INTRODUCTION — Basal cell carcinoma (BCC) is a common skin cancer that arises from the basal layer of the epidermis and its appendages (picture 1A-B). Treatment of BCC is indicated due to the locally invasive, aggressive, and destructive effects of this tumor on skin and surrounding tissues (picture 2A-B). Treatment options for BCC include surgical excision, Mohs micrographic surgery, curettage and electrodesiccation (C&E), topical agents, photodynamic therapy (PDT), cryotherapy, and radiation therapy (table 1). Tumor characteristics, such as size, location, and pathology, as well as treatment tolerability, cost, and patient preference influence the selection of treatment.
This topic will review the treatment of BCCs without aggressive clinical or pathologic features and the prognosis of BCC. The treatment of BCCs with high risk for recurrence, the epidemiology and diagnosis of BCC, the options for systemic therapy in locally advanced or metastatic BCC, and the management of BCC in patients with Gorlin syndrome are discussed separately.
FEATURES ASSOCIATED WITH LOW RISK OF RECURRENCE — The following characteristics have been proposed as features that identify BCCs with a low likelihood for recurrence after treatment in the 2021 National Comprehensive Cancer Network (NCCN) clinical practice guidelines on cutaneous BCC :
●Location and size:
•<20 mm in diameter on trunk and extremities, excluding genitalia, pretibia, hands, and feet
•Nodular or superficial histopathologic growth pattern, other nonaggressive growth patterns (infundibulocystic, fibroepithelioma of Pinkus)
•Lack of perineural invasion
•Primary lesion (not recurrent)
•Well-defined clinical borders
•No history of radiation therapy at site
PRETREATMENT EVALUATION — The assessment of risk for lesion recurrence is the most important step in the choice of treatment for BCC. It involves a detailed history (lesion history, use of immunosuppressive medications, presence of comorbidities), a physical examination, and a biopsy of the suspicious lesion.
Lesion biopsy and risk assessment — Although the diagnosis of BCC can often be made by the experienced clinician based upon the clinical and dermoscopic examination, a skin biopsy is essential to confirm the diagnosis and provide additional information on the risk for tumor recurrence following treatment. Obtaining a lesion biopsy for diagnostic confirmation is especially important for patients who are not surgical candidates before proceeding to destructive or nonsurgical treatment. (See "Epidemiology, pathogenesis, clinical features, and diagnosis of basal cell carcinoma", section on 'Biopsy'.)
Choice of treatment — A broad range of surgical and nonsurgical therapies are available for the treatment of BCC. Advantages and disadvantages of the treatment options most frequently used are summarized in the table (table 1) . Our approach to the treatment of BCC at low risk of recurrence (algorithm 1) is based on the following considerations:
●Overly aggressive management of BCCs at low risk for recurrence (see 'Features associated with low risk of recurrence' above) may result in unnecessary burdens to the patient, such as increased morbidity and discomfort, treatment and travel costs, and time lost from work and family. Conversely, inadequate treatment of lesions with aggressive features can lead to subsequent tumor recurrence, with potentially devastating consequences (picture 2A-B).
●Surgical excision is generally recommended as first-line therapy for BCC at low risk of recurrence . Alternative approaches may be appropriate in some patients, based on consideration of the following:
•Tumor-related factors (eg, superficial versus nodular, single versus multiple lesions)
•Patient-related factors (eg, age, immunosuppression, presence of comorbidities)
•Cosmetic and functional considerations
•Availability of specific techniques or specialists
•Relative efficacy and costs of treatment modalities
●Patient-specific factors play an important role in treatment selection. Physical or functional limitations that affect the ability of patients to tolerate surgery, manage wound care, apply topical therapies, or return for follow-up impact the choice of treatment.
●The cosmetic effects of treatment options must be considered. For example, patients who prefer to avoid the pigmentary changes and scarring that can result from curettage and electrodesiccation (C&E) may be better served by other interventions.
Standard surgical excision — For primary, nodular or superficial BCC <20 mm in diameter located on the trunk and extremities (excluding genitalia, pretibia, hands, and feet), we suggest standard surgical excision with postoperative margin evaluation as first-line therapy (algorithm 1). Margins of 4 to 5 mm are thought to be appropriate.
