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Background Actinic keratoses (AK) are rough scaly patches that arise on chronically ultraviolet-exposed skin and can progress to keratinocyte carcinoma. Treatment options for AK include topical medications, photodynamic therapy, cryosurgery, and laser ablation. Objective This executive summary provides a synopsis of the 18 evidence-based recommendations for the treatment of AK detailed in the Guidelines of Care for the Management of Actinic Keratosis. Methods A multidisciplinary workgroup conducted a systematic review to address 5 clinical questions on the management of AKs and applied the Grading of Recommendations Assessment, Development and Evaluation approach for assessing the certainty of the evidence and formulating and grading clinical recommendations. Graded recommendations were voted on to achieve consensus. Results Analysis of the evidence resulted in 18 recommendations, suggesting there are several effective treatments available for AK. Limitations The analysis informing the recommendations was based on the best available evidence at the time it was conducted. The results of future studies may necessitate a revision of current recommendations. Conclusions Strong recommendations are presented for using ultraviolet protection, topical imiquimod, topical 5-fluorouracil, and cryosurgery. Conditional recommendations are presented for the use of photodynamic therapy and diclofenac for the treatment of AK, both individually and as part of combination therapy regimens.

Background Actinic keratoses (AK) are rough scaly patches that arise on chronically ultraviolet-exposed skin and can progress to keratinocyte carcinoma. Objective This analysis examined the literature related to the management of AK to provide evidence-based recommendations for treatment. Grading, histologic classification, natural history, risk of progression, and dermatologic surveillance of AKs are also discussed. Methods A multidisciplinary Work Group conducted a systematic review to address 5 clinical questions on the management of AKs and applied the Grading of Recommendations, Assessment, Development, and Evaluation approach for assessing the certainty of the evidence and formulating and grading clinical recommendations. Graded recommendations were voted on to achieve consensus. Results Analysis of the evidence resulted in 18 recommendations. Limitations This analysis is based on the best available evidence at the time it was conducted. The pragmatic decision to limit the literature review to English language randomized trials may have excluded data published in other languages or limited identification of relevant long-term follow-up data. Conclusions Strong recommendations are made for using ultraviolet protection, topical imiquimod, topical 5-fluorouracil, and cryosurgery. Conditional recommendations are made for the use of photodynamic therapy and diclofenac for the treatment of AK, both individually and as part of combination therapy regimens.

Recent advances in artificial intelligence (AI) in dermatology have demonstrated the potential to improve the accuracy of skin cancer detection. These capabilities may augment current diagnostic processes and improve the approach to the management of skin cancer. To explain this technology, we discuss fundamental terminology, potential benefits, and limitations of AI, and commercial applications relevant to dermatologists. A clear understanding of the technology may help to reduce physician concerns about AI and promote its use in the clinical setting. Ultimately, the development and validation of AI technologies, their approval by regulatory agencies, and widespread adoption by dermatologists and other clinicians may enhance patient care. Technology-augmented detection of skin cancer has the potential to improve quality of life, reduce health care costs by reducing unnecessary procedures, and promote greater access to high-quality skin assessment. Dermatologists play a critical role in the responsible development and deployment of AI capabilities applied to skin cancer.

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.

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.

Verrucous candidiasis (VC) of the oral mucosa can present with pseudocarcinomatous hyperplasia, often confused with squamous cell carcinoma (SCC). Here, we describe a case of florid VC secondary to fluconazole-resistant Candida albicans and report an initial significant response to oral posaconazole and surgical excisions. However, after 12 months of close follow-up, the patient's VC progressed to frank SCC, demonstrating the malignant potential of refractory VC cases.

Traditionally, second intent healing (SIH) in the periocular region is reserved for small and/or concave defects, particularly those located on the medial canthus. The purpose of this study was to identify factors impacting outcomes of SIH for periocular tumors following Mohs micrographic surgery (MMS). 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. 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). 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.

Skin cancer is the most prevalent cancer, and its assessment remains a challenge for physicians. This study reports the application of an optical sensing method, elastic scattering spectroscopy (ESS), coupled with a classifier that was developed with machine learning, to assist in the discrimination of skin lesions that are concerning for malignancy. The method requires no special skin preparation, is non-invasive, easy to administer with minimal training, and allows rapid lesion classification. This novel approach was tested for all common forms of skin cancer. ESS spectra from a total of 1307 lesions were analyzed in a multi-center, non-randomized clinical trial. The classification algorithm was developed on a 950-lesion training dataset, and its diagnostic performance was evaluated against a 357-lesion testing dataset that was independent of the training dataset. The observed sensitivity was 100% (14/14) for melanoma and 94% (105/112) for non-melanoma skin cancer. The overall observed specificity was 36% (84/231). ESS has potential, as an adjunctive assessment tool, to assist physicians to differentiate between common benign and malignant skin lesions.

