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Background: Randomized controlled trials comparing the effectiveness of 5-fluorouracil cream, methylaminolevulinate photodynamic therapy (MAL-PDT) and surgical excision in patients with Bowen's disease are lacking., Methods: In this multicenter noninferiority trial, patients with a histologically proven Bowen's disease of 4-40 mm were randomly assigned to excision with 5 mm margin, 5% 5-fluorouracil cream twice daily for 4 weeks, or 2 sessions of MAL-PDT with 1 week interval. The primary outcome was the proportion of patients with sustained clearance at 12 months after treatment. A noninferiority margin of 22% was used., Results: Between May 2019 and January 2021, 250 patients were randomized. The proportion of patients with sustained clearance was 97.4% (75/77) after excision, 85.7% (66/77) after 5-fluorouracil, and 82.1% (64/78) after MAL-PDT. Absolute differences were -11.7% (95% CI -18.9 to -4.5; P = .0049) for 5-fluorouracil versus excision and -15.4% (95% CI -23.1 to -7.6; P = .00078) for MAL-PDT versus excision. Both noninvasive treatments significantly more often led to good or excellent cosmetic outcome., Conclusions: Based on our predefined noninferiority margin of 22%, 5-fluorourcail is noninferior to excision and associated with better cosmetic outcome. For MAL-PDT noninferiority to excision cannot be concluded. Therefore, 5-fluorouracil should be preferred over excision and MAL-PDT in treatment of Bowen's disease., Competing Interests: Conflicts of interest None disclosed., (Copyright © 2023 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Recurrent/residual basal cell carcinoma (BCC) after topical treatment may not be visible during clinical and dermatoscopic examination (CDE). Optical coherence tomography (OCT) may detect these subclinical recurrences or residues., Objective: To compare the diagnostic accuracy of CDE with that of CDE combined with OCT (CDE-OCT) for detecting recurrent/residual BCC after topical treatment of superficial BCC., Methods: In this diagnostic cohort study, the suspicion level for recurrence or residue was recorded on a 5-point confidence scale. All patients with high suspicion of recurrence or residue based on CDE and/or CDE-OCT were referred for punch biopsy. Patients with a low suspicion on CDE and CDE-OCT were asked to (voluntarily) undergo a control biopsy. Histopathologic results of the biopsy were used for verification of CDE and CDE-OCT diagnoses (gold standard)., Results: This study included 100 patients. A histopathologic recurrent/residual BCC was found in 20 patients. For recurrence or residue detection, sensitivity was 100% (20 of 20) for CDE-OCT and 60% (12 of 20) for CDE (P = .005) and specificity was 95% for CDE-OCT and 96.3% for CDE (P = .317). The area under the curve for CDE-OCT (0.98) was significantly higher than that for CDE (0.77) (P = .001)., Limitations: Results are based on 2 OCT assessors., Conclusion: Compared with CDE alone, CDE-OCT results in a significantly higher ability to detect recurrent/residual BCCs after topical treatment., Competing Interests: Conflicts of interest None disclosed., (Copyright © 2023 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Conflicts of interest Dr K. Mosterd participated in an advisory board for Michelson Diagnostics. Drs Wolswijk, Adan, and Nelemans have no conflicts of interest to declare.

