Basal Cell Skin Cancer, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology

Authors:
Chrysalyne D. Schmults Dana-Farber/Brigham and Women’s Cancer Center | Mass General Cancer Center

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Rachel Blitzblau Duke Cancer Institute

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Sumaira Z. Aasi Stanford Cancer Institute

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Murad Alam Robert H. Lurie Comprehensive Cancer Center of Northwestern University

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Arya Amini City of Hope National Medical Center

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Kristin Bibee The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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Jeremy Bordeaux Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute

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Pei-Ling Chen Moffitt Cancer Center

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Carlo M. Contreras The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute

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Dominick DiMaio Fred & Pamela Buffett Cancer Center

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Jessica M. Donigan Huntsman Cancer Institute at the University of Utah

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Jeffrey M. Farma Fox Chase Cancer Center

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Karthik Ghosh Mayo Clinic Comprehensive Cancer Center

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Kelly Harms University of Michigan Rogel Cancer Center

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Alan L. Ho Memorial Sloan Kettering Cancer Center

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John Nicholas Lukens Abramson Cancer Center at the University of Pennsylvania

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Lawrence Mark Indiana University Melvin and Bren Simon Comprehensive Cancer Center

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Theresa Medina University of Colorado Cancer Center

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Kishwer S. Nehal Memorial Sloan Kettering Cancer Center

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Paul Nghiem Fred Hutchinson Cancer Center

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Kelly Olino Yale Cancer Center/Smilow Cancer Hospital

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Soo Park UC San Diego Moores Cancer Center

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Tejesh Patel University of Tennessee Health Science Center

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Igor Puzanov Roswell Park Comprehensive Cancer Center

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Jason Rich Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

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Aleksandar Sekulic Mayo Clinic Comprehensive Cancer Center

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Ashok R. Shaha Memorial Sloan Kettering Cancer Center

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Divya Srivastava UT Southwestern Simmons Comprehensive Cancer Center

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Valencia Thomas The University of Texas MD Anderson Cancer Center

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Yaohui Gloria Xu University of Wisconsin Carbone Cancer Center

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Siegrid Yu UCSF Helen Diller Family Comprehensive Cancer Center

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Mehran Yusuf O’Neal Comprehensive Cancer Center at UAB

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Beth McCullough National Comprehensive Cancer Network

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Sara Espinosa National Comprehensive Cancer Network

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Basal cell carcinoma (BCC) is the most common form of skin cancer in the United States. Due to the high frequency, BCC occurrences are not typically recorded, and annual rates of incidence can only be estimated. Current estimated rates are 2 million Americans affected annually, and this continues to rise. Exposure to radiation, from either sunlight or previous medical therapy, is a key player in BCC development. BCC is not as aggressive as other skin cancers because it is less likely to metastasize. However, surgery and radiation are prevalent treatment options, therefore disfigurement and limitation of function are significant considerations. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) outline an updated risk stratification and treatment options available for BCC.

Overview

Basal cell carcinoma (BCC) is the most common cancer in the United States. It is estimated that BCCs occur in 2 million Americans annually, exceeding the incidence of all other cancers combined.13 BCCs are at least 2 times more common than squamous cell carcinomas (SCCs), the second most common type of skin cancer.16 Furthermore, the incidence of this common malignancy is rising rapidly.1,3,6,7 Compared with SCC, BCCs are much less likely to metastasize, with a metastatic rate of <0.1%, and thus generally have a good prognosis.810 Although rarely metastatic, BCC can produce substantial local destruction along with disfigurement and may involve extensive areas of soft tissue, cartilage, and bone.

A number of risk factors are associated with the development of BCC. The most recognized environmental carcinogen is sunlight. Evidence reveals that the relationship between sun exposure and BCC is complex and depends on the timing, pattern, and amount of ultraviolet radiation.1115 Fair skin, red or blond hair, and light eye color are associated with BCC as independent risk factors due to greater susceptibility to ultraviolet damage.13,1522 BCC risk is increased by both ultraviolet-A and -B radiation as well as by ionizing radiation. Radiation therapy (RT) for other conditions, especially at a young age, is also associated with an increased risk for developing BCC.2327 Most BCC tumors develop on skin sites exposed to radiation—either from the sun or from therapy.2325

Literature Search Criteria and Guidelines Update Methodology

Prior to the update of this version of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Basal Cell Skin Cancer, an electronic search of the PubMed database was performed to obtain key literature using the following search term: basal cell skin carcinoma. The PubMed database was chosen because it remains the most widely used resource for medical literature and indexes peer-reviewed biomedical literature.28

The search results were narrowed by selecting studies in humans published in English. Results were confined to the following article types: Clinical Trial; Guideline; Meta-Analysis; Practice Guideline; Randomized Controlled Trial; Systematic Reviews; and Validation Studies.