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 cm

Traditionally, second intent healing (SIH) in the periocular region is reserved for small and/or concave defects, particularly those located on the medial canthus.The purpose of this study was to identify factors impacting outcomes of SIH for periocular tumors following Mohs micrographic surgery (MMS).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.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).This retrospective study suggests that periorbital defects in all locations with area less than 1.04 cm

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.

Background Well-differentiated neuroendocrine tumors (WDNETs) in skin include metastases from visceral primary sites and very uncommonly, primary cutaneous carcinoid tumors. Cutaneous WDNET may present a diagnostic challenge and in particular can be mistaken for a benign skin adnexal tumor. In contrast to cutaneous adnexal tumors, metastatic adenocarcinomas to the skin are cytokeratin 5/6 (CK5/6) and p63 negative in the majority of cases. It is unclear if failure to stain with CK5/6 and p63 would be helpful in differentiating WDNETs from cutaneous adnexal neoplasms. Methods We reviewed 10 cases of cutaneous WDNETs (8 cases of metastatic disease and 2 presumed primary carcinoid tumors of the skin) and performed immunohistochemical stains for CK5/6 and p63 on all cases. Results All 10 cases were negative with both CK5/6 and p63. Conclusion Negative staining for CK5/6 and p63 can be helpful to distinguish WDNETs from cutaneous adnexal neoplasms. It is important to consider WDNETs in the differential diagnosis of cutaneous adnexal neoplasms as low-grade tumors may be the first sign of aggressive metastatic disease.

Introduction Basal cell carcinoma (BCC) is the most common malignancy in the US. Body mass index (BMI) and height have been associated with a variety of cancer types, yet the evidence regarding BCC is limited. Therefore, we evaluated BMI and height in relation to early-onset BCC (under age 40) and explored the potential role of ultraviolet (UV) radiation exposure and estrogen-related exposures in the BMI-BCC relationship. Methods BCC cases (n = 377) were identified through a central dermatopathology facility in Connecticut. Control subjects (n = 389) with benign skin conditions were randomly sampled from the same database and frequency matched to cases on age (median = 36, interquartile range 33–39), gender, and biopsy site. Participants reported weight (usual adult and at age 18), adult height, sociodemographic, phenotypic, and medical characteristics, and prior UV exposures. We calculated multivariate odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression models. Results Adult BMI was inversely associated with early-onset BCC (obese vs. normal OR = 0.43, 95% CI = 0.26–0.71). A similar inverse association was present for BMI at age 18 (OR = 0.54, 95% CI = 0.34–0.85). Excluding UV exposures from the BMI models and including estrogen-related exposures among women only did not alter the association between BMI and BCC, indicating limited mediation or confounding. We did not observe an association between adult height and BCC (OR per cm = 1.00, 95% CI = 0.98–1.02). Conclusions We found a significant inverse association between BMI and early-onset BCC, but no association between height and BCC. This association was not explained by UV exposures or estrogen-related exposures in women.

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).To review the outcomes of SCCis treated with ALA-PDT and examine factors associated with response.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.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 diameter2 cm, and longer ALA incubation time. Lesions treated with a maximum incubation time of3 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.This was a retrospective study performed at a single institution without systematic follow-up.ALA-PDT may be an effective treatment for selected cases of SCCis. Effectiveness is impacted by anatomic location, tumor diameter, and ALA incubation time.

Recent studies suggest cutaneous squamous cell carcinomas (SCCs) of the leg, particularly those occurring multiply in sun exposed skin of nonimmunosuppressed women, are a distinct clinical subtype. There are few reports of the histopathologic features of this subtype. A retrospective chart review of 4 patients with multiple SCCs on the leg was performed and a total of 35 biopsies from the legs examined. Histopathologically, the tumors lacked adjacent actinic keratosis (AK) and often had adjacent basaloid retiform proliferations. Most lesions (all but one) were well differentiated and about 40% could be classified histopathologically as keratoacanthoma. Perineural invasion was absent in all but one case. Using the American Joint Committee on Cancer (AJCC) staging criteria for SCC, 21 tumors were Stage I, and 9 Stage II. During 7-10 years of follow-up, no recurrence or metastasis occurred. Patients with multiple SCCs on the lower extremities can have a range of histopathologic features, from keratoacanthoma-like to well-differentiated SCC.

