Faculty Bibliography

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 8,901 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 (OR 1.03, 95% CI 1.01-1.05, p<0.01), history of immunosuppression (OR 4.31, 95% CI 2.59-7.10, p<0.001), higher BWH stage (T2a OR 4.14, 95% CI 2.05-8.41; T2b OR 15.96, 95% CI 8.58-31.19; T3 OR 30.27, 95% CI 10.70-79.04, all p<0.001) and LVI (OR 4.57, 95% CI 1.80-10.38, p=0.001) were independent risk factors for S-ITM. S-ITM was associated with LR (SHR 2.40, 95% CI 1.43-4.04, p<0.001), NM (SHR 1.89 (95% CI .02-3.49, p=0.04), DM (SHR 4.41, 95% CI 1.45-13.27, p=0.01), and DSD (SHR 4.48, 95% CI 2.34-8.58, p<0.001). LIMITATIONS/CONCLUSIONS:Retrospective cohort study. The rarity of S-ITM may limit statistical power. CONCLUSION/CONCLUSIONS:Patients with cSCC and S-ITM are at higher risk for poor outcomes independent of patient, tumor, and treatment characteristics.

Gene expression profiling (GEP) is making a significant impact in dermatology by providing molecular insights that complement traditional diagnostic methods for skin cancer and inflammatory dermatoses. GEP evaluates messenger RNA levels to identify disease-specific patterns that can aid in diagnosis, prognostication, and/or treatment planning. Currently, commercially available tests for melanoma and cutaneous squamous cell carcinoma are available. The development of GEP tests follows a stepwise process, including discovery, validation, and clinical implementation. Despite challenges such as cost and the need for further prospective studies, advancements in GEP hold promise for supporting more personalized approaches to patient care.

BACKGROUND:High-risk cutaneous squamous cell carcinomas (HRCSCC) have an increased likelihood of poor outcomes following surgery. Adjuvant radiation therapy (ART) may decrease this risk; however, there is limited data on its efficacy. OBJECTIVE:To evaluate whether ART is associated with reduced risks of local recurrence, locoregional recurrence, nodal metastasis, and disease-specific death in localized, fully resected HRCSCC. METHODS:A retrospective, multicenter cohort study was conducted. Competing risk modeling was performed to evaluate ART, controlling for patient, tumor, and treatment factors. RESULTS:This study included 1,267 HRCSCC, of which 155 (12.2%) received ART. ART was associated with a 50% reduction in the risk of local recurrence (CHR=0.47; 95% CI: 0.23, 0.96; p=0.04), locoregional recurrence (CHR=0.47; 95% CI: 0.26, 0.83; p=0.01), and nodal metastasis (CHR=0.45; 95% CI: 0.21, 0.98; p=0.04). The effect on disease-specific death was small and not statistically significant (CHR=0.83; 95% CI: 0.35, 1.94; p=0.66). In modeling, ART decreased the estimated 5-year cumulative incidence of local recurrence from 11.9% (95% CI, 9.4%-14.0%) to 5.9% (2.8%-9.8%), of locoregional recurrence from 17.8% (15.1%-20.3%) to 9.0% (5.1%-13.6%), and of nodal metastasis from 9.5% (7.3%-11.2%) to 4.6% (1.7%-8.5%). A subset of HRCSCC at greatest risk of poor outcomes was identified and comprised of tumors that were Brigham and Women's Hospital (BWH) stage T3, BWH stage T2 tumors with three risk factors, and/or tumors with lymphovascular invasion. Among these 246 HRCSCC, 74 (30.1%) received ART, and ART was associated with a decreased risk of locoregional recurrence (CHR=0.48; 95% CI: 0.26, 0.89; p=0.02) and nodal metastasis (CHR=0.43; 95% CI: 0.19, 0.97; p=0.04). On modeling, this subgroup experienced greater absolute reductions in the estimated 5-year incidence of locoregional recurrence from 36.6% (95% CI, 30.0%-45.3%) to 20.0% (11.1%, 31.1%) and of nodal metastasis from 21.1% (17.4%-30.9%) to 9.6% (4.2%-18.1%). CONCLUSION/CONCLUSIONS:In this retrospective multicenter cohort of HRCSCC, adjuvant radiation was associated with reduced risks of local recurrence and nodal metastasis. Prospective studies are required to further characterize the effect of adjuvant radiation on HRCSCC.

