Cutaneous squamous cell carcinoma: Primary and secondary prevention

INTRODUCTION — Cutaneous squamous cell carcinoma (cSCC) is the second most common nonmelanoma (keratinocyte) cancer after basal cell carcinoma, accounting for approximately 20 percent of all skin cancers [1]. Its incidence is increasing worldwide; in the United States, it has been estimated that over 700,000 persons were treated for cSCC in 2012 [2]. As the diagnosis and treatment of keratinocyte carcinomas imposes a high burden on health care systems, there is a need for effective primary and secondary prevention strategies [3].

Cumulative ultraviolet radiation exposure, either occupational or recreational, is the single most important risk factor for cSCC, especially in populations with lighter skin pigmentation. Additional risk factors include genetic predisposition, age, other environmental exposures (eg, arsenic, ionizing radiations), and immunosuppression. (See "Cutaneous squamous cell carcinoma: Epidemiology and risk factors".)

Primary prevention is aimed at reducing the exposure to known risk factors by using behavioral and environmental interventions, such as decreasing ultraviolet light exposure or arsenic contamination of water. Secondary prevention involves early detection and treatment of skin cancer and precursor lesions. Chemoprevention is a secondary prevention strategy for patients at high risk of developing multiple cSCCs (eg, patients with a history of cSCC, extensive sun-induced skin damage and actinic keratosis, immunosuppressed patients).

This topic will review primary and secondary prevention strategies for cSCC. The prevention and management of skin cancer in organ transplant recipients is discussed separately. The risk factors, diagnosis, and management of cSCC are also discussed separately.

●(See "Prevention and management of skin cancer in solid organ transplant recipients".)

●(See "Cutaneous squamous cell carcinoma: Epidemiology and risk factors".)

●(See "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis".)

●(See "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma (cSCC)".)

●(See "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma".)

●(See "Actinic keratosis: Epidemiology, clinical features, and diagnosis".)

●(See "Treatment of actinic keratosis".)

SUN PROTECTION — Minimizing ultraviolet light exposure by limiting the time spent in the sun in peak hours, using sunscreen, and wearing protective clothing is the most effective primary prevention strategy to reduce the incidence of cSCC and its precursors (actinic keratoses) in individuals at risk. Behavioral interventions have been shown to increase sun protection behaviors in children, adolescents, and young adults. However, there is little evidence that such interventions are associated with a reduction in the incidence and outcomes of skin cancer [4].

Evidence from randomized trials indicates that regular use of sunscreen reduces the risk of cSCC and actinic keratoses [5]:

●In a randomized trial that included 588 participants with previous actinic keratoses, individuals who used daily sun protection factor (SPF) 17 sunscreen for one summer had fewer new actinic keratoses at seven months compared with the placebo group (1.6 versus 2.3, rate ratio [RR] 0.6, 95% CI 0.54-0.71) [6]. (See "Actinic keratosis: Epidemiology, clinical features, and diagnosis".)

●In the Nambour trial that included 1621 residents randomized to use daily SPF 15 sunscreen or to use sunscreen at their usual discretionary frequency, daily use of sunscreen for 4.5 years was associated with a significantly lower incidence of cSCCs (1115 versus 1832 per 100,000 compared with no daily sunscreen) [7]. In contrast, no difference was observed in the incidence of basal cell carcinomas (BCCs).

●An extended follow-up study of the Nambour trial showed that cSCC incidence rates, both in terms of persons newly affected and number of tumors, were reduced by 35 and 38 percent, respectively, in the former sunscreen treatment group compared with the control group after eight years of follow-up (RR 0.65, 95% CI 0.43-0.98 and RR 0.68, 95% CI 0.38-0.99) [8].

●An analysis of data from the Norwegian Women and Cancer Study that included 148,781 women, of whom 653 were diagnosed with cSCC over an average follow-up of 14.3 years, showed no difference in the risk of cSCC among users of sunscreens with an SPF ≥15 versus an SPF <15 at any latitudes (hazard ratio [HR] 1.02, 95% CI 0.82-1.27) and in lower-latitude settings (HR 1.05, 95% CI 0.84-1.32) [9]. However, these results must be interpreted with caution, as information on frequency of sunscreen use, number of hours spent outdoors, and additional sun protection behavior (eg, sun avoidance, use of protective clothing) was not available.

