Standardizing Retrospective Observational Research in Cutaneous Squamous Cell Carcinoma: Expert Panel Guidelines from ITSCC.

Importance: Cutaneous squamous cell carcinoma (CSCC) is the second most common malignant disease in the US. Although it typically carries a good prognosis, a subset of CSCCs are highly aggressive, carrying regional and distant metastatic potential. Due to its high incidence, this aggressive subset is responsible for considerable mortality, with an overall annual mortality estimated to equal or even surpass melanoma. Despite this morbidity, CSCC is excluded from national cancer registries, making it difficult to study its epidemiology and outcomes. Therefore, the bulk of the CSCC literature is composed of single-center and multi-institutional retrospective cohort analyses. Given variations in reporting measures and analyses in these studies, interpretability between studies and the ability to pool results are limited. Objective: To define standardized reporting measures for retrospective CSCC studies. Findings: An expert panel was convened to determine standardized guidelines for recording and analyzing retrospective CSCC data. A total of 13 dermatologists and dermatologic surgeons with more than 5 years of posttraining experience and considerable experience with performing CSCC outcomes research were recruited to the panel. Consensus recommendations were achieved for CSCC retrospective study reporting measures, definitions, and analyses. Conclusions and Relevance: The recommendations in this report present the potential to standardize future CSCC retrospective studies. With such standardization, future work may have greater interstudy interpretability and allow for pooled analyses.

Factors affecting outcomes of second intent healing of nasal defects after Mohs micrographic surgery.

Reconstruction of nasal defects secondary to Mohs micrographic surgery (MMS) presents particular challenges related to the complex topography, skin quality, tissue laxity, and functional and aesthetic concerns of the region. Factors affecting outcomes resulting from second intent healing (SIH) on the nose have not been well described. The purpose of the study was to identify factors impacting outcomes of SIH for nasal tumors following MMS. Retrospective analysis was performed of all nasal lesions treated with MMS followed by SIH from a single surgical center over a 1.5-year period. Ninety-six cases were included. Chart review was performed, and data were collected including age, gender, nasal site, tumor type, defect size, depth, and number of MMS stages. Pre- and post-operative follow-up photographs were available for all cases. All five authors evaluated the photographs using the modified Manchester scar scale. Analysis was then conducted to identify features associated with good outcomes. Of the 96 tumors, 39 lesions (40.6%) were located on the nasal tip (including supratip), 32 (33.3%) on the ala/alar groove, 17 (17.7%) on the sidewall, and 8 (8.3%) on the dorsum. The average defect size was 0.83 cm2 (diameter of 1.06 cm ± 0.4). Defect diameter and defect depth were the factors that significantly impacted scar outcome (p < 0.001) in multivariate analysis. No significant functional deficits were reported. This retrospective study suggests that nasal defects with area less than 0.83 cm2 (or 1.06 cm diameter) and depth of defect not extending beyond the superficial fat healed well by SIH regardless of location on the nose.

Consensus-Based Recommendations on the Prevention of Squamous Cell Carcinoma in Solid Organ Transplant Recipients: A Delphi Consensus Statement.

