an actinic skin lesion, and age. As yet, there are no data to determine whether using such tools improves outcomes for patients. However, there is widespread clinical support for regular skin examinations for people with a prior history of treatment for actinic lesions (i.e. surveillance).
PP 3.1.1. Patients at very high risk of keratinocyte cancers (e.g. organ transplant recipients) should be monitored in specialist clinics at least annually.
Health system implications
There is insufficient evidence to recommend systematic activities for early detection of KCs, such as screening of the general population.
Implementation of the practice points concerning high-risk groups would not change current practice, which does not involve screening for KCs in the asymptomatic population.
Surveillance activities for patients at high to very high risk of KC (e.g. organ transplant recipients and people with prior history of skin cancer) will require skilled clinicians with training and experience in the diagnosis and management of benign and malignant skin lesions.
Surveillance of patients at high risk of KC will occur predominantly in primary care settings. Patients at very-high risk of KC, particularly organ transplant recipients, will mostly be managed by specialists.
Barriers to implementation
For patients at high or very high risk of KC, access to services staffed by appropriately skilled clinicians is a barrier to recommended surveillance in some regions.
Overall mortality from KCs is very low, and it is not known whether mortality can be reduced further by early detection. Similarly, at the population level, it is an open question whether early detection delivers morbidity benefits that outweigh the potential harms of over-diagnosis and over-treatment.
The advent of new technologies (e.g. reflectance confocal microscopy and optical coherence tomography for suspicious individual lesions; three-dimensional total body imaging, total body dermoscopy, and integrated genetic scores) which might deliver near-perfect positive predictive values for KCs and hence lessen the harms of over-treatment, could change the risk–benefit equation markedly.
Studies currently underway
A large prospective study in Queensland, the QSkin Study, has enrolled more than 45,000 participants and is following them through record-linkage to health registers and administrative databases, specifically monitoring skin cancer outcomes. That study is incorporating genetic risk prediction algorithms and health economics analyses as part of the research plan and aims to address some of the unresolved questions above.
The Skin Tumours in Allograft Recipients (STAR) study (also based in Queensland) is tracking skin cancer incidence among different groups of organ transplant recipients. STAR is also monitoring health service utilisation of study participants.
Future research priorities
A high priority for research is to determine whether targeted detection activities among people at high risk of KC is effective or efficient. Stratification tools, incorporating phenotypic, genetic and clinical data, should be tested as a method for triaging those at highest risk. In particular, the stratification of patients into ‘high’ and ‘very-high’ risk remains to be defined.
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