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There are three main types of skin cancer:
BCC and SCC are the most common forms of skin cancer and are collectively referred to as nonmelanoma skin cancers. This summary only covers the treatment of nonmelanoma skin cancers. (Refer to the PDQ summary on Melanoma Treatment for more information.)
Incidence and Mortality
Nonmelanoma skin cancer is the most commonly occurring cancer in the United States. BCC is the more common type of the two nonmelanoma types, accounting for about three-quarters of nonmelanoma skin cancers. The incidence of nonmelanoma skin cancer appears to be increasing in some, but not all  areas of the United States. Overall U.S. incidence rates have likely been increasing for a number of years. At least some of this increase may be attributable to increasing skin cancer awareness and resulting increasing investigation and biopsy of skin lesions.
Precise estimation of the total numbers and incidence rate of nonmelanoma skin cancer is not possible because reporting to cancer registries is not required. However, based on Medicare fee-for-service data, which were then extrapolated to the U.S. population, an estimated 2,152,500 persons were treated for nonmelanoma skin cancers in 2006. That number would exceed all other cases of cancer estimated by the American Cancer Society for that year, which was about 1.4 million. Although the two types of nonmelanoma skin cancer are the most common of all malignancies, they account for less than 0.1% of patient deaths caused by cancer.
Epidemiologic evidence suggests that exposure to ultraviolet (UV) radiation and the sensitivity of an individual's skin to UV radiation are risk factors for skin cancer, though the type of exposure (i.e., high-intensity exposure and short-duration exposure vs. chronic exposure) and pattern of exposure (i.e., continuous pattern vs. intermittent pattern) may differ among the three main skin cancer types.[6,7,8] All three types of skin cancer are more likely to occur in individuals of light complexion who have had substantial exposure to sunlight, and skin cancers are more common in the southern latitudes of the Northern hemisphere. In addition, the immune system may play a role in pathogenesis of skin cancers.
Organ transplant recipients receiving immunosuppressive drugs are at an elevated risk of skin cancers, particularly SCC. Arsenic exposure also increases the risk of cutaneous SCC. Serologic evidence from a population-based case-control study has shown a possible association between infection with the human papilloma virus (HPV) genus beta-species 1 and SCC.[9,10]
Other PDQ summaries containing information related to skin cancer include the following:
This evidence summary covers basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin, and the related noninvasive lesion actinic keratosis (viewed by some pathologists as a variant of in situ SCC ). Although BCC and SCC are by far the most frequent types of nonmelanoma skin cancers, approximately 82 types of skin malignancies, with a wide range of clinical behaviors, fall into the category of nonmelanoma skin cancer. Other types of malignant disease of the skin include the following:
(Refer to the PDQ summaries on Melanoma Treatment, Merkel Cell Carcinoma Treatment, Mycosis Fungoides and the Sézary Syndrome Treatment, and Kaposi Sarcoma Treatment for more information.)
BCC and SCC are both of epithelial origin. They are usually diagnosed on the basis of routine histopathology obtained from a shave, punch, or fusiform excisional biopsy.
Basal Cell Carcinoma
BCC is at least three times more common than SCC in nonimmunocompromised patients. It usually occurs on sun-exposed areas of skin, and the nose is the most frequent site. Although there are many different clinical presentations for BCC, the most characteristic type is the asymptomatic nodular or nodular ulcerative lesion that is elevated from the surrounding skin, has a pearly quality, and contains telangiectatic vessels.
BCC has a tendency to be locally destructive. High-risk areas for tumor recurrence after initial treatment include the central face (e.g., periorbital region, eyelids, nasolabial fold, or nose-cheek angle), postauricular region, pinna, ear canal, forehead, and scalp. A specific subtype of BCC is the morpheaform type. This subtype typically appears as a scar-like, firm plaque. Because of indistinct clinical tumor margins, the morpheaform type is difficult to treat adequately with traditional treatments.
BCCs are composed of nonkeratinizing cells derived from the basal cell layer of the epidermis. They are slow growing and rarely metastasize. However, they can result in serious deforming damage locally if left untreated or if local recurrences cannot be completely excised. BCCs often have a characteristic mutation in the patched 1 tumor suppressor gene (PTCH1), although the mechanism of carcinogenesis is not clear.
