Establishing Consensus for Mohs Micrographic Surgical Techniques in the Treatment of Melanoma in Situ for Future Clinical Trials: A Modified Delphi Study.

BACKGROUND: Mohs micrographic surgery (MMS) is a promising treatment modality for melanoma in situ (MIS). However, variations in surgical technique limit the generalizability of existing data and may impede future study of MMS in clinical trials. METHODS: A modified Delphi method was selected to establish consensus on optimal MMS techniques for treating MIS in future clinical trials. The Delphi method was selected due to the limited current data, the wide range of techniques used in the field, and the intention to establish a standardized technique for future clinical trials. A literature review and interviews with experienced MMS surgeons were performed to identify dimensions of the MMS technique for MIS that (1) likely impacted costs or outcomes of the procedure, and (2) showed significant variability between surgeons. A total of 8 dimensions of technical variation were selected. The Delphi process consisted of 2 rounds of voting and commentary, during which 44 expert Mohs surgeons across the United States rated their agreement with specific recommendations using a Likert scale. RESULTS: Five of eight recommendations achieved consensus in Round 1. All 3 of the remaining recommendations achieved consensus in Round 2. Techniques achieving consensus in Round 1 included the use of a starting peripheral margin of ≤5 mm, application of immunohistochemistry, frozen tissue processing, and resecting to the depth of subcutaneous fat. Consensus on the use of Wood's lamp, dermatoscope, and negative tissue controls was established in Round 2. CONCLUSIONS: This study generated 8 consensus recommendations intended to offer guidance for Mohs surgeons treating MIS. The adoption of these recommendations will promote standardization to facilitate comparisons of aggregate data in multicenter clinical trials.

Cancer stem cells release interleukin-33 within large oncosomes to promote immunosuppressive differentiation of macrophage precursors.

In squamous cell carcinoma (SCC), macrophages responding to interleukin (IL)-33 create a TGF-ß-rich stromal niche that maintains cancer stem cells (CSCs), which evade chemotherapy-induced apoptosis in part via activation of the NRF2 antioxidant program. Here, we examined how IL-33 derived from CSCs facilitates the development of an immunosuppressive microenvironment. CSCs with high NRF2 activity redistributed nuclear IL-33 to the cytoplasm and released IL-33 as cargo of large oncosomes (LOs). Mechanistically, NRF2 increased the expression of the lipid scramblase ATG9B, which exposed an "eat me" signal on the LO surface, leading to annexin A1 (ANXA1) loading. These LOs promoted the differentiation of AXNA1 receptor+ myeloid precursors into immunosuppressive macrophages. Blocking ATG9B's scramblase activity or depleting ANXA1 decreased niche macrophages and hindered tumor progression. Thus, IL-33 is released from live CSCs via LOs to promote the differentiation of alternatively activated macrophage, with potential relevance to other settings of inflammation and tissue repair.

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

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

Updates in Skin Cancer in Transplant Recipients and Immunosuppressed Patients: Review of the 2022-2023 Scientific Symposium of the International Immunosuppression and Transplant Skin Cancer Collaborative.

The International Immunosuppression and Transplant Skin Cancer Collaborative (ITSCC) and its European counterpart, Skin Care in Organ Transplant Patients-Europe (SCOPE) are comprised of physicians, surgeons, and scientist who perform integrative collaborative research focused on cutaneous malignancies that arise in solid organ transplant recipients (SOTR) and patients with other forms of long-term immunosuppression. In October 2022, ITSCC held its biennial 4-day scientific symposium in Essex, Massachusetts. This meeting was attended by members of both ITSCC and SCOPE and consisted of specialists including Mohs micrographic and dermatologic oncology surgeons, medical dermatologists, transplant dermatologists, transplant surgeons, and transplant physicians. During this symposium scientific workshop groups focusing on consensus standards for case reporting of retrospective series for invasive squamous cell carcinoma (SCC), defining immunosuppressed patient status for cohort reporting, development of multi-institutional registry for reporting rare tumors, and development of a KERACON clinical trial of interventions after a SOTRs' first cutaneous SCC were developed. The majority of the symposium focused on presentation of the most up to date research in cutaneous malignancy in SOTR and immunosuppressed patients with specific focus on chemoprevention, immunosuppression regimens, immunotherapy in SOTRs, spatial transcriptomics, and the development of cutaneous tumor registries. Here, we present a summary of the most impactful scientific updates presented at the 2022 ITSCC symposium.