The data from key PubMed articles as well as articles from additional sources deemed as relevant to these guidelines as discussed by the panel during the Guidelines update have been included in this version of the discussion section. Recommendations for which high-level evidence is lacking are based on the panel’s review of lower-level evidence and expert opinion.

Sensitive/Inclusive Language

NCCN Guidelines strive to use language that advances the goals of equity, inclusion, and representation.29 NCCN Guidelines endeavor to use language that is person-first; not stigmatizing; antiracist, anticlassist, antimisogynist, antiageist, antiableist, and antiweight biased; and inclusive of individuals of all sexual orientations and gender identities. NCCN Guidelines incorporate nongendered language, instead focusing on organ-specific recommendations. This language is both more accurate and more inclusive and can help fully address the needs of individuals of all sexual orientations and gender identities. NCCN Guidelines will continue to use the terms men, women, female, and male when citing statistics, recommendations, or data from organizations or sources that do not use inclusive terms. Most studies do not report how sex and gender data are collected and use these terms interchangeably or inconsistently. If sources do not differentiate gender from sex assigned at birth or organs present, the information is presumed to predominantly represent cisgender individuals. NCCN encourages researchers to collect more specific data in future studies and organizations to use more inclusive and accurate language in their future analyses.

Genetics

Extensive research has led to advances in the understanding of the genetics of BCC. The sonic hedgehog signaling pathway has emerged as playing a pivotal role in the pathogenesis of BCC, and mutations in a number of molecules in this pathway have been implicated in the development of the disease.3032 Mutations in the PTCH1 (patched 1) gene on chromosome 9q, which codes for the sonic hedgehog receptor, are the underlying cause of nevoid BCC syndrome and are present in approximately 30%–90% of sporadic BCCs.3341 Specific ultraviolet-induced mutations in the tumor suppressor gene p53 appear to be a common event in BCC development.35,38,41,42 Certain genetic syndromes greatly predispose affected individuals to skin cancer formation, including BCC, such as albinism43,44 and xeroderma pigmentosum (in which defects exist in ultraviolet light–induced unscheduled DNA repair).4551

Clinical Presentation and Workup

On clinical presentation of the patient with lesion suspicious of skin cancer, workup for BCC begins with a history and physical examination, biopsy, and if applicable a shave removal. A skin biopsy is then performed on any suspicious lesion. The biopsy should include deep reticular dermis. This procedure is preferred because an infiltrative histology may sometimes be present only at the deeper, advancing margins of a tumor, and superficial biopsies will frequently miss this component.52,53 After BCC diagnosis, a full skin examination is recommended, because individuals with skin cancer often have additional, concurrent precancers or cancers located at other, usually sun-exposed skin sites. These individuals are also at increased risk of developing cutaneous melanoma.54

Risk Stratification of Local BCC Based on Risk Factors for Recurrence

After the complete skin examination, a risk assessment should be performed to determine the treatment plan.55 The NCCN Panel examined risk factors for BCC associated with recurrence (see “Risk Factors for Recurrence” in the algorithm). Any high-risk factor places the skin lesion in the high-risk category, and imaging should be considered if a clinical exam is insufficient to determine disease extent. Skin lesions in populations placed at increased risk may be difficult to assess clinically; therefore, a low threshold for performing skin biopsies in these patients is necessary. Patients with locally advanced disease, which is defined as primary or recurrent extensive disease where surgery and/or RT may not result in a cure or would potentially yield a significant functional limitation, should consider imaging to determine disease extent. For rare cases when patients present with regional or distant metastatic disease at diagnosis, imaging of areas of interest can be performed when there is suspicion of extensive disease before treatment as nodal or distant metastases. Imaging studies may be clinically evident when extensive disease, such as bone involvement, perineural invasion (PNI), or deep soft tissue involvement, is suspected. If perineural disease is suspected, MRI with or without contrast is preferred.56,57 If bone disease is suspected, CT with contrast is preferred unless contraindicated. Imaging modality and targeted area should be at the discretion of the treating team based on the suspected extent of disease (ie, local, regional, metastatic). Histologic confirmation is sufficient to diagnose local recurrence, but MRI can be considered to assess extent of local disease. For nodal or distant metastases, histologic analysis and/or CT imaging can be used for confirmation and to gauge the extent of disease.

