Medical and Surgical Management of Multifocal Superficial Basal Cell Carcinoma

Basal cell carcinoma (BCC) is the most common cutaneous nonmelanoma skin cancer worldwide that predominantly appears on sun-exposed skin. Superficial basal cell carcinomas (sBCC) present clinically as erythematous scaly macules or thin papules typically on photodamaged skin.¹ These growths represent 20% of BCCs and commonly occur on the trunk and extremities in younger patients following intense sun exposure.^2,3 Histologically, they appear as clusters of small basaloid aggregates extending from the epidermis with normal intervening epidermis in a multifocal pattern (Figure 1).⁴

The multifocal nature of sBCC poses a unique treatment dilemma, as noncontiguous foci of basaloid tumor nests can extend horizontally and evade detection.¹ Current treatment modalities include topical immunomodulatory therapies, standard surgical excision, photodynamic therapy, laser, electrodesiccation and curettage (ED&C), and Mohs micrographic surgery (MMS).⁵ MMS provides the highest 5-year cure rate of 98-99% for primary BCC through complete microscopic peripheral and deep tumor margin assessment.⁶ While sBCCs are typically construed as less aggressive variants of BCC, the predilection for skip lesions, larger defect size, and higher recurrence rate make this subtype more challenging to treat with MMS. The rising incidence and associated morbidity and economic costs of sBCC compel a better understanding of these tumors to optimize therapeutic strategies to improve patient outcomes. We aim to review the existing literature on surgical and medical management of multifocal sBCC and provide an overview of the advantages, disadvantages, and limitations of each treatment modality.

A comprehensive literature search was conducted using the PubMed electronic database with the search terms, multifocal basal cell carcinoma, imiquimod, 5-fluorouracil, photodynamic therapy, and laser. Inclusion criteria were based on the relevance to the surgical and medical management of multifocal superficial BCC. Studies excluded included those with limited relevance to the topic or the treatment of multifocal sBCC, lacked sufficient data, or were published in languages other than English.

The initial search yielded 184 results and after five reviewers independently reviewed the articles and assessed their eligibility based on the inclusion and exclusion criteria. A total of 20 studies were selected for full-text review and 15 were included in the final analysis after removing articles that examined wrong outcomes or the wrong population of interest (Figure 2). Five studies were retrospective, two were prospective, one was a combined retrospective/prospective, and seven were case reports/series. The included studies were then analyzed for key findings regarding the surgical and medical management strategies for multifocal superficial basal cell carcinomas.

Medical Management
Laser/Light Therapies
Humphreys et al⁷ conducted a prospective study to evaluate the efficacy of pulsed carbon dioxide (CO2) laser for treatment of multifocal sBCC and squamous cell carcinoma in situ (SCCis). The study included 17 patients with biopsy-proven multifocal sBCC treated with either 2 or 3 passes of a pulsed CO2 laser (500 mJ, 2-4 W) followed by standard excision with 4-mm margins. All sBCCs were destroyed with three passes but residual tumors in the deep margins were observed in 5 out of 8 patients treated with only two passes of the laser. Overall, pulsed CO2 laser treatment can effectively ablate sBCCs with a minimum of 4-mm margins with three passes for complete vaporization. The treatment was well tolerated without any post-treatment complications.

Reddy et al⁸ presented a case and literature review on the use of methyl aminolevulinic acid photodynamic therapy (MAL-PDT) for the treatment of a large multifocal sBCC. The patient first underwent MMS. After six stages, roughly half of the tumor's peripheral margins remained positive for sBCC. Due to the large defect size (12.5 cm x 9 cm) and potential compromise of form and aesthetics, the authors decided to forego additional MMS stages in favor of adjuvant MAL-PDT. The patient received two consecutive treatments of adjuvant PDT with complete wound re-epithelialization in 4 weeks. Untreated defects of this size typically heal in 10-12 weeks by secondary intention.

Topical Therapies
Naik et al³ reported using topical 5-fluorouracil (5-FU) cream to treat a 51-year-old man presenting with multifocal sBCCs at 6 distinct sites on the face. Topical 5-FU cream was applied twice daily at all sites except the sBCC near the lid margin to prevent corneal toxicity. Local skin reaction to 5-FU included transient erythema, edema, and crusting. At week 12, the patient underwent excision of the eyelid sBCC with clear margins and no recurrence within six months.