IMPORTANCE: There is a paucity of evidence to guide physicians regarding prevention strategies for cutaneous squamous cell carcinoma (CSCC) in solid organ transplant recipients (SOTRs). OBJECTIVE: To examine the development and results of a Delphi process initiated to identify consensus-based medical management recommendations for prevention of CSCC in SOTRs. EVIDENCE REVIEW: Dermatologists with more than 5 years' experience treating SOTRs were invited to participate. A novel actinic damage and skin cancer index (AD-SCI), consisting of 6 ordinal stages corresponding to an increasing burden of actinic damage and CSCC, was used to guide survey design. Three sequential web-based surveys were administered from January 1, 2019, to December 31, 2020. Pursuant to Delphi principles, respondents thoroughly reviewed all peer responses between rounds. Supplemental questions were also asked to better understand panelists' rationale for their responses. FINDINGS: The Delphi panel comprised 48 dermatologists. Respondents represented 13 countries, with 27 (56%) from the US. Twenty-nine respondents (60%) were Mohs surgeons. Consensus was reached with 80% or higher concordance among respondents when presented with a statement, question, or management strategy pertaining to prevention of CSCC in SOTRs. A near-consensus category of 70% to less than 80% concordance was also defined. The AD-SCI stage-based recommendations were established if consensus or near-consensus was achieved. The panel was able to make recommendations for 5 of 6 AD-SCI stages. Key recommendations include the following: cryotherapy for scattered actinic keratosis (AK); field therapy for AK when grouped in 1 anatomical area, unless AKs are thick in which case field therapy and cryotherapy were recommended; combination lesion directed and field therapy with fluorouracil for field cancerized skin; and initiation of acitretin therapy and discussion of immunosuppression reduction or modification for patients who develop multiple skin cancers at a high rate (10 CSCCs per year) or develop high-risk CSCC (defined by a tumor with approximately ≥20% risk of nodal metastasis). No consensus recommendation was achieved for SOTRs with a first low risk CSCC. CONCLUSIONS AND RELEVANCE: Physicians may consider implementation of panel recommendations for prevention of CSCC in SOTRs while awaiting high-level-of-evidence data. Additional clinical trials are needed in areas where consensus was not reached.

A Histopathologic Scoring System for Perineural Invasion Correlates With Adverse Outcomes in Patients With Cutaneous Squamous Cell Carcinoma.

BACKGROUND: Perineural invasion (PNI) is a known risk factor for recurrence, metastasis, and death in cutaneous squamous cell carcinoma (cSCC). Current staging systems include PNI, but none define its extent or severity. OBJECTIVE: To identify histopathologic features of cSCC with PNI that may be associated with adverse outcomes. MATERIALS AND METHODS: This is a retrospective cohort study that included 45 patients with cSCC and PNI treated with surgical excision. Histopathologic slides were analyzed for 5 features of PNI: largest affected nerve diameter, number of nerves affected, depth of nerve involvement, intra- versus extratumoral PNI, and focal versus circumferential PNI. RESULTS: The median largest affected nerve diameter was 0.13 mm, and the median number of nerve structures involved was 4. After a median follow-up time of 24 months, 6 patients developed adverse outcomes, including 2 local recurrences, 4 metastases, and 2 tumor-related deaths. Univariate logistic regression analysis revealed that nerve diameter and number of affected nerves were significantly associated with adverse outcome. A composite PNI score, calculated from 5 histopathologic features, was the strongest predictor of adverse outcome (p = .020). CONCLUSION: Histopathologic features of PNI can be quantified with a composite PNI score that is significantly associated with adverse outcomes in cSCC.

Dermatofibrosarcoma protuberans in pregnancy: a case series and review of the literature.

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous sarcoma, which has been reported in pregnancy. This case series reports the clinical and histopathological findings of DFSP in pregnancy. METHODS: Eighteen cases of DFSP, including six unreported cases and 12 cases from the literature, were identified. Age, anatomic location, tumor size, changes in tumor characteristics during pregnancy, histopathological features, and treatment were recorded. Follow-up data, when available, were noted. RESULTS: The average age of the cohort was 30.6 years (range 19-38). Ten tumors (55.6%) were located on the trunk, four (22.2%) on the head and neck, three (16.7%) on the extremities, and one (5.6%) in the genitalia. Most tumors demonstrated features of conventional DFSP (12/18, 66.7%), while the remaining were identified as DFSP with fibrosarcomatous (FS) change (3/18, 16.7%), atrophic DFSP (2/18, 11.1%), and myxoid DFSP (1/18, 5.6%). Treatment was reported in 17 cases, at least nine of which were treated postpartum. Ten patients were treated with excision, while seven underwent Mohs micrographic surgery. Three patients recurred on follow-up, one with local recurrence and two with distant metastasis. CONCLUSIONS: DFSP can undergo enlargement or change in size or color in pregnancy, possibly mediated by hormones. While the majority of cases in this series represented conventional DFSP, unusual clinical and histopathological variants were also present. Treatment in most cases can be safely delayed until after delivery, but recurrent or very large tumors may require treatment prepartum. Close monitoring for recurrence or metastasis is advised.