History and Physical Examination

Location and Size

Anatomic location5864 and size6066 have been known to be a risk factor for BCC recurrence and metastasis for many years. In general, BCCs that develop in the head and neck area, which includes the “H zone” or “mask area” of the face, are more likely to recur than those that develop on the trunk and extremities. Based on a 27-year retrospective review of 5,755 BCCs, recurrences were significantly more common when tumors in high-risk locations (central face, eyebrows, nose, lips, chin, ear, temple, genitalia, nipples/areola, hands, feet, ankles, and nail units) were ≥6 mm in diameter and when tumors in moderate-risk locations (cheeks, forehead, scalp, neck, jawline, pretibial surface) were ≥10 mm in diameter.67 The American Academy of Dermatology in collaboration with American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and American Society for Mohs Surgery developed an appropriate use criteria document in the treatment of cutaneous neoplasms based on 270 clinical scenarios including 69 BCCs,68 which has been incorporated into “Risk Factors for Recurrence” within the algorithm.

Clinical Borders and Primary Versus Recurrent Disease

The low- and high-risk factors of well-defined versus ill-defined clinical tumor borders6971 and primary versus recurrent disease,62,70,72 respectively, have been extensively documented in the literature.

Immunosuppression

Settings of immunosuppression, such as organ transplantation,7378 and long-term use of psoralen and ultraviolet-A light,79,80 increase the incidence of BCC. In particular, among patients who have had organ transplants, BCC incidence is approximately 5- to 10-fold higher than in the general population,8183 occurring in up to half of patients during the 10 years after transplant.8487 Several large retrospective studies found that BCCs in patients who had received organ transplants were more likely to have the superficial histologic subtype and to occur in extracephalic locations and in younger patients (mean age of onset 15 years lower).8890 Two of these studies showed similar low recurrence rates for transplant recipients and controls.89,90 Nevertheless, because of NCCN Guidelines Panel Members’ own anecdotal experiences, the panel decided to classify BCCs developing in settings of immunosuppression as potentially high-risk tumors.

Site of Prior Radiotherapy

Tumors developing in sites of prior RT refer to primary BCCs arising in areas previously irradiated for unrelated conditions. All recurrent tumors, irrespective of prior therapy, are defined as high risk. Data from a number of studies with large sample sizes support that prior RT for unrelated, frequently benign conditions is a risk factor for BCC development.2327,91,92

Pathology

Pathologic Subtypes

Histologic subtyping of BCC as a predictor of risk of recurrence is a well-established concept.93,94 The subtypes encompassed by the term “aggressive growth pattern,” including micronodular, infiltrative, sclerosing, and morpheaform (or desmoplastic) patterns, are more likely to recur than the nodular and superficial BCC.65,69,70,72,9599 Nonaggressive subtypes include the keratotic variant, infundibulocystic variant, and fibroepithelioma of Pinkus.

Basosquamous carcinomas are tumors that have the histologic appearance of both a BCC and an SCC. Some basosquamous tumors are the result of a BCC colliding with an adjacent SCC. Others represent truly biphenotypic tumors, many of which may have started as BCC, but have subsequently undergone prominent partial squamous metaplasia.100 Data suggest that basosquamous carcinomas have a metastatic capacity that is more similar to that of SCC than BCC.101103

Perineural Involvement

PNI is uncommon in any nonmelanoma skin cancer (NMSC) (2%–6%), and develops less frequently and is less aggressive in BCC versus SCC.104109 BCC with PNI poses a greatly increased risk of recurrence and is associated with other risk factors including previous recurrent tumors, high grade, larger lesion size, and certain subtypes (infiltrating, morpheaform, and basosquamous).108,110,111 If large nerve involvement is suspected, MRI should be considered to evaluate extent and/or rule out skull involvement in those with head and neck tumors.57,112114 Additionally, in the presence of PNI, a thorough cranial nerve exam is indicated.

