Evidence-Based Consensus Recommendations for the Evolving Treatment of Patients with High-Risk and Advanced Cutaneous Squamous Cell Carcinoma.

Cutaneous squamous cell carcinoma is the second most common skin cancer in the United States. Currently, there is no standardized management approach for patients with cutaneous squamous cell carcinoma who develop metastatic or locally advanced disease and are not candidates for curative surgery or curative radiation. To address this issue, the Expert Cutaneous Squamous Cell Carcinoma Leadership program convened an expert steering committee to develop evidence-based consensus recommendations on the basis of a large, structured literature review. Consensus was achieved through modified Delphi methodology. The steering committee included five dermatologists, three medical oncologists, two head and neck surgeons, one radiation oncologist, and a patient advocacy group representative. The steering committee aligned on the following clinical topics: diagnosis and identification of patients considered not candidates for surgery; staging systems and risk stratification in cutaneous squamous cell carcinoma; the role of radiation therapy, surgery, and systemic therapy in the management of advanced disease, with a focus on immunotherapy; referral patterns; survivorship care; and inclusion of the patient's perspective. Consensus was achieved on 34 recommendations addressing 12 key clinical questions. The Expert Cutaneous Squamous Cell Carcinoma Leadership steering committee's evidence-based consensus recommendations may provide healthcare professionals with practically oriented guidance to help optimize outcomes for patients with advanced cutaneous squamous cell carcinoma.

Integrating gene expression profiling into NCCN high-risk cutaneous squamous cell carcinoma management recommendations: impact on patient management.

Objective: To integrate gene expression profiling into the management of high-risk cutaneous squamous cell carcinoma (cSCC) within the National Comprehensive Cancer Network (NCCN) guidelines to improve risk-aligned management recommendations.Methods: A cohort of 300 NCCN-defined high-risk cSCC patients, along with the American Joint Committee on Cancer (AJCC) T stage, Brigham and Women's Hospital (BWH) T stage, and known patient outcomes were analyzed. Risk classifications using a validated 40-gene expression profile (40-GEP) test and T stage were applied to NCCN patient management guidelines. Risk-directed patient management recommendations within the NCCN guidelines framework were aligned based on risk for metastasis.Results: Of the 300 NCCN high-risk cSCC patients, 159 (53.0%) were 40-GEP Class 1 and AJCC T1-T2, and 173 (57.7%) were Class 1 and BWH T1-2a, indicating low risk for metastasis and, thereby, suggesting low management intensity. The 40-GEP integration suggested high intensity management for only 24 (8.0%) patients (all Class 2B), and moderate intensity management for the remainder of the cohort.Conclusions: The 40-GEP test can be integrated within existing NCCN guideline recommendations for managing cSCC patients to help refine risk-directed management decisions. Integration of the 40-GEP test would allow >50% of this NCCN-defined high-risk cohort to be managed with the lowest intensity recommendations within the broad NCCN guidelines. High intensity management was deemed risk-appropriate for a small subpopulation (8.0%). This study demonstrates that the 40-GEP test, in combination with T stage, has clinical utility to impact patient management decisions in NCCN high-risk cSCC for improving risk-aligned management within the NCCN guidelines framework.

Immunohistochemistry utilization in the diagnosis of melanoma.

BACKGROUND: The use of immunohistochemical (IHC) stains in dermatopathology is commonplace; however, little is known regarding utilization trends in melanoma diagnosis. Current Medicare local coverage determinations (LCDs) state that most pigmented lesions, including melanoma, can be diagnosed using H&E alone. METHODS: Histopathology reports for all biopsy-proven melanomas excised between January 1, 2017 and June 30, 2018, at a single dermatology clinic, were identified with the following parameters abstracted: laboratory/dermatopathologist rendering the diagnosis, whether IHC was performed, type/number of stains utilized, presence/depth of invasion, and melanoma subtype. The association of characteristics with IHC utilization was evaluated using χ2 test for categorical variables. RESULTS: Three hundred and fifty six eligible melanomas were identified. IHC was employed in 228 (64%) of the diagnoses. Invasive melanoma was diagnosed in 199 cases (55.9%) while 157 (44.1%) were identified as melanoma in situ (MIS). Of the 228 that utilized IHC, 117 were performed on invasive melanoma (58.8%) and 111 were performed on MIS (70.7%). CONCLUSION: Our findings suggest a higher IHC usage for the diagnosis of melanoma than previously reported. Existing LCDs regarding IHC utilization in melanoma do not reflect the current state of practice. Further investigation regarding IHC utilization and the development of appropriate-use criteria for melanoma IHC is necessary.