Sunscreens and other sun protection measures are discussed in detail elsewhere. (See "Selection of sunscreen and sun-protective measures".)

IN-OFFICE SCREENING AND SELF-SURVEILLANCE — Patients with multiple actinic keratoses and/or a history of cSCC should be counseled regarding the need of periodic skin examinations by a clinician with experience in the detection and treatment of skin cancer and regular skin self-examinations [10,11]. These measures may help in detecting new primary tumors at an early stage, when they can be easily treated. (See "Screening for melanoma in adults and adolescents", section on 'Patient self-examination'.)

CHEMOPREVENTION — Chemoprevention is a secondary prevention strategy for patients at high risk of developing nonmelanoma skin cancer [12]. It is based on the concept that topical or systemic treatments may prevent the progression of subclinical precursor lesions into invasive carcinoma. Thus, chemoprevention may be appropriate in patients with a history of an invasive cSCC and extensive sun-damaged skin with numerous actinic keratoses and in select patients with a history of multiple invasive cSCCs, including solid organ transplant recipients. (See "Prevention and management of skin cancer in solid organ transplant recipients", section on 'Chemoprevention for squamous cell carcinoma' and "Treatment of actinic keratosis", section on 'Multiple thin lesions/field cancerization'.)

Systemic agents

Oral retinoids — Retinoids are vitamin A derivatives that are available in topical and oral preparations. Oral retinoids inhibit cSCC cell growth in vitro and may reduce the development of cSCC tumors in high-risk populations, such as those with a history of multiple nonmelanoma skin cancers [13,14], genetic disorders such as xeroderma pigmentosum [15,16], transplant recipients [17,18], and patients exposed to high cumulative levels of psoralen plus ultraviolet A (PUVA) therapy [19]. However, the adverse effects of systemic retinoids, including hypertriglyceridemia and hepatic toxicity, are an important limitation to their long-term use.

Examples of studies that have evaluated the use of oral retinoids for the prevention of cSCC include:

●In a randomized trial, 2297 adults with a prior history of >10 actinic keratoses or ≥2 cSCCs were randomly assigned to 25,000 international units of oral retinol daily or a placebo. At an average follow-up of four years, the active treatment group had a significantly lower rate of new cSCCs (hazard ratio [HR] 0.74, 95% CI 0.56-0.99) [14]. However, this dose of retinol was associated with an 11 percent higher triglyceride level and 3 percent higher cholesterol level, which may increase coronary artery disease risk [20]. Of note, a smaller, randomized trial of 525 patients treated with oral retinol (25,000 units per day), isotretinoin (5 to 10 mg per day), or placebo for three years found a lack of benefit with both retinol and isotretinoin [21].

●In five patients with xeroderma pigmentosum, 121 tumors occurred in the two-year interval before treatment with oral isotretinoin compared with 25 in the two years during treatment [15]. Following cessation of therapy, there was an 8.5-fold increase in tumor frequency [16].

●Randomized trials have found variable results for the efficacy of acitretin as a chemopreventive agent in organ transplant recipients [22]. Data from these trials are discussed in greater detail separately. (See "Prevention and management of skin cancer in solid organ transplant recipients", section on 'Acitretin'.)

●Among psoriasis patients treated with PUVA, the use of oral retinoids for at least 26 weeks per year was associated with a significantly decreased incidence of cSCC compared with less frequent retinoid use (196 cSCCs/1000 years versus 302 cSCCs/1000 years, respectively) [19]. The benefit was restricted to periods of high usage.

Nonsteroidal anti-inflammatory drugs — Studies in animal models suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) may prevent the development of cSCC, but human studies have led to conflicting results [23-28]. However, a meta-analysis of eight observational studies and one randomized trial found a 15 percent risk reduction associated with the use of nonaspirin NSAIDs (relative risk [RR] 0.85, 95% CI 0.78-0.94) [29].

Additional studies are necessary to determine whether there is a dose-response relationship between use of NSAIDs and reduction in cSCC risk and whether the beneficial effects on cSCC risk would outweigh the risks of long-term therapy with NSAIDs [30]. (See "NSAIDs: Adverse cardiovascular effects".)