Age and its Effect on BCC Behavior

Whether young age (typically aged ≤40 years) is an independent risk factor for aggressive BCC behavior is debatable. An analysis of a large database of patients with BCC (n=3,381) documented an increased percentage of BCC with aggressive histologic growth patterns in young persons.115 In contrast, results from other analyses of large databases (n=1,000 to >10,000) indicate that patients presenting with BCC at a young age are more likely to have the superficial subtype.116119 Other analyses report no significant differences in BCC histologic subtype between young versus older patients.120122 The relationship between tumor location and patient age is also unclear, because several studies showed that younger patients were more likely to present with BCCs on the trunk or extremities,116,121,123,124 while another found no significant association.120

Most large studies (n=50–2,000) have shown no significant association between age and recurrence rate.62,70,120,122 One multivariate analysis, however, showed a positive relationship between increasing age and likelihood of recurrence.125 Age has also been evaluated as a risk factor for developing a second or multiple BCCs and many of these studies using fairly large databases (n=200–2,500) found that the risk of developing more than one BCC is associated with increased age.65,122,124130 On the contrary, an analysis of a very large database (n=71,924) found a significantly higher risk of subsequent NMSC in patients aged <40 years at the time of their first BCC diagnosis.131 In addition, an analysis of 100 metastatic BCC cases found that patients with distant metastases tended to be younger than those with only regional metastases.132 Consistent with this idea, the Rotterdam Study showed that although the risk of developing a second BCC increased with age,130 the risk of developing multiple BCC lesions was highest in patients who were aged <65 years at the time of their first BCC diagnosis.133 Taken together, these studies suggest that young age, in and of itself, is not considered a risk factor for aggressive BCC. Nevertheless, there is a small subset of patients who develop BCC at a young age and may have particularly aggressive disease. These patients may benefit from regular follow-up.

Treatment Modalities for BCC

Curettage and Electrodesiccation

Although a fast and cost-effective technique for superficial lesions, curettage and electrodesiccation (C&E) does not allow histologic margin assessment. Studies have reported overall 5-year recurrence rates ranging from 1.2% to 40% in patients with BCC selected for C&E, with high-risk locations and histologically aggressive subtypes reporting higher recurrence rates.60,134143

This technique is deemed effective for properly selected, low-risk BCC with 3 caveats.60,140 First, C&E should not be used to treat areas with terminal hair growth such as the scalp, pubic and axillary regions, or beard area due to the risk that a tumor extending down follicular structures might not be adequately removed. Second, if the subcutaneous layer is reached during the course of C&E, then surgical removal should generally be performed instead. This change in therapy is necessary because the effectiveness of the C&E technique rests on the ability of the clinician to distinguish between firm normal dermis and soft tumor tissue when using a sharp curette. Since subcutaneous adipose is even softer than tumor tissue, the ability of the curette to distinguish and, therefore, selectively and completely remove tumor cells diminishes. Third, if C&E has been performed based only on the appearance of a low-risk tumor, biopsy results of the tissue taken at the time of C&E should be reviewed to make sure that there are no high-risk pathologic features that would require additional therapy. For tumors on the cheeks, forehead, scalp, neck, and pretibial that are less than 6 mm in depth and confined to the dermis, C&E may be considered as an alternative primary treatment option if Mohs micrographic surgery (Mohs) or resection with peripheral and deep en face margin assessment (PDEMA) and standard excision are not feasible due to patient comorbidities.

Shave Removal

Shave removal, the shaving of epidermal or dermal lesions, is a sharp removal by bowl-shaped slicing of the epidermal and dermal lesions, without including fat, and does not require suture closure.144 Like C&E, there is concern for inaccurate margin status assessment with shave removal.145 However, it is a recommended technique for low-risk BCCs located in the trunk or extremities. Shave removal studies have reported 0.5%–30% rate of recurrence over a 3- to 5-year follow-up, multiple tumors treated in single visits, and a risk for misdiagnosis of only 1%.144147

Standard Excision With Postoperative Margin Assessment

Another therapeutic option for BCC is standard surgical excision followed by postoperative pathologic evaluation of margins. This technique has been reported to achieve 5-year recurrence rates of 0.8%–17.4% for BCC, with lower recurrence rates associated with low-risk tumors and higher recurrence rates associated with high-risk tumors.134,136,142,148150 Studies have reported variable margins required to completely excise 95% of all tumor.151156 These margins have been suggested to be 2 to 4 mm for low-risk, well-demarcated tumors smaller than 2 cm,151155 whereas margins of 4 to 6 mm,152 and in one study, 8 mm,151 were suggested for high-risk BCC. Given this wide variability, studies have reported incomplete excision rates after standard excision ranging from 3.2% to 61.5% depending on tumor location, histologic subtype, and medical provider’s specialty.157166 Therefore, postoperative margin assessment and identification of clear margins are critical to ensure favorable outcomes with standard excision.