Wu et al⁹ reported a case of daily application of topical imiquimod 5% cream for the treatment of multifocal sBCC of the nose and an adjacent squamous cell carcinoma in situ (SCCis).⁹ Following 8 weeks of treatment, the SCCis completely resolved while the sBCC partially regressed and was later removed surgically. The cosmetic outcome was exceptional and at 12-month follow-up, there were no signs of recurrence of SCCis or BCC.

Plachouri et al¹⁰ presented a case detailing the use of imiquimod 5% cream to treat multiple pigmented sBCCs on the scalp of a 70-year old male. Imiquimod was applied to the sBCC daily for five consecutive days over five weeks. One small sBCC on the left frontotemporal scalp had complete resolution within 10 days of treatment, while a larger multifocal sBCC on the right frontotemporal area required additional treatment cycles to achieve clearance. Scaling, erosions, and irritation due to the inflammatory response induced by imiquimod was experienced and well tolerated by the patient.

Zou et al¹¹ and Rubin et al¹² examined the use of imiquimod 5% cream to treat multifocal sBCCs while utilizing reflectance confocal microscopy (RCM) to visualize the tumors. 4 patients with a combined 34 sBCCs were treated with imiquimod daily for five days over an average of 18.6 weeks. Follow-up visits at 12, 24, and 52 weeks with RCM demonstrated that imiquimod treatment resulted in a complete tumor clearance rate of 88.2%. Local skin reactions and hypopigmentation were the most frequently reported side effects. Rubin et al. described a case of a 60-year-old woman with recurrent scalp BCCs from longterm hydroxyurea use for essential thrombocythemia. Multiple attempts at MMS failed to attain complete tumor clearance. Application of imiquimod 5% cream achieved clinical regression, albeit with residual tumor foci at 7-month follow-up.

Retinoids
Jones et al¹³ described a case report of a 67-year-old female whose multifocal sBCC was successfully treated with etretinate. Clinical improvement in size and texture of lesion was observed at 3 months. A mastectomy was done in the same area of the previous BCC due to a palpable lump present in the patient’s breast, which revealed a benign adenoma. Histopathology of the excised skin from the mastectomy showed complete resolution of the sBCC.

Surgical Management
Emmet et al¹⁴ and Bozan et al¹⁵ observed recurrences of various BCC tumors after standard surgical excision. In Emmet et al,¹⁴ 2277 cases of BCC were examined and 617 (27.1%) of them were multifocal sBCCs. After standard surgical excision, 14 (2.2%) multifocal sBCC’s recurred, which necessitated second surgical excision with no further recurrence. In Bozan et al,¹⁵ 154 BCCs were examined in 130 patients, out of which,¹⁴ (9.1%) were multifocal sBCC. A total of 23 BCCs had positive margins, but only 6 had a recurrence after a mean follow-up of 70 months after surgical treatments such as primary excision, transpositional flap, and advancement flap. Two out of six recurrences were multifocal sBCCs and required re-excision. After a mean followup of 51 months for the recurrent patients, 3 out of 6 cases had a second recurrence which warranted a third excision. The study did not specify the BCC types of these 3 recurrences.

Friedman et al¹⁶ evaluated 29 patients with margin positive BCC in a group of 339 patients who underwent BCC resection to characterize risk factors that predispose to BCC recurrence with positive margins. All 339 BCCs occurred on the head and neck region. 29 patients had margin-positive BCCs (8.6%), of whom 10 patients underwent re-resection of margin-positive tumors within two months, while 15 did not, and four patients were lost to follow-up. All 15 patients who did not undergo re-resection developed recurrent tumors within an average of one year (range, 1-4 years). The histology subtype included mixed (6), multifocal (4), sclerosing (3), and nodular (2). The study suggested that nodular BCC is more amenable to surgical extirpation compared to mixed, multifocal, and sclerosing subtypes. Nonetheless, the authors advocate for a more aggressive immediate re-resection of margin-positive BCCs, particularly when lesions are multifocal or have sclerosing component.

Madani et al¹⁷ reported that incomplete Mohs micrographic surgery (MMS) due to unresectable tumor is exceedingly rare, occurring at a frequency of approximately 0.15% (15 out of 10,346 procedures). Risk factors for unresectable disease include large tumor size, subclinical extension, invasion of bone and deep tissues, recurrent tumors, anatomic location along embryonic

fusion planes, and tumor type and histologic subtype. Of these, 4 cases were attributed to residual multifocal BCC and the rest to invasive cutaneous squamous cell carcinoma and dermatofibrosarcoma protuberans. Two cases with BCC had bony invasion and extension to orbit/external auditory meatus. Of the 4 patients with multifocal skin involvement, one patient underwent ED&C, two patients had extensive postoperative dermabrasion, and the fourth patient was monitored clinically.