Background: Metastatic basal cell carcinoma (mBCC) is a very rare entity, and diagnosis can be challenging. Therapeutic options are limited, and response to targeted therapy is poor., Objective: To demonstrate a clonal relationship between BCCs and their metastases and to explore which hedgehog pathway-related mutations are involved in mBCC., Methods: Genetic analysis was conducted in 10 primary BCCs and their metastases. Genes relevant for BCC development were analyzed in tumor and metastasis material with small molecule molecular inversion probes (smMIPs) for PTCH1, PTCH2, SMO, SUFU, GLI2, and TP53 or with targeted next generation sequencing of the same genes and CDKN2A, CDKN2B, CIC, DAXX, DDX3X, FUBP1, NF1, NF2, PTEN, SETD2, TRAF7, and the TERT promoter., Results: In 8 of 10 patients, identical gene mutations could be demonstrated in the primary tumors and their metastases. A broad spectrum of mutations was found. Four patients had SMO mutations in their tumor or metastasis, or both. All SMO mutations found were known to cause resistance to targeted therapy with vismodegib., Limitations: In 2 patients there was insufficient qualitative DNA available for genetic analysis., Conclusions: Molecular testing can help to identify the origin of a BCC metastasis and may be of prognostic and therapeutic value., (Copyright © 2019 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Nodular basal cell carcinoma (nBCC) is mostly treated with surgical excision. Interest in minimally invasive treatment of these low-risk tumors is increasing. We assessed the effectiveness of nBCC treatment with curettage and imiquimod cream compared with surgical excision., Methods: Patients with nBCC included in this randomized, controlled noninferiority trial were randomly assigned to either a curettage and imiquimod cream group or a surgical excision group. The primary endpoint was the proportion of patients free from treatment failure 1 year after the end of treatment. A prespecified noninferiority margin of 8% was used. A modified intention-to-treat and a per-protocol analysis was performed (ClinicalTrials.gov identifier NCT02242929)., Results: One hundred forty-five patients were randomized: 73 to the curettage and imiquimod cream group and 72 to the surgical excision group. The proportion of patients free of recurrence after 12 months was 86.3% (63/73) for the curettage and imiquimod group and 100% (72/72) for the surgical excision group. The difference in efficacy was -13.7% (95% confidence interval -21.6% to -5.8%; 1-sided P = .0004) favoring surgical excision., Conclusion: Noninferiority of curettage and imiquimod cream cannot be concluded. Given the still high efficacy of curettage and imiquimod cream and the indolent growth pattern of nBCC, curettage and imiquimod could still be a valuable treatment option with the possibility to prevent overuse of excisions. However, it cannot replace surgical excision., (Copyright © 2020 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: There have been concerns that recurrences after noninvasive therapy for basal cell carcinoma (BCC) transform into a "more aggressive" histologic subtype., Objective: We sought to evaluate the proportion of patients with a nonsuperficial treatment failure after noninvasive therapy for superficial BCC., Methods: An observational study was performed using data from a single blind, noninferiority, randomized controlled trial (March 2008-August 2010) with 5-year follow-up in patients with primary superficial BCC treated with methylaminolevulinate-photodynamic therapy, 5-fluorouracil, or imiquimod. Data were used from 166 adults with a histologically confirmed treatment failure., Results: A nonsuperficial subtype was found in 64 of 166 treatment failures (38.6%). Proportions with a more aggressive subtype than the primary tumor were 51.3% (38/74) for early and 28.3% (26/92) for later treatment failures (P = .003). The proportion of more aggressive early failures was significantly lower after imiquimod (26.3%) compared with methylaminolevulinate-photodynamic therapy (54.8%, P = .086) and 5-fluorouracil (66.7%, P = .011)., Limitations: There was limited information on the exact time of occurrence of treatment failures., Conclusion: More aggressive treatment failure recurrences after noninvasive therapy for superficial BCC occur most often within the first 3 months posttreatment, probably indicating underdiagnosis of more aggressive components in the primary tumor rather than transformation., (Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: The suturing technique and its associated complications could affect cosmetic outcome after facial surgery. Literature on this topic is limited., Objective: To compare the cosmetic results 12 months after treatment