Treatment of basal cell carcinomas at high risk for recurrence

INTRODUCTION — Basal cell carcinoma (BCC) is a common skin cancer that arises from the basal layer of the epidermis and its appendages. Treatment of BCC is indicated due to the locally invasive, aggressive, and destructive effects of BCC on skin and surrounding tissues (picture 1A-B).

Tumor characteristics, such as size, location, and pathology, influence the likelihood for deep tumor invasion and recurrence of BCC after treatment. Lesions at high risk for recurrence may benefit from removal with surgical procedures that allow for complete peripheral and deep margin assessment, such as Mohs micrographic surgery (MMS) and staged excision with circumferential margin assessment. Alternative therapies include conventional surgical excision and radiation therapy (RT).

The treatment of BCCs with clinical or pathologic features associated with increased risk for recurrence will be reviewed here. The risk factors, clinical manifestations, and prognosis of BCC, as well as the management of less aggressive BCCs, are reviewed separately. The management of locally advanced and metastatic BCC is also discussed separately.

●(See "Basal cell carcinoma: Epidemiology, pathogenesis, clinical features, and diagnosis".)

●(See "Treatment and prognosis of basal cell carcinoma at low risk of recurrence".)

●(See "Systemic treatment of advanced basal cell and cutaneous squamous cell carcinomas not amenable to local therapies".)

FEATURES ASSOCIATED WITH HIGH RISK FOR RECURRENCE — Certain clinical and pathologic features of basal cell carcinoma (BCC) are associated with an elevated risk for recurrence after treatment. Recurrent BCC may reappear months to years after initial treatment, leading to local tissue destruction, morbidity, increased risk for metastasis, and the need for retreatment (picture 1A-B).

The following characteristics have been proposed as factors associated with increased risk for tumor recurrence in the 2021 National Comprehensive Cancer Network (NCCN) clinical practice guidelines on cutaneous BCC. The presence of any of these factors places the tumor in the high-risk category [1]:

●Tumors of any size on the head and neck, including:

•Tumors on the "mask area" of the face (ie, nose, lips, eyelids, eyebrows, periorbital skin, chin, mandible, ears, preauricular and postauricular areas, temples (figure 1))

•Tumors on nonmask area of the face (ie, cheeks, forehead (picture 2A-B))

•Tumors on neck and scalp

•Tumors on hands, feet, and genitalia

●Tumors ≥20 mm in diameter on trunk and extremities, excluding hands and feet

●Lesions with poorly defined borders

●Recurrent lesions

●Lesions in sites of prior radiation therapy (RT)

●Aggressive pathologic features:

•Micronodular, morpheaform, sclerosing, or mixed infiltrative (picture 3)

•Basosquamous (keratinizing) or carcinosarcomatous

●Perineural invasion

●Immunocompromised patient (eg, solid organ and hematopoietic cell transplant recipients; patients with immune deficiencies, including congenital disorders and HIV/AIDS, and autoimmune disorders; patients treated with immunosuppressive therapies; cancer patients on immunotherapies or checkpoint inhibitors)

The designation of tumor location and size as important determinants for the selection of appropriate treatment is based upon the following factors:

●Many areas on the face represent embryologic cleavage planes; these sites provide relatively little resistance to tumor invasion.

●High-risk sites often have a high density of hair follicles and sebaceous glands. The physical presence of these structures makes eradication of tumors with curettage and electrodesiccation (C&E) and nonsurgical therapies less reliable.

●Involvement of critical structures, such as the eyelid, or cosmetically sensitive areas makes complete tumor removal without cosmetic or functional impairment difficult.

●Large tumors may have extensive subclinical growth, requiring wider excisional margins for disease clearance and accounting for lower rates of response to destructive therapies.