Mohs surgery is not indicated for primary BCCs on the trunk or extremities that lack aggressive clinical or histopathologic features because other procedures have similar efficacy and are less time consuming and costly. (See "Treatment of basal cell carcinomas at high risk for recurrence", section on 'Mohs micrographic surgery'.)
The surgical defect is typically immediately repaired either by side-side closure or the use of adjacent tissue flaps or skin grafts. This allows wound healing to be completed within one to two weeks. The type of closure depends upon several factors, including the size, depth, and location of the defect; the availability and laxity of nearby tissue; and patient and clinician preference.
The appropriateness of 4 to 5 mm margins is supported by the results of a 2010 meta-analysis of 37 studies, most of which were observational . The analysis of pooled data from 10,261 patients with 16,066 low-risk, nodular BCCs treated with surgical excision found that mean recurrence rates for BCCs excised with 5, 4, 3, and 2 mm surgical margins were 0.4, 1.6, 2.6, and 4 percent, respectively . Rates of pathologically confirmed complete excisions were similar for surgical margins between 3 and 5 mm.
The efficacy of standard surgical excision compared with other treatment modalities for BCC has been evaluated in several randomized trials and in a network meta-analysis [5-13]. Recurrence rates for standard excision were less than 5 percent and consistently lower than those associated with nonsurgical treatment modalities.
Advantages and disadvantages of surgical excision compared with other treatment modalities are summarized in the table (table 1). Surgical excision can be performed faster than Mohs surgery, is relatively inexpensive if frozen sections are not performed, and provides some information on surgical margins. Excision is typically performed in an outpatient setting under local anesthesia and is usually well tolerated. The long-term cosmetic and functional results are usually superior compared with radiation therapy.
Curettage and electrodesiccation — Curettage and electrodesiccation (C&E) is an alternative, first-line option for the treatment of superficial, low-risk BCCs, especially in older patients who would have difficulty returning for suture removal after surgery and would not be concerned about a more visible scar (algorithm 1). C&E is not recommended for BCCs located on terminal hair-bearing skin, due to the risk of follicular extension of the tumor.
C&E is generally well tolerated. An unpleasant smell of smoke is produced during the procedure. Minor, harmless electrical shocks may occur in improperly grounded patients who inadvertently touch metal on the treatment table. (See "Minor dermatologic procedures", section on 'Curettage and electrodesiccation'.)
Although C&E is a fast and easily performed treatment for BCC, the procedure does not allow histologic confirmation of tumor removal, is highly operator dependent, and requires considerable experience to achieve complete tumor removal and low recurrence rates. Clinicians must be cognizant that many apparently superficial BCCs have, in fact, a mixed histology. In such cases, C&E is likely to result in incomplete tumor removal.
The efficacy of C&E for BCC has not been evaluated in high-quality studies. Evidence from observational studies indicates that C&E provides varying cure rates, depending upon the tumor size and location and the experience of the clinician performing the procedure:
●A review of six studies including over 4000 patients with BCC treated with C&E found recurrence rates ranging from 6 to 19 percent .
●In a single-institution study, the recurrence rate was 5 percent for small BCCs (<6 mm) in high-risk areas of the face, 18 percent for larger tumors in the same areas, and 3 percent for tumors in low-risk sites (ie, neck, trunk, extremities) .
SECOND-LINE THERAPIES — For patients who are not surgical candidates or prefer to avoid surgery, second-line therapies for low-risk superficial or nodular lesions include topical therapies (ie, imiquimod, topical fluorouracil), photodynamic therapy (PDT), or cryosurgery. The choice depends on the clinician's experience and the patient's characteristics and preferences (algorithm 1). An example of a patient characteristic is difficulty with wound healing on the lower legs due to edema.
Imiquimod — Imiquimod 5% cream is an immune response modifier that is approved by the US Food and Drug Administration (FDA) for the treatment of superficial BCCs.