The clinical margins chosen by the panel for the primary treatment of low-risk BCC are based on the work of Zitelli et al.167 Their analysis indicated that for well-circumscribed BCC lesions smaller than 2 cm in diameter, excision with 4-mm clinical margins should result in complete removal in more than 95% of cases. The indications for this approach were also expanded to include re-excision of low-risk primary BCC if positive margins are obtained after an initial excision with postoperative margin assessment. For high-risk BCC, standard excision with wider surgical margins is recommended as the primary treatment. Due to the wide variability of clinical characteristics that may define a high-risk tumor, it is not feasible to recommend a defined margin for standard excision of high-risk BCC. Keen awareness of the subclinical extension of BCC is advised when selecting a treatment modality without complete margin assessment for a high-risk tumor. These margins may need to be modified based on tumor- or patient-specific factors. When standard excision with wider surgical margins yields positive margins, Mohs or other forms of PDEMA or standard re-excision are recommended (if PDEMA is not feasible).

For either low-risk or high-risk BCC, when standard excision is used, tissue rearrangement (eg, flap reconstruction, extensive undermining) should not be undertaken until clear margins are identified. Second intention healing, linear repair, or skin graft are acceptable options.

Mohs and PDEMA

Mohs is the preferred surgical technique over standard excision for re-excision of low-risk BCC after positive margins with standard excision, as well as the primary surgical technique of choice for high-risk BCC because it allows intraoperative analysis of 100% of the excision margin. Mohs is also recommended when standard excision with wider surgical margins is unable to achieve negative margins in high-risk BCC. Two meta-analyses published in 1,989 associated Mohs with 5-year recurrence rates of 1.0% for primary BCC, and 5.6% for recurrent BCC.134,142 In these studies, the recurrence rates for Mohs were lower than those for standard excision (10.1% and 17.4% for primary and recurrent BCC, respectively), and lower than those for any other treatment modality included in the analysis (C&E, cryotherapy, and RT).134,142 Studies on the long-term outcomes (∼4 years) of Mohs have reported overall recurrence rates of 2.9%–3.8%,168,169 specifically 0%–6.5% for primary and 4%–20% for recurrent BCCs.94,170175 The only prospective randomized trial comparing Mohs to standard excision reported fewer 10-year recurrences with Mohs for both primary (2.5% vs 4.1%; P=.397) and recurrent BCC (2.4% vs 12.1%; P=.015), although the difference was only statistically significant for recurrent tumors. Importantly, a large proportion of recurrences occurred more than 5 years after treatment.143,176,177 Besides lower recurrence rates, Mohs has also been associated with significant tissue sparing compared with standard excision.178,179 It has been demonstrated that H-zone location, recurrent tumor, aggressive subtype, PNI, and tumor size greater than or equal to 11 mm are significantly associated with two or more Mohs stages.110,180 However, superficial BCC, despite being generally considered less aggressive, was shown in a Brazilian study to be 9.03 times more likely to require more than one Mohs stage, likely due to “skip areas” and clinically indistinct borders.181

Excision with PDEMA with permanent section analysis or intraoperative frozen section analysis is an acceptable alternative to Mohs provided it includes a complete assessment of all deep and peripheral margins. A 5-year recurrence rate of 0.58% has been reported with slow Mohs using formalin-fixed paraffin-embedded sections and delayed closure in a UK-based prospective study.182 The descriptive term PDEMA underscores the panel’s belief that complete histologic assessment of the entire marginal surface is the key to optimal tumor removal. For more information, refer to the NCCN Guidelines for Squamous Cell Skin Cancer (available at NCCN.org).

Radiation Therapy

Although surgery is the mainstay of local treatment for BCC, consideration of function and patient preference and other factors may lead to the choice of RT as primary therapy for nonsurgical candidates for both low-risk and high-risk disease and patients with advanced BCC (locally advanced, nodal, and metastatic BCC).183 The recommendations for RT extend to additional treatment of low-risk BCC after positive margins with standard excision. RT is also recommended for high-risk BCC as additional treatment after standard excision, Mohs, or other forms of PDEMA with positive margins and adjuvant treatment after negative margins in case of extensive perineural or large-nerve involvement.184 In these patients, local control has been reported to be 50%–90% with postoperative RT.183,185 There are conflicting data about the value of adjuvant RT after margin-negative surgical excision, particularly after Mohs. For patients with high-risk BCC who have undergone multiple resections and for whom further surgery is not feasible, RT is recommended as part of multidisciplinary consultation if residual disease is present. For specifics about the application of RT, see “Principles of Radiation Therapy” in the algorithm.

