Surgical excision versus topical 5% 5-fluorouracil and photodynamic therapy in treatment of Bowen's disease: A multicenter randomized controlled trial.

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.

European consensus-based interdisciplinary guideline for diagnosis, treatment and prevention of actinic keratoses, epithelial UV-induced dysplasia and field cancerization on behalf of European Association of Dermato-Oncology, European Dermatology Forum, European Academy of Dermatology and Venereology and Union of Medical Specialists (Union Européenne des Médecins Spécialistes).

A collaboration of multidisciplinary experts from the European Association of Dermato-Oncology, the European Dermatology Forum, the European Academy of Dermatology and Venereology, and the European Union of Medical Specialists was formed to develop European recommendations on AK diagnosis and treatment, based on current literature and expert consensus. This guideline addresses the epidemiology, diagnostics, risk stratification and treatments in immunocompetent as well as immunosuppressed patients. Actinic keratoses (AK) are potential precursors of cutaneous squamous cell carcinoma (cSCC) and display typical histopathologic and immunohistochemical features of this malignancy in an early stage. They can develop into cSSC in situ and become invasive in a low percentage of cases. AK is the most frequent neoplasia in white populations, frequently occurring within a cancerous field induced by ultraviolet radiation. Since it cannot be predicted, which lesion will progress to cSCC and when treatment is usually recommended. The diagnosis of AK and field cancerization is made by clinical examination. Dermatoscopy, confocal microscopy, optical coherence tomography or line-field confocal-OCT can help in the differential diagnosis of AK and other skin neoplasms. A biopsy is indicated in clinically and/or dermatoscopically suspicious and/or treatment-refractory lesions. The choice of treatment depends on patients' and lesion characteristics. For single non-hyperkeratotic lesions, the treatment can be started upon patient's request with destructive treatments or topical treatments. For multiple lesions, field cancerization treatment is advised with topical treatments and photodynamic therapy. Preventive measures such as sun protection, self-examination and repeated field cancerization treatments of previously affected skin areas in high-risk patients are advised.

Optical coherence tomography for diagnosing recurrent or residual basal cell carcinoma after topical treatment: A diagnostic cohort study.

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.

Optical coherence tomography versus punch biopsy for diagnosis of basal cell carcinoma: a multicentre, randomised, non-inferiority trial.

BACKGROUND: Punch biopsy is the gold standard for diagnosis and subtyping of basal cell carcinoma. The aim of this study was to assess whether use of optical coherence tomography (OCT), a non-invasive imaging tool, might avoid the need for biopsy. METHODS: In a multicentre, randomised, non-inferiority trial, patients (aged ≥18 years) with an indication for biopsy of a suspected basal cell carcinoma outside the H-zone (high-risk zone) of the face were randomly assigned (1:1) to receive either OCT or punch biopsy (regular care) via a web-based randomisation system. Patients were enrolled from three participating centres in the Netherlands: Maastricht University Medical Centre+, Catharina Hospital Eindhoven, and Zuyderland Medical Centre Heerlen. Stratification factors for randomisation were participating centre and the grade of clinical basal cell carcinoma suspicion (high vs low). The primary endpoint was the proportion of patients free from a recurrent or residual lesion (malignant or premalignant) 12 months after treatment. Modified intention-to-treat and per-protocol analyses were conducted, with a predefined non-inferiority margin of -10%. This trial is registered with ClinicalTrials.gov number, NCT03848078, and is complete. FINDINGS: Between Feb 25, 2019, and Sept 2, 2020, 598 patients were enrolled and randomly assigned to either the regular care group (n=299) or the OCT group (n=299). Data on the primary endpoint were available in 553 patients (n=268 in the regular care group, n=285 in the OCT group). After median follow-up of 12·7 months (IQR 11·2-14·1) in the OCT group and 12·6 months (10·8-14·3) in the regular care group, 253 (94%) of 268 patients in the OCT group and 266 (93%) of 285 patients in the regular care group were free from recurrent or residual lesions (malignant or pre-malignant) 12 months after treatment. According to our modified intention-to-treat analysis, the absolute difference (OCT vs regular care) was 1·07% (95% CI -2·93 to 5·06; one-sided p=0·30), with the lower limit of the 95% CI not exceeding the predefined non-inferiority margin of -10%. Per-protocol analyses led to proportions free from a residual or recurrent lesion (premalignant or malignant) of 95% (250 of 263) in the OCT group and 94% (262 of 278) in the regular care group, and an absolute difference of 0·81% (95% CI -2·98 to 4·60; one-sided p=0·34). INTERPRETATION: OCT-guided diagnosis and treatment of basal cell carcinoma is non-inferior to regular care punch biopsy. Implementation of OCT for diagnosis of basal cell carcinoma could reduce the number of consultations and invasive procedures. FUNDING: The Netherlands Organization for Health Research and Development and Maurits en Anna de Kock Stichting.