APPROACH TO MANAGEMENT — Our approach to the management of high-risk basal cell carcinoma (BCC) is generally consistent with published guidelines (algorithm 1) [1-3]:

●Mohs micrographic surgery (MMS) and staged excision with complete circumferential peripheral and deep margin assessment (CCPDMA) are the preferred treatments for BCCs at high risk for recurrence, in particular for tumors on the head and neck, hands and feet, pretibia, and genitalia [2,4-9]. MMS is a specialized surgical technique that uses intraoperative frozen horizontal sections and allows for the histologic evaluation of the entire peripheral and deep margins of the tumor while minimizing the amount of normal tissue that must be resected [10] (see "Mohs surgery"). Staged excision with CCPDMA allows complete assessment of tissue margins utilizing formalin-fixed tissue, rather than the rapidly processed frozen sections used in standard Mohs surgery.

●Alternative options for the treatment of high-risk lesions include standard surgical excision and radiation therapy (RT). Both options have advantages and disadvantages (table 1):

•Standard surgical excision has long-term recurrence rates higher than MMS [11] and provides pathologic assessment of only a small fraction of the excisional margin (estimated to be <1 percent) but is faster, less expensive, and more widely available than MMS. (See 'Standard surgical excision' below.)

•RT is an important treatment option for older patients with high-risk BCC who are not surgical candidates. Disadvantages of RT include a lower cure rate, the need for multiple clinic visits, high cost, and potential risk for long-term adverse effects. (See 'Primary radiation therapy' below.)

●Curettage and electrodesiccation (C&E) should not be used for the treatment of most lesions with more aggressive clinical or pathologic features, although it can achieve high cure rates for primary BCCs at low risk for recurrence located on the trunk or extremities [12-14]. Topical therapies and photodynamic therapy (PDT) should not be used for the treatment of high-risk BCC as well.

SURGICAL CANDIDATES

Mohs micrographic surgery — For the treatment of basal cell carcinoma (BCC) at high risk of recurrence, we suggest Mohs micrographic surgery (MMS), if available, as first-line therapy for tumors of any size on high-risk areas of the face ("mask area" (figure 1)), on nonmask areas of the face (ie, cheeks, forehead), scalp, pretibia, hands, feet, and genitalia (algorithm 1) [15].

MMS allows for the control of 100 percent of the tumor margins while minimizing the resection of normal tissue. Even for small tumors, MMS allows for the identification of inapparent tumor extensions while maximizing normal tissue sparing (see "Mohs surgery"):

●Efficacy – One randomized trial with an extended follow-up and several large case series support the long-term efficacy of MMS for the treatment of high-risk BCC [7,8,11,16-18]:

•One randomized trial compared standard excision with MMS for the treatment of 408 primary, high-risk, facial BCCs and 204 recurrent, facial BCCs [7]. At the 30-month follow-up, the recurrence rates were 2 and 3 percent for primary BCCs treated with MMS and standard excision, respectively, and 0 and 3 percent for recurrent BCCs treated with MMS and standard excision, respectively. However, in an extended follow-up study of the same cohort, the 10-year recurrence rates were lower in the MMS group than in the standard excision group for primary BCCs (4.4 percent [95% CI 1.9-9.8] versus 12.2 percent [95% CI 7.3-19.8], respectively) as well as for recurrent tumors (3.9 percent [95% CI 1.3-11.7] versus 13.5 percent [95% CI 7.6-23.2], respectively) [11].

•In a large, Australian series of 819 patients with periocular BCCs treated with MMS, among the 346 patients who had strict, five-year follow-up, seven (2 percent) had recurrences [16]. All recurrences occurred in a subgroup of 90 previously recurrent tumors (with up to three recurrences before MMS), whereas no recurrences occurred in the primary BCC group.

The recurrence rate after Mohs surgery appears to be higher for lesions with histologic evidence for perineural invasion. In a series of 3020 patients with BCC (including 78 patients with BCCs with perineural invasion), five-year recurrence rates for patients with or without perineural invasion were 8 and 2 percent, respectively [19].

