Faculty Bibliography

BACKGROUND:Penile cancer is a rare malignancy, the most common subtype of which is squamous cell carcinoma (SCC). Organ-sparing surgery (OSS) is the first-line treatment for early-stage tumors given the quality-of-life impairments of penectomy. However, the rarity of penile SCC has made the large-scale study of the efficacy of surgical approaches difficult. OBJECTIVE:To evaluate the rates of positive margins with the surgical approaches for penile SCC. METHODS:Retrospective cohort study of adult patients with excised penile SCC from the National Cancer Database diagnosed from 2004 to 2019. RESULTS:We found that treatment of penile SCC with OSS resulted in a positive margin rate of 18.8% (SE: 0.7%) versus 9.7% (SE: 0.4%) with partial penectomy and was associated with twice the odds of a positive margin compared with partial penectomy (odds ratio 2.312; p < .001). Positive margins were associated with poorer overall survival on multivariable analysis (hazard ratio 1.528; p < .01). CONCLUSION/CONCLUSIONS:OSS for penile SCC results in high rates of positive margins, which are associated with poorer overall survival. Use of margin-controlled surgery may improve local control for these tumors while minimizing functional damage to an anatomically sensitive organ, allowing for the most optimal quality-of-life outcomes.

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.

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.

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.

IMPORTANCE/UNASSIGNED:Cutaneous squamous cell carcinoma (CSCC) risk stratification is central to management, and physicians rely on tumor staging systems to estimate risk. The Brigham and Women's Hospital (BWH) T staging system predicts risk based on 4 tumor risk factors (RFs). However, stage is not precisely associated with the number of RFs, as BWH stage T2b includes CSCCs with 2 and 3 RFs. OBJECTIVE/UNASSIGNED:To determine how RF number is associated with the risk of recurrence, metastasis, and disease-related death. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This retrospective multination cohort study of CSCCs diagnosed between October 1, 1991, and July 19, 2023, was conducted at 12 centers in the US (10), Spain (1), and Brazil (1). Invasive CSCCs with confirmed negative margins longer than 14 days were included. Tumors were excluded if they were metastatic at presentation or received adjuvant therapy. Data were analyzed from October 2023 to August 2024. INTERVENTIONS OR EXPOSURES/UNASSIGNED:CSCCs were stratified by the number of the following RFs (0, 1, 2, 3, or 4): a diameter of 2 cm or larger, poorly differentiated histology, tumor extension beyond subcutaneous fat, and large caliber nerve invasion. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Five-year cumulative incidences of local recurrence, nodal metastasis, distant metastasis, and disease-specific death. RESULTS/UNASSIGNED:A total of 16 844 CSCCs were included (5978 female individuals [35.5%]; median [IQR] age, 73.9 [65.7-81.8] years), with 0 (12 657 [75.1%]), 1 (2892 [17.2%]), 2 (1015 [6.0%]), 3 ( 225 [1.3%]) or 4 (55 [0.3%]) RFs. Median (IQ) follow up time was 33.6 (14.5-60.3) months. For local recurrence, the risk increased as the number of RF increased from 0 (1.7%; 95% CI, 1.5%-2.0%) to 1 (5.0%; 95% CI, 4.1%-5.9%) to 2 (8.8%; 95% CI, 7.0%-11.0%) to 3 (16.0%; 95% CI, 11.0%-22.0%) to 4 (33.0%; 95% CI, 19.0%-47.0%; P < .001 for between-group differences). This increase was also observed for nodal metastasis (0.6% [95% CI, 0.4%-0.7%] vs 3.6% [95% CI, 2.9%-4.4%] vs 11.0% [95% CI, 9.2%-13.0%] vs 20.0% [95% CI, 15.0%-26.0%] vs 28.0% [95% CI, 15.0%-42.0%], respectively; P < .001), distant metastasis (0.2% [95% CI, 0.1%-0.3%] vs 1.1% [95% CI, 0.7%-1.6%] vs 2.3% [95% CI, 1.4%-3.4%] vs 7.9% [95% CI, 4.6%-12.0%] vs 8.4% [95% CI, 2.6%-19.0%], respectively; P < .001), and disease-specific death (0.3% [95% CI, 0.2%-0.4%] vs 1.9% [95% CI, 1.4%-2.7%] vs 5.4% [95% CI, 4.0%-7.0%] vs 11.0% [95% CI, 6.7%-16.0%] vs 25% [95% CI, 12%-39%], respectively; P < .001). CSCCs with 3 RFs had higher cumulative incidences of local recurrence (1.6-fold), nodal metastasis (1.9-fold), distant metastasis (4.3-fold), and disease-specific death (1.9-fold) compared with those with 2 RFs. CONCLUSIONS AND RELEVANCE/UNASSIGNED:The results of this cohort study suggest that the number of RFs is an indicator of risk, and among BWH T2b tumors, those with 3 RFs represent a higher risk subset.

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.