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, skin colour, and outdoor behaviour, and is as high as 400/100,000 in Australia. People with fair skin colour who have high sun exposure and sunburn easily with little or no 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 actinic (solar) keratosis? What is the optimal margin for primary excision of cutaneous squamous cell carcinoma (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 August 2013 (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 five 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: sunscreens, primary excision, and radiotherapy after surgery.
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, skin colour, and outdoor behaviour, and is as high as 400/100,000 in Australia.
People with fair skin colour who have high sun exposure and sunburn easily with little or no tanning, people with xeroderma pigmentosum, and people who are immunosuppressed are most susceptible to squamous cell carcinoma.
Regular sunscreen application to the head, neck, arms, and hands seems to reduce the incidence of squamous cell carcinoma more than discretionary use or no use.
The evidence regarding regular use of sunscreen to reduce squamous cell carcinoma is from an RCT of adults in a subtropical community in Queensland, Australia, half of whom had previous actinic keratoses. The generalisability of these findings will be influenced by climate and seasonality, among other factors.
Regular sunscreen application to the head, neck, arms, and hands also seems to reduce the rate of acquisition of actinic (solar) keratoses more than discretionary or no use. Daily sunscreen application seems to reduce the incidence of new actinic keratoses in people who had previous actinic keratoses.
With regard to surgery, we found no RCTs to assess the optimal primary excision margin required to prevent recurrence of squamous cell carcinoma.
As with all kinds of surgery, there is a potential for tissue destruction and scarring, particularly of vital structures such as eyelids, lip margins, and motor and sensory nerves.
We do not know whether radiotherapy after surgery reduces local recurrence compared with surgery alone.
Although not measured, there is potential for long-term scar deterioration with post-radiation depigmentation and gradual development of chronic radiodermatitis, including telangiectasiae, thinning of the skin, and hyperkeratosis.
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 on exposed skin vary markedly around the world according to latitude, skin colour, and outdoor behaviour. Reported incidence thus ranges from negligible in black populations, to rates of around 23/100,000 in England (though 33/100,000 in the South West) and 37/100,000 in Scotland in 2003, to 60/100,000 in Canada in 2006, to 290/100,000 in Arizona in 1991 and up to around 400/100,000 in Australia in 2002.
Aetiology/ Risk factors
People with fair skin colour who have high sun exposure and sunburn easily with little or no 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, such that those who work outdoors are at higher risk than those who work indoors. Clinical signs of chronic skin damage, especially actinic (solar) keratoses, are also predictive factors for cutaneous squamous cell carcinoma. In people with multiple actinic keratoses (more than 15), the risk of squamous cell carcinoma is 10 to 15 times greater than in people with no actinic keratoses.
Prognosis
Prognosis is related to the location and size of tumour, histological pattern, depth of invasion, perineural involvement, and immunosuppression. The most common site of squamous cell carcinoma is the head and neck. Follow-up of 315 consecutive patients with primary cutaneous squamous cell carcinoma of the head and neck for an average of 4 years in Thessaloniki, Greece, showed grade of differentiation, perineural involvement, the presence of inflammation, and T-stage were independent predictors for overall survival. Stage, inflammation, and perineural involvement predicted recurrence-free survival. Factors associated with poor outcomes for squamous cell carcinoma with perineural invasion were studied in a hospital series of 114 adults in Boston, MA (US). Tumours with large nerve invasion (at least 0.1 mm in calibre) rather than small (unspecified) nerve invasion were more likely to have other risk factors, including tumour diameter of 2 cm or greater, invasion beyond the subcutaneous fat, multiple nerve involvement, infiltrative growth, or lymphovascular invasion. Tumour diameter of 2 cm or greater predicted local recurrence; having multiple (of the above) risk factors predicted nodal metastasis; and lymphovascular invasion predicted death from disease.
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 actinic (solar) keratoses; mortality from squamous cell carcinoma. Primary excision: Local recurrence (i.e., recurrence of original lesion at original site up to 5 years post-excision); cosmetic outcome (i.e., scarring, effect on facial expression, necessity for skin grafts); survival. Radiotherapy after surgery: Local recurrence (i.e., recurrence of original lesion at original site up to 5 years post-radiotherapy); regional recurrence (i.e., recurrence in an area drained by the regional lymph node up to 5 years post-radiotherapy); survival.