Squamous Cell Carcinoma
SCCs also tend to occur on sun-exposed portions of the skin, such as the ears, lower lip, and dorsa of the hands. However, SCCs that arise in areas of non–sun-exposed skin or that originate de novo on areas of sun-exposed skin are prognostically worse because they have a greater tendency to metastasize than those that occur on sun-exposed skin that develop from actinic keratosis. People with chronic sun damage, sites of prior burns, arsenic exposure, chronic cutaneous inflammation as seen in longstanding skin ulcers, and sites of previous x-ray therapy are predisposed to the development of SCC.
SCCs are composed of keratinizing cells. These tumors are more aggressive than BCCs and have a range of growth, invasive, and metastatic potential. Prognosis is associated with the degree of differentiation, and tumor grade is reported as part of the staging system. A four-grade system (G1–G4) is most common, but two- and three-grade systems may also be used. Mutations in the PTCH1 tumor suppressor gene have been reported in SCCs removed from patients with a prior history of multiple BCCs.
SCC in situ (also called Bowen disease) is a noninvasive lesion. It may be difficult to distinguish it pathologically from a benign inflammatory process. The risk of development into invasive SCC is low, reportedly in the 3% to 4% range.
Actinic keratoses are potential precursors of SCC, but the rate of progression is extremely low, and the vast majority do not become SCCs. These typically red, scaly patches usually arise on areas of chronically sun-exposed skin and are likely to be found on the face and dorsal aspects of the hand.
There are separate staging systems in the 7th edition of the American Joint Committee on Cancer's (AJCC) AJCC Cancer Staging Manual for carcinomas of the eyelid versus other skin surfaces.[1,2] The staging system for non-eyelid skin cancers is primarily designed for squamous cell carcinomas (SCCs). The staging system for carcinoma of the eyelid addresses carcinomas of all histologies.
Basal cell carcinoma (BCC) rarely metastasizes, thus, a metastatic work-up is usually not necessary. Regional lymph nodes should be routinely examined in all cases of SCC, especially for high-risk tumors appearing on the lips, ears, perianal and perigenital regions, or high-risk areas of the hand. In addition, regional lymph nodes should be examined with particular care in cases of SCCs arising in sites of chronic ulceration or inflammation, burn scars, or sites of previous radiation therapy treatment.
Table 2 has a separate list of risk features that should be evaluated for non-eyelid carcinomas; the relevant risk features should also be evaluated for SCCs of the eyelid. Even with relatively small tumor size, SCCs that occur in immunosuppressed patients tend to have more aggressive behavior than SCCs in nonimmunosuppressed patients. Although not a formal part of the AJCC staging system, it is recommended that centers prospectively studying SCC record the presence and type of immunosuppression in addition to the risk features listed in Table 2.
Staging for Cutaneous SCC and Other Cutaneous Carcinomas (Excluding Carcinoma of the Eyelid)
The American Joint Committee on Cancer has designated staging by TNM classification. The TNM classification is used to stage both BCC and SCC.
Patients with a primary cutaneous SCC or other cutaneous carcinoma with no evidence (i.e., clinical, radiologic, or pathologic) of regional or distant metastases are divided into the following two stages:
In instances where there is clinical concern about extension of the tumor into bone and radiologic evaluation has been performed (and is negative), these data may be included to support the stage I versus stage II designation. Tumors that are 2 cm or less in size can be upstaged to stage II if they contain two or more high-risk features.
Stage III patients are those with either of the following:
Stage IV patients are those with any of the following:
Staging for Carcinomas of the Eyelid
The AJCC has designated staging by TNM classification. The TNM classification is used to stage all cell types of eyelid carcinomas.
There is a wide range of treatment approaches, including excision, radiation therapy, cryosurgery, electrodesiccation and curettage, photodynamic or laser-beam light exposure, and topical therapies. Mohs micrographic surgery is a form of tumor excision that involves progressive radial sectioning and real-time examination of the resection margins until adequate uninvolved margins have been achieved, avoiding wider margins than needed. Each of these methods is useful in specific clinical situations. Depending on case selection, these methods have recurrence-free rates ranging from 85% to 95%.
A systematic review of 27 randomized controlled trials comparing various treatments for BCC has been published. Eighteen of the studies were published in full, and nine were published in abstract form only. Only 19 of the 27 trials were analyzed by intention-to-treat criteria. Because the case fatality rate of BCC is so low, the primary endpoint of most trials is complete response and/or recurrence rate after treatment. Most of the identified studies had short follow-up times (only one study had a follow-up as long as 4 years) and were not of high quality. Short follow-up periods will lead to overestimates of tumor control. A literature review of recurrence rates in case series with long-term follow-up after treatment of BCCs indicated that only 50% of recurrences occurred within the first 2 years, 66% after 3 years, and 18% after 5 years. A rule of thumb was that the 10-year recurrence rates were about double the 2-year recurrence rates.