●Disadvantages of Mohs micrographic surgery – Disadvantages of Mohs micrographic surgery (MMS) include duration and costs. A typical MMS procedure may last a few hours, and more complicated cases can take longer. Reconstruction following MMS may be performed the same day or at a subsequent time, depending on the anticipated length of the repair. A significant amount of the total time is spent with the histologic preparation and analysis; during this time, patients are temporarily bandaged and may await the final results in a waiting room. A small minority of patients may find it difficult to tolerate a procedure of this length.

MMS is more expensive than standard, office-based surgical excision and is more expensive than excision with intraoperative frozen sections in an operating room. Whether MMS is cost effective remains controversial, as some studies do not factor in the cost of retreating tumors that recur [20-23], and cost determination and accounting for surgery differs considerably among countries.

Staged excision with circumferential margin assessment — Staged excision with complete circumferential peripheral and deep margin assessment (CCPDMA) is an alternative to MMS for high-risk BCCs. It involves complete assessment of tissue margins utilizing formalin-fixed tissue, rather than the rapidly processed frozen sections used in standard MMS. This procedure is performed without the equipment and technician expertise required for frozen tissue processing (see "Mohs surgery", section on 'Surgical technique'):

●Efficacy – In large series of BCCs including periocular and recurrent tumors, staged excision with CCPDMA was associated with five-year cure rates of 97 to 99 percent [24-26].

●Disadvantages – The time required to attain pathology results from formalin-fixed tissue specimens delays wound closure for days and leads to the need for repeat office visits. Thus, the procedure is less desirable than MMS for some patients.

Standard surgical excision — Standard excision with postoperative margin assessment is a treatment option for select high-risk tumors on the trunk and extremities (except the hands and feet).

There are no data from randomized trials addressing the appropriate margin size for high-risk BCC. However, it is recommended to use margins wider than 4 to 5 mm (deemed to be appropriate for low-risk BCC), as feasible, depending on the specific location of the tumor [1]. This recommendation is supported by indirect evidence from observational studies using MMS and randomized trials evaluating the efficacy of standard surgical excision compared with other treatment modalities:

●In an observational study of 306 patients with facial BCCs (approximately 90 percent in the mask area and with micronodular or infiltrative histology) excised with MMS, complete excision was obtained in 74 percent of tumors with 2 mm margins, in 94 percent of tumors with 3 mm margins, and in 99 percent of tumors with 4 mm margins [27].

●In a 2010 meta-analysis of 37 studies, most of which were observational, the analysis of pooled data from 10,261 patients with 16,066 nodular BCCs treated with surgical excision found that the 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 [28]. The rates of pathologically confirmed complete excisions were similar for surgical margins between 3 and 5 mm.

●A randomized trial compared standard surgical excision with Mohs surgery for the treatment of 408 primary, high-risk, facial BCCs [7]. Tumors assigned to standard excision were excised with 3 mm margins and, if incompletely excised, re-excised with 3 mm margins. In cases of two incomplete excisions, tumors were treated with MMS. At 30 months, the recurrence rates were similar in the standard excision and MMS groups (3 and 2 percent, respectively). Two extended, follow-up studies of the same cohort found 5- and 10-year recurrence rates of 4 and 12 percent, respectively, in the standard excision group and 2.5 and 4.4 percent, respectively, in the Mohs surgery group [8,11].

NONSURGICAL CANDIDATES

Primary radiation therapy — For patients with high-risk basal cell carcinoma (BCC) who are not surgical candidates (eg, older patients, patients with multiple comorbidities who may not tolerate surgery, patients who decline surgery), primary radiation therapy (RT) is the preferred alternative treatment option (algorithm 1) [29]. External beam RT is usually administered in a fractionated schedule that requires treatments on consecutive weekdays for four or more weeks.

