Faculty Bibliography

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.

IMPORTANCE/OBJECTIVE: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/METHODS:A retrospective, multinational cohort study of CSCCs diagnosed between January 10, 1991, and December 31, 2023. SETTING/METHODS:Twelve centers across the United States (10), Spain (1), and Brazil (1). PARTICIPANTS/METHODS: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/METHODS:Tumors were staged according to both the AJCC8 TNM staging system and the BWH tumor classification. MAIN OUTCOMES AND MEASURES/METHODS: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/CONCLUSIONS: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: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: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.

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.