Indications and administration — We generally use imiquimod for the treatment of primary, superficial BCCs in the following circumstances:
●Low-risk sites, where recurrence is unlikely to be accompanied by substantial morbidity
●Patient preference to avoid surgery
●Concerns regarding the potential for an unsatisfactory cosmetic result or difficulty with surgical wound healing
A standard regimen involves the application of imiquimod at bedtime five days per week for six weeks or until the target reaction of erythema, crusting, and scab formation develops. Many patients achieve an exuberant and sufficient inflammatory response in less than six weeks.
Because of the concern for consistent patient adherence to the longer treatment period suggested for nodular BCC, the lower cure rate, and the availability of more effective treatments [7,16], imiquimod is not routinely used for the treatment of nodular BCC. Imiquimod may be used for the treatment of nonsuperficial BCCs only in those patients who are poor surgical candidates or who have limited life expectancy.
Adverse effects — Local skin irritation is an expected side effect of imiquimod therapy. Patients may experience itching, weeping, redness, soreness, bleeding, and/or pain within the treated area . Although the cosmetic outcome is excellent in most cases, hypopigmentation may develop after therapy . Topical imiquimod treatment can be associated with systemic effects, including fatigue and an influenza-like illness. Exfoliative dermatitis and angioedema have also been reported.
Evidence of efficacy — Randomized trials have demonstrated that imiquimod can be effective for superficial BCC:
●Imiquimod versus placebo:
•The efficacy of imiquimod for superficial BCC is supported by the pooled results of two identical, multicenter, randomized trials that compared imiquimod 5% cream (applied once daily five or seven times per week for six weeks) with vehicle in a total of 724 patients with superficial BCC . Twelve weeks after treatment, the histologic clearance rates for the five- and seven-day imiquimod treatment groups were 82 and 79 percent, respectively, compared with 3 percent in the vehicle-treated group. The severity of erythema, erosion, and scabbing/crusting was associated with higher clearance rates. Long-term follow-up was not reported.
•A beneficial effect of imiquimod was also demonstrated in a randomized trial that assessed the response of superficial BCC to six weeks of daily therapy with imiquimod 5% cream . Twelve weeks after treatment, histologic clearance rates in the imiquimod and vehicle groups were 80 and 6 percent, respectively.
●Imiquimod versus surgery – Although treatment with imiquimod is often successful, clinicians should be aware that the likelihood of treatment success is higher with surgical excision:
•An unblinded trial (the SINS study) in which 257 patients with superficial BCC and 244 patients with nodular BCC were randomly assigned to treatment with imiquimod 5% cream (once daily for six weeks for superficial BCC and once daily for 12 weeks for nodular BCC) or surgical excision with a 4 mm margin found that patients treated with surgical excision were significantly less likely to experience treatment failure or tumor recurrence within three years . At three years, the clinical cure rates from surgical excision and imiquimod were 98 and 85 percent, respectively, for patients with superficial BCC and 99 and 82 percent, respectively, for patients with nodular BCC. The study excluded tumors in sites associated with high risk for subclinical spread, including the nose, ear, eyelid, eyebrow, and temple. Histologic cure rates were not assessed.
•A subsequent analysis of the five-year, follow-up data of the SINS study participants found that the cure rates for surgery and imiquimod for superficial BCC were 97 and 84 percent, respectively (recurrence rate difference 13 percent, 95% CI 3.9-22.2) . For nodular BCC, the cure rates for surgery and imiquimod were 99 and 81 percent, respectively (recurrence rate difference 17.7 percent, 95% CI 8.0-27.5). Of note, in the period between three and five years, there were only two additional recurrences (one in the surgery group and one in the imiquimod group).
●Imiquimod versus methyl aminolevulinate-photodynamic therapy – A randomized trial (601 participants) compared two treatments separated by one week of methyl aminolevulinate-photodynamic therapy (MAL-PDT; available in Europe but not in the United States), imiquimod 5% cream (once-daily applications five days per week for six weeks), and topical fluorouracil 5% cream (twice-daily applications for four weeks) for the treatment of superficial BCC . The proportions of patients who achieved histologic clearance at 3 and 12 months after treatment were 83.4 percent in the imiquimod group (95% CI 78.2-88.9) versus 72.8 percent in the MAL-PDT group (95% CI 66.8-79.4) .
