ABSTRACT
Although smoothened inhibitors (SMOi) have demonstrated efficacy in the management of basal cell carcinoma, no guidelines are available on how to utilize SMOi in the treatment of Gorlin syndrome (GS). This review's objective is to assess the clinical response to SMOi in GS, provide practical guidance for clinicians, and identify areas for future research. Through comprehensive searches of previous publications and expert opinion, this review demonstrates that intermittent dosing of SMOi and daily dosing have similar efficacy. While the adverse events of SMOi may result in their discontinuation during treatment of GS, intermittent dosing may improve compliance.
ABSTRACT
Importance: Extramammary Paget disease (EMPD) is a rare, highly recurrent cutaneous malignant neoplasm of unclear origin. EMPD arises most commonly on the vulvar and penoscrotal skin. It is not presently known how anatomic subtype of EMPD affects disease presentation and management. Objective: To compare demographic and tumor characteristics and treatment approaches for different EMPD subtypes. Recommendations for diagnosis and treatment are presented. Data Sources: MEDLINE, Embase, Web of Science Core Collection, and Cochrane Reviews CENTRAL from December 1, 1990, to October 24, 2022. Study Selection: Articles were excluded if they were not in English, reported fewer than 3 patients, did not specify information by anatomic subtype, or contained no case-level data. Metastatic cases on presentation were also excluded. Data Extraction and Synthesis: Abstracts of 1295 eligible articles were independently reviewed by 5 coauthors, and 135 articles retained. Reporting was in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. The analysis was cunducted in August 2019 and updated in November 2022. Findings: Most vulvar EMPD cases were asymptomatic, and diagnosis was relatively delayed (mean, 25.1 months). Although most vulvar EMPD cases were intraepidermal (1247/1773 [70.3%]), radical surgeries were still performed in almost one-third of cases. Despite this aggressive surgical approach, 481 of 1423 (34%) recurred, commonly confined to the skin and mucosa (177/198 [89.4%]). By contrast, 152 of 1101 penoscrotal EMPD cases (14%) recurred, but more than one-third of these recurrences were regional or associated with distant metastases (54 of 152 [35.5%]). Perianal EMPD cases recurred in one-third of cases (74/218 [33.9%]), with one-third of these recurrences being regional or associated with distant metastasis (20 of 74 [27.0%]). Perianal EMPD also had the highest rate of invasive disease (50% of cases). Conclusions and Relevance: The diagnosis and treatment of EMPD should differ based on anatomic subtypes. Considerations for updated practice may include less morbid treatments for vulvar EMPD, which is primarily epidermal, and close surveillance for local recurrence in vulvar EMPD and metastatic recurrence in perianal EMPD. Recurrences in penoscrotal subtype were less common, and selective surveillance in this subtype may be considered. Limitations of this study include the lack of replication cohorts and the exclusion of studies that did not stratify outcomes by anatomic subtype.
Subject(s)
Paget Disease, Extramammary , Female , Humans , Paget Disease, Extramammary/diagnosis , Paget Disease, Extramammary/surgery , Paget Disease, Extramammary/pathology , Perineum/pathology , Vulva/pathologyABSTRACT
Surgical site infections (SSIs) contribute to morbidity and are costly to the healthcare system. To identify factors associated with SSIs. Case-control study analyzing the Nationwide Readmission Database (NRD). We identified 45,445 SSIs. Infection rates were higher in those who were obese (BMI ≥ 30) (OR: 1.39, 95% CI 1.28-1.51), tobacco users (OR: 1.08, 95% CI 1.02-1.15), diagnosed with diabetes (OR: 1.16, 95% CI 1.10-1.22), with Elixhauser Comorbidity Index ≥ 2 (OR: 1.14, 95% CI 1.09-1.20), admitted to hospital for 4-6 days (OR: 1.35, 95% CI 1.29-1.42), in medium-size hospital (OR: 1.15, 95% CI 1.05-1.26), or large-size hospital (OR: 1.43, 95% CI 1.31-1.56). In contrast, patients who were 60-79 years old (OR: 0.78, 95% CI 0.73-0.84), 80 years or older (OR: 0.66, 95% CI 0.59-0.73), female (OR: 0.95, 95% CI 0.91-0.99), underweight (BMI < 18.5) (OR: 0.14, 95% CI 0.03-0.59), in a non-metropolitan hospital (OR: 0.83, 95% CI 0.75-0.91), self-pay (OR: 0.82, 95% CI 0.74-0.91), or covered by Medicare (OR: 0.86, 95% CI 0.80-0.91) had lower odds. Initial data entry to NRD is susceptible to human error. Patients who are obese, use tobacco, have multiple comorbidities, and have long hospital stays in medium-to-large-size hospitals are at risk of SSIs. Conversely, odds of SSIs are lower in females, age ≥ 60, BMI < 18.5, self-pay or Medicare (versus private insurance), or at smaller hospitals. Understanding factors associated with SSIs may help surgeons anticipate complications.