Two meta-analyses reported 5-year recurrence rates of 8.7% and 9.8% after RT on primary and recurrent BCC, respectively.134,142 Retrospective analyses of BCC treated with RT have reported 5-year local control, cure, or complete response rates ranging from 93% to 96%,186189 and 5-year recurrence rates from 4% to 16%.190192 Efficacy of RT was better for BCCs that were less advanced, primary (vs recurrent), or with a smaller diameter or nodular histologic subtype.186,187,189191 A prospective study randomizing 347 patients to receive either surgery (standard excision with free margins ≥2 mm from visible borders) or RT as primary treatment of BCC reported higher recurrence rates with RT than surgery (7.5% vs 0.7%; P=.003),193 poorer cosmetic outcomes, and more postoperative complications.194

A small number of prospective studies have reported high rates of tumor control with specific radiation dose fractionation regimens for small BCCs.193,195,196 A systematic review and meta-analysis also reported hypofractionated RT regimens associated with positive cosmetic outcomes.197 The panel recommends ranges of electron beam dose and fractionation that can be used for definite RT and postoperative adjuvant RT. Isotope-based brachytherapy can be an effective treatment for certain sites of disease, particularly on the head and neck.198201 However, there are insufficient long-term efficacy and safety data to support the routine use of electronic surface brachytherapy.202,203

Superficial Therapies

In patients with superficial BCC, therapies such as topical imiquimod, topical 5-fluorouracil (5-FU), or photodynamic therapy (PDT) may be considered, although cure rates are approximately 10% lower than for surgical treatment modalities.204206 Another option for patients with superficial BCC is cryotherapy.207 These options are also recommended for patients for whom surgery or RT is contraindicated or impractical.

Topical Therapies

Imiquimod was found to be effective for treating nodular and superficial BCC in randomized studies.208213 Two 5-year follow-up studies reported overall treatment success rates of 80.4% and 77.9%, respectively, in patients with superficial BCC treated with imiquimod.212,214 Recurrence seems to be associated with tumor thickness.215 A phase III randomized trial in patients with superficial or nodular BCC showed that imiquimod provided an 82.5% clinical success rate.216,217 For all of these studies, tumors in the H-zone were excluded. Although the clinical success rate was significantly higher with surgical excision using a 4-mm margin (97.7%; P<.001), cosmetic outcomes by dermatologic assessment were significantly better with imiquimod (excellent/good at 3-year follow-up: 61% vs 36%; P<.001). Another topical cream with efficacy against BCC is 5-FU,218,219 which has been shown in a large randomized trial to have a 5-year tumor-free survival probability of 70.0%.205,220,221 Other studies have reported cure rates of up to 90% with this treatment.222224

Photodynamic Therapy

PDT with photosensitizing agents including 5-aminolevulinic acid (ALA) and porfimer sodium is another option for superficial BCC.225227 Multiple randomized trials and a meta-analysis have shown that rates of excellent or good cosmetic outcomes were higher with PDT versus surgery, although surgery was superior to PDT in terms of disease control.149,228235 Data from clinical trials reported cure rates from 60% to 100% by PDT for patients with BCC.231,236241 Most of these studies have focused on the superficial and nodular histologic subtypes, and several have found higher cure rates for superficial versus nodular subtypes in both low- and high-risk locations.231,236,241 Ulceration and thickness are associated with lower response to therapy,241 and within the nodular subtype, cure rates are better with thinner lesions.230 Clinical studies have demonstrated PDT activity against “difficult-to-treat” lesions, with a 24-month complete response rate of 78%.236,242 Currently, PDT is being used at some NCCN Member Institutions for premalignant or superficial low-risk lesions on any location on the body, although response rates may be higher on the face and scalp.243,244

Cryotherapy

Cryotherapy has been used for many years as a fast and cost-effective means for removal of BCCs.207 Systematic reviews of historical data in primary BCCs have reported recurrence rates for cryotherapy ranging from 0% to 13%, and mean recurrence rates from pooled analyses ranging between 3% and 4%.134,136,245,246 In prospective trials, cryotherapy has been shown to result in recurrence rates ranging from 5% to 39%.195,247249 A key limitation of cryotherapy is poorer cosmetic outcomes compared with other treatment options, as demonstrated by prospective randomized trials.248250