Optimization of Tissue Digestion Methods for Characterization of Photoaged Skin by Single Cell RNA Sequencing Reveals Preferential Enrichment of T Cell Subsets.

Healthy human skin tissue is often used as a control for comparison to diseased skin in patients with skin pathologies, including skin cancers or other inflammatory conditions such as atopic dermatitis or psoriasis. Although non-affected skin from these patients is a more appropriate choice for comparison, there is a paucity of studies examining such tissue. This lack is exacerbated by the difficulty of processing skin tissue for experimental analysis. In addition, choosing a processing protocol for skin tissue which preserves cell viability and identity while sufficiently dissociating cells for single-cell analysis is not a trivial task. Here, we compare three digestion methods for human skin tissue, evaluating the cell yield and viability for each protocol. We find that the use of a sequential dissociation method with multiple enzymatic digestion steps produces the highest cell viability. Using single-cell sequencing, we show this method results in a relative increase in the proportion of non-antigen-presenting mast cells and CD8 T cells as well as a relative decrease in the proportion of antigen-presenting mast cells and KYNU+ CD4 T cells. Overall, our findings support the use of this sequential digestion method on freshly processed human skin samples for optimal cell yield and viability.

An Update and Review of Clinical Outcomes Using Immunohistochemical Stains in Mohs Micrographic Surgery for Melanoma.

BACKGROUND: Mohs micrographic surgery (MMS) provides optimal margin control through complete peripheral and deep margin assessment. The treatment of melanoma using MMS has historically been limited by difficulty in interpreting melanocytes using frozen sections. Immunohistochemical (IHC) staining, a technique whereby chromogen-tagged antibodies are used to detect antigens of interest, has revolutionized the surgical treatment of melanoma. OBJECTIVES: This article provides an update and literature review of current IHC stains used in MMS for melanoma, their sensitivities and specificities, and clinical outcomes. MATERIALS AND METHODS: A PubMed search was performed using keywords including "immunohistochemistry," "staining," and "Mohs surgery." Articles related to the use of IHC staining for the treatment of melanoma with MMS were included. RESULTS: Six IHC stains met the criteria for the review including melanoma antigen recognized by T cells (MART-1), SRY-related HMG-box (SOX10), microphthalmia-associated transcription factor, HMB-45, MEL-5, S-100, and preferentially expressed antigen in melanoma. CONCLUSION: The adaptation of IHC methods to frozen sections has enabled MMS to become a preferred treatment option for melanoma in special-site areas. Future studies are needed to standardize IHC techniques and to define best practices when using frozen section in the treatment of melanoma.

CAPABLE: A Scoring System Utilizing Patient-Reported Measures to Evaluate Patient Experience After Mohs Surgery.

BACKGROUND: Patient experience metrics are gaining prominence in health care. We introduce the CAPABLE survey to assess postoperative experiences of Mohs surgery patients. OBJECTIVE: We sought to determine whether CAPABLE scores aligned with overall patient satisfaction in Mohs surgery. METHODS: This was a cross-sectional, survey-based study of patients presenting for their first postoperative visit after Mohs surgery. The CAPABLE survey included questions on postoperative instructions, activity limitations, pain control, provider accessibility, and bleeding, followed by 2 overall satisfaction questions taken from the Outpatient and Ambulatory Surgery Consumer Assessment of Healthcare Providers and Systems survey. The pilot study took place at the University of Texas Dell Medical School (DMS), followed by a validation study ( n = 206) at DMS and Oregon Health and Science University (OHSU). We assessed for correlations between CAPABLE scores and overall satisfaction. RESULTS: In the pilot study ( n = 137), overall CAPABLE scores and scores of individual CAPABLE components correlated positively with overall satisfaction.In the multisite validation study ( n = 206) spanning DMS and OHSU, CAPABLE scores correlated positively with overall satisfaction. CONCLUSION: The CAPABLE survey is a concise tool for assessing specific, actionable components of the postoperative patient experience in Mohs surgery, while correlating with overall patient satisfaction.