●Tumor thickness and response rate – The thickness of a superficial BCC may influence the likelihood of response to imiquimod therapy. A retrospective study of 127 biopsy specimens from superficial BCCs that were subsequently treated with imiquimod (applied five days per week for six weeks) found that while 11 of 19 tumors >0.4 mm deep recurred after treatment, 0 of 108 tumors ≤0.4 mm deep recurred (mean follow-up 34 months, range 3 to 91 months) . If these findings are supported by future investigations, the depth of superficial BCC may become a consideration in the selection of imiquimod treatment.
●Adjuvant imiquimod for nodular basal cell carcinoma – The few randomized trials that have evaluated the use of imiquimod as an adjunctive therapy for nodular BCC prior to surgical excision have yielded conflicting findings [22,23]. In a randomized trial of 70 patients with nodular BCC on the face, four weeks of imiquimod treatment prior to Mohs surgery was associated with reductions in tumor size and surgical defect size. However, a smaller, randomized trial failed to find a statistically significant benefit of adjuvant imiquimod therapy . There is also a theoretical concern that pretreatment with imiquimod could contribute to false-negative surgical margins by leaving noncontiguous areas of residual tumor .
●Imiquimod for basal cell carcinoma in patients with basal cell nevus syndrome and xeroderma pigmentosum – Case reports suggest that imiquimod 5% cream may have a role in treating BCCs in patients with basal cell nevus syndrome and xeroderma pigmentosum [25-28]. These patients are predisposed to developing numerous skin cancers, including BCCs, and their multiple lesions can be quite difficult to manage. In this setting, topical treatment of primary early, small, or superficial BCCs can be a valuable asset. (See "Nevoid basal cell carcinoma syndrome (Gorlin syndrome)" and "The genodermatoses: An overview", section on 'Xeroderma pigmentosum'.)
Topical fluorouracil — Fluorouracil is an antimetabolite that inhibits DNA synthesis and cell proliferation, resulting in tumor necrosis. Topical fluorouracil 5% cream is approved by the US FDA for the treatment of superficial BCCs.
Indications and administration — Topical fluorouracil 5% cream or solution is an approved topical treatment for superficial BCC. However, extensive clinical experience indicates that this treatment modality should be restricted to superficial BCCs in noncritical locations [29,30]. Topical fluorouracil is applied twice daily for four to six weeks. However, some patients may experience a sufficient, vigorous, inflammatory reaction in two to three weeks.
Adverse effects — Scarring has been reported in 9 to 16 percent of patients utilizing topical fluorouracil for the treatment of superficial BCC or squamous cell carcinoma in situ . Patients should avoid intense sun exposure during treatment.
Other unusual side effects include temporary, reversible onycholysis and onychodystrophy; persistent telangiectasias; hypertrophic scarring in high-risk areas; and bullous pemphigoid.
Systemic absorption of topical fluorouracil can cause cardiac ischemia and other life-threatening systemic toxicities in the rare patient with an inherited deficiency in the metabolizing enzyme dihydropyrimidine dehydrogenase (DPD) [31,32]. (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Fluorouracil'.)
Evidence of efficacy — Evidence from high-quality studies supporting the use of topical fluorouracil for the treatment of superficial BCC is limited:
●In a randomized trial (601 participants) comparing MAL-PDT (two treatments separated by one week), imiquimod 5% cream (once-daily applications five days per week for six weeks), and topical fluorouracil 5% cream (twice-daily applications for four weeks) for the treatment of superficial BCC, the proportions of patients who achieved histologic clearance at 3 and 12 months after treatment in the MAL-PDT, imiquimod, and fluorouracil groups were 72.8 percent (95% CI 66.8-79.4), 83.4 percent (95% CI 78.2-88.9), and 80.1 percent (95% CI 74.7-85.9), respectively .
●A five-year extension of the above trial revealed that the probability of tumor-free survival for MAL-PDT was 63 percent (95% CI 55.3-69.2), for imiquimod was 81 percent (95% CI 74.0-85.6), and for fluorouracil was 70 percent (95% CI 62.9-76.0), showing that imiquimod is superior to MAL-PDT and fluorouracil for primary, superficial BCCs .