and complications associated with simple interrupted sutures (SIS) versus running subcuticular sutures (RSS) in facial surgery., Methods: A randomized, controlled multicenter trial was performed. Adults receiving dermatologic surgery on the face were randomized to receive SIS or RSS for wound closure. The primary outcome was the overall opinion score on the Patient and Observer Scar Assessment Scale (POSAS) 12 months after surgery. Secondary outcomes were the complication rates and scores according to alternative methods for assessment of cosmetic outcome. The observer of cosmetic outcome was blinded to treatment assignment., Results: 142 patients were randomized to receive SIS (n = 73) or RSS (n = 69). Twelve months after surgery, the median score of the overall opinion on the POSAS was 2.0 (range 1-8) according to the patients and 3.0 (range 1-8) according to the observer in both groups. In the RSS group, hyper- or hypoesthesia was reported more often., Limitations: The cosmetic result was assessed by 1 observer., Conclusion: SIS and RSS in facial surgery resulted in comparable cosmetic outcomes. RSS was more often associated with hyper- or hypoesthesia., (Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Nonsteroidal anti-inflammatory drugs and vitamin-D derivatives can target signaling pathways activated in basal cell carcinoma (BCC)., Objective: We investigated the efficacy of topically applied diclofenac sodium 3% gel, calcitriol 3 μg/g ointment, and a combination of both in superficial BCC (sBCC) and nodular BCC., Methods: Patients with a primary, histologically proven sBCC (n = 64) or nodular BCC (n = 64) were randomized to topical diclofenac, calcitriol, combination of both, or no topical treatment (control group). After self-application twice daily under occlusion (8 weeks), tumors were excised. Primary outcome was posttreatment expression levels of proliferation (Ki-67) and antiapoptosis (B-cell lymphoma [Bcl-2]) immunohistochemical markers. Secondary outcomes were histologic clearance, adverse events, application-site reactions, and patient compliance., Results: sBCC treated with diclofenac showed a significant decrease in Ki-67 (P < .001) and Bcl-2 (P = .001), and after combination therapy for Ki-67 (P = .012). Complete histologic tumor regression was seen in 64.3% (P = .0003) of sBCC (diclofenac) and 43.8% (P = .007) of sBCC (combination therapy) compared with 0.0% of controls. No significant changes were found in nodular BCC. Application-site reactions were mostly mild to moderate., Limitations: The sample size was small., Conclusion: Our results suggest that topical diclofenac is a promising new treatment for sBCC. Its mode of action differs from available noninvasive therapies, and thus has an additive value., (Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: There is limited literature on efficacy using a 2-fold illumination scheme in aminolevulinic acid (ALA) photodynamic therapy for superficial basal cell carcinoma (sBCC)., Objectives: We sought to determine the efficacy of ALA photodynamic therapy for sBCC using a 2-fold illumination scheme after a single ALA application. Treatment failure within 12 months posttreatment was assessed., Methods: In this retrospective case series and cohort study, electronic files from patients treated between January 2010 and August 2011 were reviewed. Follow-up data were gathered until March 2014., Results: A total of 323 sBCC were analyzed for recurrence. Cumulative probability of clinical recurrence-free survival was 88.8% (95% confidence interval [CI] 85.4-92.4), 81.8% (95% CI 77.3-86.3), and 77.1% (95% CI 71.0-83.6) at 12, 24, and 48 months, respectively. For histologically confirmed recurrences this was 90.2% (95% CI 86.9-93.5), 85.4% (95% CI 75.5-89.3), and 81.8% (95% CI 75.5-88.1), respectively. A worse recurrence-free survival for tumors in the head and neck area and tumors larger than 10 mm was observed., Limitations: The retrospective nature and the lack of a control group are limitations., Conclusions: ALA photodynamic therapy using a 2-fold illumination scheme might be a feasible treatment option with acceptable long-term results for small sBCC located outside the head and neck area., (Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Noninvasive treatments are frequently used in treatment of superficial basal cell carcinoma (sBCC) because of better cosmetic results, lower costs, and less burden on health care services when compared with surgical excision. However, probability of treatment failure is higher after noninvasive therapies and may depend on histologic tumor characteristics., Objective: We sought to investigate whether tumor thickness and adnexal extension are determinants of treatment failure in sBCC treated