Subject(s)
Medicare , Surgical Wound Infection , Humans , Female , Aged , United States/epidemiology , Middle Aged , Surgical Wound Infection/epidemiology , Surgical Wound Infection/etiology , Case-Control Studies , Risk Factors , Obesity/epidemiology , Hospitals , Retrospective StudiesSubject(s)
Melanoma , Skin Neoplasms , Humans , Cross-Sectional Studies , Skin Neoplasms/pathology , Melanoma/pathologyABSTRACT
BACKGROUND: There is considerable variation in the literature regarding the dermatopathologic diagnostic features of and reporting guidelines for actinic keratosis (AK) and cutaneous squamous cell carcinoma (cSCC). OBJECTIVE: To develop consensus recommendations regarding diagnostic criteria, nomenclature, and reporting of AK and cSCC. METHODS: Literature review and cross-sectional multiround Delphi process including an international group of expert dermatopathologists followed by a consensus meeting. RESULTS: Consensus was achieved regarding the key dermatopathologic features necessary for diagnosing cSCC, AK, and associated variants; grading of degree of cellular differentiation in cSCC; utility of immunohistochemistry for diagnosis of cSCC; and pathologic features that should be reported for cSCC and AK. LIMITATIONS: Consensus was not achieved on all questions considered. CONCLUSION: Despite the lack of clarity in the literature, there is consensus among expert dermatopathologists regarding diagnostic criteria and appropriate reporting of AK and cSCC. Widespread implementation of these consensus recommendations may improve communication between dermatopathologists and clinicians, facilitating appropriate treatment of AK and cSCC.
Subject(s)
Carcinoma, Squamous Cell , Keratosis, Actinic , Skin Neoplasms , Humans , Carcinoma, Squamous Cell/diagnosis , Carcinoma, Squamous Cell/pathology , Consensus , Cross-Sectional Studies , Keratosis, Actinic/pathology , Skin Neoplasms/diagnosis , Skin Neoplasms/pathologyABSTRACT
Exaggerated healing and remodeling after skin injury may cause hypertrophic and keloidal scars, which are associated with functional and quality of life impairment. There is limited guidance available regarding the relative effectiveness of therapies for hypertrophic scars and keloids. In this review, we aim to compare the effectiveness of treatments for hypertrophic scars and keloids. MEDLINE, Embase, Scopus, and the Cochrane Collaboration database were searched from inception to March 2019 for randomized control trials of treatments for hypertrophic and keloid scars that included 20 or more patients. Outcomes evaluated included the standardized mean reduction in scarring and adverse events. The type of scar and the demographic features were analyzed for their effect on clinical outcome. Based on 25 included clinical trials, intralesional injection (64.1% [95% CI 60.8-67.5%]) may be more effective than physical (29.9% [95% CI 28.9-30.9%]) or topical treatments (34% [95% CI 31.8-36.8%]). Combination of 5-fluorouracil and triamcinolone (9:1 dilution) appeared superior among intralesional treatments for keloids. Ablative laser and pulsed-dye laser were the most useful laser treatments. Regression modeling showed laser treatment response was linked to Fitzpatrick skin type (p = 0.002). Adverse events were uncommon for all treatments and mostly transient. Intralesional treatments for keloid and hypertrophic scars may be the most reliable treatment option to improve pathologic scars, while laser treatment may have specific benefits for Fitzpatrick skin types I-III over types IV-VI. Management of pathological scars is an area of critical need, where appropriate treatment can have a significant impact on quality of life.