Capecitabine — Capecitabine is a prodrug of 5-fluorourcil that is metabolized by thymidine phosphorylase, which is often overexpressed in certain carcinomas. Low-dose oral capecitabine has been used for chemoprevention in organ transplant recipients who develop more than two cSCCs in six months. Two small case series demonstrated that low-dose capecitabine significantly reduced the incidence of cSCC in organ transplant recipients, with relatively manageable adverse effects [31,32]. (See "Prevention and management of skin cancer in solid organ transplant recipients", section on 'Capecitabine'.)

Topical agents

Topical retinoids — A large, multicenter, randomized trial (n = 1131) sought to investigate the effect of topical tretinoin on the prevention of cSCC and basal cell carcinoma (BCC) [33]. Patients were treated with tretinoin 0.1% cream or a vehicle control for 1.5 to 5.5 years. Treatment with tretinoin was not effective for chemoprevention in this trial; statistically significant differences in the proportions of patients who had developed an invasive cSCC (28 versus 31 percent) or a BCC (53 versus 54 percent) after five years were not detected. The trial was terminated prematurely due to an increase in mortality observed in the treatment group. However, the authors questioned the validity of this finding [34].

Topical fluorouracil — A single course of topical fluorouracil (daily application for up to four weeks) as "field treatment" for actinic keratosis has been shown to reduce the development of new actinic keratoses, a marker for increased risk of cSCC in older male patients with multiple previous keratinocyte cancers [35-37] (see "Treatment of actinic keratosis", section on 'Topical fluorouracil'). However, only a few studies have evaluated topical fluorouracil for the prevention of cSCC in high-risk patients, and its efficacy in this regard remains uncertain:

●In a randomized trial, 932 participants with a history of at least two keratinocyte cancers in the previous five years were instructed to apply topical fluorouracil 5% cream or vehicle cream twice daily to the face and ears for four weeks (a total of 56 doses) [38]. The primary study endpoints were surgically treated BCC or squamous cell carcinoma (SCC) on the face or ears. Although in the first year following treatment less participants in the treatment group developed a cSCC compared with the placebo group (1 versus 4 percent), no difference was noted between the fluorouracil and control groups in time to the first BCC or cSCC for the overall four-year study period. After a median follow-up time of 2.8 years, the proportions of patients who underwent surgical excision for one or more BCCs or cSCCs were 32 and 11 percent, respectively, in the fluorouracil group and 32 and 12 percent, respectively, in the control group.

●A small, randomized trial compared the efficacy of a four-day course of topical calcipotriol plus topical fluorouracil with topical fluorouracil plus vehicle for the prevention of cSCC in 130 patients with 4 to 15 actinic keratoses within a 25 cm² area on the face, scalp, or upper extremities [39]. At three years following treatment, fewer patients in the calcipotriol plus topical fluorouracil group than in the control group developed a cSCC on their treated face and scalp (2 out of 30 versus 11 out of 40, respectively; HR 0.22, 95% CI 0.05-0.97). However, these results should be interpreted with caution due to the small sample size of the trial and the large number of patients lost to follow-up.

Imiquimod — Field therapy of actinic keratosis with imiquimod seems to be as effective as topical fluorouracil in decreasing the risk of developing cSCC in the treated field. Imiquimod 5% cream is typically applied to an involved area of ≤25 cm² twice weekly for 16 weeks. (See "Treatment of actinic keratosis", section on 'Imiquimod'.)

●In a retrospective, cohort study from a large health care delivery system in the United States, all patients with actinic keratosis who had been prescribed field treatment with topical fluorouracil (n = 5062) or imiquimod (n = 638) in 2007 were followed up for the development of any subsequent keratinocyte carcinomas (cSCC or BCC) and site-specific tumors arising in the treated field [40]. A multivariate analysis showed no significant difference between the two treatments in the risks of site-specific keratinocyte carcinomas (HR 0.96, 95% CI 0.81-1.14).

●A pooled analysis of two randomized trials that included a total of 479 immunocompetent patients with 5 to 10 typical, visible actinic keratosis lesions in one contiguous area of up to 50 cm² on the face or scalp evaluated the long-term efficacy of diclofenac applied twice daily for 12 weeks compared with two four-week cycles of imiquimod administered four weeks apart [41]. The primary endpoint (histologic change to a higher histologic grade of actinic keratosis or development of invasive SCC) in the treated area was observed in more patients in the diclofenac group than in the imiquimod group (11 versus 5.4 percent, respectively; absolute risk difference -5.6 percent, 95% CI -10.7 to -0.7) up to 36 months post-treatment.