Farhi et al¹⁸ evaluated 362 BCCs from 284 patients, of which 191 (52.7%) occurred on the face with the nose (10%), eyelids (4.2%), ears (2.2%), and lips (2%) being the most common location. The most frequent histologic BCC subtypes were superficial (35.3%), nodular (34.7%), and infiltrative (26.7%). The median surgical margins were 4 mm (range, 2.5-5mm) for low-risk BCC and 5 mm (range, 5-10 mm) for high-risk BCC. Incomplete excisions occurred in 10.3% of cases and included 8.6% of positive lateral margins and 2.5% of positive deep margins, with 0.8% overlap between positive lateral and deep margins. Incomplete excisions reported in this retrospective analysis were associated with infiltrative and multifocal superficial BCC histologic subtypes and anatomic location on the nose and eyelids. The authors advocated immediate re-excision with MMS to treat recurrent high-risk BCC.

Lim et al¹⁹ compared frequency of subclinical extension (SCE) between different histologic subtypes of BCC in a prospective multicenter study involving 17 Mohs surgeons and 1686 cases of BCC treated with MMS. SCE was defined as the number of MMS stages required to clear the tumor and is a prominent feature of biological aggressive subtypes of BCC. The study stratified SCE into high (higher than average) risk SCE (1.9 stages, 1.0 SD) and low (lower than average) risk SCE (1.6 stages, 0.9 SD). The highrisk SCE category included morpheaform (2.1), infiltrative (1.9), metatypical (1.9), mixed (1.8), and superficial (1.8). Superficial BCC can exhibit subclinical extension and recurrence frequency comparable to that of aggressive BCC subtypes. Furthermore, sBCC was the most common subtype to undergo histologic drift, increasing in frequency (16% to 25.8%) from initial index biopsy to final MMS. The study revealed a high predilection of sBCC to exhibit SCE and HS, for which margin control with MMS is most applicable.

Alice Mina et al²⁰ conducted a retrospective review of 158 sBCC on the head and neck treated with MMS from 112 patients at a single institution. 105 (66.5%) of the sBCC occurred in women, most commonly on the central face including nose and perioral sites.²⁰ The average Mohs stage for sBCC in this cohort was 2.6 ranging from 2.2 stages on the lateral face to 2.9 on the forehead, which is notably higher than the national average of 1.9 Mohs stages for all BCC.²¹ 4 (2.5%) lesions recurred clinically after 1 year despite negative margins and were associated with high risk features including large size (2 cm²), 4 or more Mohs stages, and high risk locations on the central face. The size of the initial sBCC was significantly smaller than the ultimate defect size after MMS in all anatomic locations. A subset of 4 patients had residual foci of BCC after MMS that were treated with a 6-week course of topical imiquimod 5 times a week or 5-FU twice a day for 4 weeks with no evidence of tumor recurrence at 5 year follow-up.²⁰

Superficial basal cell carcinomas (sBCC) represent a distinct histopathologic variant with propensity to exhibit multifocal extension of noncontiguous tumor islands. More Mohs stages (2.9) were required to clear sBCC on the central face compared to national average of 2.1 stages for all BCC on central face. Furthermore, the final defect size of sBCC following MMS was significantly larger than anticipated ranging from 2.5 to 38.5- fold increase from baseline size.²⁰ Various medical and surgical therapeutics have been utilized individually and in combination to treat sBCC.

Surgical Management
Mohs micrographic surgery (MMS) is the gold standard treatment for BCC based on patient and tumor characteristics outlined by Mohs Appropriate Use Criteria (MAUC). This algorithm was initially devised to address the appropriateness of MMS for 270 scenarios of cutaneous malignancy including sBCC. MacFarlane and colleagues contend that MAUC for sBCC should evolve as additional empirical evidence come to light.²² They advocate that subclinical extension and tendency for noncontiguous spread of sBCC in high-risk "Zone H" location primarily on the face make sBCC appropriate for MMS.²² Petersen et al. examined 133 cases of sBCC treated with MMS and found that a significant majority of sBCC occurred in Zone H of the face with more aggressive mixed histology, thereby justifying MMS for sBCC in high-risk areas.³⁵