Basal cell carcinoma recurring after treatment with topical fluorouracil — There is some concern that BCCs recurring after treatment with topical fluorouracil may be of a more aggressive subtype [34-36]. A study using the data from a multicenter, randomized trial comparing MAL-PDT, imiquimod, and topical fluorouracil for the treatment of superficial BCC  analyzed the histologic subtypes of 166 early or late treatment failures (three months post-treatment and later during follow-up) within the treatment subgroups . Overall, a nonsuperficial, more aggressive subtype was found in 64 of 166 treatment failures (39 percent). Among early treatment failures, the proportion of aggressive subtypes was highest after treatment with topical fluorouracil, followed by MAL-PDT and imiquimod (67, 55, and 26 percent, respectively).
Photodynamic therapy — Photodynamic therapy (PDT) is a noninvasive, nonscarring treatment option for superficial BCCs . PDT consists of topical application of a photosensitizer (methyl aminolevulinate [MAL] or 5-aminolevulinic acid [ALA]) followed, after a variable incubation time, by irradiation with a red or blue light . Of note, MAL-PDT is available in Europe but not in the United States. (See "Photodynamic therapy".)
Although PDT has been approved in Europe, Canada, Australia, and other countries worldwide for the treatment of superficial and thin nodular BCC when other available therapies are not acceptable, US FDA approval has not been granted for the treatment of BCC.
Adverse effects from topical PDT include prolonged photosensitivity (up to two to three days in our experience), pain, burning, erythema, edema, ulceration, and temporary pigmentary change at the treated site. Healing is usually complete within two weeks, scarring is unusual, and cosmetic results are good. In a randomized trial comparing MAL-PDT with imiquimod and topical fluorouracil in patients with superficial BCC, the proportion of patients with good or excellent cosmetic results was similar in all treatment groups (90 percent in the MAL-PDT group, 82 percent in the imiquimod group, and 85 percent in the topical fluorouracil group) .
Several randomized trials and meta-analyses have compared the efficacy of PDT with other therapies for superficial BCC . Most studies have used MAL-PDT. As only a few small studies have compared MAL-PDT with ALA-PDT for the treatment of BCC, whether the two modalities have the same efficacy remains uncertain :
●A noninferiority randomized trial that compared MAL-PDT, imiquimod 5% cream, and topical fluorouracil 5% cream in 601 participants with superficial BCC found results that favored imiquimod over MAL-PDT . The proportions of patients who achieved the primary endpoint (tumor-free status at 3 and 12 months after treatment) in the MAL-PDT, imiquimod, and topical fluorouracil groups were 72.8 percent (95% CI 66.8-79.4), 83.4 percent (95% CI 78.2-88.9), and 80.1 percent (95% CI 74.7-85.9), respectively. The only statistically significant difference in treatment effect occurred between patients in the MAL-PDT and imiquimod groups (difference = 10.6 percent [95% CI 1.5-19.5] in favor of imiquimod).
●The five-year, follow-up results of the same trial showed that imiquimod was superior to both MAL-PDT and topical fluorouracil, with cumulative probabilities of tumor-free survival of 62.7 percent for MAL-PDT (95% CI 55.3-69.2), 80.5 percent for imiquimod (95% CI 74.0-85.6), and 70 percent for topical fluorouracil (95% CI 62.9-76.0) .
●In a meta-analysis of two trials comparing PDT with surgical excision, the risk of recurrence after ≥1 year was much higher for PDT than for surgical excision (pooled relative risk 13.19, 95% CI 2.58-63.37) . In one of the trials (196 participants), the clinical recurrence rate after 12 months was 9.3 percent in patients treated with PDT versus 0 percent in patients treated with conventional excision .