Comparisons of Superficial Therapies

Several randomized studies and meta-analyses have compared superficial therapies for BCC (Table 1). In summary, these studies indicate that in patients with superficial BCC, PDT has similar efficacy as cryotherapy but much better cosmetic outcomes. Whereas a meta-analysis of 23 randomized and nonrandomized trials found no significant difference in efficacy for PDT versus imiquimod,251 a randomized trial showed that treatment success was more likely with imiquimod.205,221 This study also shows superior imiquimod outcomes compared with 5-FU cream. Exploratory subanalyses found that treatment success rates were significantly higher with imiquimod for tumors that are large or truncal, whereas PDT provided significantly better outcomes in older patients with lesions on the lower extremities.252 Safety results showed that while PDT causes moderate to severe pain during treatment administration, imiquimod and 5-FU are more likely to cause moderate to severe local swelling, erosion, crust formation, itching, and wound infections.220 Both cryotherapy and PDT are associated with pain during and after treatment, and data from a randomized trial indicate a trend toward a higher likelihood of pain with PDT.248

Table 1.

Studies Comparing Superficial Therapies in Patients With Superficial BCC

Table 1.

Nicotinamide in Reducing BCC Development

Data from phase II and phase III randomized trials indicated that treatment of actinic keratoses with nicotinamide reduced the occurrence of new BCCs, specifically by 20% at 12-month follow-up.253,254 This is supported by data from another study.255 Other agents that might be effective for the prevention of BCC in individuals at high risk for developing NMSCs include celecoxib,256 acitretin,257 capecitabine,258 and tazarotene.259

Systemic Therapy

For advanced BCC, systemic therapy is recommended as a treatment option for locally advanced (laBCC), metastatic (mBCC), and nodal BCC after multidisciplinary consultation. Other options include surgery, RT, and palliation and best supportive care for certain patients. The systemic therapy options for BCC include hedgehog pathway inhibitor (HHI) and immunotherapy. Vismodegib and cemiplimab are currently recommended options for all advanced BCCs while sonidegib is only recommended for nodal and laBCC.

Hedgehog Pathway Inhibitors

Vismodegib is an HHI approved by the US FDA for the treatment of adults with laBCC or mBCC that has recurred following surgery, or those who are not candidates for surgery or RT.260 The 9-month follow-up data from the SHH4476g trial, a centrally reported, multicenter, phase I, open-label study, had an initial enrollment of 104 patients (laBCC, n=71; mBCC, n=33); however, pathology results excluded 8 patients with laBCC from the efficacy analysis (n=63). This trial reported an objective response rate of 30% in the mBCC group and 43% in the laBCC group, with a median duration of response (DOR) of 7.6 months and 9.5-month median progression-free survival.261 A 39-month follow-up to these data from the ERIVANCE trial, an investigator-reported, multicenter, phase II trial, conveyed an objective response rate of 48.5% in the mBCC group and 60.3% in the laBCC group, with a median DOR of 14.8 months and 26.2 months for each group, respectively.261264 Results from these trials for vismodegib in BCC are summarized in Table 2. According to these data, nearly all patients treated with vismodegib experienced at least one treatment-emergent adverse event, but a significant proportion of these were low grade (grade ≤2).261263 Serious adverse events occurred in 25%–32% of patients in these studies. The most common adverse events included muscle spasms, alopecia, taste loss, weight loss, decreased appetite, fatigue, nausea, and diarrhea.

Table 2.

Hedgehog Pathway Inhibitors in Advanced BCCa

Table 2.

Vismodegib has also been tested as BCC treatment and prophylaxis in patients with nevoid BCC syndrome. A randomized phase II study in patients with nevoid BCC syndrome and at least 10 operable BCC lesions found that vismodegib significantly reduced incidence of new BCC lesions compared with placebo, and also significantly reduced the size of existing lesions and the number of surgeries needed to remove BCC lesions.265267

Sonidegib is another FDA-approved HHI agent for the treatment of patients with laBCC that has recurred following surgery or RT, or who are not candidates for surgery or RT.268 Sonidegib is FDA approved for laBCC. The 42-month follow-up data from the centrally reported randomized, multicenter, phase II BOLT trial reported similar objective response rates for the 200-mg and 800-mg doses tested among patients with laBCC (56% and 46%, respectively), while there was a 2-fold difference for patients with mBCC (8% and 17%, respectively).269273 This trial also reported, for each dose and patient group, median DOR and progression-free survival results that are summarized in Table 2. The 30-month investigator-reviewed data for the BOLT trial analyzing only the 200-mg dose showed a higher objective response rate of 71.2% for laBCC and 23.1% for mBCC (Table 2).271,274 As with vismodegib, nearly all patients experienced at least one AE, and the most common AEs were muscle spasms, dysgeusia, alopecia, nausea, weight decrease, and fatigue. Elevated creatinine kinase was also frequently observed and was one of the most common grade 3–4 AEs, along with elevated lipase.

