BACKGROUND:Current staging systems for head and neck cutaneous squamous cell carcinoma (HNCSCC), such as AJCC8 and BWH, often fail to adequately stratify high-risk patients, particularly due to the exclusion of important biological and host factors. This study aimed to identify independent prognostic factors for HNCSCC outcomes in the largest multi-institutional retrospective series to date. METHODS:De-identified data from 8,610 primary HNCSCC tumors, treated with curative intent surgery across multiple international centers, were analyzed. Outcomes included local recurrence (LR), locoregional metastasis (LM), distant metastasis (DM), and disease-specific death (DSD). Multivariable Fine-Gray subdistribution hazard regression models with robust standard errors clustered at the patient level were fitted to generate exploratory hypotheses regarding independent hazard determinants. RESULTS:During a median follow-up of 31.4 months (IQR 14.2-52.8), the cumulative incidence was 3.3% for LR, 2.7% for LM, 0.5% for DM, and 1.2% for DSD. Multivariable analysis confirmed that tumor diameter, poor differentiation, deep invasion, and large-caliber perineural invasion (LCPNI) were the strongest predictors, being significantly associated with at least three of the four outcomes. Notably, factors currently excluded from or weighted differently in staging systems also proved critical: Immunosuppression was significantly associated with LR (SHR 2.03) and DSD (SHR 1.70); and lymphovascular invasion (LVI) was independently associated with LM (SHR 3.00). Poor differentiation demonstrated high prognostic impact, being a significant predictor for all four endpoints. CONCLUSION:Tumor diameter, poor differentiation, deep invasion, LCPNI, immunosuppression status, and LVI are the most critical independent factors for HNCSCC prognosis. Our multi-institutional data provide a robust framework for hypothesis generation, highlighting that incorporating host biological features and non-anatomic variables could significantly refine future staging system discussions.

BACKGROUND:Immunosuppression is associated with a higher risk of developing cutaneous squamous cell carcinoma (CSCC) and more aggressive tumors, but its role as an independent predictor of poor outcomes remains unclear. OBJECTIVE:To determine whether immunosuppression independently predicts poor outcomes in CSCC. METHODS:This was a retrospective cohort study with pooled data from 12 international centers. Demographics, immunosuppression status, tumor characteristics, treatment, and outcomes were collected. Univariable and multivariable marginal Fine and Gray competing risk analyses were performed. Subgroup multivariable analyses were performed on the organ transplant and chronic lymphocytic leukemia cohorts. RESULTS:A total of 11,930 patients with 18,760 tumors (14,766 in immunocompetent and 3994 in immunosuppressed) were included. Immunosuppressed patients had a higher prevalence of high-risk tumor features and poor disease outcomes. On multivariable analysis, immunosuppression was independently associated with local recurrence (LR), distant metastasis, disease-specific death (DSD), and major poor outcomes. Organ transplantation was predictive of LR, distant metastasis, and DSD, whereas chronic lymphocytic leukemia independently predicted LR, DSD, and major poor outcomes. LIMITATIONS:A retrospective design, potential for data heterogeneity. CONCLUSIONS:Immunosuppression is an independent risk factor for major poor outcomes in CSCC and should be included in risk nomograms.

Background While Brigham and Women's Hospital T1 cutaneous squamous cell carcinomas are overall low risk, a small subset develop poor outcomes. Objective To evaluate the impact of minor risk factors on poor outcomes in T1 tumors. Methods Data were collected retrospectively from 11 centers. Univariable and multivariable regression analyses were performed evaluating the impact of minor risk factors (moderate differentiation, diameter 1-2 centimeters, fat invasion, and small-caliber perineural invasion) on poor outcomes. Cumulative incidence function plots were created for time to poor outcomes by number of minor risk factors. Results A total of 15,481 Brigham and Women'’s Hospital T1 tumors were included, of which 90 (0.58%) developed major poor outcomes and 332 (2.1%) developed any poor outcome. Minor risk factors that were significant on multivariable analysis included moderate differentiation, diameter, and subcutaneous fat invasion. Cumulative incidence function plots demonstrated an increased risk of poor outcomes with presence of multiple minor risk factors; the risk of metastasis and major poor outcomes exceeded 5% in tumors with 3 minor risk factors. Limitations Retrospective design, limited number of major poor outcomes. Conclusion T1 tumors with multiple minor risk factors may be eligible for closer surveillance. Future staging systems should consider incorporating both major and minor risk factors.