with topical methylaminolevulinate-photodynamic therapy, imiquimod, or 5-fluorouracil., Methods: Data were derived from a randomized controlled trial on the effectiveness of methylaminolevulinate photodynamic therapy, imiquimod, and 5-fluorouracil for treatment of sBCC (ISRCTN79701845). For tumors with treatment failure (n = 112) and a randomly selected control group of tumors without treatment failure (n = 224) data on tumor thickness and adnexal extension were retrospectively collected. Treatment failure was defined as a clinically and histologically persistent or recurrent tumor within 1-year posttreatment., Results: Tumor thickness of included patients ranged from 0.2 to 1.0 mm. Tumor thickness and adnexal extension of sBCC were not significantly associated with treatment failure of methylaminolevulinate photodynamic therapy, imiquimod, or 5-fluorouracil., Limitations: Follow-up period of 1 year is a limitation., Conclusion: There seems to be no need to determine tumor thickness or adnexal extension in sBCC before treatment., (Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Although effective in superficial basal cell carcinoma (BCC), the treatment effect of photodynamic therapy (PDT) in nodular BCC (nBCC) is still questionable. The relation between tumor thickness and PDT failure is unclear., Objective: We sought to compare long-term effectiveness of fractionated 20% 5-aminolevulinic acid (ALA)-PDT with prior partial debulking versus surgical excision in nBCC. The effect of tumor thickness on ALA-PDT failure was analyzed., Methods: 173 primary, histologically proven nBCCs in 151 patients were randomized to fractionated ALA-PDT (n = 85) or surgical excision (n = 88). Two PDT illuminations were performed with a 1-hour interval. Follow-up was at least 5 years posttreatment. Clinical recurrences were confirmed histologically., Results: A total of 171 nBCCs were treated and had a median follow-up of 67 months (range 0-106). At 60 months, 23 tumors had recurred in the ALA-PDT group and 2 tumors in the surgical excision group. Cumulative recurrence probabilities 5 years posttreatment were 30.7% (95% confidence interval [CI] 21.5%-42.6%) for ALA-PDT and 2.3% (95% CI 0.6%-8.8%) for surgical excision (P < .0001). Two tumors in the ALA-PDT group recurred at 72 and 91 months posttreatment. Cumulative probability of recurrence-free survival post-PDT was 65.0% (95% CI 51%-76%) for nBCC measuring greater than 0.7 mm in thickness and 94.4% (95% CI 67%-99%, P = .018) for tumors less than or equal to 0.7 mm., Limitations: Tumor thickness on punch biopsy specimen might differ from the total lesion thickness., Conclusions: In nBCC, 5-year cumulative probability of recurrence after surgical excision is lower than after fractionated ALA-PDT with prior debulking. Although surgical excision remains the gold standard of treatment, PDT might be an alternative for inoperable patients with thin (≤0.7 mm) nBCC., (Copyright © 2013 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

Background: The type of treatment for a basal cell carcinoma (BCC) depends on the histologic subtype. Histologic examination is usually performed on incisional biopsy specimens. In primary BCC, the histologic subtype is correctly identified with a punch biopsy in 80.7% of cases. In recurrent BCC, correct identification is more difficult because of discontinuous growth caused by scar formation. Because an aggressive histologic subtype has a significantly higher risk for recurrence in these tumors, the histologic subtype is at least as important in recurrent BCC as it is in primary BCC., Objective: To investigate the correlation between histologic findings on punch biopsy specimens and subsequent excision specimens in recurrent BCC. Furthermore, we sought to clarify how often an aggressive histologic subtype was missed, based on the punch biopsy specimen., Methods: We compared the histologic subtype in a punch biopsy specimen with the subsequent excision specimen in recurrent BCC. All BCCs were coded and judged randomly by the same dermatopathologist., Results: In 24 of 73 investigated BCCs (32.9%), the histologic subtype of the initial biopsy did not match with the histologic subtype of the subsequent excision. Of the 37 excised BCCs with an aggressive histologic subtype, 7 (19%) were missed by the initial punch biopsy., Limitations: Intraobserver variation may have affected the results of this study., Conclusions: Discriminating tumors with any aggressive growth is relevant for treatment. However, in recurrent BCC, the histology of the biopsy specimen does not always correlate with the histology of the definitive excision. This may have important therapeutic implications., (Copyright © 2010 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)