Faculty Bibliography

BACKGROUND:While Brigham and Women's Hospital (BWH) T1 cutaneous squamous cell carcinomas (CSCCs) 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 was 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 [PNI]) on poor outcomes. Cumulative incidence function (CIF) plots were created for time to poor outcomes by number of minor risk factors. RESULTS:15,481 BWH 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. CIF 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/CONCLUSIONS:Retrospective design, limited number of major poor outcomes. CONCLUSION/CONCLUSIONS: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.

Primary cutaneous squamous cell carcinoma (cSCC) is responsible for ~10,000 deaths annually in the United States. Stratification of risk of poor outcome at initial biopsy would significantly impact clinical decision-making during the initial post operative period where intervention has been shown to be most effective. Using whole-slide images (WSI) from 163 patients from 3 institutions, we developed a self supervised deep-learning model to predict poor outcomes in cSCC patients from histopathological features at initial diagnosis, and validated it using WSI from 563 patients, collected from two other academic institutions. For disease-free survival prediction, the model attained a concordance index of 0.73 in the development cohort and 0.84 in the Mayo cohort. The model's interpretability revealed that features like poor differentiation and deep invasion were strongly associated with poor prognosis. Furthermore, the model is effective in stratifying risk among BWH T2a and AJCC T2, known for outcome heterogeneity.

Hair follicle neogenesis (HFN) occurs following large skin excisions in mice, serving as a rare regenerative model in mammalian wound healing. Wound healing typically results in fibrosis in mice and humans. We previously showed small skin excisions in mice result in scarring devoid of HFN, displaying features of non-regenerative healing, and Hedgehog (Hh) activation in the dermis of such wounds can induce HFN. In this study, we sought to verify the role of dermal Wnt/β-catenin signaling in HFN, as this pathway is essential for HF development, but is also paradoxically well-characterized in fibrosis of adult wounds. By deletion of β-catenin in large wound myofibroblasts, we show Wnt/β-catenin signaling is required for endogenous mechanisms of HFN. Through utilizing a combined mouse model that simultaneously induces deletion of β-catenin and constitutive activation of Smoothened (Smo) in myofibroblasts, we also found β-catenin is required for Hh-driven DP formation. Transcriptome analysis confirms Wnt/β-catenin and Hh pathways are activated in dermal papilla (DP) cells. Our results indicate that Wnt-active fibrotic status may also create a permissive state for the regenerative function of Hh, suggesting that activation of both Wnt and Hh pathways in skin wound fibroblasts must be ensured in future strategies to promote HFN.

BACKGROUND:Impaired immunity may drive the increased incidence and aggression of cutaneous squamous cell carcinoma (cSCC) in patients with hematologic malignancy; however, precise mechanisms and prognostic biomarkers remain undefined. CD73 maintains elevated immunosuppressive adenosine levels and is associated with poor prognosis in several tumor microenvironments. OBJECTIVE:Identify poor outcome biomarkers in patients with cSCC and hematologic malignancy. MATERIALS AND METHODS/METHODS:Differentially expressed genes in tumors from patients with hematologic malignancy experiencing good (n = 8) versus poor (n = 7) outcomes were identified by NanoString analysis. Results were validated at the protein level using CD73 immunohistochemistry in cSCC patients with (n = 38) and without (n = 29) hematologic malignancy. RESULTS:Forty-eight genes were differentially expressed in tumors from patients with hematologic malignancy experiencing good versus poor outcomes. CD73 gene expression was >2-fold higher in patients with poor versus good outcomes or normal skin. Significantly increased CD73 protein levels were observed in cSCC tumors with poor versus good outcomes from patients with hematologic malignancies (p < .01), whereas no differences were noted in tumors with poor versus good outcomes from patients without hematologic malignancies (p = .49). CONCLUSION/CONCLUSIONS:CD73 is highly expressed in poor prognosis cSCC from patients with hematologic malignancy and may represent a useful biomarker and potential therapeutic target.