Randomized Trial of Four Treatment Approaches for Actinic Keratosis.

BACKGROUND: Actinic keratosis is the most frequent premalignant skin disease in the white population. In current guidelines, no clear recommendations are made about which treatment is preferred. METHODS: We investigated the effectiveness of four frequently used field-directed treatments (for multiple lesions in a continuous area). Patients with a clinical diagnosis of five or more actinic keratosis lesions on the head, involving one continuous area of 25 to 100 cm2, were enrolled at four Dutch hospitals. Patients were randomly assigned to treatment with 5% fluorouracil cream, 5% imiquimod cream, methyl aminolevulinate photodynamic therapy (MAL-PDT), or 0.015% ingenol mebutate gel. The primary outcome was the proportion of patients with a reduction of 75% or more in the number of actinic keratosis lesions from baseline to 12 months after the end of treatment. Both a modified intention-to-treat analysis and a per-protocol analysis were performed. RESULTS: A total of 624 patients were included from November 2014 through March 2017. At 12 months after the end of treatment, the cumulative probability of remaining free from treatment failure was significantly higher among patients who received fluorouracil (74.7%; 95% confidence interval [CI], 66.8 to 81.0) than among those who received imiquimod (53.9%; 95% CI, 45.4 to 61.6), MAL-PDT (37.7%; 95% CI, 30.0 to 45.3), or ingenol mebutate (28.9%; 95% CI, 21.8 to 36.3). As compared with fluorouracil, the hazard ratio for treatment failure was 2.03 (95% CI, 1.36 to 3.04) with imiquimod, 2.73 (95% CI, 1.87 to 3.99) with MAL-PDT, and 3.33 (95% CI, 2.29 to 4.85) with ingenol mebutate (P≤0.001 for all comparisons). No unexpected toxic effects were documented. CONCLUSIONS: At 12 months after the end of treatment in patients with multiple actinic keratosis lesions on the head, 5% fluorouracil cream was the most effective of four field-directed treatments. (Funded by the Netherlands Organization for Health Research and Development; ClinicalTrials.gov number, NCT02281682.).

Long-Term Efficacy of Photodynamic Therapy with Fractionated 5-Aminolevulinic Acid 20% versus Conventional Two-Stage Topical Methyl Aminolevulinate for Superficial Basal-Cell Carcinoma.

BACKGROUND: Photodynamic therapy (PDT) is a noninvasive treatment for patients with superficial basal-cell carcinoma (sBCC). The efficacy of PDT may vary with different photosensitizers and treatment schedules. OBJECTIVE: Our objective was to evaluate whether fractionated 5-aminolevulinic acid 20% (ALA)-PDT is superior to conventional two-stage methyl aminolevulinate (MAL)-PDT for sBCC. METHODS: We present the 5 years results of a single-blind, randomized, multicenter trial. 162 patients with a histologically confirmed primary sBCC were randomized to fractionated ALA-PDT or MAL-PDT. RESULTS: The 5-year tumor-free survival rate was 70.7% (95% CI 58.2-80.1%) for ALA-PDT and 76.5% (95% CI 64.4-85.0%) for MAL-PDT. In the first 3 years, there was no significant difference in risk of treatment failure (HR = 1.53, p = 0.283), but in the long-term, the risk of recurrence was significantly lower following MAL-PDT compared to ALA-PDT (HR = 0.125, p = 0.049). As judged by patients, the esthetic result was good-excellent in 96.8% (61/63) and 94.4% (56/59) of patients treated with ALA-PDT and MAL-PDT, respectively (p = 0.631). CONCLUSION: The long-term efficacy is significantly higher for conventional two-stage MAL-PDT than for fractionated ALA-PDT, whereas there was no significant difference in esthetic outcome between the treatments at 5 years after treatment. These results indicate that fractionated ALA-PDT offers no benefit over conventional two-stage MAL-PDT.

Update on Hedgehog Pathway Inhibitor Therapy for Patients with Basal Cell Naevus Syndrome or High-frequency Basal Cell Carcinoma.