Vitamins and dietary supplements — Several studies have investigated the association of diet and dietary supplements with the risk of cSCC with uncertain or conflicting results:

●One large, United States, cohort study including nearly 86,000 female nurses and 44,000 male health professionals from the Nurses' Health Study and the Health Professionals Follow-up Study followed up for 14 and 10 years, respectively, concluded that dietary vitamin A, C, and E; folate; and carotenoids have no effect in preventing cSCC [42]. A reanalysis of data from the same cohorts after an additional 16 years of follow-up found that higher intakes of total vitamin A, retinol, and some carotenoids (alfa-carotene, beta-cryptoxanthin, lycopene, and lutein/zeaxanthin) were associated with a modest reduction in cSCC risk, after adjusting for known risk factors for cSCC [43]. However, as participants with higher intake of vitamin A tended to have healthier behaviors (eg, higher levels of physical activity, lower prevalence of smoking and alcohol consumption), a confounding effect of sun protection behaviors (eg, use of sunscreen, sun avoidance), which were not assessed in this study, cannot be excluded.

●An analysis of data from a randomized trial of vitamin D supplementation among Australians aged ≥60 years found that vitamin D supplementation (60,000 international units monthly for five years) did not reduce the incidence of keratinocytic cancer excisions, the incidence of other actinic lesions treated with cryotherapy or serial curettage, or time to first keratinocytic cancer excision [44].

●Three randomized trials of beta-carotene supplementation for cSCC prevention showed no protective or harmful effects [7,45,46].

●The efficacy of oral nicotinamide (vitamin B3), a dietary supplement available over the counter, for the prevention of nonmelanoma skin cancer was evaluated in a 2015 phase III, randomized trial [47]. In this study, 386 immunocompetent participants (mean age 66 years) with ≥2 histologically confirmed nonmelanoma skin cancers in the past five years were treated with 500 mg of nicotinamide twice daily or placebo for 12 months. At the end of the study, the rate reduction for cSCC was 30 percent (95% CI 0 to 51 percent). However, no benefit was observed after treatment discontinuation.

These results are insufficient to make any recommendation about the use of nicotinamide for the chemoprevention of cSCC. Further studies are needed to evaluate the efficacy and safety of long-term treatment and to establish the optimal dose.

●Self-reported use of grape seed extract as a dietary supplement was associated with a reduced risk for cSCC in a study of 415 patients with cSCC and their matched controls (adjusted odds ratio [OR] 0.26, 95% CI 0.08-0.89) [48]. Further studies are necessary to corroborate these findings prior to a recommendation for the use of grape seed extract for this indication.

●A retrospective study of an older southwestern population suggested that consumption of D-limonene found in citrus peels and hot black tea was associated with decreased cSCC risk [49]. In contrast, a case-control study of 415 patients with cSCC and their matched controls showed no reduction of cSCC risk amongst those who regularly consumed tea [50].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Nonmelanoma skin cancer".)

SUMMARY AND RECOMMENDATIONS

●Sun protection – Reducing ultraviolet radiation exposure by limiting the time spent in the sun during peak hours, using sunscreen, and wearing sun-protective clothing is the most effective primary prevention strategy to reduce the incidence of cutaneous squamous cell carcinoma (cSCC) and precursor lesions (actinic keratoses). (See 'Sun protection' above and "Selection of sunscreen and sun-protective measures".)

●Screening and early diagnosis – Early diagnosis and treatment of cSCC is crucial in high-risk patients with multiple precursor lesions (actinic keratoses) and/or a history of cSCC. High-risk patients should be educated about the importance of periodic skin examinations by a clinician with experience in skin cancer detection and treatment and regular skin self-examinations. (See 'In-office screening and self-surveillance' above.)

●Chemoprevention

•Systemic agents – Systemic chemoprevention does not have an established role in the prevention of cSCC. While oral retinoids may have some benefit in select high-risk patients, such as organ transplant recipients, their side effects inhibit prolonged use. (See 'Systemic agents' above and "Prevention and management of skin cancer in solid organ transplant recipients".)

•Topical agents – "Field treatment" with topical fluorouracil or imiquimod may be useful for the long-term control of actinic keratoses in patients with multiple actinic keratoses with or without a history of cSCC. However, their efficacy in the prevention of invasive cSCC remains uncertain. (See 'Topical agents' above and "Treatment of actinic keratosis".)