BACKGROUND:The use of Mohs micrographic surgery as a treatment for melanoma is rising, but the reliability of Mohs surgeons in assessing MART-1 melanoma en-face margins has not been evaluated. OBJECTIVE:To evaluate interrater and intrarater reliability of Mohs surgeons in interpreting margins of early-stage melanoma. METHODS:Twenty Mohs surgeons were asked to independently review images of frozen section MART-1 en-face peripheral margins of in situ or early-stage melanoma. Surgeons determined margins as positive or negative at initial evaluation and 6 weeks later. Primary outcomes were interrater and intrarater reliability. RESULTS:Interrater agreement was 84.1% (95% confidence interval [CI]: 75.5%-92.8%) for assessment 1 and 87.5% (95% CI: 78.4%-96.4%) for assessment 2, with kappa values 0.68 (95% CI: 0.50-0.82) and 0.75 (95% CI: 0.57-0.88). Average intrarater percent agreement was 95.0% (95% CI: 70.6%-100.0%) with average kappa 0.90 (95% CI: 0.50-1.00). CONCLUSION:Substantial interrater and nearly perfect intrarater agreement was identified among surgeons assessing melanoma margins utilizing MART-1 immunostaining, demonstrating consistent and reproducible assessment of melanoma margins during Mohs cases.

BACKGROUND:Data are limited regarding the performance of staging systems for non-head and neck cutaneous squamous cell carcinomas (non-HNCSCCs). OBJECTIVE:The aim of this study was to evaluate the performance of the Brigham and Women's Hospital (BWH) and American Joint Committee on Cancer 8th edition (AJCC8) staging system in predicting poor outcomes in non-HNCSCCs. PATIENTS AND METHODS:Demographics, tumor features and stages, and outcomes for non-HNCSCCs were collected retrospectively from 11 institutions in two countries. Poor outcomes included local recurrence, metastasis, and disease-specific death; major poor outcomes excluded local recurrence. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), concordance index (c-index), and 3-year cumulative incidence were calculated. Cumulative incidence function (CIF) plots were created. RESULTS:9300 non-HNCSCCs were included. Ninety-five tumors (1%) resulted in major poor outcomes; 250 (2.7%) resulted in poor outcomes. The rate of local recurrence was 1.9%, and the rate of nodal metastasis was 0.74%. Major poor outcomes were predicted with sensitivities 0.48/0.49, specificities 0.98/0.96, PPVs 0.17/0.13, NPVs 0.99/0.99, and c-indices 0.73/0.74 for BWH/AJCC8. Poor outcomes were predicted with sensitivities 0.24/0.26, specificities 0.98/0.97, PPVs 0.22/0.17, NPVs 0.98/0.98, and c-indices 0.61/0.61 for BWH/AJCC8. CONCLUSIONS:Both systems performed similarly in predicting poor outcomes in non-HNCSCCs. Specificity and NPV were high, sensitivity and PPV were low, and c-indices were moderately high. As the c-indices were comparable to those seen in the HNCSCC literature, it is reasonable to use the BWH and AJCC8 staging systems for tumors located off the head and neck. However, further refinement of CSCC staging systems is needed to improve prognostication.

IMPORTANCE:Risk stratification of cutaneous squamous cell carcinoma (CSCC) is central to effective management. Despite advancements in the 8th edition of the American Joint Committee on Cancer (AJCC8) staging system, the distinctiveness of T-stages remains limited. OBJECTIVE:To evaluate the effectiveness of the Brigham and Women's Hospital (BWH) and the AJCC8 staging systems in predicting poor outcomes in head and neck (HN) CSCC. DESIGN:A retrospective, multinational cohort study of CSCCs diagnosed between January 10, 1991, and December 31, 2023. SETTING:Twelve centers across the United States (10), Spain (1), and Brazil (1). PARTICIPANTS:Patients with invasive CSCC who underwent curative-intent surgical treatment. Exclusions included cases of lip CSCC, cases with prior HN cancer with associated regional disease, patients with a history of chemotherapy/radiotherapy for other HN neoplasms, and recurrent primary tumors. EXPOSURE:Tumors were staged according to both the AJCC8 TNM staging system and the BWH tumor classification. MAIN OUTCOMES AND MEASURES:Local recurrence (LR), nodal recurrence (NR), distant recurrence (DR), and disease-specific death (DSD). RESULTS:A total of 9852 excised tumors from 3168 patients were included. The 2 systems had comparable monotonicity and homogeneity. Significant differences could be observed in 5-year cumulative incidence for DSD in both BWH and AJCC8, and also for LR in BWH. Higher T-stages exhibited similar curves regarding NR and DR for both AJCC8 and BWH staging systems. Overall, we observed high specificity and NPV, low sensitivity and PPV, and moderately high c-indices for both the BWH and AJCC8 staging systems in predicting the main outcomes for HNCSCC. CONCLUSION AND RELEVANCE:Current AJCC8 and BWH staging systems can accurately predict survival in HNCSCC, although there are still important characteristics to be addressed in future staging systems for better stratification according to the other main outcomes.