Level of Evidence Review for a Gene Expression Profile Test for Cutaneous Melanoma.

BACKGROUND: The advent of molecular medicine may allow for individualized cancer prognostication, which should enable better clinical management and, hopefully, improve patient outcomes. A 31-gene expression profile (31-GEP) test is currently available for patients diagnosed with cutaneous melanoma; this test helps inform patients' individual treatment plans, especially when combined with traditional biomarkers. OBJECTIVE: The objective of this study was to review the current literature and establish the level of evidence for a cutaneous melanoma 31-GEP test. METHODS: A review of seven development and validation studies for the 31-GEP test was conducted. The respective strengths and weaknesses of each study were applied to the level of evidence criteria from major organizations that publish guidelines for melanoma management: American Joint Committee on Cancer, National Comprehensive Cancer Network, and American Academy of Dermatology. RESULTS: Evaluating each study led to classifying the 31-GEP test as level I/II, I-IIIB, and IIA according to American Joint Committee on Cancer, National Comprehensive Cancer Network, and American Academy of Dermatology criteria, respectively. This stands in contrast to the official unrated status conferred by the American Joint Committee on Cancer and National Comprehensive Cancer Network and the II/IIIC rating designated by the American Academy of Dermatology. CONCLUSIONS: Differences between the authors' findings and official published ratings may be attributed to chronological issues, as many of the studies were not yet published when the aforementioned organizations conducted their reviews. There was also difficulty in applying the National Comprehensive Cancer Network criteria to this prognostic test, as their guidelines were intended for evaluation of predictive markers. Nevertheless, based upon the most current data available, integration of the 31-GEP test into clinical practice may be warranted in certain clinical situations.

A multistep approach to improving biopsy site identification in dermatology: physician, staff, and patient roles based on a Delphi consensus.

IMPORTANCE: Excisional skin cancer surgery is a common procedure, with no formal consensus for mitigating the risk of wrong-site cutaneous surgery. OBJECTIVE: To systematically consider the usefulness and feasibility of proposed methods for correct biopsy site identification in dermatology. EVIDENCE REVIEW: Survey study with a formal consensus process. Item development was via a literature review and expert interviews, followed by 2 stages of a Delphi process to develop consensus recommendations. FINDINGS: In total, 2323 articles were reviewed in the literature search, with data extraction from 14. Twenty-five experts underwent 30-minute structured interviews, which were transcribed and coded. The resulting survey was composed of 42 proposed interventions by multiple stakeholders (biopsying physicians, operating physicians, nurses, ancillary staff, patients, caregivers, and family members) at 3 time points (day of biopsy, delay and consultation period, and day of definitive surgery). Two rounds of a Delphi process with 59 experts (25 academic and 34 private practice) scored the survey. Strong consensus was obtained on 14 behaviors, and moderate consensus was obtained on 21 other behaviors. In addition, a 2-state simultaneous algorithm was developed to model surgeon behavior on the day of definitive surgery based on surgeon and patient perceptions. CONCLUSIONS AND RELEVANCE: When definitive surgery is performed after the initial biopsy and by a different surgeon, procedures can be implemented at several time points to increase the likelihood of correct site identification. The specific circumstances of a case suggest which methods may be most appropriate and feasible, and some may be implemented. The risk of wrong-site cutaneous surgery can be reduced but not eliminated.

Radiation therapy for widespread actinic keratoses.

OBJECTIVE: To profile 16 patients with widespread and resistant actinic keratoses (AKs) treated with radiation therapy. DESIGN: Chart review and phone interviews of 16 patients who were treated with radiation therapy between 2003 and 2010. SETTING: A specialized dermatological practice primarily treating patients with skin cancer. PARTICIPANTS: The study population at the time of treatment was aged 70 to 87 with a mean age of 79.6 years and included 14 men and two women. MEASUREMENTS: Patients were followed at two weeks and six months after treatment to assess clinical outcome. All adverse effects were recorded. Patients were contacted for phone interview to assess patient satisfaction after treatment. RESULTS: Patients all had significant reduction of AKs in the radiation field with a majority (90%) reporting they were "very satisfied" with their treatment outcome. Of 16 patients at two weeks post-treatment, 13 had complete clinical resolution of their AK after radiation therapy. Three of 16 patients had significant reduction (50-99%) in AK in the treatment field. Patients reported improved quality of life, a reduced need for frequent clinic visits, and long-term remission from the development of new AKs within the treatment field. CONCLUSION: Patients meeting suggested specific criteria developed by the authors may be treated successfully with radiation therapy with good outcomes at six-month follow up and high levels of patient satisfaction.

Sentinel lymph node biopsy and completion lymph node dissection for malignant melanoma are not standard of care.

