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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.

Importance: Perineural invasion (PNI) is an adverse risk feature in cutaneous squamous cell carcinoma (CSCC) that affects patient prognosis and disease management. However, research comparing different PNI patterns on patient outcomes is limited., Objective: To compare 4 assessments of PNI in CSCC, their associations with poor outcomes, and implications for their inclusion in the Brigham and Women's Hospital (BWH) staging system., Design, Setting, and Participants: This retrospective cohort study was performed at a single tertiary care institution and compared 4 PNI assessments: nerve caliber, number of involved nerves per section, PNI maximal depth, and PNI location with respect to tumor. Patients with primary, localized, invasive CSCC with PNI diagnosed between January 1, 2000, and December 31, 2017, were identified via an electronic in-house database. Available pathology slides were secondarily reviewed by study authors. Relevant patient and tumor characteristics and outcomes were abstracted from the medical record. Data analysis was performed between September 6 and October 20, 2022., Main Outcomes and Measures: Risks of recurrence, disease-specific death, and a composite end point (any poor outcome) were calculated via multivariable stepwise Fine and Gray competing-risks regression. Considered revisions to the BWH staging system were assessed via receiver operating characteristic curves and test characteristics., Results: This study included 140 patients with CSCC, with a mean (SD) age of 75.1 (11.2) years. More than half of the patients were men (93 [66.4%]), and most identified as White (132 [94.3%]). Of the 4 PNI assessments studied, only involvement of multiple nerves was associated with poor outcomes. Perineural invasion of 5 or more distinct nerves (extensive PNI [ePNI]) was independently associated with local recurrence (subhazard ratio [SHR], 13.83 [95% CI, 3.50-54.62]; P < .001), disease-specific death (SHR, 6.20 [95% CI, 1.59-24.21]; P = .009), and any poor outcome (SHR, 10.21 [95% CI, 2.88-36.15]; P < .001). A revised BWH staging system with substitution of ePNI for large-caliber PNI resulted in improved area under the curve and test characteristics compared with current BWH staging criteria that use nerve caliber as the measure of PNI., Conclusions and Relevance: The findings of this cohort study suggest that ePNI is the best prognostic measure of PNI. Because ePNI obviated the need for a micrometer and had superior prognostic capacity to nerve caliber in this cohort, ePNI should be considered for inclusion in CSCC tumor staging. Inclusion of ePNI as a high-risk factor in CSCC staging systems may optimize patient selection for primary treatment and adjuvant interventions.

Importance: The 2022 National Comprehensive Cancer Network (NCCN) reclassified cutaneous squamous cell carcinoma (CSCC) into low-, high-, and very high-risk groups to better risk stratify tumors. Mohs micrographic surgery (Mohs) or peripheral and deep en face margin assessment (PDEMA) became preferred surgical modalities for high- and very high-risk tumors. This new risk stratification and the recommendation for Mohs or PDEMA in high- and very high-risk groups have not been validated., Objective: To compare outcomes in very high-, high-, and low-risk NCCN groups of CSCCs and in CSCCs treated with Mohs or PDEMA compared with wide local excision (WLE)., Design, Setting, and Participants: This retrospective cohort study of CSCCs was performed in 2 tertiary care academic medical centers. Patients 18 years or older and diagnosed between January 1, 1996, and December 31, 2019, at Brigham and Women's Hospital and Cleveland Clinic Foundation were included. Data were analyzed from October 20, 2021, to March 29, 2023., Exposures: NCCN risk group, Mohs or PDEMA, and WLE., Main Outcomes and Measures: Local recurrence (LR), nodal metastasis (NM), distant metastasis (DM), and disease-specific death (DSD)., Results: A total of 10 196 tumors from 8727 patients were stratified by NCCN guidelines into low-, high-, and very high-risk groups (6003 [59.0%] men; mean [SD] age, 72.4 [11.8] years). Compared with the low-risk group, the high- and very high-risk groups demonstrated a greater risk of LR (high-risk subhazard ratio [SHR], 1.99 [95% CI, 1.21-3.27; P = .007]; very high-risk SHR, 12.66 [95% CI, 7.86-20.39; P < .001]), NM (high-risk SHR, 4.26 [95% CI, 1.28-14.23; P = .02]; very high-risk SHR, 62.98 [95% CI, 19.24-206.17; P < .001]), DM (high-risk SHR, 2.2 × 107 [95% CI, 4.7 × 103-1.1 × 1011; P < .001]; very high-risk SHR, 6.3 × 108 [95% CI, 1.4 × 105-2.9 × 1012; P < .001]), and DSD (high-risk SHR, 4.02 [95% CI, 1.18-13.71; P = .03]; very high-risk SHR, 93.87 [95% CI, 29.19-301.85; P < .001]). Adjusted 5-year cumulative incidence was significantly higher in very high- vs high- and low-risk groups for LR (9.4% [95% CI, 9.2%-14.0%] vs 1.5% [95% CI, 1.4%-2.1%] and 0.8% [95% CI, 0.5%-1.2%], respectively), NM (7.3% [95% CI, 6.8%-10.9%] vs 0.5% [95% CI, 0.4%-0.8%] and 0.1% [95% CI, 0.03%-0.3%], respectively), DM (3.9% [95% CI, 2.6%-5.6%] vs 0.1% [95% CI, 0.04%-0.2%] and 0.01% [95% CI, not applicable], respectively), and DSD (10.5% [95% CI, 10.3%-15.4%] vs 0.5% [95% CI, 0.4%-0.8%] and 0.1% [95% CI, 0.04%-0.3%], respectively). Compared with CSCCs treated with WLE, those treated with Mohs or PDEMA had lower risk of LR (SHR, 0.65 [95% CI, 0.46-0.90]; P = .009), DM (SHR, 0.38 [95% CI, 0.18-0.83]; P = .02), and DSD (SHR, 0.55 [95% CI, 0.36-0.84]; P = .006)., Conclusions and Relevance: The findings of this cohort study suggest that the NCCN high- and very high-risk groups identify CSCCs at greatest risk for developing poor outcomes. Further, Mohs or PDEMA resulted in lower LR, DM, and DSD compared with WLE.