Methods
Clinical Evidence search and appraisal August 2013. The following databases were used to identify studies for this systematic review: Medline 1966 to August 2013, Embase 1980 to August 2013, and The Cochrane Database of Systematic Reviews 2013, issue 8 (1966 to date of issue). Additional searches were carried out in the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Titles and abstracts identified by the initial search, run by an information specialist, were first assessed against predefined criteria by an evidence scanner. Full texts for potentially relevant studies were then assessed against predefined criteria by an evidence analyst. Studies selected for inclusion were discussed with an expert contributor. All data relevant to the review were then extracted by an evidence analyst. Study design criteria for inclusion in this review were: published RCTs and systematic reviews of RCTs in the English language, at least single-blinded, and containing >20 individuals of whom >80% were followed up. There was no minimum length of follow-up. We excluded all studies described as 'open', 'open label', or not blinded unless blinding was impossible. We included RCTs and systematic reviews of RCTs where harms of an included intervention were assessed, applying the same study design criteria for inclusion as we did for benefits. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the 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 (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.
GRADE Evaluation of interventions for Squamous cell carcinoma of the skin (non-metastatic).
| Important outcomes | Incidence rates | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| Does the use of sunscreen help prevent cutaneous squamous cell carcinoma and actinic (solar) keratosis? | |||||||||
| 1 (1621) | Incidence rates | Regular sunscreen use versus discretionary or no use | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for restricted population (subtropical) |
| 1 (588) | Incidence rates | Daily sunscreen use versus placebo | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for restricted population (all participants had previous actinic [solar] keratoses) |
| 1 (1621) | Incidence rates | Regular sunscreen use versus discretionary or no use | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for restricted population (subtropical, half of participants had previous actinic [solar] keratoses) |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- 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.
- 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
Adèle C. Green, QIMR Berghofer Institute of Medical Research, Brisbane, Australia.
Penelope McBride, Banyo Clinic, Brisbane, Australia.
References
- 1.Lomas A, Leonardi-Bee J, Bath-Hextall F. A systematic review of worldwide incidence of nonmelanoma skin cancer. Br J Dermatol 2012;166:1069–1080. [DOI] [PubMed] [Google Scholar]
- 2.Green A, Battistutta D, Hart V, et al, the Nambour Study Group. Skin cancer in a subtropical Australian population: incidence and lack of association with occupation. Am J Epidemiol 1996;144:1034–1040. [DOI] [PubMed] [Google Scholar]
- 3.English DR, Armstrong BK, Kricker A, et al. Demographic characteristics, pigmentary and cutaneous risk factors for squamous cell carcinoma: a case-control study. Int J Cancer 1998;76:628–634. [DOI] [PubMed] [Google Scholar]
- 4.Kraemer KH, Lee MM, Andrews AD, et al. The role of sunlight and DNA repair in melanoma and nonmelanoma skin cancer. The xeroderma pigmentosum paradigm. Arch Dermatol 1994;130:1018–1021. [PubMed] [Google Scholar]
- 5.Harwood CA, Mesher D, McGregor JM, et al. A surveillance model for skin cancer in organ transplant recipients: a 22-year prospective study in an ethnically diverse population. Am J Transplant 2013;13:119–129. [DOI] [PubMed] [Google Scholar]
- 6.Milon A, Bulliard JL, Vuilleumier L,et al. Estimating the contribution of occupational solar ultraviolet exposure to skin cancer. Br J Dermatol 2014;170:157–164. [DOI] [PubMed] [Google Scholar]
- 7.Lebwohl M. Actinic keratosis: epidemiology and progression to squamous cell carcinoma. Br J Dermatol 2003;149(suppl 66):31–33. [DOI] [PubMed] [Google Scholar]
- 8.Johnson TM, Rowe DE, Nelson BR, et al. Squamous cell carcinoma of the skin (excluding lip and oral mucosa). J Am Acad Dermatol 1992;26:467–484. [DOI] [PubMed] [Google Scholar]
- 9.Rowe DE, Carroll RJ, Day CL. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. J Am Acad Dermatol 1992;26:976–990. [DOI] [PubMed] [Google Scholar]