Association of Treatment Facility Characteristics With Overall Survival After Mohs Micrographic Surgery for T1a-T2a Invasive Melanoma.

Importance: Early-stage melanoma, among the most common cancers in the US, is typically treated with wide local excision. However, recent advances in immunohistochemistry have led to an increasing number of these cases being excised via Mohs micrographic surgery (MMS). Although studies of resections for other cancers have reported that facility-level factors are associated with patient outcomes, it is not yet established how these factors may affect outcomes for patients treated with Mohs micrographic surgery. Objective: To evaluate the association of treatment center academic affiliation and case volume with long-term patient survival after MMS for T1a-T2a invasive melanoma. Design, Setting, and Participants: In a retrospective cohort study, 4062 adults with nonmetastatic, T1a-T2a melanoma diagnosed from 2004 to 2014 and treated with MMS in the National Cancer Database (NCDB) were identified. The NCDB includes all reportable cases from Commission on Cancer-accredited facilities and is estimated to capture approximately 50% of all incident melanomas in the US. Multivariable survival analyses were conducted using Cox proportional hazards models. Data analysis was conducted from February 27 to August 18, 2020. Exposures: Treatment facility characteristics. Main Outcomes and Measures: Overall survival. Results: The study population included 4062 patients (2213 [54.5%] men; median [SD] age, 60 [16.3] years) treated at 462 centers. Sixty-two centers were top decile-volume facilities (TDVFs), which treated 1757 patients (61.9%). Most TDVFs were academic institutions (37 of 62 [59.7%]). On multivariable analysis, treatment at an academic center was associated with a nearly 30% reduction in hazard of death (hazard ratio, 0.730; 95% CI, 0.596-0.895). In a separate analysis, treatment at TDVFs was also associated with improved survival (hazard ratio, 0.795; 95% CI, 0.648-0.977). Conclusions and Relevance: In this cohort study, treatment of patients with T1a-T2a invasive melanoma excised with MMS at academic and top decile-volume (≥8 cases per year) facilities was associated with improved long-term survival compared with those excised by MMS at nonacademic and low-volume facilities. Identification and protocolization of the practices of these facilities may help to reduce survival differences between centers.

Ultradeep sequencing differentiates patterns of skin clonal mutations associated with sun-exposure status and skin cancer burden.

In ultraviolet (UV) radiation-exposed skin, mutations fuel clonal cell growth. The relationship between UV exposure and the accumulation of clonal mutations (CMs) and the correlation between CMs and skin cancer risk are largely unexplored. We characterized 450 individual-matched sun-exposed (SE) and non-SE (NE) normal human skin samples. The number and relative contribution of CMs were significantly different between SE and NE areas. Furthermore, we identified hotspots in TP53, NOTCH1, and GRM3 where mutations were significantly associated with UV exposure. In the normal skin from patients with cutaneous squamous cell carcinoma, we found that the cancer burden was associated with the UV-induced mutations, with the difference mostly conferred by the low-frequency CMs. These findings provide previously unknown information on UV's carcinogenic effect and pave the road for future development of quantitative assessment of subclinical UV damage and skin cancer risk.

Predicting outcomes following second intent healing of periocular surgical defects.