Fractionation limits treatment-related late effects in normal tissues, but the frequent visits may be problematic for many patients. Hypofractionated regimens, with higher doses per fraction delivered one to three times per week for two to three weeks, appear to be more acceptable to older and frail patients despite an increased risk of late adverse effects [30].

RT should be considered a treatment of last resort for previously irradiated, recurrent BCCs because of the risk of cumulative radiation toxicity [31].

Efficacy — Most large series report overall five-year cure rates of 91 to 93 percent for previously untreated BCCs, with rates as high as 96 percent for smaller BCCs at low risk for recurrence [32-34]. For patients with recurrent BCCs, the reported cure rates are somewhat lower, generally between 86 and 91 percent [32-35]:

●In the only randomized trial comparing surgery with radiotherapy in 347 patients with facial BCC <40 mm, the primary endpoint was the failure rate (persistent or recurrent disease) after four years of follow-up. Of the 173 patients in the radiotherapy group, 55 percent were treated with interstitial brachytherapy, 33 percent were treated with contact brachytherapy, and 12 percent were treated with conventional radiotherapy. The four-year recurrence rate was 0.7 percent (95% CI 0.1-3.9) in the surgery group and 7.5 percent (95% CI 4.2-13.1) in the radiotherapy group [36]. More patients in the surgery group than in the radiotherapy group were satisfied with the cosmetic results. Eighty-seven percent of the surgery-treated patients and 69 percent of the radiation-treated patients considered the cosmetic result as good (p <0.01).

●A systematic review and network meta-analysis of various treatments for BCC showed similar recurrence rates for standard surgery (3.3 percent, 95% CI 1.3-7.8 percent), Mohs surgery (3.8 percent, 95% CI 0.7-18.9 percent), curettage and diathermy (5.9 percent, 95% CI 0.7-34.9 percent), and radiotherapy (3.2 percent, 95% CI 0.6-16.1 percent) [37].

BCCs that recur following RT may behave more aggressively than those recurring after surgical procedures, with higher rates of second recurrence and distant metastasis [38].

Although early reports suggested a poor outcome with RT alone for larger or more deeply invasive tumors (ie, those involving cartilage, bone, and/or muscle), series using modern RT techniques, such as volumetric modulated arc therapy (VMAT), suggest excellent control rates with good cosmesis and functional outcomes. In several reports, three- to five-year locoregional control rates were 86 to 91 percent for large and/or locally advanced BCCs with RT [32,34,39-42].

Advantages and disadvantages — The major advantages of RT are the relative sparing of cosmetically and functionally important structures, its noninvasive and painless nature, and its utility for many patients who are not candidates for surgical intervention or for whom it is difficult to attain histologic clearance. In addition, the relative sparing of normal healthy tissue can offer superior cosmetic results for tumors located on or around the lips, nose, and eyelids. However, these favorable cosmetic results may deteriorate with time [39,43].

Disadvantages of RT include a lower cure rate compared with surgical procedures, the need for multiple clinic visits, high cost, and potential risk for long-term adverse effects. Unlike surgical excision or Mohs surgery, RT does not provide histologic control of the tumor margins. RT is considerably more expensive than other treatments and is associated with a number of short-term and long-term side effects. (See 'Adverse events' below.)

Contraindications — RT is generally avoided for tumors located on areas of poor vascularity and wear-and-tear sites (eg, regions below the elbow or knee [pretibial region and dorsum of the hand], cartilage [ear], and bony prominences). The skin in these areas is subject to greater trauma and tension and is more prone to break down and ulcerate as a result of the atrophy and poor vascularity of irradiated tissue.

RT should never be used in patients with basal cell nevus syndrome, where RT may induce numerous skin cancers that are difficult to manage (see "Nevoid basal cell carcinoma syndrome (Gorlin syndrome)", section on 'Risk factors for basal cell carcinoma'). In addition, RT should be avoided in younger patients due to worsening functional and cosmetic results with time and the risk of developing a secondary cancer in the treatment field.