Background The safety and tolerability of Flublok ® , a purified recombinant hemagglutinin seasonal influenza vaccine, was compared to AFLURIA ® in a randomized, blinded clinical trial in adults ≥50 years of age with attention to hypersensitivity reactions. Methods This blinded, randomized trial of healthy adults ≥50 years of age compared safety of Flublok vs. AFLURIA with respect to pre-specified possible hypersensitivity: “rash,” “urticaria,” “swelling” and “non-dependent edema;” solicited reactogenicity and unsolicited adverse events. Subject-reported outcomes were collected for 30 days after vaccination. All adverse event terms were reviewed by physicians blinded to vaccine group, who added other terms possibly reflecting hypersensitivity. Case records of subjects with possible hypersensitivity were adjudicated by independent experts blinded to treatment assignment to identify likely hypersensitivity reactions. Non-inferiority of the incidence of hypersensitivity in the two vaccine groups was pre-defined as an absolute difference with an upper bound of 2-sided 95% confidence limits ≤0.015. Results A total of 2640 subjects were enrolled, evenly split in age cohorts of 50–64 and ≥65 years. Fifty-two subjects reported at least one term possibly representing hypersensitivity, with a slight imbalance of 31 on Flublok and 21 on AFLURIA. The adjudicators determined that six and four subjects on Flublok and AFLURIA, respectively, likely met clinical criteria for hypersensitivity, yielding a difference in incidence between the two vaccine groups of 0.15% (upper bound of 2-sided 95% CI = 0.9%). Reactogenicity and overall adverse event profiles were similar across both vaccines. Conclusions Flublok was non-inferior to AFLURIA in adults ≥50 years of age with respect to expert-adjudicated events of likely hypersensitivity during 30 days following vaccination (Sponsored by Protein Sciences Corporation; ClinicalTrials.gov number NCT01825200 ).

p53 is considered the guardian of the genome and as such has numerous functions. The TP53 gene is the most commonly mutated gene in cancer, and yet the exact biological significance of such mutations remains unclear. There are at least 12 different isoforms of p53, and the complexity of the p53 pathway may be in part related to these isoforms. Prior research has often not teased out what isoforms of p53 are being studied, and there is evidence in the literature that p53 isoforms are expressed differently. In this paper, we document the staining pattern of p53β isoforms in the skin and correlate it with mutational status in a subgroup of squamous proliferations of the skin. p53β isoforms are present in the cytoplasm of the differentiated layer of the epidermis and hair follicles (granular layer, infundibular and isthmus–catagen). p53β isoforms are diffusely expressed within the cytoplasm of well-differentiated squamous tumours with tetramerisation (C-terminal) domain mutations in TP53. Our results lend support to p53β isoforms being a marker of differentiation in keratinocytes.

Importance The US Food and Drug Administration approves Class III medical devices via the premarket approval pathway, often requiring clinical data on safety and efficacy. Manufacturers can submit incremental device changes via supplemental applications, which are not subjected to such vetting measures and can cause understudied changes that lead to drift from a device’s original design. Objectives To characterize the postapproval changes to Class III dermatologic devices and to evaluate inconsistencies in the use of the premarket approval pathway. Design, Setting, and Participants This study was a cross-sectional retrospective cohort analysis of a public US Food and Drug Administration database for premarket approval of devices. Included were dermatologic devices approved by the US Food and Drug Administration between January 1, 1980, and November 1, 2016, through the premarket pathway for device approval. Main Outcomes and Measures Original devices were identified, and their supplements were characterized chronologically, by review track, and by modification category. Results The 27 dermatologic devices studied consisted of 14 injectables, 11 photodynamic therapies, a dermal replacement matrix, and a diagnostic imaging instrument. Supplemental applications are increasingly used: the data-requiring panel-track pathway was the least common approach (2.8% [16 of 562 supplements]), while the 30-day track, which does not require clinical data, was most frequently used (42.5% [239 of 562 supplements]). Four devices (14.8%) underwent low-risk recalls (Class II or Class III), and 10 devices (37.0%) were voluntarily withdrawn. Conclusions and Relevance As manufacturers make increasing use of supplemental applications, minor device changes may occur without supporting clinical data, which could pose a safety risk to patients.

The incidence of melanoma has steadily increased over the past 3 decades, with melanoma in situ comprising a disproportionately high percentage of the rising incidence. Our understanding of melanoma in situ has been shaped by epidemiologic and clinical studies. Central to a review of melanoma in situ is a focus on its epidemiology, pathology, biologic behavior, treatment, and clinical outcome, which may differ significantly from that of malignant melanoma. Part I of this continuing medical education article reviews the epidemiology, risk factors, and clinical features of melanoma in situ; part II covers the histopathology, treatment options, and clinical management.