Subject(s)
Cicatrix, Hypertrophic , Keloid , Humans , Keloid/pathology , Cicatrix, Hypertrophic/pathology , Quality of Life , Hypertrophy/complications , Hypertrophy/drug therapy , Fluorouracil , Treatment Outcome , Injections, IntralesionalABSTRACT
Cutaneous mesenchymal sarcomas are rare malignancies that include dermatofibrosarcoma protuberans, atypical fibroxanthoma, pleomorphic dermal sarcoma, cutaneous angiosarcoma, myofibrosarcoma, and leiomyosarcoma. These tumors lack consensus guidelines on staging and management. Treatment of local disease involves complete surgical removal but recurrence rates are higher compared with more common forms of nonmelanoma skin cancer. Cutaneous angiosarcoma, pleomorphic dermal sarcoma, and subcutaneous leiomyosarcoma have increased risk of metastatic spread and lower survival rate. Further research is needed on targeted therapies for these more aggressive sarcomas.
Subject(s)
Hemangiosarcoma , Histiocytoma, Malignant Fibrous , Leiomyosarcoma , Sarcoma , Skin Neoplasms , Humans , Hemangiosarcoma/pathology , Leiomyosarcoma/pathology , Skin Neoplasms/surgery , Skin Neoplasms/pathology , Sarcoma/surgery , Sarcoma/pathologyABSTRACT
Treatment of actinic keratoses (AKs) can help lower the risk of eventual skin cancer and address field pre-cancerization. This review compares the different therapeutic options for actinic keratosis. Databases used include Medline, EMBASE, Web of Science and the Cochrane Library from inception to December 2019. Randomized control trials that were related to any approved or recognized treatment for actinic keratosis were included. 1186 studies were found, of which 80 with 6748 patients were included in the analysis. A network meta-analysis was not possible due to interstudy heterogeneity. The greatest degree of improvement was seen with photodynamic therapy (PDT) used adjunctively with other modalities, but this was not significantly different compared to other treatments. PDT, cryotherapy, imiquimod, ingenol mebutate (IMB), 5-fluorouracil (5-FU), trichloroacetic acid (TCA), and ablative fractional laser (AFXL), were all non-inferior to one another in terms of percent clearance of AKs, but the lowest rates of clearance were seen with diclofenac sodium. When results were substratified by body site, 5-FU, combination PDT and combination 5-FU with calcipotriol were the most beneficial for AKs on the head and neck, although they often caused the highest proportion of initial side effects. Absence of randomized control trials for surgical treatments and non-ablative laser limits comparison of these treatments to other modalities. Limitations include the lack of standardized outcome reporting limited the comparability of results across trials. The results of this analysis do not account for individual patient risk or cumulative risk for development of skin cancer. At present, PDT, cryotherapy, imiquimod, IMB, 5-FU, TCA, AFXL, and combination treatments are similarly efficacious in reducing AKs in immunocompetent patients.Registration: N/A.
