Abstract
Introduction
Cutaneous squamous cell carcinoma is a malignant tumour of keratinocytes arising in the epidermis, with histological evidence of dermal invasion. Incidence varies by country and skin colour, and is as high as 400/100,000 in Australia. People with fair skin colour who sunburn easily without tanning, people with xeroderma pigmentosum, and people who are immunosuppressed are most susceptible to squamous cell carcinoma.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: Does the use of sunscreen help prevent cutaneous squamous cell carcinoma and solar keratosis? What is the optimal margin for primary excision of cutaneous squamous cell carcinoma (non-metastatic)? Does micrographically controlled surgery result in lower rates of local recurrence than standard primary excision in people with squamous cell carcinoma of the skin (non-metastatic)? Does radiotherapy after surgery affect local recurrence of cutaneous squamous cell carcinoma in people with squamous cell carcinoma of the skin (non-metastatic)? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 11 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: micrographically controlled surgery, primary excision, radiotherapy after surgery, and sunscreens.
Key Points
Cutaneous squamous cell carcinoma is a malignant tumour of keratinocytes arising in the epidermis, with histological evidence of dermal invasion.
Incidence varies by country and skin colour, and is as high as 400/100,000 in Australia.
People with fair skin colour who sunburn easily without tanning, people with xeroderma pigmentosum, and people who are immunosuppressed are most susceptible to squamous cell carcinoma.
Daily use of sunscreen to the head, neck, arms, and hands seems to reduce the incidence of squamous cell carcinoma more than discretionary use.
Daily sunscreen to the head, neck, arms, and hands also seems to reduce the rate of acquisition of solar keratoses more than discretionary use, and to reduce the incidence of new solar keratoses in people who had previous solar keratoses.
With regard to surgery, we found no evidence to assess the optimal primary excision margin required to prevent recurrence of squamous cell carcinoma.
We also found no evidence examining whether micrographically controlled surgery is more beneficial than primary excision, although it is generally considered more tissue-sparing because of its specificity in determining the amount of normal surrounding tissue removed.
We do not know whether radiotherapy after surgery reduces local recurrence compared with surgery alone.
About this condition
Definition
Cutaneous squamous cell carcinoma is a malignant tumour of keratinocytes arising in the epidermis, showing histological evidence of dermal invasion.
Incidence/ Prevalence
Incidence rates are often derived from surveys, because few cancer registries routinely collect notifications of squamous cell carcinoma of the skin. Incidence rates on exposed skin vary markedly around the world according to skin colour and latitude, and range from negligible rates in black populations to around 25/100,000 in men and 10/100,000 in white populations living in continental Europe (with up to double these rates in Northern Ireland) to rates of about 400/100,000 in Australia.
Aetiology/ Risk factors
People with fair skin colour who sunburn easily without tanning, people with xeroderma pigmentosum, and those who are immunosuppressed are susceptible to squamous cell carcinoma. The strongest environmental risk factor for squamous cell carcinoma is chronic sun exposure. Cohort and case control studies have found that the risk of squamous cell carcinoma is three times greater in people with fair skin colour, a propensity to burn on initial exposure to sunlight, or a history of multiple sunburns. Clinical signs of chronic skin damage, especially solar keratoses, are also risk factors for cutaneous squamous cell carcinoma. In people with multiple solar keratoses (more than 15), the risk of squamous cell carcinoma is 10 to 15 times greater than in people with no solar keratoses.
Prognosis
Prognosis is related to the location and size of tumour, histological pattern, depth of invasion, perineural involvement, and immunosuppression. A worldwide review of 95 case series, each consisting of at least 20 people, found that the overall metastasis rate for squamous cell carcinoma on the ear was 11% and on the lip 14%, compared with an average for all sites of 5%. A review of 71 case series found that lesions less than 2 cm in diameter have less than half the local recurrence rate compared with lesions greater than 2 cm (7% with lesions less than 2 cm v 15% with lesions greater than 2 cm), and less than one third of the rate of metastasis (9% with lesions less than 2 cm v 30% with lesions greater than 2 cm).
Aims of intervention
To prevent the occurrence of squamous cell carcinoma; to achieve cure by eradicating local disease including micro-invasive disease; to reduce mortality.
Outcomes
Prevention: Incidence rates of cutaneous squamous cell carcinoma and prevalence rates of solar keratoses; mortality from squamous cell carcinoma. Primary excision: Local recurrence; survival; cosmetic outcome. Radiotherapy after surgery: Local recurrence; regional recurrence; survival.
Methods
Clinical Evidence search and appraisal October 2009. The following databases were used to identify studies for this systematic review: Medline 1966 to October 2009, Embase 1980 to October 2009, and The Cochrane Database of Systematic Reviews 2009, Issue 3 (1966 to date of issue). An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language, at least single blinded, and containing more than 20 individuals of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. We also searched for cohort and case control studies on included interventions. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ). The categorisation of the quality of the evidence (into high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table 1.
GRADE evaluation of interventions for squamous cell carcinoma of the skin (non-metastatic)
| Important outcomes | Incidence rates, adverse effects | ||||||||
| Number of studies (participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| Does the use of sunscreen help to prevent cutaneous squamous cell carcinoma? | |||||||||
| 1 (1621) | Incidence rates | Daily use v discretionary use in development of squamous cell carcinoma | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for restricted population (subtropical) |
| 1 (588) | Incidence rates | Daily use v placebo in development of solar keratoses | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for restricted population (all participants had previous solar keratoses) |
| 1 in 2 reports (1621) | Incidence rates | Daily use v discretionary use in development of solar keratoses | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for restricted population (subtropical, half of participants had previous solar keratoses) |
Type of evidence: 4 = RCT. Consistency: similarity of results across studies.Directness: generalisability of population or outcomes.Effect size: based on relative risk or odds ratio.
Glossary
- Hyperkeratosis
Increased scaling on the surface of the skin.
- Micrographically controlled surgery
Does not use standard excision margins as the basis for achieving tumour clearance. The visible tumour and a thin margin of apparently normal skin are removed, mapped, and examined microscopically using a specialised sectioning technique at the time of surgery, and the surgery continues until there is microscopic confirmation of complete tumour clearance, at which stage the wound is closed.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Perineural invasion
Tumour invasion along (not in) a nerve.
- Radiodermatitis
Chronic non-malignant changes in the skin owing to excessive radiation.
- Telangiectasiae
Permanently dilated small blood vessels in the skin.
- Xeroderma pigmentosum
An inherited disorder with defective repair of DNA damage caused by ultraviolet radiation, resulting in sun related skin cancers of all types at an early age.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
Contributor Information
Professor Adèle C Green, Queensland Institute of Medical Research, Brisbane, Australia.
Penelope McBride, Queensland Institute of Medical Research, Brisbane, Australia.
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