Importance: Unlike Merkel cell carcinoma and melanoma, satellitosis or in-transit metastasis (S-ITM) is not incorporated into the current cutaneous squamous cell carcinoma (CSCC) staging systems. It is important to determine if the clinical outcomes of S-ITM are relevant to prognosis for patients with CSCC., Objectives: To evaluate the association of S-ITM with clinical outcomes in patients with CSCC and to determine its prognostic implications., Design, Settings, and Participants: A dual-institution (Cleveland Clinic and Brigham and Women's Hospital) database was queried for patients who were treated for CSCC in 2010 to 2020. Patients who were node-negative and had S-ITM-the presence of dermal lesions between the primary tumor and first-echelon lymphatic nodal basins at any point in the disease course-were identified. Subcohorts of patients with T3N0 tumors, T4N0 tumors (bone invasive), N1 to 3, and M1 disease were identified for comparison. The American Joint Committee on Cancer staging system was used to define cancer stages. Data were analyzed from January 15 to March 31, 2021., Main Outcomes and Measures: Pairwise comparison of CSCC recurrence and disease-specific survival in patients with and without S-ITM was performed using Cox proportional hazard modeling. Kaplan-Meier and Fine-Gray competing risk methods were used to estimate disease-specific survival and CSCC recurrence, respectively., Results: In a total of 518 patients with CSCC, S-ITM was present in 72 (13.9 %) patients (median age [range], 73.9 [31.6-95.8] years; 59 [82%] men; 69 [96%] White non-Hispanic individuals; 25 [35%] patients with immunosuppression) who were node-negative. The subcohorts were composed of 341 patients with T3N0 cancer, 36 with T4N0, 70 with N1 to 3, and 19 with M1 disease. Pairwise comparisons between disease levels using Cox proportional hazard model demonstrated lower cumulative incidence of CSCC recurrence rates in the T3N0 (HR, 0.21; 95% CI, 0.14-0.30; P < .001) and T4N0 (HR, 0.36; 95% CI, 0.19-0.68; P = .001) cohorts compared with the S-ITM cohort. No significant difference was observed between patients who were node-positive and those with S-ITM (HR, 0.74; 95% CI, 0.48-1.14; P = .16). The 5-year disease-specific survival rates were 76% for T3N0, 64% for T4N0, 41% for S-ITM, and 39% for N1 to 3. Compared with the S-ITM cohort, DSS was significantly higher in the T3N0 (HR, 0.23; 95% CI, 0.15-0.35; P < .0001) and T4N0 (HR, 0.37; 95% CI, 0.19-0.76; P = .01) cohorts, and not significantly different in the node-positive (HR, 0.77; 95% CI, 0.84-3.93; P = .30) and metastatic cohorts (HR, 1.81; 95% CI, 0.84-3.93; P = .13)., Conclusions and Relevance: This multi-institutional cohort study found that patients with CSCC and S-ITM appear to have clinical outcomes comparable to those of patients who are node-positive, and an increased risk of recurrence and worse survival compared with patients who have T3 and T4 disease. These outcomes are similar to those observed for Merkel cell carcinoma and melanoma. Given that S-ITM may be a powerful prognostic factor, it should be incorporated into clinical staging systems.