Treatment for Basal Cell Carcinoma of the Skin
Treatment options include the following:
Excision with margin evaluation
This traditional surgical treatment usually relies on surgical margins ranging from 3 mm to 10 mm, depending on the diameter of the tumor. Re-excision may be required if the surgical margin is found to be inadequate on permanent sectioning. For example, in one trial, 35 of 199 (18%) primary BCCs were incompletely excised by the initial surgery and underwent a re-excision. In addition, many laboratories examine only a small fraction of the total tumor margin pathologically. Therefore, the declaration of tumor-free margins can be subject to sampling error.
Excision has been compared in randomized trials to radiation therapy, Mohs micrographic surgery, photodynamic therapy (PDT), and cryosurgery:
At 4 years (mean follow-up of 41 months), the actuarial failure rates (confirmed persistent or recurrent tumor) were 0.7% and 7.5% in the surgery and radiation therapy arms, respectively (P = .003). The cosmetic results were also rated as better after surgery by both patients and dermatologists, and also by three independent judges. At 4 years, 87% of surgery patients rated cosmesis as good versus 69% of radiation therapy patients.[Level of evidence: 1iiDii]
After 30 months of follow-up, the recurrence rate was 5 out of 171 tumors (3%) in the excision group and 3 out of 160 (2%) in the Mohs micrographic surgery group (absolute difference = 1%; 95% confidence interval [CI], -2.5%–+3.7%; P = .724). There was no difference in complication rates, and overall cosmetic outcomes were similar. Total operative costs were nearly twice as high in the Mohs group (405.79 Euros vs. 216.86 Euros (P < .001).[Level of evidence 1iiDii]
At 3 months, the complete response (CR) rate in the surgery group was 51 out of 52 lesions (98%) versus 48 out of 53 lesions (91%) in the PDT group (P = .25). CR rates assessed at 12 months were 96% versus 83% (P = .15).[Level of evidence: 1iiDiv] The investigators interpreted the results as noninferiority of PDT, but the study may have been underpowered. Both the investigators and the patients, however, rated the cosmetic results as either excellent or good in a higher proportion of PDT treatments at each time point of follow-up. At 12 months, patient ratings of excellent or good were 98% versus 84% (P = .03) and investigator ratings were 79% versus 38% (P = .001).
At 1 year, there were no recurrences in the excision group versus three in the cryosurgery group (P = NS), but this is a very short follow-up time. Patients and five independent professionals who were blinded to the treatment arm rated the cosmetic outcomes. Their overall assessments favored excision.[Level of evidence 1iiDiv]
Mohs micrographic surgery
Mohs micrographic surgery is a specialized technique used with the intent to achieve the narrowest margins necessary to avoid tumor recurrence, while maximally preserving cosmesis. It is best suited to management of tumors in cosmetically sensitive areas or for tumors that have recurred after initial excision (e.g., eyelid periorbital area, nasolabial fold, nose-cheek angle, posterior cheek sulcus, pinna, ear canal, forehead, scalp, fingers, and genitalia).[9,10] It is also often used to treat tumors with poorly defined clinical borders.
Mohs micrographic surgery requires special training. The tumor is microscopically delineated, with serial radial resection, until it is completely removed as assessed with real-time frozen sections. Noncontrolled case series suggested that the disease control rates were superior to other treatment methods for BCC.[9,11,12] However, as noted in the section on excision, the disease control rate was not clearly better when directly compared to surgical excision of facial BCCs in a randomized trial of primary BCCs.
Radiation therapy is particularly useful in the management of patients with primary lesions that would otherwise require difficult or extensive surgery (e.g., nose or ears). Radiation therapy eliminates the need for skin grafting when surgery would result in an extensive defect. Cosmetic results are generally good, with a small amount of hypopigmentation or telangiectasia in the treatment port. Radiation therapy can also be used for lesions that recur after a primary surgical approach. Radiation therapy is avoided in patients with conditions that predispose them to radiation-induced cancers, such as xeroderma pigmentosum or basal cell nevus syndrome.