BACKGROUND: Traditionally, second intent healing (SIH) in the periocular region is reserved for small and/or concave defects, particularly those located on the medial canthus. AIM: The purpose of this study was to identify factors impacting outcomes of SIH for periocular tumors following Mohs micrographic surgery (MMS). METHODS: Retrospective analysis was performed of all periocular lesions treated with MMS followed by SIH from a single academic surgical center over a 5-year period. Data regarding tumor characteristics and follow-up was recorded. The modified Manchester scale was utilized to evaluate scar outcomes. RESULTS: Of the 39 tumors included, 14 (35.9%) were located on the lower eyelid, 12 (30.8%) on the upper eyelid, 6 (15.4%) on the lateral canthus, and 7 (17.9%) on the medial canthus. Involvement of the eyelid margin was seen in 11 (28.2%) of cases. The average defect diameter and area were 1.3 cm and 1.04 cm-squared. Twenty-three cases (59.0%) healed with optimal results. Larger defects were significantly associated with poorer outcomes of SIH (odds ratio 0.205, p = 0.017 by multivariate analysis). Anatomic location, involvement of the lid margin, age, and follow-up interval were not significant factors; however, medial canthus defects were least likely to heal with optimal results. On average, medial canthal lesions were larger in size (mean diameter 1.76 cm, mean area 1.97 cm-squared). CONCLUSIONS: This retrospective study suggests that periorbital defects in all locations with area less than 1.04 cm2 heal well by SIH. In this cohort, larger lesions on the medial canthus healed with worse outcomes.

Photodynamic therapy for cutaneous squamous cell carcinoma in situ: Impact of anatomic location, tumor diameter, and incubation time on effectiveness.

BACKGROUND: Photodynamic therapy (PDT) has been reported as a treatment for cutaneous squamous cell carcinoma in situ (SCCis), but only limited data are available on the effectiveness of PDT with aminolevulinic acid (ALA-PDT). OBJECTIVE: To review the outcomes of SCCis treated with ALA-PDT and examine factors associated with response. METHODS: A retrospective review identified 58 patients with 68 primary SCCis lesions treated with ALA-PDT and blue light illumination. Patient demographics, lesion features, treatment details, clinical response, and subsequent recurrence were extracted from medical record reviews. RESULTS: On completion of PDT the initial complete response rate was 77.9% and was not associated with the number of PDT treatments. On multivariate analysis factors associated with response were location on the face, tumor diameter <2 cm, and longer ALA incubation time. Lesions treated with a maximum incubation time of <3 hours had a 53.3% response compared with 84.9% for longer incubation. Subsequent recurrence of SCCis was noted in 7 of 53 cases (13.2%) at a median time of 11.7 months. LIMITATIONS: This was a retrospective study performed at a single institution without systematic follow-up. CONCLUSIONS: ALA-PDT may be an effective treatment for selected cases of SCCis. Effectiveness is impacted by anatomic location, tumor diameter, and ALA incubation time.

Comparison of Survival After Mohs Micrographic Surgery vs Wide Margin Excision for Early-Stage Invasive Melanoma.