Nodular BCCs are less likely than superficial BCCs to respond to treatment with PDT, with reported cure rates ranging from 10 to 76 percent [43-45]. PDT was compared with surgical excision in a multicenter trial in which 109 patients with nodular BCC were randomly assigned to MAL-PDT or surgical excision . Sixty-six patients completed follow-up for five years. Based upon the available data, the estimated sustained complete response rate was significantly lower with MAL-PDT (76 versus 96 percent with surgery). However, a good or excellent cosmetic outcome was significantly more frequent in patients treated with PDT (87 versus 54 percent).
Cryosurgery — Cryosurgery is infrequently used for the treatment of BCC. This technique uses liquid nitrogen to freeze the tumor. Curettage prior to cryosurgery reduces the tumor bulk and allows for a better definition of the treatment field. Cytotoxicity results from the formation of extracellular and intracellular ice crystals, hypertonic damage, disruption of the cellular phospholipid membrane, and vascular damage through vascular stasis . Reported recurrence rates for primary BCCs range from 4 to 17 percent [14,47]. Treatment can result in permanent hypopigmentation or scarring.
In one randomized trial (228 tumors in 97 patients, mean diameter 10.7 mm, range 5 to 20 mm), cryosurgery was compared with curettage alone for the treatment of nonfacial, superficial BCCs . At one year, five tumors in the curettage group and none in the cryosurgery group showed histopathologic tumor recurrence, resulting in a clearance rate of 95.7 percent for curettage and 100 percent for cryosurgery. The median wound-healing times were shorter with curettage than with cryosurgery (four versus five weeks).
Cryosurgery is cost effective and requires minimal anesthesia, but there are several disadvantages (table 2). The procedure is contraindicated in patients with lesions with features associated with a high risk for recurrence, those who are concerned about a poor cosmetic outcome, and those with a physiologic intolerance to cold (table 3).
Radiation therapy — Primary radiation therapy is a therapeutic option for the treatment of high-risk BCC in patients who are poor candidates for surgical intervention. It may also be an option for patients with multiple low-risk tumors in a localized area on the trunk or extremities. Radiation therapy for BCC is discussed in greater detail separately. (See "Treatment of basal cell carcinomas at high risk for recurrence", section on 'Primary radiation therapy'.)
Intralesional therapy — Intralesional therapies with interferons, topical fluorouracil, or bleomycin are infrequently used for the management of BCC [49,50]. A systematic review of open-label studies, case series, and the few randomized trials of intralesional interferon for BCC found overall cure rates for interferon beta, interferon alfa-2a, and interferon alfa-2b of 63, 68, and 76 percent, respectively . Of note, interferon alfa-2b has been discontinued by the major supplier in 2019.
Evidence on the long-term efficacy of intralesional therapies is limited. This approach is generally reserved for patients in whom surgical therapy is not an option, especially in the setting of lesions at high risk for recurrence.
Older patients/nonsurgical candidates — In older patients or patients with multiple comorbidities who may not tolerate surgery, low-risk superficial or nodular BCCs can be treated with topical imiquimod or topical fluorouracil. Other options include photodynamic therapy (PDT) and cryosurgery. Nonsurgical approaches are also indicated in patients with BCC on the lower extremities or on other challenging anatomic sites with limited surgical reconstructive options. (See 'Imiquimod' above and 'Topical fluorouracil' above and 'Photodynamic therapy' above and 'Cryosurgery' above.)
Tumors excised with positive margins — Our approach to the management of incompletely excised, low-risk BCCs is as follows:
●Conventional surgical re-excision is an appropriate option for incompletely excised lesions located on the trunk or extremities. Mohs surgery may be preferred for areas where tissue conservation is a priority.
●Patients with incompletely excised lesions that are not surgically amenable or who are not candidates for additional surgery can be treated with radiation therapy. Lesions that cannot be completely removed with surgical re-excision or Mohs surgery can also be treated with postoperative radiation . (See "Treatment of basal cell carcinomas at high risk for recurrence", section on 'Primary radiation therapy'.)
●A close clinical follow-up is warranted for patients who choose to defer treatment for incompletely excised lesions. Patients should be evaluated at least every three to six months for the first two years after treatment and then at least once or twice per year. More frequent follow-up may be appropriate, depending on the clinical scenario.