As noted above, radiation therapy has been compared to excision in a randomized trial that showed better response and cosmesis associated with surgery.[5,6]
In a single-center, randomized trial, radiation was superior to cryotherapy in local control at 2 years in 93 patients with primary BCCs. Patients were randomly assigned to receive either EBRT (130 kV x-rays, dosimetry depending upon lesion size) or cryotherapy (two freeze-thaw cycles with liquid nitrogen by spray gun). Patients with lesions on the nose or ear were excluded, since the investigators felt that electron beam therapy is the treatment of choice in these locations. By 1 year, the recurrence rates in the radiation and cryotherapy arms were 4% and 39%, respectively, in a per-protocol analysis. The investigators did not perform a statistical analysis, but the authors of a systematic literature review calculated a relative risk of 0.11 in favor of radiation (95% CI, 0.03–0.43).[Level of evidence 1iiDiv]
Curettage and electrodesiccation
This procedure is also sometimes called electrosurgery. It is a widely employed method for removing primary BCCs, especially superficial lesions of the neck, trunk, and extremities that are considered to be at low risk for recurrence. A sharp curette is used to scrape away the tumor down to its base, followed by electrodesiccation of the lesion base. Although it is a quick method for destroying the tumor, the adequacy of treatment cannot be assessed immediately since the surgeon cannot visually detect the depth of microscopic tumor invasion.
A Cochrane Collaboration systematic review found no randomized trials comparing this treatment method with other approaches. In a large, single-center case series of 2,314 previously untreated BCCs managed at a major skin cancer unit, the 5-year recurrence rate of BCCs of the neck, trunk, and extremities was 3.3%. However, rates increased substantially for tumors larger than 6 mm in diameter at other anatomic sites.[Level of evidence 3iiiDii]
Cryosurgery may be considered for patients with small, clinically well-defined primary tumors. It is infrequently used for the management of BCC, but may be useful for patients with medical conditions that preclude other types of surgery.
Contraindications include abnormal cold tolerance, cryoglobulinemia, cryofibrinogenemia, Raynaud disease (in the case of lesions on hands and feet), and platelet deficiency disorders. Additional contraindications to cryosurgery include tumors of the scalp, ala nasi, nasolabial fold, tragus, postauricular sulcus, free eyelid margin, upper lip vermillion border, lower legs, and tumors near nerves. Caution should also be used before treating nodular ulcerative neoplasia more than 3 cm in diameter, carcinomas fixed to the underlying bone or cartilage, tumors situated on the lateral margins of the fingers and at the ulnar fossa of the elbow, or recurrent carcinomas following surgical excision.
Edema is common following treatment, especially around the periorbital region, temple, and forehead. Treated tumors usually exude necrotic material after which an eschar forms and persists for about 4 weeks. Permanent pigment loss at the treatment site is unavoidable, so the treatment is not well suited to dark-skinned patients. Atrophy and hypertrophic scarring have been reported as well as instances of motor and sensory neuropathy.
As noted in the section above on radiation therapy, a small 93-patient trial comparing cryosurgery to radiation therapy, with only 1 year of follow-up, showed a statistically significant higher recurrence rate with cryosurgery than radiation (39% vs. 4%).
In a small, single-center, randomized study, 88 patients were assigned to either cryosurgery in two freeze-thaw cycles or PDT using delta-aminolevulinic acid as the photosensitizing agent and 635 nm wavelength light with 60 J/cm2 energy delivered by Nd:YAG laser versus cryosurgery in two freeze-thaw cycles. Overall clinical efficacy was similar in evaluable lesions at 1 year (5/39 recurrences for cryosurgery vs. 2/44 recurrences for PDT), but more re-treatments were needed with PDT to achieve complete responses.[Level of evidence 1iiD] Cosmetic outcomes favored PDT (93% good or excellent after PDT vs. 54% after cryosurgery, P < .001). In another randomized study of 118 patients, reported in abstract form only, cryosurgery was compared with PDT with methyl aminolevulinic acid.[18,19] Tumor control rates at 3 years were similar (74%), but cosmetic outcomes were better in the PDT group. These cryosurgery-PDT comparisons were reported on a per-protocol basis rather than an intent-to-treat basis.[18,19][Level of evidence 1iiDiv]
Photodynamic therapy with photosensitizers is used in the management of a wide spectrum of superficial epithelial tumors. A topical photosensitizing agent such as 5-aminolevulinic acid or methyl aminolevulinate is applied to the tumor, followed by exposure to a specific wavelength of light (whether laser or broad band), depending upon the absorption characteristics of the photosensitizer. In the case of multiple BCCs, short-acting systemic (intravenous) photosensitizers such as verteporfin have been used investigationally. Upon light activation, the photosensitizer reacts with oxygen in the tissue to form singlet oxygen species, resulting in local cell destruction.