Summary Background Previous epidemiological studies of overall alcohol intake and basal cell carcinoma (BCC) are inconsistent, with some evidence for differences by type of alcoholic beverage. While alcohol may enhance the carcinogenicity of ultraviolet (UV) radiation, this has not been evaluated in existing epidemiological studies. Objectives To evaluate alcohol intake in relation to early-onset BCC, and explore potential interactions with UV exposure. Methods Basal cell carcinoma cases (n = 380) and controls with benign skin conditions (n = 390) under 40 years of age were identified through Yale Dermatopathology. Participants provided information on lifetime alcohol intake, including type of beverage, during an in-person interview. Self-reported data on indoor tanning and outdoor sunbathing were used to categorize UV exposure. We calculated odds ratios (OR) and 95% confidence intervals (CIs) using unconditional multivariate logistic regression in the full sample and in women only. Results There was no statistically significant association between lifetime alcohol intake and early-onset BCC overall [above median intake vs. no regular alcohol intake (OR 1·10, 95% CI 0·69–1·73)] or in women only (OR 1·21, 95% CI 0·73–2·01). Similarly, intake of red wine, white wine, beer or spirits and mixed drinks was not associated with early-onset BCC. In exploratory analyses, we saw limited evidence for an interaction (Pinteraction = 0·003), with highest risk for high alcohol and high UV exposures, especially in women, but subgroup risk estimates had wide and overlapping CIs. Conclusions Overall, we did not observe any clear association between lifetime alcohol intake and early-onset BCC.

Background Some patients develop a disproportionate number of cutaneous squamous cell carcinomas (SCCs) on their lower extremity (LE). Objective We sought to characterize the clinical features, treatment, and outcome in patients who develop multiple LE SCCs. Methods We identified 22 patients with 4 or more biopsy-diagnosed LE SCCs during a 4.5-year study period. The location, size, treatment, and clinical outcome of each LE SCC were recorded. Results Of the 22 patients studied, 18 were female. Of the 360 SCCs our patients developed, 260 (72.2%) were on the LE. The incidence of SCCs in these patients was nearly 7 times greater than the incidence of basal cell carcinoma in the same patients. Limitations The number of patients is small and limits definitive conclusions about prevalence of SCCs on the LE in the general population. Conclusions LE SCCs are a distinct subset of cutaneous SCCs and may have distinctive clinical features and biologic behavior requiring additional study.

Background Women with multiple squamous cell carcinomas (SCCs) of the legs have a striking clinical phenotype. Numerous tumors can develop in a short period of time. Objective Because histopathologic findings can vary in women with multiple SCC lesions, from keratoacanthoma-like to well-differentiated SCC, we hypothesized that TP53 variants might shed light on the appropriate classification. Methods We sequenced TP53 in 30 SCCs from 6 women who had multiple SCCs on their legs during a 21-month time frame. Results Histopathologic analysis showed 16 of the 30 lesions did not have prominent cytologic atypia and were distinguished by having expanded follicle-like structures composed of large, glassy, eosinophilic keratinocytes; these lesions resembled keratoacanthoma and were categorized as keratoacanthoma-like squamous proliferations (KASPs). The 14 remaining tumors had more prominent cytologic atypia and remained classified as SCC. Twenty of 30 tumors (including the KASPs) from the 6 different patients lacked detectable TP53 mutations. Ten of the 14 tumors that remained classified as SCC had detectable TP53 mutations. Limitations This is a small series. Conclusion These findings suggest that some cutaneous squamous proliferations on the legs of women with multiple lesions lack prominent cytologic atypia as well as TP53 mutations and might be more akin to keratoacanthoma than SCC or might represent a reactive phenomenon.

Recent studies suggest cutaneous squamous cell carcinomas (SCCs) of the leg, particularly those occurring multiply in sun exposed skin of nonimmunosuppressed women, are a distinct clinical subtype. There are few reports of the histopathologic features of this subtype. A retrospective chart review of 4 patients with multiple SCCs on the leg was performed and a total of 35 biopsies from the legs examined. Histopathologically, the tumors lacked adjacent actinic keratosis (AK) and often had adjacent basaloid retiform proliferations. Most lesions (all but one) were well differentiated and about 40% could be classified histopathologically as keratoacanthoma. Perineural invasion was absent in all but one case. Using the American Joint Committee on Cancer (AJCC) staging criteria for SCC, 21 tumors were Stage I, and 9 Stage II. During 7-10 years of follow-up, no recurrence or metastasis occurred. Patients with multiple SCCs on the lower extremities can have a range of histopathologic features, from keratoacanthoma-like to well-differentiated SCC.