The overall rate of incompletely excised BCCs (all sites, all risk groups) is approximately 11 percent [52-57]. In a single-institution series of 3957 BCCs excised in 2358 patients, 14 percent were incompletely excised. The recurrence rate for incompletely excised tumors was 26.8 percent versus 5.9 percent for completely excised tumors .
Due to the relatively high risk for lesion recurrence of incompletely excised BCCs, a thorough discussion on the risks and benefits of re-excision versus observation is prudent with all patients with incompletely excised BCCs. Factors such as patient preference, tumor morphology and location, morbidity of delayed additional surgery, and patient tolerance for an additional procedure influence the decision of whether to proceed with additional therapy and affect the choice of treatment.
Nonsurgical treatment failures — Recurrent BCCs following treatment with topical therapies or PDT are considered high-risk tumors. We treat these lesions with conventional re-excision or Mohs micrographic surgery. (See "Treatment of basal cell carcinomas at high risk for recurrence".)
There are reports of the transformation of primary, nonaggressive BCC into "more aggressive," recurrent subtypes (eg, nodular, infiltrative, or morpheaform) following failure of topical treatments or PDT [34-36]. A secondary study using the data from a randomized trial comparing methyl aminolevulinate-photodynamic therapy (MAL-PDT), imiquimod, and topical fluorouracil for the treatment of superficial BCC analyzed the histologic subtypes of 166 early or late treatment failures (three months post-treatment and later during follow-up) within the treatment subgroups . Overall, a nonsuperficial, more aggressive subtype was found in 64 of 166 treatment failures (39 percent). Among early treatment failures, the proportion of aggressive subtypes was highest after treatment with topical fluorouracil, followed by MAL-PDT and imiquimod (67, 55, and 26 percent, respectively).
EMERGING THERAPIES — Advances in molecular therapy may lead to additional treatment options for BCC. A nonrandomized, open-label study of nine patients with biopsy-proven, nodular BCC found that intralesional injection of Dz13, a DNAzyme that targets Jun messenger RNA, was well tolerated and may have an inhibitory effect on BCC . Additional studies are necessary to determine the efficacy and safety of Dz13 as a therapeutic intervention for BCC.
Laser therapy, in particular the 1064 nm neodymium-doped yttrium aluminum garnet (Nd:YAG) laser, has been used with promising results in small series of patients with nonfacial BCC who were poor surgical candidates [60,61]. However, larger studies with extended follow-up are needed to determine the role of laser therapy in the treatment of low-risk BCC.
PROGNOSIS — The prognosis for most patients with primary, low-risk BCC is excellent. These lesions are typically slow growing, and metastatic disease is a very rare event. If left untreated, these cancers may result in significant morbidity. BCCs can cause considerable disfigurement by locally destroying skin, cartilage, and even bone (picture 2A-B). Untreated, advanced lesions typically ulcerate, creating wound care problems.
Risk of new primary skin cancers — Approximately 15 percent of patients with one BCC subsequently develop another primary BCC within one year, and 35 percent of patients develop a new BCC within five years after their original diagnosis [62-64]. This risk increases to approximately 34 percent within one year and 75 percent within five years for patients with more than one previous BCC . Younger patients may also be at increased risk for multiple lesions.
In a Dutch cohort study of people aged 55 years and older (n = 10,820), the risk of developing an additional BCC was significantly lower among those who developed the first lesion after age 75 years (adjusted odds ratio [OR] 0.58, 95% CI 0.47-0.71) . Other factors that increased the risk for additional BCCs included red hair, high educational level, and the upper extremities as the location of the first BCC.
Although the greatest risk for a subsequent BCC is within the first two years, at least one study suggests that annual risk remains high throughout five years and is 10 to 12 times the rate expected in the general population (ie, 10 to 12 percent versus 1 percent per year) . Roughly one-fourth of these patients will detect the new BCCs themselves, underscoring the importance of periodic full skin examinations by a medical practitioner . Earlier detection may discover tumors that are smaller, less aggressive, and at a lower risk of recurrence.
Patients who develop a BCC are also at increased risk of developing both squamous cell carcinoma and melanoma . The risk of subsequently developing melanoma appears to be over threefold greater than the general population .