In case series, PDT has been associated with high initial CR rates. However, substantial regrowth rates of up to 50% have been reported with long-term follow-up. A randomized trial of PDT versus excision is summarized in the section on simple excision above. Two small trials, one reported in abstract form only, comparing PDT with cryosurgery are summarized in the cryosurgery section above, showing similar antitumor efficacy but better cosmesis with PDT.[17,18,19]
Topical fluorouracil (5-FU)
Topical 5-FU, as a 5% cream, may be useful in specific limited circumstances. It is a Food and Drug Administration (FDA)-approved treatment for superficial BCCs in patients for whom conventional methods are impractical, such as individuals with multiple lesions or difficult treatment sites. Safety and efficacy in other indications have not been established.[22,23][Level of evidence: 3iiiDiv] Given the superficial nature of its effects, nonvisible dermal involvement may persist, giving a false impression of treatment success. In addition, the brisk accompanying inflammatory reaction may cause substantial skin toxicity and discomfort in a large proportion of patients.
Imiquimod topical therapy
Imiquimod is an agonist for the toll-like receptor 7 and/or 8, inducing a helper T-cell cytokine cascade and interferon production. It purportedly acts as an immunomodulator. It is available as a 5% cream and is used in schedules ranging from twice weekly to twice daily over 5 to 15 weeks. Most of the experience is limited to case series of BCCs that are less than 2 cm2 in area and that are not in high-risk locations (i.e., within 1 cm of the hairline, eyes, nose, mouth, ear; or in the anogenital, hand, or foot regions). Follow-up times have also been generally short. Reported CR rates vary widely, from about 40% to 100%.[Level of evidence 3iiiDiv]
There have been a number of randomized trials of imiquimod.[24,25,26,27,28,29] However, the designs of all of them make interpretation of long-term efficacy impossible. Most were industry-sponsored dose-finding studies, with small numbers of patients on any given regimen; and patients were only followed for 6 to 12 weeks, with excision at that time to determine histologic response.[Level of evidence 1iDiv] Therefore, although imiquimod is an FDA-approved treatment for superficial BCCs, some investigators in the field do not recommend it for initial monotherapy for BCC; some reserve it for patients with small lesions in low-risk sites who cannot undergo treatment with more established therapies.
Carbon dioxide laser
This method is used very infrequently in the management of BCC because of the difficulty in controlling tumor margins. Few clinicians have extensive experience with the technique for BCC treatment. There are no randomized trials comparing it with other modalities.
Treatment for Recurrent Basal Cell Carcinoma of the Skin
After treatment for BCC, patients should be followed clinically and examined regularly. Most recurrences occur within 5 years, but as noted above, about 18% of recurrences are diagnosed beyond that point. Patients who develop a primary BCC are also at increased risk of subsequent primary skin cancers because the susceptibility of their sun-damaged skin to additional cancers persists.[31,32,33] This effect is sometimes termed field carcinogenesis. Age at diagnosis of the first BCC (<65 years), red hair, and initial BCC on the upper extremities appear to be associated with higher risk of subsequent new BCCs.
Mohs micrographic surgery is commonly used for local recurrences of BCC. In a separate group within a randomized trial comparing excision to Mohs micrographic surgery for primary BCCs, 204 recurrent BCCs were randomly assigned to excision versus Mohs micrographic surgery. The recurrence rates were 8 out of 102 patients and 2 out of 102 patients, respectively, after a mean follow-up of 2.08 years (P = NS).[Level of evidence 1iiDii] There were more postoperative complications, including wound infections, graft necrosis, or bleeding in the excision group than the Mohs surgery group (19% vs. 8%, P = .021). As with primary tumors, the operative costs associated with Mohs surgery were higher than with excision (489.06 Euros vs. 323.49 Euros [P = .001]).
Treatment for Metastatic Basal Cell Carcinoma (or Locally Advanced Disease Untreatable by Local Modalities)
Hedgehog pathway inhibitors
BCCs frequently exhibit constitutive activation of the Hedgehog/PTCH1-signaling pathway. Two inhibitors of smoothened, a transmembrane protein involved in the Hedgehog pathway, are approved for the treatment of adults with metastatic BCC, patients with locally advanced BCC that has recurred after surgery, and patients who are not candidates for surgery or radiation therapy.