Pathologic Upstaging of Cutaneous Melanoma After Mohs Micrographic Surgery.

BACKGROUND: Mohs micrographic surgery (MMS) is used for melanoma in situ (MIS) and thin invasive melanomas, particularly on the head and neck, during which a debulk section is typically prepared. Tumor upstaging occurs if the debulking specimen meets criteria for an increased tumor (T) stage per the American Joint Committee on Cancer 8th edition compared with the initial biopsy. Upstaging can alter survival and recurrence outcomes, resulting in increased patient morbidity and mortality. OBJECTIVE: To determine the rate of cutaneous melanoma upstaging during MMS. MATERIALS AND METHODS: A multicenter study was performed. Information from electronic medical records from 3 dermatologic surgeons performing MMS for cutaneous melanoma were logged from January 1, 2017 to December 31, 2021. Deidentified information regarding patient demographics and tumor characteristics was recorded. RESULTS: Three-hundred and ten cases of cutaneous melanoma treated with MMS were identified. 2.3% of cases were upstaged, ranging from T1a to T3a. No significant risk factors for upstaging were identified. CONCLUSION: Our data demonstrate a lower rate of cutaneous melanoma upstaging during MMS than the current literature. Differences may be accounted for because of differing patient populations, cutaneous melanoma detection at an earlier clinical stage, and evolving melanoma histologic criteria.

Double V-Y Island Pedicle Flap for Dorsal Hand Reconstruction Following Mohs Micrographic Surgery.

Medium to large defects on the dorsal hand pose a reconstructive challenge following dermatologic surgery. Repairs in this location can be complicated by a paucity of adjacent tissue reservoirs, competing tension vectors, thin cutaneous tissue, and superficial tendons and vasculature. In such cases, a double V-Y island pedicle flap is an effective reconstructive solution. It preserves hand function, harnesses local tissue with a robust blood supply, facilitates complete closure, and provides skin that closely matches the original's color and texture. Here, we present the repair of a medium to large dorsal hand defect after Mohs micrographic surgery for melanoma in situ, using a double V-Y island pedicle flap.

Tranexamic Acid Prevention of Hemorrhagic Complications Following Interpolated Flap Repair: A Single-Center, Retrospective, Cohort Study.

BACKGROUND: Tranexamic acid (TXA) is increasingly being used to prevent hemorrhagic complications after dermatologic surgery. Interpolated flap repairs following Mohs micrographic surgery are at risk for increased bleeding events and unplanned health care utilization, particularly among patients on antithrombotic medication. OBJECTIVE: To assess bleeding events after interpolated flap repair in patients receiving TXA compared with those who did not. MATERIALS AND METHODS: A retrospective review identified interpolated flap repairs in a 5-year period. Hemorrhagic complications were analyzed, defined as major bleeding events, which included all unplanned medical visits, and minor bleeding events, which included any unplanned patient phone calls or messages through electronic medical record. RESULTS: One hundred fifteen patients had interpolated flap repair during the 5-year period, of which 21 (18.3%) received TXA postprocedure. Twenty-seven bleeding events were identified in the non-TXA group compared with 1 event in the TXA-treated group. Patients who received TXA were less likely to have had a bleeding event (28.7% vs 4.8%, p < .01). CONCLUSION: Patients undergoing interpolation flap repair were less likely to experience a bleeding event after subcutaneous injection of TXA.

Bilateral Transposition Flaps With Split-Thickness Skin Grafting of Secondary Defects After a Large Mohs Micrographic Surgery Defect With Exposed Calvarium.

Large, full-thickness defects of the scalp create a common reconstructive dilemma following Mohs micrographic surgery. In cases with exposed calvarium, transposition flap(s) followed by split-thickness skin graft(s) to the secondary defect is an effective method of reconstruction that allows for same-day repair, full defect coverage, and good functional outcomes. Herein, we present the reconstruction of a large scalp defect utilizing bilateral transposition flaps followed by split-thickness skin grafts of the secondary defects.

Postoperative Complications After Interpolated Flap Repair for Mohs Defects of the Nose: A Multicenter Prospective Cohort Study.