Subject(s)
Keratosis, Actinic , Photochemotherapy , Skin Neoplasms , Humans , Keratosis, Actinic/drug therapy , Imiquimod/therapeutic use , Photochemotherapy/methods , Treatment Outcome , Skin Neoplasms/drug therapy , FluorouracilABSTRACT
Importance: Laser-assisted drug delivery (LADD) is used for various medical and cosmetic applications. However, there is insufficient evidence-based guidance to assist clinicians performing LADD. Objective: To develop recommendations for the safe and effective use of LADD. Evidence Review: A systematic literature review of Cochrane Central Register of Controlled Trials, Embase, and MEDLINE was conducted in December 2019 to identify publications reporting research on LADD. A multidisciplinary panel was convened to draft recommendations informed by the systematic review; they were refined through 2 rounds of Delphi survey, 2 consensus meetings, and iterative review by all panelists until unanimous consensus was achieved. Findings: Of the 48 published studies of ablative fractional LADD that met inclusion criteria, 4 were cosmetic studies; 21, oncologic; and 23, medical (not cosmetic/oncologic), and 6 publications of nonablative fractional LADD were included at the request of the expert panel, producing a total of 54 studies. Thirty-four studies (63.0%) were deemed to have low risk of bias, 17 studies (31.5%) had moderate risk, and 3 (5.5%) had serious risk. The key findings that informed the guidelines developed by the expert panel were as follows: LADD is safe in adults and adolescents (≥12 years) with all Fitzpatrick skin types and in patients with immunosuppression; it is an effective treatment for actinic keratosis, cutaneous squamous cell carcinoma in situ, actinic cheilitis, hypertrophic scars, and keloids; it is useful for epidermal and dermal analgesia; drug delivery may be increased through the application of heat, pressure, or occlusion, or by using an aqueous drug solution; laser settings should be selected to ensure that channel diameter is greater than the delivered molecule; antibiotic prophylaxis is not recommended, except with impaired wound healing; antiviral prophylaxis is recommended when treating the face and genitalia; and antifungal prophylaxis is not recommended. The guideline's 15 recommendations address 5 areas of LADD use: (I) indications and contraindications; (II) parameters to report; (III) optimization of drug delivery; (IV) safety considerations; and (V) prophylaxis for bacterial, viral, and fungal infections. Conclusions and Relevance: This systematic review and Delphi consensus approach culminated in an evidence-based clinical practice guideline for safe and effective use of LADD in a variety of applications. Future research will further improve our understanding of this novel treatment technique.
Subject(s)
Carcinoma, Squamous Cell , Skin Neoplasms , Adult , Humans , Adolescent , Pharmaceutical Preparations , Antifungal Agents , Lasers , Antiviral AgentsABSTRACT
BACKGROUND: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS/TEN overlap syndrome are rare, severe cutaneous adverse reactions usually triggered by medications. In addition to tertiary-level supportive care, various systemic therapies have been used including glucocorticoids, intravenous immunoglobulins (IVIGs), cyclosporin, N-acetylcysteine, thalidomide, infliximab, etanercept, and plasmapheresis. There is an unmet need to understand the efficacy of these interventions. OBJECTIVES: To assess the effects of systemic therapies (medicines delivered orally, intramuscularly, or intravenously) for the treatment of SJS, TEN, and SJS/TEN overlap syndrome. SEARCH METHODS: We searched the following databases up to March 2021: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, and Embase. We also searched five clinical trial registers, the reference lists of all included studies and of key review articles, and a number of drug manufacturer websites. We searched for errata or retractions of included studies. SELECTION CRITERIA: We included only randomised controlled trials (RCTs) and prospective observational comparative studies of participants of any age with a clinical diagnosis of SJS, TEN, or SJS/TEN overlap syndrome. We included all systemic therapies studied to date and permitted comparisons between each therapy, as well as between therapy and placebo. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as specified by Cochrane. Our primary outcomes were SJS/TEN-specific mortality and adverse effects leading to discontinuation of SJS/TEN therapy. Secondary outcomes included time to complete re-epithelialisation, intensive care unit length of stay, total hospital length of stay, illness sequelae, and other adverse effects attributed to systemic therapy. We rated the certainty of the evidence for each outcome using GRADE. MAIN RESULTS: We included nine studies with a total of 308 participants (131 males and 155 females) from seven countries. We included two studies in the quantitative meta-analysis. We included three RCTs and six prospective, controlled observational studies. Sample sizes ranged from 10 to 91. Most studies did not report study duration or time to follow-up. Two studies reported a mean SCORe of Toxic Epidermal Necrosis (SCORTEN) of 3 and 1.9. Seven studies did not report SCORTEN, although four of these studies reported average or ranges of body surface area (BSA) (means ranging from 44% to 51%). Two studies were set in burns units, two in dermatology wards, one in an intensive care unit, one in a paediatric ward, and three in unspecified inpatient units. Seven studies reported a mean age, which ranged from 29 to 56 years. Two studies included paediatric participants (23 children). We assessed the results from one of three RCTs as low risk of bias in all domains, one as high, and one as some concerns. We judged the results from all six prospective observational comparative studies to be at a high risk of bias. We downgraded the certainty of the evidence because of serious risk of bias concerns and for imprecision due to small numbers of participants. The interventions assessed included systemic corticosteroids, tumour necrosis factor-alpha (TNF-alpha) inhibitors, cyclosporin, thalidomide, N-acetylcysteine, IVIG, and supportive care. No data were available for the main comparisons of interest as specified in the review protocol: etanercept versus cyclosporin, etanercept versus IVIG, IVIG versus supportive care, IVIG versus cyclosporin, and cyclosporin versus corticosteroids. Corticosteroids versus no corticosteroids It is uncertain if there is any difference between corticosteroids (methylprednisolone 4 mg/kg/day for two more days after fever had subsided and no new lesions had developed) and no corticosteroids on disease-specific mortality (risk ratio (RR) 2.55, 95% confidence interval (CI) 0.72 to 9.03; 2 studies; 56 participants; very low-certainty evidence). Time to complete re-epithelialisation, length of hospital stay, and adverse effects leading to discontinuation of therapy were not reported. IVIG versus no IVIG It is uncertain if there is any difference between IVIG (0.2 to 0.5 g/kg cumulative dose over three days) and no IVIG in risk of disease-specific mortality (RR 0.33, 95% CI 0.04 to 2.91); time to complete re-epithelialisation (mean difference (MD) -2.93 days, 95% CI -4.4 to -1.46); or length of hospital stay (MD -2.00 days, 95% CI -5.81 to 1.81). All results in this comparison were based on one study with 36 participants, and very low-certainty evidence. Adverse effects leading to discontinuation of therapy were not reported. Etanercept (TNF-alpha inhibitor) versus corticosteroids Etanercept (25 mg (50 mg if weight > 65 kg) twice weekly "until skin lesions healed") may reduce disease-specific mortality compared to corticosteroids (intravenous prednisolone 1 to 1.5 mg/kg/day "until skin lesions healed") (RR 0.51, 95% CI 0.16 to 1.63; 1 study; 91 participants; low-certainty evidence); however, the CIs were consistent with possible benefit and possible harm. Serious adverse events, such as sepsis and respiratory failure, were reported in 5 of 48 participants with etanercept and 9 of 43 participants with corticosteroids, but it was not clear if they led to discontinuation of therapy. Time to complete re-epithelialisation and length of hospital stay were not reported. Cyclosporin versus IVIG It is uncertain if there is any difference between cyclosporin (3 mg/kg/day or intravenous 1 mg/kg/day until complete re-epithelialisation, then tapered off (10 mg/day reduction every 48 hours)) and IVIG (continuous infusion 0.75 g/kg/day for 4 days (total dose 3 g/kg) in participants with normal renal function) in risk of disease-specific mortality (RR 0.13, 95% CI 0.02 to 0.98, 1 study; 22 participants; very low-certainty evidence). Time to complete re-epithelialisation, length of hospital stay, and adverse effects leading to discontinuation of therapy were not reported. No studies measured intensive care unit length of stay. AUTHORS' CONCLUSIONS: When compared to corticosteroids, etanercept may result in mortality reduction. For the following comparisons, the certainty of the evidence for disease-specific mortality is very low: corticosteroids versus no corticosteroids, IVIG versus no IVIG and cyclosporin versus IVIG. There is a need for more multicentric studies, focused on the most important clinical comparisons, to provide reliable answers about the best treatments for SJS/TEN.