Another topical inhibitor under investigation has produced objective responses in patients with nevoid BCC syndrome.[Level of evidence: 3iiiDiv]
FDA approval was supported by an international, multicenter, open-label, two-cohort trial enrolling 104 patients: 33 with metastatic BCC and 71 with locally advanced BCC with inoperable disease or for whom surgery was inappropriate.[Level of evidence: 3iiiDiv] Patients received vismodegib 150 mg daily. Objective response rate (RR) assessed by an independent review committee was the primary endpoint. The study was sized to test whether the RR was greater than 10% in patients with metastatic BCC and greater than 20% in patients with locally advanced BCC by exact binomial 1-sided tests.
Of the 104 patients, 96 were evaluable for RR, with 8 patients who had locally advanced BCC excluded from analysis after the independent pathologist did not identify BCC in the biopsy specimens. In both cohorts, median duration of treatment was 10.2 months (range, 0.7–18.7 months). In 33 patients with metastatic BCC, RR was 30% (95% CI, 16–48; P = .001). In 63 patients with locally advanced BCC, RR was 43% (95% CI, 31–56; P < .001), with complete responses in 13 patients (21%). In both cohorts, median duration of response was 7.6 months.
The most common adverse events were muscle spasms, alopecia, dysgeusia, weight loss, and fatigue. Adverse events led to discontinuation in 12% of patients.
There were fatal adverse events in seven patients with unknown relationship to the study drug; three deaths from unknown causes, and one death each from hypovolemic shock, myocardial infarction, meningeal disease, and ischemic stroke.
Sonidegib was evaluated at two doses in a multinational, double-blind, multiple-cohort trial conducted in patients with metastatic BCC (n = 36) or locally advanced BCC (n = 194).[Level of evidence: 1iDiv] Patients were randomly assigned (in a 2:1 fashion) to receive 200 mg or 800 mg orally, once a day. The primary endpoint was RR, with data collected up to 6 months after randomization of the last patient and determined by blinded central review.
A sample size of 210 patients was targeted to ensure 150 patients for the primary efficacy analysis, which required locally advanced disease to be assessable by modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Success was prespecified as a 30% RR. In the 200-mg cohort, a central review identified 18 of 42 patients with locally advanced BCC (43%; 95% CI, 28–59) and 2 of 13 patients with metastatic BCC (15%; 95% CI, 2–45) who had an objective response and qualified for the primary efficacy analysis. The median duration of response has not been reached. RR was similar in the two-dose cohorts, with fewer adverse events at the lower dose, leading to FDA approval of the 200-mg once-daily dose.
Frequent adverse events included muscle spasms, alopecia, dysgeusia, fatigue, nausea decreased weight, decreased appetite, myalgia, pain, and vomiting.
Four patients in the 800-mg cohort died during the study: two from cardiac death and two from metastatic disease progression.
Cisplatin, alone or in combination with other drugs, is the most commonly reported chemotherapy agent and, in case reports or very small case series, demonstrates occasional tumor responses.[38,39] Other agents have been reported but have low-associated response rates, including cyclophosphamide, vinblastine, 5-FU, methotrexate, and doxorubicin.
Because there is no curative therapy, clinical trials are appropriate.
Information about ongoing clinical trials is available from the NCI website.
Current Clinical Trials
Check the list of NCI-supported cancer clinical trials that are now accepting patients with basal cell carcinoma of the skin. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI website.
Localized squamous cell carcinoma (SCC) of the skin is a highly curable disease. There are a variety of treatment approaches to localized SCC, including excision, radiation therapy, cryosurgery, and electrodesiccation and curettage. Mohs micrographic surgery is a form of tumor excision that involves progressive radial sectioning and real-time examination of the resection margins until adequate uninvolved margins have been achieved, avoiding wider margins than needed.
There is little or no good-quality evidence that allows direct comparison of outcomes for patients with sporadic, clinically localized SCCs treated with local therapies. A systematic literature review found only one randomized controlled trial in the management of such patients, and that trial compared adjuvant therapy to observation after initial local therapy rather than different local therapies. In that small single-center trial, 66 patients with high-risk, clinically localized SCC were assigned randomly, after surgical excision of the primary tumor (with or without radiation, depending on clinical judgment), to receive either combined 13-cis-retinoic acid (1 mg/kg orally per day) plus interferon-alpha (3 × 106 U subcutaneously 3 times/week) for 6 months or to observation. In the 65 evaluable patients after a median follow-up of 21.5 months, there was no difference in the combined (primary) endpoint of SCC recurrence or second primary tumor (45% vs. 38%; hazard ratio = 1.13; 95% confidence interval [CI], 0.53–2.41), nor in either of the individual components of the primary endpoint.[Level of evidence 1iiDii]
Absent high-quality evidence from controlled clinical trials, the management of clinically localized cutaneous SCC is based upon case series and consensus statements from experts. The commonly used treatments are listed below.