Some patients with basal cell carcinoma develop a large number of basal cell carcinomas during their lives. The most common underlying genetic disease that causes multiple basal cell carcinomas is basal cell naevus syndrome. Basal cell naevus syndrome is caused by a germline mutation in patched-1 (PTCH1), a tumour suppressor gene of the hedgehog signalling pathway. However, in a significant portion of patients with multiple basal cell carcinomas, no underlying genetic cause is found. Nevertheless, these patients can experience a treatment burden comparable to that of patients with basal cell naevus syndrome. They are referred to as high-frequency basal cell carcinoma patients. Hedgehog pathway inhibitors were the first group of targeted therapy for basal cell carcinomas. This study reviews the literature on hedgehog pathway inhibitor therapy for patients with basal cell naevus syndrome and high-frequency basal cell carcinoma, to provide an overview on efficacy, safety, dosing regimens, tumour resistance and reoccurrence, and health-related quality of life.

Eight years of experience with vismodegib for advanced and multiple basal cell carcinoma patients in the Netherlands: a retrospective cohort study.

BACKGROUND: Vismodegib has been used for the treatment of locally advanced basal cell carcinoma (laBCC) and metastatic BCC (mBCC) since 2011. Most efficacy and safety data are provided by clinical trials. This study evaluates the effectiveness of vismodegib for the treatment of laBCC, mBCC and basal cell nevus syndrome (BCNS) patients, and the tumour characteristics associated with a higher probability of achieving a complete response in the Netherlands. METHODS: A retrospective cohort study that included all patients ≥18 years with histologically proven basal cell carcinoma that received ≥1 dose of vismodegib between July 2011 and September 2019 in the Netherlands. RESULTS: In total, 48 laBCC, 11 mBCC and 19 BCNS patients were included. Median progression-free survival was 10.3 months (95% confidence interval (CI), 7.5-22.6) for laBCC, 11.7 (95% CI, 5.2-17.5) for mBCC and 19.1 (95% CI, 7.4-20.2) for BCNS. Larger laBCCs were associated with a lower probability of complete response (hazard ratio (HR) 0.77 per increase in cm, p = 0.02). Of all BCNS patients, 63% received ≥2 treatment sequences with vismodegib; all achieved partial responses. CONCLUSIONS: Half of the aBCC patients progress within 1 year after the start of vismodegib treatment. More research is needed to investigate other treatment strategies after vismodegib progression and to evaluate long-term effects of repetitive vismodegib treatment.

Molecular testing in metastatic basal cell carcinoma.

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.

Diagnostic Value of Optical Coherence Tomography Image Features for Diagnosis of Basal Cell Carcinoma.

Optical coherence tomography (OCT) is a non-invasive diagnostic method. Numerous morphological OCT features have been described for diagnosis of basal cell carcinoma (BCC). The aim of this study is to evaluate the diagnostic value of established OCT features and to explore whether the use of a small set of OCT features enables accurate discrimination between BCC and non-BCC lesions and between BCC subtypes. For each lesion, the presence or absence of specific OCT features was recorded. Histopathology was used as a gold standard. Diagnostic parameters were calculated for each OCT feature, and multivariate logistic regression analyses were performed to evaluate the loss in discriminative ability when using a small subset of OCT features instead of all features that are characteristic for BCC according to the literature. The results show that the use of a limited number of OCT features allows for good discrimination of superficial BCC from non-superficial BCC and non-BCC lesions. The prevalence of BCC was 75.3% (225/299) and the proposed diagnostic algorithm enabled detection of 97.8% of BCC lesions (220/225). Subtyping without the need for biopsy was possible in 132 of 299 patients (44%), with a predictive value for presence of superficial BCC of 84.3% vs 98.8% for presence of non-superficial BCC.

Topical Application of Glycerol Increases Penetration Depth of Optical Coherence Tomography in Diagnosis of Basal Cell Carcinoma.

Optical coherence tomography is a non-invasive imaging technique that enables high-resolution in vivo imaging of skin. Although optical coherence tomography is promising for diagnosing basal cell carcinoma, its limited penetration depth may impede basal cell carcinoma subtyping. This study evaluated whether topical application of glycerol can increase penetration depth and improve the image quality and visibility of characteristic features of basal cell carcinoma. A total of 61 patients with a total of 72 basal cell carcinomas were included. Optical coherence tomography scans were obtained before and after application of an 85% glyce-rol solution. The mean penetration depth of each optical coherence tomography scan was acquired by automatically tracing both skin surface and the point of signal loss using a custom-made MATLAB program. Mean ± standard deviation penetration depth increased from 883 ± 108 to 904 ± 88 µm before and after glycerol application, respectively (p = 0.005). Topical application of glycerol leads to a significant 2.4% increase in penetration depth. However, no significant differences in image quality and visibility of basal cell carcinoma features were found.

Surgery versus combined treatment with curettage and imiquimod for nodular basal cell carcinoma: One-year results of a noninferiority, randomized, controlled trial.

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.