BackgroundBasal cell carcinoma (BCC) is the most common malignancy in the US. Body mass index (BMI) and height have been associated with a variety of cancer types, yet the evidence regarding BCC is limited. Therefore, we evaluated BMI and height in relation to early- onset BCC and explored the potential role of ultraviolet (UV) radiation exposure as well as estrogen-related exposures in the BMI-BCC relationship.MethodsBCC cases (n=377) diagnosed under age 40 were identified through a central dermatopathology facility in Connecticut. Control subjects (n=389) were randomly sampled from the same database and frequency matched to cases on age, gender, and biopsy site. Participants reported weight (usual adult and at age 18), adult height, sociodemographic, phenotypic, and medical characteristics, and prior UV exposures. We calculated multivariate odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression models.ResultsAdult BMI was inversely associated with early-onset BCC (obese vs. normal OR=0.43, 95% CI=0.26-0.71). A similar inverse association was present for BMI at age 18 (OR=0.54, 95% CI=0.34-0.85). Excluding UV exposures from the BMI models and including estrogen-related exposures among females only did not alter the association between BMI and BCC, indicating limited mediation or confounding. We did not observe an association between adult height and BCC (OR per cm=1.00, 95% CI=0.98-1.02).ConclusionWe found a significant inverse association between BMI and early-onset BCC, but no association between height and BCC. This association was not explained by UV exposures in this population or estrogen-related exposures among only the females

Author(s): Cartmel, Brenda; Mayne, Susan T; Bale, Allen E; Gelernter, Joel; DeWan, Andrew; Leffell, David J; Pagoto, Sherry; Spain, Peter; Ferrucci, Leah M | Abstract: Growing evidence suggests some individuals may exhibit dependence to ultraviolet light, a known carcinogen; however, few studies have investigated predictors of tanning dependence (TD).A sub-set of early-onset basal cell carcinoma case-control study participants completed an online survey. The modified-Cut down, Annoyed, Guilty, Eye-opener (mCAGE) and a questionnaire based on the addiction criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (mDSM-IV-TR) were used to classify participants having‘Symptoms of TD’ if they met criteria for TD on both questionnaires, ‘Tendency for TD’ if met criteria on only one questionnaire, or ‘Not TD’. We also assessed lifetime alcohol dependence, nicotine dependence, seasonal affective disorder (SAD), ‘exercise addiction,’ and depression. We compared TD groups with multivariate logistic regression.499 individuals reported volitional tanning and 24.4% were classified as having ‘Symptoms of TD’ and 24.4% as having a ‘Tendency for TD’. Women were more likely to have ‘Symptoms of TD’ (odds ratio (OR)=6.93; 95% Confidence Interval (95% CI)=(3.36-14.27)) or a ‘Tendency for TD’ (OR=2.82; 95% CI=1.59-4.98) than men. Alcohol dependence (OR=6.55; 95% CI=3.19-13.42), alcohol abuse (OR=3.16; 95% CI=1.81-5.51), risk of ‘exercise addiction’ (OR=5.47; 95%=1.15-26.06) and SAD (OR=2.77; 95% CI=1.26-6.09) were all significant predictors for ‘Symptoms of TD’. Alcohol dependence (OR=3.66; 95% CI=1.84-7.31) and alcohol abuse (OR=2.60; 95% CI=1.53-4.41) were significant predictors for ‘Tendency for TD.’Knowledge of associations between TD and gender, alcohol dependence/abuse, SAD, and ‘exercise addiction’ may be helpful to practitioners in treating TD and for targeting skin cancer preventive interventions for those with TD.

Basal cell carcinoma (BCC) incidence is increasing, particularly among adults under the age of 40 years. Pigment-related characteristics are associated with BCC in older populations, but epidemiologic studies among younger individuals and analyses of phenotype-genotype interactions are limited. We examined self-reported phenotypes and melanocortin 1 receptor gene (MC1R) variants in relation to early-onset BCC. BCC cases (n=377) and controls with benign skin conditions (n=390) under the age of 40 years were identified through Yale's Dermatopathology database. Factors most strongly associated with early-onset BCC were skin reaction to first summer sun for 1 hour (severe sunburn vs. tan odds ratio (OR)=12.27, 95% confidence interval (CI)=4.08-36.94) and skin color (very fair vs. olive OR=11.06, 95% CI=5.90-20.74). Individuals with two or more MC1R non-synonymous variants were 3.59 times (95% CI=2.37-5.43) more likely to have BCC than those without non-synonymous variants. All host characteristics and MC1R were more strongly associated with multiple BCC case status (37% of cases) than a single BCC case status. MC1R, number of moles, skin reaction to first summer sun for 1 hour, and hair and skin color were independently associated with BCC. BCC risk conferred by MC1R tended to be stronger among those with darker pigment phenotypes, traditionally considered to be at low risk of skin cancer.