Treatment for Squamous Cell Carcinoma of the Skin
Surgical excision with margin evaluation
Excision is probably the most common therapy for SCC. This traditional surgical treatment usually relies on surgical margins ranging from 4 mm to 10 mm, depending on the diameter of the tumor and degree of differentiation. In a prospective case series of 141 SCCs, a 4-mm margin was adequate to encompass all subclinical microscopic tumor extension in more than 95% of well-differentiated tumors up to 19 mm in diameter. Wider margins of 6 mm to 10 mm were needed for larger or less-differentiated tumors or tumors in high-risk locations (e.g., scalp, ears, eyelids, nose, and lips). Re-excision may be required if the surgical margin is found to be inadequate on permanent sectioning.
Mohs micrographic surgery is a specialized technique used to achieve the narrowest margins necessary to avoid tumor recurrence, while maximally preserving cosmesis. In case series, it has been associated with a lower local recurrence rate than the other local modalities, but there are no randomized trials allowing direct comparison. This surgery is best suited to the management of tumors in cosmetically sensitive areas or for tumors that have recurred after initial excision (e.g., eyelid periorbital area, nasolabial fold, nose-cheek angle, posterior cheek sulcus, pinna, ear canal, forehead, scalp, fingers, and genitalia).[7,8]
Mohs micrographic surgery is also often used to treat high-risk tumors with poorly defined clinical borders or with perineural invasion. The method requires special training. The tumor is microscopically delineated, with serial radial resection, until it is completely removed as assessed with real-time frozen sections. Nevertheless, since the technique removes tumor growing in contiguity and may miss noncontiguous in-transit cutaneous micrometastases, some practitioners remove an additional margin of skin in high-risk lesions even after the Mohs surgical procedure confirms uninvolved margins.[Level of evidence: 3iiiDiv]
Radiation therapy is a logical treatment choice, particularly for patients with primary lesions requiring difficult or extensive surgery (e.g., nose, lip, or ears).[4,9] Radiation therapy eliminates the need for skin grafting when surgery would result in an extensive defect. Cosmetic results are generally good, with a small amount of hypopigmentation or telangiectasia in the treatment port. Radiation therapy can also be used for lesions that recur after a primary surgical approach. Radiation therapy is avoided in patients with conditions that predispose them to radiation-induced cancers, such as xeroderma pigmentosum or basal cell nevus syndrome.
Although radiation therapy, with or without excision of the primary tumor, is used for histologically proven clinical lymph node metastases and has been associated with favorable disease-free survival rates, the retrospective nature of these case series makes it difficult to know the impact of nodal radiation on survival.[11,12][Level of evidence 3iiiDii]
This procedure is also sometimes called electrosurgery. A sharp curette is used to scrape the tumor down to its base, followed by electrodesiccation of the lesion base. Although it is a quick method for destroying the tumor, the adequacy of treatment cannot be assessed immediately since the surgeon cannot visually detect the depth of microscopic tumor invasion. Its use is limited to small (<1 cm), well-defined, and well-differentiated tumors.[Level of evidence: 3iiiDii]
Cryosurgery may be considered for patients with small, clinically well-defined primary tumors. It may be useful for patients with medical conditions that preclude other types of surgery. Contraindications include abnormal cold tolerance, cryoglobulinemia, cryofibrinogenemia, Raynaud disease (in the case of lesions on hands and feet), and platelet deficiency disorders. Additional contraindications to cryosurgery include tumors of the scalp, ala nasi, nasolabial fold, tragus, postauricular sulcus, free eyelid margin, upper lip vermillion border, lower legs, and tumors near nerves. Caution should also be used before treating nodular ulcerative neoplasia more than 3 cm in diameter, carcinomas fixed to the underlying bone or cartilage, tumors situated on the lateral margins of the fingers and at the ulnar fossa of the elbow, or recurrent carcinomas following surgical excision.
Edema is common following treatment, especially around the periorbital region, temple, and forehead. Treated tumors usually exude necrotic material after which an eschar forms and persists for about 4 weeks. Permanent pigment loss at the treatment site is unavoidable, so the treatment is not well suited to dark-skinned patients. Atrophy and hypertrophic scarring have been reported as well as instances of motor and sensory neuropathy.