- 10.Kyrgidis A, Tzellos TG, Kechagias N, et al. Cutaneous squamous cell carcinoma (SCC) of the head and neck: risk factors of overall and recurrence-free survival. Eur J Cancer 2010;46:1563–1572. [DOI] [PubMed] [Google Scholar]
- 11.Carter JB, Johnson MM, Chua TL, et al. Outcomes of primary cutaneous squamous cell carcinoma with perineural invasion: an 11-year cohort study. JAMA Dermatol 2013;149:35–41. [DOI] [PubMed] [Google Scholar]
- 12.Green A, Williams G, Neale R, et al. Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomised controlled trial. Lancet 1999;354:723–729. [Erratum in: Lancet 1999;354:1038] [DOI] [PubMed] [Google Scholar]
- 13.Van Der Pols JC, Williams GM, Pandeya N, et al. Prolonged prevention of squamous cell carcinoma of the skin with regular sunscreen use. Cancer Epidemiol Biomarkers Prev 2006;15:2546–2548. [DOI] [PubMed] [Google Scholar]
- 14.World Health Organization. Ultraviolet radiation and the INTERSUN Programme. 2014. Available at http://www.who.int/uv/sun_protection/en/ (last accessed 14 August 2014). [Google Scholar]
- 15.Diffey BL. Sunscreens and UVA protection: a major issue of minor importance. Photochem Photobiol 2001;74:61–63. [DOI] [PubMed] [Google Scholar]
- 16.Liu W, Wang X, Lai W, et al. Sunburn protection as a function of sunscreen application thickness differs between high and low SPFs. Photodermatol Photoimmunol Photomed 2012;28:120–126. [DOI] [PubMed] [Google Scholar]
- 17.Thompson SC, Jolley D, Marks R. Reduction of solar keratoses by regular sunscreen use. N Engl J Med 1993;329:1147–1151. [DOI] [PubMed] [Google Scholar]
- 18.Darlington S, Williams G, Neale R, et al. A randomized controlled trial to assess sunscreen application and beta carotene supplementation in the prevention of solar keratoses. Arch Dermatol 2003;139:451–455. [DOI] [PubMed] [Google Scholar]
- 19.Brodland DG, Zitelli JA. Surgical margins for excision of primary cutaneous squamous cell carcinoma. J Am Acad Dermatol 1992;27:241–248. [DOI] [PubMed] [Google Scholar]
- 20.Thomas DJ, King AR, Peat BG. Excision margins for nonmelanotic skin cancer. Plast Reconstr Surg 2003;112:57–63. [DOI] [PubMed] [Google Scholar]
- 21.de Visscher JGAM, Botke G, Schakenradd JACM, et al. A comparison of results after radiotherapy and surgery for stage 1 squamous cell carcinoma of the lower lip. Head Neck 1999:526–530. [DOI] [PubMed] [Google Scholar]
- 22.Ashby MA, Smith J, Ainslie J, et al. Treatment of nonmelanoma skin cancer at a large Australian Center. Cancer 1989;6:1863–1871. [DOI] [PubMed] [Google Scholar]
- 23.Eroglu A, Berberoglu U, Berreroglu S. Risk factors related to locoregional recurrence in squamous cell carcinoma of the skin. J Surg Oncol 1996;61:124–130. [DOI] [PubMed] [Google Scholar]
- 24.McCombe D, MacGill, Ainslie J, et al. Squamous cell carcinoma of the lip: a retrospective review of the Peter MacCallum Cancer Institute experience 1979–88. Aust NZ J Surg 2000;70:358–361. [DOI] [PubMed] [Google Scholar]
- 25.Yoon M, Chougule P, Dufresne R, et al. Localised carcinoma of the external ear is an unrecognised aggressive disease with a high propensity for local regional recurrence. Am J Surg 1992;164:574–577. [DOI] [PubMed] [Google Scholar]
- 26.Zitsch RP, Park CW, Renner GJ, et al. Outcome analysis for lip carcinoma. Otolaryngol Head Neck Surg 1995;113:589–596. [DOI] [PubMed] [Google Scholar]
- 27.Bovill ES, Cullen KW, Barrett W, et al. Clinical and histological findings in re-excision of incompletely excised cutaneous squamous cell carcinoma. J Plast Reconstruct Aesthet Surgery: JPRAS 2009;62:457–461. [DOI] [PubMed] [Google Scholar]
- 28.Glass RL, Perez-Mesa C. Management of inadequately excised epidermoid carcinoma. Arch Surg 1974;108:50–51. [DOI] [PubMed] [Google Scholar]
- 29.Glass RL, Spratt JS, Perez-Mesa C. The fate of inadequately excised epidermoid carcinoma of the skin. Surg Gynaecol Obstet 1966;122:245–248. [PubMed] [Google Scholar]
- 30.Shimm DS, Wilder RB. Radiation therapy for squamous cell carcinoma of the skin. Am J Clin Oncol 1991;14:381–386. [DOI] [PubMed] [Google Scholar]
- 31.McCord MW, Mendenhall WM, Parsons JT, et al. Skin cancer of the head and neck with clinical perineural invasion. Int J Radiat Oncol Biol Phys 2000;47:89–93. [DOI] [PubMed] [Google Scholar]
- 32.Williams LS, Mancuso AA, Mendenhall WM. Perineural spread of cutaneous squamous and basal cell carcinoma: CT and MR detection and its impact on patient management and prognosis. Int J Radiat Oncol Biol Phys 2001;49:1061–1069. [DOI] [PubMed] [Google Scholar]
- 33.Holmkvist KA, Roenigk RK. Squamous cell carcinoma of the lip treated with Mohs' micrographic surgery: outcome at 5 years. J Am Acad Dermatol 1998;38:960–966. [DOI] [PubMed] [Google Scholar]