Malignant melanoma is a cutaneous malignancy characterized by high metastatic potential and an unpredictable course. Enormous amounts of research have been done into surgical and adjunctive therapies for melanoma. Given the regularity with which sentinel lymph node biopsy and completion lymph node dissection are performed at private and academic hospitals, it would seem that evidence supporting these procedures is not controversial. A growing body of studies, however, points to sentinel lymph node biopsy and completion lymph node dissection as ineffective treatment for malignant melanoma and necessitates a discussion of what constitutes standard of care.

Vehicle-controlled, double-blind, randomized study of imiquimod 5% cream applied 3 days per week in one or two courses of treatment for actinic keratoses on the head.

BACKGROUND: A shorter dosing regimen of imiquimod for the treatment of actinic keratosis may be effective, with long-term clinical benefits. OBJECTIVE: Imiquimod in one or two shorter courses of treatment was evaluated. METHODS: Patients with actinic keratosis lesions on the head applied imiquimod or vehicle cream 3x/wk for 4 weeks (course 1). Patients with remaining lesions received another course of treatment. Complete and partial clearance rates were evaluated after course 1, after course 2 (overall), and 1 year later. RESULTS: Complete clearance rates were 26.8% (course 1) and 53.7% (overall). Partial clearance rates were 36.6% (course 1) and 61.0% (overall). One-year follow-up recurrence rates were 39% (imiquimod) and 57% (vehicle). LIMITATIONS: Blinded investigators may have been biased toward patients treated with imiquimod identified by treatment site reactions. CONCLUSION: Imiquimod 3x/wk in one or two courses of treatment appears to be effective for the treatment of actinic keratoses on the head, providing long-term clinical benefits. Some recurrences do occur, so long-term follow-up is recommended.

Safety and efficacy of a new extended-release formulation of minocycline.

The complete safety and efficacy of a new extended-release (ER) minocycline hydrochloride formulation were assessed in an analysis of a phase 2 dose-finding study and 2 phase 3 safety and efficacy studies. The studies were similar in design, subject populations, and shared common dose groups of subjects given ER minocycline 1 mg/kg daily or placebo over 12 weeks. The similar designs were prospective, multicenter, randomized, double-blinded, and placebo-controlled. A total of 1038 subjects with moderate to severe acne were available for the pooled analysis. Independently, each study showed that treatment with ER-minocycline significantly reduced (P < .001) the number of inflammatory lesions and significantly improved (P < .001) their Evaluator's Global Severity Assessment (EGSA) scores (phase 3 studies). Analysis of the pooled population confirmed the results of the individual studies. The percentage of subjects reporting acute vestibular adverse events (AVAEs) was comparable between those receiving the ER-minocycline 1-mg/kg dose and placebo (approximately 10% of subjects in each group) for both the individual studies and the pooled population. It was concluded that a novel ER-minocycline formulation that delivers consistent levels of drug at a 1-mg/kg dose reduces dose-dependent AVAEs while reducing inflammatory lesions and improving the overall appearance of patients with acne vulgaris.

Dietary supplements: altered coagulation and effects on bruising.

BACKGROUND: Patient use of dietary supplements that alter coagulation or have an effect on bruising is becoming increasingly common. OBJECTIVE: To identify and describe dietary supplements that alter coagulation or are reported to alter bruising during and after surgical procedures. METHODS: The MEDLINE, Cochrane Collaboration, and International Bibliographic Information on Dietary Supplements databases were searched for articles using the search words "bruising," "bleeding," "coagulation," "hemostasis," "herbal medicine," "alternative medicine," and "dietary supplement." Additional sources were obtained from manual searches of recent journal articles. RESULTS: In vivo and in vitro evidence supports the notion that many dietary supplements alter coagulation. Limited evidence is available to support anecdotal claims of diminished postoperative bruising after the use of dietary supplements. CONCLUSION: Surgeons should be aware that many of their patients are taking dietary supplements that may alter coagulation. Because most patients will not readily volunteer this information, specific steps should be taken to obtain it prior to more extensive surgical procedures.

Evaluation of the American Joint Committee on Cancer staging system for cutaneous squamous cell carcinoma and proposal of a new staging system.