Subject(s)
Autoimmune Diseases , Stevens-Johnson Syndrome , Acetylcysteine , Adrenal Cortex Hormones/therapeutic use , Adult , Autoimmune Diseases/drug therapy , Child , Cyclosporine/therapeutic use , Etanercept , Female , Humans , Immunoglobulins, Intravenous/therapeutic use , Male , Middle Aged , Observational Studies as Topic , Stevens-Johnson Syndrome/drug therapy , Thalidomide , Tumor Necrosis Factor-alphaABSTRACT
IMPORTANCE: Extramammary Paget disease (EMPD) is a frequently recurring malignant neoplasm with metastatic potential that presents in older adults on the genital, perianal, and axillary skin. Extramammary Paget disease can precede or occur along with internal malignant neoplasms. OBJECTIVE: To develop recommendations for the care of adults with EMPD. EVIDENCE REVIEW: A systematic review of the literature on EMPD from January 1990 to September 18, 2019, was conducted using MEDLINE, Embase, Web of Science Core Collection, and Cochrane Libraries. Analysis included 483 studies. A multidisciplinary expert panel evaluation of the findings led to the development of clinical care recommendations for EMPD. FINDINGS: The key findings were as follows: (1) Multiple skin biopsies, including those of any nodular areas, are critical for diagnosis. (2) Malignant neoplasm screening appropriate for age and anatomical site should be performed at baseline to distinguish between primary and secondary EMPD. (3) Routine use of sentinel lymph node biopsy or lymph node dissection is not recommended. (4) For intraepidermal EMPD, surgical and nonsurgical treatments may be used depending on patient and tumor characteristics, although cure rates may be superior with surgical approaches. For invasive EMPD, surgical resection with curative intent is preferred. (5) Patients with unresectable intraepidermal EMPD or patients who are medically unable to undergo surgery may receive nonsurgical treatments, including radiotherapy, imiquimod, photodynamic therapy, carbon dioxide laser therapy, or other modalities. (6) Distant metastatic disease may be treated with chemotherapy or individualized targeted approaches. (7) Close follow-up to monitor for recurrence is recommended for at least the first 5 years. CONCLUSIONS AND RELEVANCE: Clinical practice guidelines for EMPD provide guidance regarding recommended diagnostic approaches, differentiation between invasive and noninvasive disease, and use of surgical vs nonsurgical treatments. Prospective registries may further improve our understanding of the natural history of the disease in primary vs secondary EMPD, clarify features of high-risk tumors, and identify superior management approaches.
Subject(s)
Paget Disease, Extramammary , Skin Neoplasms , Aged , Humans , Imiquimod/therapeutic use , Paget Disease, Extramammary/diagnosis , Paget Disease, Extramammary/pathology , Paget Disease, Extramammary/therapy , Prospective Studies , Sentinel Lymph Node Biopsy , Skin Neoplasms/diagnosis , Skin Neoplasms/pathology , Skin Neoplasms/therapySubject(s)
COVID-19 , Pandemics , COVID-19/epidemiology , Emergencies , Humans , Pandemics/prevention & control , Practice Guidelines as TopicABSTRACT
BACKGROUND: Mohs micrographic surgery or wide local excision is the treatment of choice for fibrohistiocytic tumors with metastatic potential, including atypical fibroxanthoma (AFX) and cutaneous undifferentiated pleomorphic sarcoma (cUPS). Since margin clearance is the strongest predictor of clinical recurrence, improved recommendations for appropriate surgical margins help delineate uniform excision margins when intraoperative margin assessment is not available. OBJECTIVE: To determine appropriate surgical wide local excision margins for AFX and cUPS. METHODS: Literature search (Ovid MEDLINE, Embase, Web of Science, and Cochrane Library from inception to March 2020) to detect case-level data. Estimation of margins required using a mathematical model based on extracted cases without recurrences. RESULTS: Probabilistic modeling based on 100 cases extracted from 37 studies showed peripheral clearance margin (ie, wide local excision margin) calculated to clear 95% of all tumors was 2 cm for AFX and 3 cm for cUPS. AFX tumors 1 cm or less required a margin of 1 cm. LIMITATIONS: Data were extracted from published cases. CONCLUSIONS: Atypical fibroxanthoma removed with at least a 2-cm peripheral excision margin is less likely to recur. Smaller tumors 1 cm or less can be treated with a more conservative margin. Margin-control surgical techniques are recommended to ensure complete removal while minimizing surgical morbidity.