The management of SCC in situ (Bowen disease) is similar to good-risk SCC. However, since it is noninvasive, surgical excision, including Mohs micrographic surgery, is usually not necessary. In addition, high complete response (CR) rates are achievable with photodynamic therapy (PDT). In a multicenter trial, 229 patients (209 evaluated in the per-protocol/per-lesion analysis) were randomly assigned to receive PDT (methyl aminolevulinate + 570–670 nm red light; n = 91), placebo cream with red light (n = 15); or treatment by physician choice (cryotherapy, n = 77; topical 5-fluorouracil, n = 26). The sustained complete clinical response rates at 12 months were 80%, 67%, and 69% in the three respective active therapy groups (P = .04 for the comparison between PDT and the two combined physician-choice groups).[Level of evidence 1iiDii] The cosmetic results were best in the PDT group. (For comparison, the CR rates at 3 months for PDT and placebo/PDT were 93% and 21%, respectively.)
Treatment for Recurrent Squamous Cell Carcinoma of the Skin
SCCs have definite metastatic potential, and patients should be followed regularly after initial treatment. Overall, local recurrence rates after treatment of primary SCCs ranged from about 3% to 23%, depending upon anatomic site. About 58% of local recurrences manifest within 1 year, 83% within 3 years, and 95% within 5 years. The metastatic rate for primary tumors of sun-exposed skin is 5%; for tumors of the external ear, 9%; and for tumors of the lip, 14%. Metastases occur at an even higher rate for primary SCCs in scar carcinomas or in nonexposed areas of skin (about 38%). About 69% of metastases are diagnosed within 1 year, 91% within 3 years, and 96% within 5 years. Tumors that are 2 cm or larger in diameter, 4 mm or greater in depth, or poorly differentiated have a relatively bad prognosis  and even higher local recurrence and metastasis rates than those listed. Reported rates also vary by treatment modality, with the lowest rates associated with Mohs micrographic surgery, but at least some of the variation may be the result of patient selection factors; no randomized trials directly compare the various local treatment modalities.
Recurrent nonmetastatic SCCs are considered high risk and are generally treated with excision, often using Mohs micrographic surgery. Radiation therapy is used for lesions that cannot be completely resected.
As is the case with BCC, patients who develop a primary SCC are also at increased risk of subsequent primary skin cancers because the susceptibility of their sun-damaged skin to additional cancers persists.[15,16]
Treatment for Metastatic Squamous Cell Carcinoma (or Advanced Disease Untreatable by Local Modalities)
As is the case with BCC, metastatic and far-advanced SCC is unusual, and reports of systemic therapy are limited to case reports and very small case series with tumor response as the endpoint.[Level of evidence 3iiiDiv] Cisplatin-based regimens appear to be associated with high initial tumor response rates.[17,18] High response rates have also been reported with the use of 13-cis-retinoic acid plus interferon-alpha-2a. Since there is no standard therapy, clinical trials are appropriate if available. Information about ongoing clinical trials is available from the NCI website.
Check the list of NCI-supported cancer clinical trials that are now accepting patients with squamous cell carcinoma of the skin. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Actinic keratoses commonly appear in areas of chronic sun exposure, such as the face and dorsa of the hands. Actinic cheilitis is a related condition that usually appears on the lower lips. These conditions represent early epithelial transformation that may eventually evolve into invasive SCC.
Actinic keratosis is a noninvasive lesion. The progression rate is extremely low. In a prospective study, the progression rate to SCC was less than 1 in 1,000 per year, calling into question the cost effectiveness of treating all actinic keratoses to prevent SCC. Moreover, in a population-based longitudinal study, there was an approximately 26% spontaneous regression rate of solar keratoses within 1 year of a screening examination. Therefore, studies designed to test the efficacy of any treatment for progression of actinic keratoses to SCC are impractical (or impossible). Nevertheless, a variety of treatment approaches have been reviewed.
Treatment for Actinic Keratosis
Check the list of NCI-supported cancer clinical trials that are now accepting patients with actinic keratosis. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Basal Cell Carcinoma of the Skin Treatment
Editorial changes were made to this section.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of skin cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
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Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
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Levels of Evidence
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The preferred citation for this PDQ summary is:
National Cancer Institute: PDQ® Skin Cancer Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://www.cancer.gov/types/skin/hp/skin-treatment-pdq. Accessed <MM/DD/YYYY>.
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Last Revised: 2016-01-29
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