Adverse events — Most patients experience some temporary fatigue during RT. Other acute, expected side effects of RT include localized erythema and edema, scaling, and pain. Occasionally, ulceration with bleeding and infection can develop. These skin reactions tend to peak at the end of the course of RT and during the first 10 to 14 days after completion. Healing generally starts at approximately two weeks following the final fraction. (See "Radiation dermatitis".)

Late effects of radiation within the treatment field may include the following:

●Permanent alopecia occurs within the treatment field. Patients should be advised of this prior to treatment, and pretreatment counseling is essential.

●Chronic radiation dermatitis generally appears months to years following therapy and is characterized by permanently mottled areas of hypopigmentation and hyperpigmentation; a dry, hyperkeratotic, atrophic, shiny epidermis; telangiectasias; and dermal fibrosis. These are generally a cosmetic issue and rarely cause any symptoms. Patients who have received larger doses (>3 to 4 Gy) per fraction are more likely to develop these changes.

●Other possible late effects within the radiation field could include cataract, dry eye, and ectropion for periocular disease. These are uncommon events that should be avoided with proper shielding during therapy.

●Radiation-induced cutaneous malignancies (both BCCs and squamous cell cancers) may develop within irradiated sites [44,45]. These secondary cancers can occur from five years to several decades following RT and are thought to behave aggressively, with a higher likelihood of subclinical extension than other skin cancers.

Risk factors for secondary cancers after RT include higher radiation doses, larger radiation fields, sun-exposed sites, fair skin, and early age of radiation exposure. Although some investigators think that the risk of radiation-induced cutaneous malignancy is theoretically smaller using modern conformal techniques to minimize the dose to the surrounding normal structures, RT continues to be avoided in young people and in those with genetic susceptibility to radiation-induced malignancies (table 2) [46,47].

Other therapies — Photodynamic therapy (PDT) and imiquimod have been used in a few studies of patients with BCC with high-risk features. However, because data supporting these interventions for high-risk lesions are very limited, their routine use for high-risk BCCs is not recommended:

●Two observational studies of methyl aminolevulinate (MAL)-PDT for patients with high-risk BCC reported recurrence rates of 18 to 24 percent at 24 months [48,49].

●In a few small series of patients with eyelid BCC, imiquimod was used with variable results [50-53].

●In a small, randomized trial including 27 patients with primary, nodular BCCs of the eyelid comparing imiquimod with RT, both treatments were effective in inducing histopathologic remission at 3 months and sustained clinical remission at 24 months [54].

The use of PDT and imiquimod for low-risk BCC is discussed elsewhere. (See "Treatment and prognosis of basal cell carcinoma at low risk of recurrence", section on 'Imiquimod' and "Treatment and prognosis of basal cell carcinoma at low risk of recurrence", section on 'Photodynamic therapy'.)

SPECIAL SITUATIONS

Tumors excised with positive margins — Basal cell carcinomas (BCCs) may not be excised completely. Rates of margin positivity of 10 to 27 percent have been reported for high-risk BCCs excised with standard excision or Mohs micrographic surgery (MMS) [55-57].

In patients with positive margins after standard surgical excision, re-excision with either MMS or staged excision with complete circumferential peripheral and deep margin assessment (CCPDMA) should be performed. If clear margins cannot be achieved with either of those modalities, adjuvant radiation therapy (RT), systemic hedgehog pathway inhibitors, and multidisciplinary tumor board consultation should be considered (algorithm 1) [1].

Adjuvant RT has been used postoperatively in patients with incompletely resected tumors. In a series of 55 patients with BCC located in the head/neck region (74 percent on the face) treated with adjuvant RT after surgical excision, the recurrence rate was 3.6 percent [58].

Recurrent tumors — Recurrent BCCs, especially those located in high-risk sites, are candidates for MMS, particularly because recurrent tumors tend to develop more aggressive histologic subtypes [59]. In a randomized trial that included 201 recurrent, facial BCCs treated with standard excision or MMS, the recurrence rate was 3 percent after standard excision and 0 percent after MMS [7].