Friedman et al¹⁶ and Farhi et al¹⁸ emphasize the importance of complete BCC excision with margin control to minimize recurrence rates. Margin-positive BCCs, especially those with multifocal or sclerosing features, poses a greater chance of reoccurrence if not properly re-excised. Furthermore, incomplete excisions and recurrence are associated with more aggressive histologic subtypes including infiltrative and multifocal sBCC.¹⁸ Madani et al¹⁷ and Lim et al¹⁹ demonstrated the efficacy of MMS in achieving tumor extirpation with 100% margin assessment particularly in cases of unresectable disease or subclinical extension. Collectively, these authors advocate early and aggressive management of sBCCs in high-risk "Zone H" with MMS.

Medical Management
CO2 lasers, photodynamic therapy, and retinoids are effective nonsurgical treatment modalities for sBCC. CO2 lasers deliver

a pulse of high energy that superficially ablates tumor tissue. Humphreys et al⁷ reported the successful treatment of sBCC using three passes of CO2 laser. MAL-PDT exerts its antitumor effect through selective uptake by rapidly dividing tumor cells and cytotoxicity through generation of reactive oxygen.²³ Reddy et al. found that MAL-PDT not only achieved tumor clearance, but also resulted in faster wound healing. The proposed mechanism is stimulation of fibroblast proliferation, epidermal stem cell migration, and granulation tissue formation.²⁴ Jones et al showed resolution of sBCC after treatment with etretinate. Systemic retinoids help regulate various tumorigenesis pathways crucial to BCC development, including TIG-3, PTCH1- Gli, and the PI3K-AKT-mTOR pathways.²⁵ Although previous case reports have described the efficacy of retinoids, they are not FDA approved and have not shown consistency in the treatment of BCC.^26,27

5-FU and imiquimod are two FDA approved topical creams to treat sBCCs. 5-FU is an anti-metabolite that blocks the formation of deoxythymidine mono-phosphate necessary for DNA synthesis.²⁸ Naik et al reported the successful use of 5-FU for periorbital sBCC and endorsed its potential as a cost-effective, non-invasive, and well-tolerated therapy.²⁹ Imiquimod, an immunomodulatory, works by binding to toll-like receptor 7 whose downstream effects induce a Th1 response.³⁰ Cytotoxic CD8+ T-cells can induce cellular cytotoxicity in tumor cells including BCC.³¹ Local topical application of imiquimod 5% cream resulted in tumor regression and improved cosmetic outcomes. Wu et al⁹ and Rubin et al,¹² noted that while imiquimod achieved clinical improvement of multifocal sBCCs, residual foci of BCC remained. In one study, only 88.2% of the 34 multifocal sBCC’s showed complete resolution.¹¹ The most common sideeffects reported with use of both topical agents include local erythema, scaling, crusting, and inflammation.^9-12,29

Combination Strategy
Multifocal sBCCs render tumor extirpation by MMS a treatment conundrum as foci of skip lesions can occur subclinically necessitating multiple stages for complete tumor clearance. Some authors advocate for an aggressive approach with additional Mohs stages to remove these multifocal "skip" lesions entirely to achieve complete margin control. Taking extra Mohs stages may result in large defects requiring more complicated repairs, prolonged healing time, and untoward complications, largely undermining the tissue-sparing goal of MMS. The application of adjuvant immunomodulators to MMS might be a viable option for clearance of residual tumor following surgical debulking of multifocal sBCC. Alice Mina reported that in 4 patients with sBCC treated with MMS, noncontiguous foci of sBCC were not operated further due to increased cosmetic and functional impairment. All 4 patients received imiquimod or 5-FU cream with clinical clearance of sBCC at 5 year follow-up.²⁰ Adjuvant treatment with topical imiquimod or 5-FU and close follow-up is a useful strategy for microscopically evident sBCC following tumor excision with MMS.

Evaluation and management of multifocal sBCC requires a multidisciplinary approach with appropriate preoperative planning and consideration for termination of MMS in cases where complete resection is not feasible. Nonsurgical therapeutics include ED&C, dermabrasion, ablative lasers, PDT, retinoids, and topical immunomodulators. Integration of adjuvant imiquimod or 5FU for microscopically evident sBCC after MMS is an emerging therapeutic strategy.

All authors have no conflicts of interest, financial interests, or patents to declare. No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article. No new data were generated or analyzed in this research. Retrospective chart review. Waiver of patient consent.

Tian Ran Zhu MD rzhu689@gmail.com