Background: Among the 1.5 million cases of cutaneous squamous cell carcinoma (cSCC) diagnosed annually in the United States, a subset of aggressive tumors recur or metastasize. Treatment options include total margin-controlled surgery, such as Mohs micrographic surgery or other forms of peripheral and deep en face margin assessment (MMS/PDEMA), and standard excision with postoperative vertical section margin assessment (SEVMA). NCCN Guidelines recommend MMS/PDEMA for the management of cSCC classified as very high risk based on NCCN risk stratification criteria. This study aims to validate the recommendation of MMS/PDEMA as the preferred surgical approach for NCCN very high-risk cSCCs, using data from a multicenter, multinational cohort. Methods: A multicenter cohort study was conducted across 12 sites, including 10 in the United States, 1 in Spain, and 1 in Brazil, comprising 2,752 primary NCCN very high-risk cSCCs treated with MMS/PDEMA or SEVMA. Propensity score-weighted analysis was used to balance baseline characteristics. Outcomes included local recurrence (LR), nodal metastasis (NM), distant metastasis (DM), and disease-specific death (DSD). Results: After balancing baseline characteristics, SEVMA was associated with a 2-fold higher rate of poor outcomes, including recurrence, metastasis, and DSD, compared with MMS/ PDEMA. The 3-year cumulative incidence of poor outcomes was higher for SEVMA: LR (12.5% vs 5.9%), NM (11.6% vs 6.0%), DM (4.3% vs 1.9%), and DSD (6.2% vs 3.3%). Conclusions: This study supports the NCCN recommendation of MMS/PDEMA for NCCN very high-risk cSCC, showing reduced recurrence, metastasis, and cSCC-specific mortality compared with SEVMA.

BACKGROUND:Satellitosis or in-transit metastasis (S-ITM) from cutaneous squamous cell carcinoma (cSCC) is associated with poor outcomes but is not included in current staging guidelines. OBJECTIVE:To determine risk factors and prognostic significance of S-ITM. METHODS:This cohort study included 8901 patients with cSCC from 12 institutions (1998-2023). Risk factors for S-ITM were calculated using logistic regression. Outcomes were compared with 1:2 propensity score matched controls using a Fine-Gray subdistribution hazard model. RESULTS:Seventy-seven patients developed S-ITM. Increased patient age (odds ratio [OR], 1.03; 95% CI, 1.01-1.05; P < .01), history of immunosuppression (OR, 4.31; 95% CI, 2.59-7.10; P < .001), higher Brigham and Women's Hospital stage (T2a OR, 4.14; 95% CI, 2.05-8.41; T2b OR, 15.96; 95% CI, 8.58-31.19; and T3 OR, 30.27; 95% CI, 10.70-79.04; all P < .001), and lymphovascular invasion (OR, 4.57; 95% CI, 1.80-10.38; P = .001) were independent risk factors for S-ITM. S-ITM was associated with local recurrence (subhazard ratio [SHR], 2.40; 95% CI, 1.43-4.04; P < .001), nodal metastasis (SHR, 1.89; 95% CI, 0.02-3.49; P = .04), distant metastasis (SHR, 4.41; 95% CI, 1.45-13.27; P = .01), and disease-specific death (SHR, 4.48; 95% CI, 2.34-8.58; P < .001). LIMITATIONS:Retrospective cohort study. The rarity of S-ITM may limit statistical power. CONCLUSION:Patients with cSCC and S-ITM are at higher risk for poor outcomes independent of patient, tumor, and treatment characteristics.

BACKGROUND:Lymphovascular invasion (LVI) is regarded as a high-risk feature of cutaneous squamous cell carcinoma (CSCC) but is currently absent from CSCC staging systems. OBJECTIVE:To assess whether LVI serves as an independent predictor of major poor outcomes in CSCC. METHODS:Twelve centers contributed to a multinational CSCC database. Clinical and pathologic risk factors, treatment, and patient outcomes were retrospectively collected. CSCCs were stratified based on LVI status. Tumors that developed major poor outcomes defined as nodal metastasis, in-transit metastasis, distant metastasis, and disease-specific death were identified. RESULTS:A total of 23,166 CSCCs were identified, 179 were LVI+ tumors (0.8%). LVI+ tumors had a higher cumulative incidence of major poor outcomes than those without LVI (33.5% vs 3.2% at 3 years; overall cumulative incidence function P < .001). In an adjusted analysis, LVI+ tumors had an 82% increase in the rate of developing major poor outcomes when compared to LVI- tumors (subdistribution hazard ratio = 1.82; P = .002). Notably, LVI+ low-stage Brigham and Women's Hospital (BWH) tumors (T1 or T2a) had a greater cumulative incidence of major poor outcomes compared to LVI- BWH low-stage tumors (20.7% vs 1.61% at 3 years, overall cumulative incidence function P < .001). LIMITATIONS:Retrospective study design. CONCLUSION:The presence of LVI in CSCC is a high-risk feature that is an independent predictor of metastasis and disease-specific death in both low and high BWH stage tumors.

Cutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer, with rising incidence. While most CSCCs are cured with surgical intervention, a subset will develop poor outcomes. Despite its prevalence, CSCC is excluded from national cancer registries in the United States and many other countries. This poses a significant challenge, as most CSCC studies are single or dual-center retrospective cohort studies with small sample sizes or based on European registries. To address this barrier, 12 institutions in the United States, Spain, and Brazil pooled retrospective tumor data to establish the largest CSCC cohort to date with 23,166 tumors. In this protocol, we provide detailed methods and cohort information for this pooled database. Of the 12 centers, 10 are in the United States, 1 is in Spain, and 1 is in Brazil; this includes 10 academic centers, 1 private practice, and 1 private philanthropic hospital. Patient information (demographics and immunosuppression status), tumor details, treatment history, disease outcomes, and follow-up duration were collected. We present inclusion and exclusion criteria for each of the 12 centers, including date ranges, age restrictions, and follow up specifications. Three centers only included tumors treated with Mohs surgery, and 1 center only included tumors treated with excision. One site included only head and neck tumors, and 8 centers excluded mucosal and genital tumors. Five institutions included only higher risk CSCCs, with varying definitions. Disease outcomes included local recurrence, nodal metastasis, satellite/in-transit metastasis, distant metastasis, disease-specific death, and overall mortality. This multi-institutional, international database is a significant step forward in refining our understanding of CSCC, as it has the largest sample size to date allowing for analyses with improved power and external validity. Multiple analyses utilizing this pooled dataset are currently underway. This published protocol with detailed methods and cohort information will enhance the transparency and interpretation of these studies.

Although many patients with advanced melanoma benefit from targeted immune checkpoint blockade inhibiting programmed death-1 (PD-1) or cytotoxic T-lymphocyte antigen-4, many do not respond and some even progress while on therapy, prompting the need for other treatment options.1 The literature is sparse regarding the effectiveness of intralesional talimogene laherparepvec (T-VEC) in patients with progression of metastatic melanoma while on PD-1 inhibitor therapy. Here, we describe a patient with progressive locoregional melanoma metastases resistant to PD-1 inhibitor therapy who achieved complete response with intralesional T-VEC.

BACKGROUND:Mohs surgery for melanoma has been performed for many decades, but advances in the use of immunohistochemistry with frozen sections during Mohs surgery have allowed for more accurate, reliable, and efficient margin assessment with improved local control of the disease. OBJECTIVE:To describe the use of MART-1 in treating melanoma with Mohs surgery and serve as a primer for the Mohs surgeon adding melanoma cases to their repertoire. MATERIALS AND METHODS:Review of the literature and discussion of experience with Mohs for melanoma. RESULTS:Practical approach and pitfalls when assessing margins using MART-1 immunohistochemistry during Mohs surgery for the treatment of melanoma. CONCLUSION:Mohs for melanoma is an expanding field-education of Mohs surgeons and increasing the practice of this technique has the potential to improve patient outcomes.

BACKGROUND Marginally recurrent melanoma (MRM) manifests immediately adjacent to or within a scar and arises from incomplete tumor clearance after primary treatment. Little is known about the progression and treatment of MRM after all forms of excision. OBJECTIVE To determine the invasive growth potential, tumor-stage progression, and outcomes of those with MRM. METHODS One hundred forty patients with MRM were collected from 5 practice databases. All patients were treated with Mohs micrographic surgery. They were evaluated for Breslow depth and tumor stage change from the time of primary treatment and recurrent treatment. RESULTS Of 101 cases initially treated as melanoma in situ, 13 (12.9%) marginally recurred with invasive disease at the time of Mohs micrographic surgery. The median thickness of these recurrent melanomas was 0.58 mm. Of 39 cases initially treated as invasive melanoma, 10 (25.6%) marginally recurred with a greater Breslow depth. The median increase in thickness from initial treatment to recurrence was 1.31 mm. CONCLUSION Marginally recurrent melanoma retains its invasive growth potential. This can lead to Breslow depth increase, tumor-stage progression, and a worse prognosis on recurrence. Obtaining tumor-free margins is critical in initial and recurrence treatments.