BACKGROUND: Dermatologists perform most interpolated flaps after skin cancer resection. Prospective, multicenter data on complications after interpolated flap repair in this setting are limited. OBJECTIVE: To determine the rate of physician-reported complications after interpolated flap repair of the nose. METHODS: Multicenter, prospective cohort study of 169 patients undergoing 2-stage interpolated flap repair of post-Mohs nasal defects. Frequency of bleeding, infection, dehiscence, necrosis, hospitalization, and death in the 30 days after flap placement and flap takedown are reported. RESULTS: Patients experienced 23 complications after flap placement (13.61%) and 6 complications after flap takedown (3.55%) that were related to the surgical procedure. The most frequent complication after flap placement was bleeding (9, 5.33%, 95% confidence interval [CI]: 2.83%-9.82%). The most frequent complication after flap takedown was infection (5, 2.96%, 95% CI: 1.27%-6.74%). There was one hospitalization related to an adverse reaction to antibiotics. There were no deaths. CONCLUSION: Most complications after interpolated flap repair for post-Mohs defects of the nose are minor and are associated with flap placement. Interpolated flap repair for post-Mohs defects can be performed safely in the outpatient setting under local anesthesia.

Permanent section margin concordance after Mohs micrographic surgery with immunohistochemistry for invasive melanoma and melanoma in situ: A retrospective dual-center analysis.

BACKGROUND: Mohs micrographic surgery (MMS) for melanoma practices vary among dermatologic surgeons. The implementation of immunohistochemical staining in MMS for melanoma mitigates challenges associated with slide interpretation; however, the reliability of melanoma antigen recognized by T cells 1 (MART-1), the preferred immunostain for melanoma, has yet to be compared with permanent section pathology. OBJECTIVE: To assess concordance rates of MART-1 frozen sections and permanent section pathologic interpretation of melanoma treated with MMS. METHODS: A dual-center retrospective analysis was conducted to collect concordance and demographic data. Chi-square tests were performed for group comparisons of categorical variables. RESULTS: Of the 379 permanent sections sent, 367 were concordant with frozen section pathology for an overall concordance rate of 96.8%. Cases were stratified into indeterminately concordant and indisputably concordant. Twenty-two (6%) of cases were indeterminately concordant, whereas 345 (94.0%) of cases were indisputably concordant. LIMITATIONS: The concordance rate is derived from a comparison of adjacent tissue margins, an inevitable consequence of utilizing 2 techniques. CONCLUSION: To the author's knowledge, this study represents the largest investigation examining concordance rates of MART-1 frozen sections in Mohs for melanoma. High concordance disputes the ongoing need for additional permanent margins when using MART-1 in routine cases.

Patient-Reported Nasal Function and Appearance After Interpolation Flap Repair Following Skin Cancer Resection: A Multicenter Prospective Cohort Study.

Objective: Among patients undergoing two-stage interpolated flap repair of nasal defects, nasal function, and appearance before surgery and at 16 weeks after flap takedown were compared using the Nasal Appearance and Function Evaluation Questionnaire (NAFEQ). Design: Multicenter prospective cohort study. Methods: Adult patients with a nasal skin cancer anticipated to require two-stage interpolation flap repair completed the NAFEQ before surgery, at 1 week after flap placement, 4 weeks after flap takedown, and 16 weeks after flap takedown. Results: One hundred sixty-nine patients were enrolled, with 138 patients completing both presurgical and 16-week post-takedown NAFEQs. Overall NAFEQ score increased by 1.09 points (1.91% improvement, confidence interval [95% CI -0.34 to 2.53]). NAFEQ functional subscale increased by 0.72 points (2.58% increase; 95% CI [0.10-1.35]) and appearance subscale increased by 0.37 points (1.28% improvement, 95% CI [-0.65 to 1.39]). Conclusion: At 16 weeks after flap takedown, patients' perceptions of their nasal function and appearance are similar to or slightly improved when compared with their presurgical assessments.

Efficacy of Abemaciclib in the Management of Refractory Metastatic Extramammary Paget's Disease.

Published systemic therapy options for metastatic extramammary Paget's disease have largely been anecdotal due to the rarity of this disease, which has precluded the ability to conduct clinical trials. We describe the favorable response of a 72-year-old man with extramammary Paget's disease, whose disease has been controlled with the CDK4/6 inhibitor, abemaciclib. The rationale behind the selection of this therapy is discussed.