Desmoplastic trichoepithelioma (DTE) is a benign follicular tumor occurring most commonly within facial skin of young and middle-aged women, morphologically characterized by a superficial dermal proliferation of basaloid cells growing in narrow strands embedded in a desmoplastic stroma associated with small keratinizing cysts. DTE must be distinguished from other benign epithelial proliferations such as syringoma, microcystic adnexal carcinoma and infiltrating basal cell carcinoma. Among morphological features useful in that distinction, perineural involvement is considered a feature indicative of malignancy. We present a series of seven DTEs with otherwise typical presentation and morphology, nevertheless showing epithelium present in the perineural spaces of adjacent small dermal nerves. Patients ranged in age from 14 to 66 years (mean 44 years). All seven tumors were restricted to dermis, showed strands of basaloid epithelium in desmoplastic stroma and contained CK20-positive cells. Additionally, five of five examined tumors displayed diffuse expression of p75 neurotrophin receptor. Five patients were followed up clinically (follow-up time range: 2 months-4 years). No tumor recurrence was observed in any of these patients. We postulate that perineural involvement is an unusual feature of DTE that should not be equated with malignancy or lead to unnecessary over-treatment.

Growing evidence suggests that some individuals may exhibit symptoms of dependence to ultraviolet light, a known carcinogen, in the context of tanning. Genetic associations with tanning dependence (TD) have not yet been explored. We conducted an exome-wide association study in 79 individuals who exhibited symptoms of TD and 213 individuals with volitional exposure to ultraviolet light, but who were not TD based on three TD scales. A total of 300 000 mostly exomic single nucleotide polymorphisms primarily in coding regions were assessed using an Affymetrix Axiom array. We performed a gene burden test with Bonferroni correction for the number of genes examined (P 0.05/14 904 = 3.36 × 10(-6) ). One gene, patched domain containing 2 (PTCHD2), yielded a statistically significant P-value of 2.5 × 10(-6) (OR = 0.27) with fewer individuals classified as TD having a minor allele at this locus. These results require replication, but are the first to support a specific genetic association with TD.

Basal cell carcinoma (BCC) is the most common malignancy worldwide, arising from non-keratinizing cells within the basal layer of the epidermis. The incidence of BCC continues to rise annually, increasing the burden of management of these carcinomas and the morbidity associated with their treatment. While surgical interventions such as Mohs micrographic surgery and surgical excision are the standard of care and yield the highest cure rates, the number of non-surgical interventions approved for the treatment of BCC continues to expand. We review various surgical and non-surgical approaches to the treatment of BCC, focusing on targeted molecular therapies that are approved for locally advanced or recurrent disease.

Adenosquamous carcinoma, a rare tumor of the skin with few reported cases in the literature, has not been studied with p63, cytokeratin 5/6 and cytokeratin 7. We stained nine such tumors with these markers. Histologically, the tumors showed superficial, atypical islands of keratinocytes in close association with islands displaying glandular differentiation. Clinically, lesions favored the head and trunk, and a subset of cases showed aggressive behavior. All tumors marked with p63 and cytokeratin 5/6, substantiating that diffuse positivity with these stains is supportive of a primary cutaneous origin. Six tumors stained focally in luminal areas with cytokeratin 7. Recognition of adenosquamous carcinoma is important for appropriate therapy, and stains for p63 and cytokeratin 5/6 may be helpful in ruling out metastatic adenocarcinoma.

Background The low recurrence rate and tissue-sparing benefit associated with Mohs micrographic surgery (MMS) requires accurate interpretation of frozen sections by the MMS surgeon. Objective We sought to assess concordance between dermatopathologists and MMS surgeons when reporting cutaneous malignancy in the MMS setting. Methods This study is a retrospective analysis of 1156 slides submitted during 10 years as part of a pre-existing randomized, blinded, quality assurance protocol. Slides were read by one of 5 dermatopathologists and represent cases from 3 MMS surgeons and 5 MMS fellows. Agreement or disagreement was recorded. Results Of the 1156 slides, 32 slides (2.8%) were disparate. Aside from differences regarding intraepidermal neoplasia, the concordance rate was 99.7%. Limitations This study represents data collected at a single institution in the United States alone. Conclusion There was statistically significant concordance between MMS surgeons and dermatopathologists in frozen section interpretation in the MMS setting. Discordance was primarily related to the interpretation of in situ malignancy.