IMPORTANCE: Melanoma is among the most common malignant neoplasms in the United States, with 91 270 cases estimated to be diagnosed in 2018. Since 2012, Mohs micrographic surgery (MMS) has gained popularity in the treatment of melanoma in situ. Although current guidelines for invasive melanoma without nodal metastases recommend surgery with wide margin excision (WME), use of MMS for this disease has increased as well, particularly in early stages. How the survival outcomes after each procedure compare with one another for early-stage invasive melanoma is unknown to date. OBJECTIVE: To evaluate overall survival of patients with stage I melanoma defined by the American Joint Committee on Cancer Cancer Staging Manual, 8th edition (AJCC-8) after MMS vs traditional WME. DESIGN, SETTING, AND ANALYSIS: This retrospective cohort study includes all patients with AJCC-8 stage I melanoma who underwent MMS or WME in the National Cancer Database with a diagnosis from January 1, 2004, through December 31, 2014. The National Cancer Database includes all reportable cases from Commission on Cancer-accredited facilities and represents approximately 50% of all newly diagnosed melanoma cases in the United States. Data were analyzed from November 13, 2018, through June 9, 2019. EXPOSURES: MMS vs WME. MAIN OUTCOMES AND MEASURES: Overall survival evaluated using multivariable Cox proportional hazards regression analysis. RESULTS: A total of 70 319 eligible patients (52.3% male and 47.7% female; median [SD] age, 57.0 [16.2] years) were identified, including 67 085 treated with WME and 3234 treated with MMS. Multivariable Cox proportional hazards regression survival analysis controlling for clinical and tumor factors revealed that treatment with MMS was associated with a modest improvement in overall survival relative to WME (hazard ratio [HR], 0.86; 95% CI, 0.76-0.97). Propensity score-matched analysis of cohorts of patients treated with MMS vs WME also found modestly improved survival for those treated with MMS (HR, 0.82; 95% CI, 0.68-0.98). Academic facilities were more likely to use MMS than nonacademic facilities (odds ratio, 2.03; 95% CI, 1.88-2.18). CONCLUSIONS AND RELEVANCE: These findings suggest that Mohs surgery may provide an alternative approach to traditional WME for appropriately selected cases of AJCC-8 stage I melanoma without compromising patient survival.

Comparison of Mohs Surgery and Surgical Excision in the Treatment of Localized Sebaceous Carcinoma.

BACKGROUND: It remains controversial if Mohs surgery is superior to surgical excision in treating localized sebaceous carcinoma. OBJECTIVE: To compare Mohs surgery and surgical excision for treating patients with localized sebaceous carcinoma. MATERIALS AND METHODS: The US National Cancer Database was used to identify patients with histologically confirmed Stage 0 to 2 sebaceous carcinoma from 2004 to 2014. Clinicopathologic and socioeconomic factors were compared between treatment groups using the chi-square test. Overall survival (OS) was evaluated by log-rank test, multivariable Cox proportional hazard regression, and propensity score-matched analysis. Relative survival analyses compared with age- and sex-matched US population were performed. RESULTS: Of 1,265 patients, 234 received Mohs surgery and 1,031 received surgical excision. Mohs surgery had a higher rate of negative margin (p = .004). On multivariate Cox regression analysis, Mohs surgery was associated with longer OS than surgical excision (HR: 0.703, 95% CI: 0.496-0.995, p = .047). The survival benefit of Mohs surgery persisted on relative survival analysis and propensity score-matched analysis (p = .0385), after matching the 2 groups on patient and disease characteristics. CONCLUSION: Patients who received Mohs surgery had significantly longer OS when compared with those who received surgical excision. Prospective clinical trials comparing these treatment paradigms are warranted.

Recent advances in field cancerization and management of multiple cutaneous squamous cell carcinomas.

Cutaneous squamous cell carcinoma (SCC) is among the most common cancers in humans, and many patients with SCC will develop multiple tumors within their lifetime. The field cancerization concept, originally proposed over 60 years ago, hypothesized that multiple primary cancers may arise simultaneously and coexist with subclinical precursor lesions within a defined field. Genetic sequencing of SCC and precursor lesions has identified what may be the earliest clonal proliferations in SCC development and confirmed that field cancerization in the skin is mediated by ultraviolet radiation. For patients with multiple SCCs and severe actinic damage, treatment of precursor lesions within a cancerized field can decrease the risk of subsequent cancer development. Sunblock is an effective intervention for field cancerization, even in patients with established disease. There is now direct evidence that field therapy with topical 5-fluorouracil is effective in reducing the incidence of subsequent SCC, and there is indirect evidence suggesting that topical imiquimod, topical ingenol mebutate, and photodynamic therapy are similarly effective. There is limited direct evidence to show that systemic acitretin or nicotinamide can decrease incident SCC in patients with field cancerization. In this review, an approach to the management of patients with multiple SCCs and field cancerization is presented along with the rationale to support field-directed therapy.