Other cancers — Both BCC and cutaneous squamous cell carcinoma have been associated with a modest increase in the incidence of subsequent extracutaneous malignancies . Individuals who develop frequent BCCs may harbor germline defects in DNA repair genes and are at increased risk of developing internal malignancies . The relationship of nonmelanoma skin cancers to second malignancies is discussed separately. (See "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma (cSCC)", section on 'Other second cancers'.)
FOLLOW-UP — Close follow-up is required following treatment to detect both local recurrences and new skin cancers and to assess the post-treatment course. Most dermatologists recommend re-evaluation every six months for the first year following treatment and then annually. In the absence of a recurrent tumor, a new primary BCC, or new actinic keratoses, further follow-up can be at longer intervals and at the clinician's discretion.
Approximately 50 percent of recurrences are apparent within the first two years, 66 percent are apparent within three years, 80 percent are apparent within five years, and roughly 20 percent are apparent between 5 and 10 years following treatment of an initial BCC .
Periodic evaluation for local recurrence should not only include visual inspection but also palpation of the skin and adjacent structures to determine the presence of deeper recurrences. Patients should be asked about any visible, textural, or sensory changes of the treated area and any suspicious or questionable areas confirmed histologically with a biopsy. For suspected, deeper recurrences, one or more punch biopsies should be obtained.
EDUCATION REGARDING PREVENTIVE MEASURES — An important component of follow-up in a patient with a skin cancer is education concerning modification of risk factors.
Although the impact of sun avoidance in decreasing the risk of further BCCs is unclear, it seems prudent to advocate sun protection in patients with a history of skin cancer, especially in patients with fair skin . These recommendations generally include sun avoidance during peak hours (10 AM to 4 PM); use of a broad-spectrum sunscreen (both ultraviolet A [UVA] and ultraviolet B [UVB]); wearing sun-protective clothing, sunglasses, and a broad-brimmed hat; avoiding sunbathing and tanning salons; and practicing routine self-skin examinations monthly. (See "Primary prevention of melanoma" and "Selection of sunscreen and sun-protective measures".)
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".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Non-melanoma skin cancer (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Evaluation of the risk of recurrence – The assessment of risk for lesion recurrence is the first and most important step in the choice of treatment for basal cell carcinoma (BCC). A skin biopsy is essential to confirm the diagnosis and provide additional information on the risk for tumor recurrence following treatment. Low-risk features include primary lesion, size <20 mm on trunk and extremities (excluding pretibia, hands, and feet), nodular or superficial histology, and immunocompetent patient. (See 'Features associated with low risk of recurrence' above and 'Pretreatment evaluation' above.)
●Management – The approach to management is summarized in the algorithm (algorithm 1):
•Surgical candidates – For primary, nodular or superficial, low-risk BCCs, we suggest surgical excision (Grade 2B). We generally use standard excision with 4 to 5 mm margins and postoperative margin assessment. Curettage and electrodesiccation (C&E) is an alternative, first-line therapy for low-risk BCC. (See 'First-line therapies' above.)
•Nonsurgical candidates – Therapeutic options for patients with low-risk BCC who are not surgical candidates or who prefer to avoid surgery include topical therapies (imiquimod or topical fluorouracil), C&E, and photodynamic therapy (PDT). The choice depends on the clinician's experience and the patient's characteristics and preferences. We generally prefer treatment with imiquimod or topical fluorouracil. (See 'Second-line therapies' above.)
•Incompletely excised basal cell carcinoma – For the management of incompletely excised, low-risk BCCs located on the trunk or extremities, standard surgical re-excision or Mohs surgery is an appropriate option. We use this same approach for recurrent lesions following treatment with topical agents. (See 'Tumors excised with positive margins' above and 'Nonsurgical treatment failures' above.)
●Follow-up – Following treatment, close follow-up is required to detect both local recurrences and new skin cancers and to assess the post-treatment course. Most dermatologists recommend re-evaluation every six months for the first year following treatment and then annually. (See 'Follow-up' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Timothy K Chartier, MD (deceased), who contributed to an earlier version of this topic review.
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