As the incidence of nonmelanoma skin cancer (NMSC) increases, so does the number of modalities used to treat this condition. Surgery is the most frequent approach used to treat NMSC, and clinicians usually perform Mohs micrographic surgery, conventional excision, electrodesiccation and curettage or cryosurgery. The 'gold standard' for treatment continues to be Mohs micrographic surgery, but owing to the time and expense involved with this procedure, it is indicated only in patients with aggressive tumors or those where disfigurement or functional impairment is a risk. Although radiation therapy is effective, its use is limited because of the side effects induced; radiation therapy can be used in certain patients who are not surgical candidates. Newer noninvasive options for NMSC include topical chemotherapeutics, biological-immune-response modifiers, retinoids, and photodynamic therapy, which can be used particularly in patients with superficial tumors. Treatments should be tailored to tumor type, location, size, and histological pattern, and although surgical methods remain the most frequently used, newer noninvasive treatments can be used in select tumors and may reduce morbidity.

Background As a marker of genetic susceptibility and shared lifestyle characteristics, family history of cancer is often used to evaluate an individual's risk for developing a particular malignancy. With comprehensive data on pigment characteristics, lifestyle factors, and melanocortin 1 receptor ( MC1R ) gene sequence, we sought to clarify the role of family history of skin cancer in early-onset basal cell carcinoma (BCC). Materials and methods Early onset BCC cases ( n =376) and controls with benign skin conditions ( n =383) under age 40 were identified through Yale dermatopathology. Self-report data on family history of skin cancer (melanoma and non-melanoma skin cancer), including age of onset in relatives, was available from a structured interview. Participants also provided saliva samples for sequencing of MC1R . Results A family history of skin cancer was associated with an increased risk of early-onset BCC (OR 2.49, 95% CI 1.80–3.45). In multivariate models, family history remained a strong risk factor for early-onset BCC after adjustment for pigment characteristics, UV exposure, and MC1R genotype (OR 2.41, 95% CI 1.74–3.35). Conclusions Risk for BCC varied based upon the type and age of onset of skin cancer among affected relatives; individuals with a first-degree relative diagnosed with skin cancer prior to age 50 were at highest risk for BCC (OR 4.79, 95% CI 2.90–7.90). Even after taking into account potential confounding effects of MC1R genotype and various lifestyle factors that close relatives may share, family history of skin cancer remained strongly associated with early-onset BCC.

Nonmelanoma skin cancers (NMSCs) are the most common cancers in white populations in the world (1). Basal cell carcinoma (BCC), which accounts for 70%–80% of NMSCs (2, 3), has increased dramatically in recent decades, notably among young women (1, 4–6). BCC is treatable and unlikely to result in death; however, it can be associated with both significant morbidity and health-care costs (2, 7). The ability to identify those at highest risk of early-onset BCC could focus public health efforts and mitigate the imminent epidemic. There are few BCC risk prediction models (8, 9), yet several exist for melanoma (8–16) that typically evaluate demographic, phenotypic, and clinical factors. The melanocortin 1 receptor gene, MC1R, has been consistently associated with high-risk skin cancer phenotypes, including red hair and fair skin; however, common variants of MC1R are also now recognized as contributing to the risk of melanoma (9, 11, 17, 18) and NMSC (9, 19, 20) independent of phenotype. Consequently, the MC1R genotype has improved prediction in several melanoma (8, 9, 11, 12) and NMSC (8, 9) models. Indoor tanning has recently emerged as an important risk factor for both melanoma (21, 22) and NMSC (23) and seems particularly relevant for skin cancer in younger populations (24–26). Of the 3 published prediction models that evaluated the additive prediction of indoor tanning (8, 11, 12), only 1 model, for melanoma, observed increased predictive ability (12). Given the increase in indoor tanning in young populations and the high incidence of BCC, we were interested in evaluating whether MC1R and indoor tanning added to the predictive ability of BCC risk models, as seen in some melanoma risk models. Thus, we examined the utility of 2 existing skin cancer risk prediction models that included MC1R and indoor tanning in the setting of early-onset BCC. We then built a novel risk prediction model in the same early-onset BCC case-control population, with careful consideration of the additive prediction of indoor tanning and the MC1R genotype.