Cumulative Sum Analysis for the Learning Curve of Optical Coherence Tomography Assisted Diagnosis of Basal Cell Carcinoma.

The amount of training needed to correctly interpret optical coherence tomography scans of the skin is undefined. The aim of this study was to illustrate how cumulative sum charts can be used to determine how many optical coherence tomography scans novice assessors should evaluate in order to obtain competence in diagnosing basal cell carcinoma. Four hundred lesions suspected for non-melanoma skin cancer were evaluated by optical coherence tomography in combination with clinical photographs, using a 5-point confidence scale. The diagnostic error rate (sum of false-negative and false-positive optical coherence tomography results/total number of cases) was used to evaluate performance, with histopathological diagnosis as the reference standard. Acceptable and unacceptable error rates were set at 16% and 25%, respectively. Adequate performance was reached after assessing 183-311 scans, dependent on the cut-off for a positive test result. In conclusion, cumulative sum analysis is useful to monitor the progress of optical coherence tomography trainees. The caseload necessary for training is substantial.

Histologic subtype of treatment failures after noninvasive therapy for superficial basal cell carcinoma: An observational study.

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.

Trends in the Incidence of Bowen Disease Based on a Single-Center Study in the Netherlands.

BACKGROUND: Incidence trends of nonmelanoma skin cancer show an increase. Few data have been published about the incidence of Bowen disease (BD). Three previous studies, conducted more than 15 years ago in North America, found large variation in incidence rates in Caucasians, and trends over longer periods have never been studied. OBJECTIVE: To estimate the incidence of BD in a Caucasian population in Northern Europe (Maastricht, the Netherlands) between 2003 and 2013. METHODS: Primary and histologically confirmed BD, diagnosed in Maastricht, the Netherlands, in the years 2003, 2008, and 2013, was retrieved from a pathology database. Age-standardized and sex-specific incidence rates per 100,000 inhabitants were calculated by using the age distribution of the European standard population of 2013. RESULTS: A statistically significant increase in the annual age-standardized incidence rates per 100,000 people was found from 8.1 (95% confidence interval [CI] 3.7-12.5) in 2003 to 68.9 (95% CI 57.2-80.7) in 2013 (p < .001). For women, there was an increase from 7.7/100,000 (95% CI 2.0-13.4) in 2003 to 76.8/100,000 (95% CI 60.2-93.5) in 2013, respectively (p < .001). An increase from 8.8/100,000 (95% CI 1.8-15.9) in 2003 to 59.2/100,000 men (95% CI 42.8-75.6) in 2013 (p < .001) was found. CONCLUSION: These findings suggest an increase in the annual age-standardized incidence rates in BD.

PTCH1 isoform 1b is the major transcript in the development of basal cell nevus syndrome.

Basal cell nevus syndrome (BCNS) is an autosomal dominant disorder most commonly caused by a germline mutation in the PTCH1 gene. PTCH1 is known to have different isoforms with different functional properties and expression patterns among tissues. We detected a novel, pathogenic de novo mutation in PTCH1 isoform 1b (c.114delG) in a BCNS patient. Furthermore, we elucidated the specific expression pattern of PTCH1 isoforms in normal skin, BCC and peripheral blood by studying expression of different PTCH1 isoforms. Human skin showed expression of isoforms 1b and 1d, while peripheral blood additionally showed 1a and 1e expression. BCCs showed expression of all isoforms. Here we report a patient with a novel, isoform 1b specific mutation in PTCH1 and thereby distinguish PTCH1 isoform 1b as the major transcript in the development of BCNS.

Risk Factors for Surgical Site Infections in Dermatological Surgery.

Current literature on risk factors for surgical site infection (SSI) in dermatological surgery in the absence of antibiotic prophylaxis is limited. The aim of this study was to retrospectively evaluate patients presenting for dermatological surgery. A total of 1,977 procedures were reviewed. SSI was clinically suspected in 79 (4.0%) patients and confirmed by culture in 38 (1.9%). Using the strictest definition of SSI (clinical symptoms with positive culture) significantly higher risk of SSI was found for location on the ear (odds ratio (OR) 6.03, 95% confidence interval (95% CI) 2.12-17.15), larger defects (OR 1.08 per cm2 increase, 95% CI 1.03-1.14), closure with flaps (OR 6.35, 95% CI 1.33-30.28) and secondary intention (OR 3.01, 95% CI 1.11-8.13). These characteristics were also associated with higher risk of clinically suspected SSI regardless of culture results with slightly lower ORs. In conclusion, the risk of acquiring a SSI is increased in surgeries performed on the ear, in larger wounds and in defects closed with flaps or healed by secondary intention.