PURPOSE: To identify and propose corrections for deficiencies in the American Joint Committee on Cancer (AJCC) system for staging cutaneous squamous cell carcinoma (CSCC). MATERIALS AND METHODS: Prognostic factors for CSCC were identified by retrospective analysis of the published literature. Limitations and deficiencies in the current AJCC staging system for CSCC were then determined using these prognostic factors. RESULTS: Size, histologic differentiation, location, previous treatment, depth of invasion, tumor thickness, histologic subtype, perineural spread, and scar etiology are the most powerful tumor prognostic indicators in patients with localized disease. The most important prognostic factors for patients with nodal metastases are the location, number, and size of the positive lymph nodes. Proposed changes for the T classification include increased stratification of tumor size, identification of patients with perineural invasion, and the addition of tumor thickness or depth of invasion. The N classification has been expanded to include the number and size of nodal metastases. CONCLUSION: The current AJCC staging system for carcinoma of the skin has deficiencies that limit its use for CSCC. The proposed TMN staging system for CSCC more accurately reflects the prognosis and natural history of CSCC.

Imiquimod 5% cream for the treatment of actinic keratosis: results from two phase III, randomized, double-blind, parallel group, vehicle-controlled trials.

BACKGROUND: The immune system plays a critical role in the development and pathogenesis of actinic keratosis (AK). Imiquimod has been shown to stimulate the cutaneous immune response and be effective for the treatment of nonmelanoma skin cancers. OBJECTIVE: Two phase III, randomized, double-blind, vehicle-controlled studies evaluated the efficacy of imiquimod 5% cream compared with vehicle in the treatment of AK lesions on the face and balding scalp. METHODS: A total of 436 participants at 24 centers in the United States and Canada were randomized to either imiquimod 5% or vehicle cream. Study cream was applied one time per day, 2 days per week for 16 weeks. Clearance of AK lesions was clinically assessed at an 8-week posttreatment visit. RESULTS: The complete clearance rate was 45.1% for the imiquimod group and 3.2% for the vehicle group. The difference in complete clearance rates (imiquimod minus vehicle) was 41.9% with a 95% confidence interval of 34.9% to 49%. The partial (> or =75%) clearance rate was 59.1% for the imiquimod group and 11.8% for the vehicle group. The difference in partial clearance rates (imiquimod minus vehicle) was 47.3% with a 95% confidence interval of 39.5% to 55.1%. The median percent reduction in AK lesions was 83.3% for the imiquimod group and 0% for the vehicle group. Local skin reactions were common. Severe erythema was reported by 17.7% of participants who received imiquimod and 2.3% of participants who received vehicle. Overall, imiquimod was very well tolerated. CONCLUSION: Imiquimod 5% cream used 2 times per week for 16 weeks is an effective and well-tolerated treatment for AK.

Histopathologic evaluation of cutaneous squamous cell carcinoma: results of a survey among dermatopathologists.

BACKGROUND: There are numerous histopathologic features related to prognosis in cutaneous squamous cell carcinoma (CSCC). We hypothesize that there is no uniform approach toward the reporting of these features. This may be related to differing opinions on their prognostic use. METHODS: A written survey concerning the microscopic evaluation of CSCC was sent to 120 dermatopathologists in the United States and Canada. Respondents were asked whether they comment on specific microscopic features of CSCC, and whether they believe that each specific feature can predict prognosis. RESULTS: The response rate was 78%. Histologic type, and the presence of perineural or vascular/lymphatic invasion, is reported by most dermatopathologists (90%, 96%, and 95%, respectively). These features are also thought to predict prognosis by the majority of respondents. Only 54% report histologic grade, and 49% think grade predicts prognosis. Depth is reported anatomically by 63%, but by only 8% in actual millimeters of invasion. However, 55% think tumor depth predicts prognosis. A total of 43% report the presence of an associated actinic keratosis, although very few (16%) think it predicts prognosis. Very few comment on the presence of inflammation. CONCLUSIONS: Histopathologic reporting of CSCC is not uniform among dermatopathologists. Also, there appears to be differing opinions on the use of certain histopathologic features for predicting prognosis.

Use of alternative therapies by patients undergoing surgery for nonmelanoma skin cancer.

BACKGROUND: The use of alternative therapies is becoming increasingly common and may result in unwanted side effects and drug interactions. OBJECTIVE: To determine the frequency of alternative medicine use by patients undergoing Mohs surgery for nonmelanoma skin cancer. METHODS: A written survey concerning use of alternative therapies was given to patients undergoing Mohs surgery for nonmelanoma skin cancer. A follow-up telephone survey was used to clarify positive responses. RESULTS: Thirty-six of 192 (18.8%) patients with nonmelanoma skin cancer reported using some type of alternative therapy. Almost all patients were using these therapies for conditions unrelated to their nonmelanoma skin cancer. Herbs and botanicals were the most common type of alternative therapy utilized. CONCLUSION: Physicians performing Mohs surgery should be aware that a significant number of their patients use alternative therapies. Since most patients do not readily volunteer information about alternative medicine usage, specific steps should be taken to obtain this information.