Background Squamous cell carcinoma in situ (SCCis) has been reported to involve the hair follicle epithelium. Deep follicular invasion is often cited as a cause of treatment failure. Objective We sought to define the frequency and the depth of hair follicle invasion by SCCis. Methods The study included both a retrospective review of intraoperative pathology specimens from 42 SCCis cases treated with Mohs micrographic surgery and a prospective evaluation of serially sectioned SCCis tissue from 12 additional patients. Pathology specimens were analyzed for follicular invasion of SCCis. Results SCCis invasion of the superficial hair follicle infundibulum was observed in 61.3% to 87.5% of cases in the 2 cohorts, whereas invasion of the isthmus and lower follicle was observed in only 8.3% to 12.5% of cases. In most tumors the depth of follicular invasion was comparable with the thickness of the surrounding epidermis. The maximum observed depth of follicular invasion was 0.82 mm. Limitations The study was performed on a limited number of cases referred for surgery at a single institution. Conclusions Although SCCis invasion of the upper hair follicle infundibulum is common, deep invasion below the level of the surrounding epidermis is rare. This may have implications for optimal therapy of this condition.

Non-healing, chronic wounds are a growing public health problem and may stem from insufficient angiogenesis in affected sites. Here, we have developed a fibrin formulation that allows adipose-derived mesenchymal stromal cells (ADSCs) to form tubular structures in vitro. The tubular structures express markers of endothelium, including CD31 and VE-Cadherin, as well as the pericyte marker NG2. The ability for the MSCs to form tubular structures within the fibrin gels was directly dependent on the stoichiometric ratios of thrombin and fibrinogen and the resulting gel concentration, as well as on the presence of bFGF. Fibrin gel formulations that varied in stiffness were tested. ADSCs that are embedded in a stiff fibrin formulation express VE-cadherin and CD31 as shown by PCR, FACS and immunostaining. Confocal imaging analysis demonstrated that tubular structures formed, containing visible lumens, in the stiff fibrin gels in vitro. There was also a difference in the amounts of bFGF secreted by ADSCs grown in the stiffer gels as compared to softer gels. Additionally, hAT-MSCs gave rise to perfusable vessels that were VE-cadherin positive after subcutaneous injection into mice, whereas the softer fibrin formulation containing ADSCs did not. The application of ADSCs delivered in the stiff fibrin gels allowed for the wounds to heal more quickly, as assessed by wound size, amount of granulation tissue and collagen content. Interestingly, following 5 days of healing, the ADSCs remained within the fibrin gel and did not integrate into the granulation tissue of healing wounds in vivo. These data show that ADSCs are able to form tubular structures within fibrin gels, and may also contribute to faster wound healing, as compared with no treatment or to wounds treated with fibrin gels devoid of ADSCs.

Melanoma in situ (MIS) poses special challenges with regard to histopathology, treatment, and clinical management. The negligible mortality and normal life expectancy associated with patients with MIS should guide treatment for this tumor. Similarly, the approach to treatment should take into account the potential for MIS to transform into invasive melanoma, which has a significant impact on morbidity and mortality. Part II of this continuing medical education article reviews the histologic features, treatment, and management of MIS.

BACKGROUND Nevoid basal cell carcinoma syndrome (NBCC) is an autosomal dominant disorder characterized by developmental abnormalities and neoplasms including basal cell carcinoma (BCC) and sarcomas (i.e. leiomyosarcoma, rhabdomyosarcoma, and fibrosarcoma). Primary cutaneous carcinosarcoma (PCC), a rare tumor composed of malignant epithelial and mesenchymal components, has never been previously described in association with this syndrome. CASE REPORT A 61-year-old Hispanic man with a history of NBCC presented with a 4 cm nodule on the right proximal medial thigh. PATHOLOGIC FINDINGS: Areas of typical BCC merged with intersecting fascicles of large atypical spindle cells that stained for vimentin and were negative for actin, desmin, CD-34, and S-100 protein. Scattered bizarre solitary cytokeratin-positive epithelioid cells were embedded within the fibrocytic proliferation. CONCLUSIONS Several carcinosarcomas have been reported to contain BCC as the malignant epithelial component, but to our knowledge, this is the first report of PCC associated with NBCC. Mutation in patched tumor suppressor gene on chromosome 9q occurs in BCCs of NBCC, and aberrancies on chromosome 9q are also reported in some carcinosarcomas. It is possible that the known genetic defect on chromosome 9 in this patient contributed to the development of carcinosarcoma. Bhattacharjee P, Leffell D, McNiff JM. Primary cutaneous carcinosarcoma arising in a patient with nevoid basal cell carcinoma syndrome.

This article reviews the indications and techniques for performing a bilobed flap for reconstruction of surgical wounds. Various examples of surgical defects where a bilobed flap can be used are shown. Possible complications and pitfalls are also reviewed.