IMPORTANCE/UNASSIGNED:There exists substantial heterogeneity in outcomes within T stages for patients with cutaneous squamous cell carcinoma (cSCC). OBJECTIVE/UNASSIGNED:To determine whether a customized generative pretrained transformer model, trained on a comprehensive dataset with more than 1 trillion parameters and equipped with relevant focused context and retrieval augmented generation (RAG), could excel in aggregating and interpreting vast quantities of data to develop a novel class-based risk stratification system that outperforms the current standards. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:To build the RAG knowledge base, a systematic review of the literature was conducted that addressed risk factors for poor outcomes in cSCC. Using the RAG-enabled generative pretrained transformer (GPT) model, we developed a novel class-based risk stratification system that assigned point values for risk factors, culminating in a GPT-based prognostication system called the artificial intelligence-derived risk score (AIRIS). The system's performance was validated on a combined prospective and retrospective cohort of 2379 primary cSCC tumors (1996-2023) with at least 36 months of follow-up, against Brigham and Women's Hospital (BWH) and American Joint Committee on Cancer Staging Manual, eighth edition (AJCC8) systems in stratifying risk for locoregional recurrence (LR), nodal metastasis (NM), distant metastasis (DM), and disease-specific death (DSD). MAIN OUTCOMES AND MEASURES/UNASSIGNED:Performance metrics evaluated included distinctiveness, homogeneity, and monotonicity, as defined by the AJCC8, as well as sensitivity, specificity, positive predictive value, negative predictive value, accuracy, the area under the receiver operating characteristic curve, and concordance. RESULTS/UNASSIGNED:The median age at diagnosis was 73 (IQR, 64-81) years, with 38.5% female patients and 61.5% male patients. The AIRIS prognostication system demonstrated superior sensitivity across all outcomes (LR, 49.1%; NM, 73.7%; DM, 82.5%; and DSD, 72.2%) and the highest area under the receiver operating characteristic curve values (LR, 0.69; NM, 0.81; DM, 0.85; and DSD, 0.80), indicating significantly enhanced discriminative capability compared with the BWH and AJCC8 systems. While all systems were comparably distinctive, the AIRIS prognostication system consistently demonstrated the lowest proportion of tumors exhibiting poor outcomes in low-risk categories, suggesting its improved homogeneity and monotonicity. CONCLUSIONS AND RELEVANCE/UNASSIGNED:The results of this diagnostic study suggest that the AIRIS system outperforms the existing BWH and AJCC8 prognostication systems, potentially providing a more effective tool for predicting poor outcomes in cSCC. This study illustrates the potential of large language models in refining prognostic tools, offering implications for treating patients with cancer.

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 < 0.001). 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 (SHR) = 1.82; p = 0.002). Notably, LVI+ low-stage 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 < 0.001). LIMITATIONS/CONCLUSIONS: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.

Mohs micrographic surgery (MMS) is a tissue-sparing surgical technique that is the standard of care for treatment of several cutaneous malignancies. Current US and international guidelines recommend wide local excision as the first-line surgical therapy for noninvasive melanoma, and use of MMS may be appropriate for melanoma-in-situ, lentigo maligna, and potentially thin invasive malignant melanoma. Based on available literature, MMS can potentially result in lower recurrence rates of melanoma, especially when using immunostaining. This chapter explores the existing evidence supporting MMS for treatment of melanoma as well as its challenges.

BACKGROUND:Cutaneous squamous cell carcinoma (CSCC) is a prevalent disease for which improved risk stratification strategies are needed. OBJECTIVE:To develop a novel prognostic model (herein "riSCC") for CSCC and compare riSCC performance to Brigham and Women's Hospital and American Joint Committee on Cancer Staging eighth edition T staging systems. METHODS:Retrospective 12-center, multinational cohort study of CSCCs from 1991 to 2023. Clinical and pathologic risk factors, treatments, and outcomes were collected. Fine-Gray model was employed for each outcome with inverse probability of treatment weighting. A final model was trained for prospective use and estimation of hazard ratios. RESULTS:Twenty-three thousand one hundred sixty-six localized CSCC tumors were included. riSCC prognostic model performed superiorly to American Joint Committee on Cancer eighth edition and Brigham and Women's Hospital T staging for all outcomes. At 5 years, the C-index for riSCC ranged from 0.74 for local recurrence to 0.87 for disease specific death. LIMITATIONS/CONCLUSIONS:Retrospective study design. CONCLUSION/CONCLUSIONS:riSCC prognostic model offers fine-grained risk estimates and improved stratification for important CSCC outcomes compared to T staging systems.