A key limitation to HHI therapies is that advanced BCC can develop resistance, which limits the DOR. A small investigator-initiated trial in patients with vismodegib-resistant advanced BCC observed no responses during treatment with sonidegib for a median of 6 weeks (range, 3–58 weeks), and in 5 of 9 patients with disease progression.275

Ongoing clinical research is exploring various dosing regimens of vismodegib and sonidegib in a variety of BCC treatment settings, including in the neoadjuvant setting, in patients with multiple BCCs or with radiation-induced multiple BCCs of the scalp, and as maintenance therapy after laBCC complete remission.276281 Notably, in the neoadjuvant setting, although one trial reported negative results (unmet predefined complete histologic clearance rate),277 results from 2 studies indicated vismodegib may reduce surgical defect area and allow for downstaging of the surgical procedure for laBCCs in functionally sensitive locations.276,279 The VISMEO trial, a centrally reported, phase II, open-label study, had an enrollment of 55 patients with laBCC. This study reported an objective response rate of 71%, with 36.4% recurrence at the 3-year follow-up.279 Some of these studies included small numbers of patients, and thus their results need to be carefully interpreted.

Other HHIs are also being tested in patients with BCC to see if they can provide higher rates of response, more durable responses, responses in less advanced BCC, or responses in BCC resistant to vismodegib. Results from phase I–II trials with small BCC sample sizes (n<40) have shown that itraconazole and saridegib can elicit responses in patients with BCC, although not in patients who previously received vismodegib.282,283

Immunotherapy

Cemiplimab-rwlc is an anti-PD-1 immunotherapy that is FDA-approved for patients with laBCC or mBCC who were previously treated with an HHI or for whom an HHI is not appropriate.284 Cemiplimab is a recommended treatment option for certain patients with advanced BCC including in the neoadjuvant setting for laBCC. A centrally reported, multicenter, phase II, open-label trial tested cemiplimab-rwlc (n=84) for patients with laBCC where local invasion precluding complete resection or in locations for which surgery may result in severe disfigurement or dysfunction and whose disease has progressed on or was intolerant to prior HHI therapy.285 This study reported a median follow-up of 15 months, objective response rate of 31%, and grade 3–4 treatment-emergent adverse events in 48% of patients, while serious adverse events occurred in 35% of patients.285

Due to the rarity of advanced cases, the literature on chemotherapy for BCC is limited to case reports.286292

Follow-up

Follow-up for BCC should include a history and physical examination, along with a complete skin examination every 6 to 12 months for the first 5 years, and then at least annually for life. Imaging may be considered if clinical examination is insufficient for following the disease. Follow-up with a dermatologist is strongly recommended if any of the following criteria are met: past or imminent solid organ, marrow, or hematopoietic cell transplant; ≥1 cutaneous melanomas in the past 5 years; or ≥4 NMSCs within the past 5 years.

Imaging modality and targeted area should be at the discretion of the treating team based on the suspected extent of disease (ie, local, regional, metastatic). Histologic confirmation is sufficient to diagnose local recurrence, but imaging can be considered to assess extent of disease. As part of follow-up, the patients should be educated on sun protection and self-examination. For local recurrence, the primary treatment pathway for high-risk BCC should be followed. For locally advanced, nodal metastases, and distant metastases, the appropriate path should be followed as found within “Advanced BCC” in the algorithm.

An estimated 30%–50% of patients with BCC will develop another BCC within 5 years.126,129,293296 This represents a 10-fold increase in risk compared with the general population.294 Patients with a prior BCC are also at increased risk of developing SCC and cutaneous melanoma.126,296 A prospective population-based cohort study found that development of a second BCC is most likely during the short-term follow-up period after diagnosis of the first lesion.133 Therefore, close follow-up of patients with BCC in both the short- and long-term is critical.

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