Locally advanced tumors/metastatic disease — The management of locally advanced BCC not amenable to treatment with surgery or RT with systemic therapies, including inhibitors of the hedgehog pathway (eg, vismodegib, sonidegib), immune checkpoint inhibitors, or chemotherapy is discussed in detail elsewhere. (See "Systemic treatment of advanced basal cell and cutaneous squamous cell carcinomas not amenable to local therapies".)

PROGNOSIS AND FOLLOW-UP — The prognosis for most patients with high-risk, primary basal cell carcinoma (BCC) is excellent. Metastatic disease is a very rare event, estimated to occur in 0.0029 to 0.05 percent of patients [60-62]. Metastatic lesions usually occur in association with deeply invasive or large lesions; common sites for metastasis include the regional lymph nodes, lungs, bones, skin, and liver [63]. (See "Evaluation for locoregional and distant metastases in cutaneous squamous cell and basal cell carcinoma", section on 'Basal cell carcinoma'.)

Metastatic BCC generally has been considered to have a very poor prognosis. A review of 194 published cases of metastatic BCC between 1981 and 2011 found a median survival after diagnosis of metastatic disease of 10 months (range 0.5 to 108 months) [63]. However, a more favorable prognosis is suggested by a retrospective study of 10 patients evaluated at a single academic medical center between 1997 and 2011. Median overall survival following a diagnosis of metastatic BCC was 7.3 years (95% CI 1.62 to infinity) at the cut-off date of the study, with seven patients still alive at the end of the assessment period [64]. Of note, all patients in the retrospective study received adjuvant treatment, including six who received treatment with the hedgehog pathway inhibitor vismodegib. (See "Systemic treatment of advanced basal cell and cutaneous squamous cell carcinomas not amenable to local therapies".)

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" and "Society guideline links: Mohs surgery".)

SUMMARY AND RECOMMENDATIONS

●High-risk features – Basal cell carcinomas (BCCs) with any of the following features are considered at high risk of recurrence:

•Tumors of any size on the head and neck, hands, feet, and genitalia

•Tumors ≥20 mm in diameter on trunk and extremities, excluding hands and feet

•Lesions with poorly defined borders

•Recurrent lesions

•Lesions in sites of prior radiation therapy (RT)

•Aggressive pathologic features (micronodular, morpheaform, sclerosing, or mixed infiltrative, basosquamous, carcinosarcomatous)

•Perineural invasion

•Immunocompromised patient

●Management (algorithm 1):

•For surgical candidates with high-risk BCCs of any size located on the head and neck, hands, feet, and genitalia, we suggest Mohs micrographic surgery (MMS) rather than standard surgical excision or primary RT (Grade 2C). Even for small tumors, MMS allows for the identification of inapparent tumor extensions while maximizing normal tissue sparing. In settings where MMS is not available, standard surgical excision with margins wider than 4 to 5 mm or staged excision with complete circumferential peripheral and deep margin assessment (CCPDMA) are alternative surgical approaches. (See 'Surgical candidates' above.)

•For patients who are nonsurgical candidates (eg, older patients, patients with multiple comorbidities who may not tolerate surgery, patients who decline surgery), we suggest primary RT rather than photodynamic therapy (PDT) or imiquimod (Grade 2C). RT is contraindicated for tumors located on areas of poor vascularity; in younger patients, due to worsening functional and cosmetic results with time; and in patients with Gorlin syndrome, as RT can increase the risk of developing further BCCs. (See 'Nonsurgical candidates' above.)

●The management of locally advanced BCC not amenable to treatment with surgery or RT with systemic therapies is discussed separately. (See "Systemic treatment of advanced basal cell and cutaneous squamous cell carcinomas not amenable to local therapies".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Timothy K Chartier, MD (deceased), who contributed to an earlier version of this topic review.