Importance: Brigham and Women's tumor classification (BWH) better predicts poor outcomes than American Joint Committee on Cancer (AJCC) 7th edition (AJCC 7). AJCC 8th edition (AJCC 8) has not been evaluated., Objectives: To compare BWH and AJCC 8 tumor classifications for head and neck cutaneous squamous cell carcinoma (HNCSCC)., Design, Setting, and Participants: A total of 459 patients with 680 HNCSCCs in this cohort study were staged via BWH and AJCC 8 classifications and poor outcomes (ie, local recurrence [LR], nodal metastasis [NM], disease specific death [DSD], and overall survival [OS]) were compared. The study was carried out at a single academic tertiary care center in Boston, Massachusetts., Main Outcomes and Measures: Distinctiveness (outcome differences between tumor class), homogeneity (outcome similarity within tumor class), monotonicity (outcome worsening with increasing tumor class), and C statistic., Results: A total of 680 HNCSCCs in 459 patients were included in this study, of which 313 (68%) were men with the mean (SD) age of 70.2 (12.7) years. The AJCC 8 (T3/T4) and BWH (T2b/T3) high tumor classes accounted for 121 (18%) vs 63 (9%), 17 (71%) vs 16 (70%), and 11 (85%) vs 12 (92%) of total cases, metastases, and deaths, respectively. The AJCC 8 T2 and T3 comprised 23% of cases and had statistically indistinguishable outcomes. The BWH had higher specificity (93%) and positive predictive value (30%) for identifying cases at risk for metastasis or death. C statistics showed BWH to be superior in predicting NM and DSD (P = .01 and P = .005, respectively), but there was no difference for LR and OS., Conclusions and Relevance: Lack of distinction between AJCC T2 and T3 resulted in a 23% subset of HNCSCCs with significant risk of metastasis and death-too large of a group for routine nodal staging or consideration of adjuvant therapy. The BWH identifies the same number of poor outcomes in a 9% subset of HNCSCCs, thus minimizing inappropriate upstaging of low-risk disease.

Importance: Perineural invasion (PNI) in cutaneous squamous cell carcinoma (CSCC) has been associated with an increased risk of poor outcomes. Patients with PNI may present with clinical symptoms and/or radiologic evidence of PNI (clinical PNI [CPNI]), yet most patients are asymptomatic and PNI is often found on histologic examination (incidental PNI [IPNI]). Evidence-based estimates of the risks of disease-related outcomes comparing IPNI and CPNI are limited in the dermatology literature., Objectives: To review and synthesize outcomes data for patients with CSCC and CPNI or IPNI., Data Sources: A systematic review was conducted in MEDLINE and EMBASE for English-language articles published since inception to November 11, 2016., Study Selection: All studies that reported a disease-related outcome (local recurrence, nodal metastasis, distant metastasis, or disease-specific death) of CSCCs with CPNI and IPNI were included., Data Extraction and Synthesis: Articles were screened for eligibility, and any possible discrepancies in this screening were resolved. Data extracted included study characteristics, tumor characteristics, treatments performed, and disease-related outcomes. Overall risks of disease-related outcomes were generated by pooling patients from eligible studies. χ2 Statistics and Fisher exact tests were used to evaluate differences in disease-related outcomes., Main Outcomes and Measures: Risks of disease-related outcomes and 5-year recurrence-free, disease-specific, and overall survival., Results: A total of 12 studies containing 241 patients with CPNI and 381 patients with IPNI were included in the systematic review and analysis. The overall risks of local recurrence and disease-specific death were significantly higher in patients with CSCC and CPNI compared with those with CSCC and IPNI (local recurrence, 37% vs 17%; P < .001; disease-specific death, 27% vs 6%; P < .001). The risks of nodal metastasis and distant metastasis did not differ significantly by PNI classification. Patients with CSCC and CPNI had poorer mean 5-year recurrence-free survival and disease-specific survival compared with patients with IPNI (recurrence-free survival, 61% vs 76%; P = .009; disease-specific survival, 70% vs 88%; P = .002)., Conclusions and Relevance: Patients with CSCC and CPNI are at an increased risk of local recurrence and disease-specific death compared with patients with CSCC and IPNI and have a 30% risk of death. Patients with PNI may benefit from increased long-term surveillance. Further studies are needed to establish standardized guidelines on follow-up and dermatologic surveillance in this high-risk patient population.