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Multicenter Study
. 2025 Jun 1;161(6):597-604.
doi: 10.1001/jamadermatol.2025.0128.

Risk Factor Number and Recurrence, Metastasis, and Disease-Related Death in Cutaneous Squamous Cell Carcinoma

Nina A Ran  1 , Emily E Granger  2 , David G Brodland  3 , Javier Cañueto  4 , David R Carr  5 , Joi B Carter  6 , John A Carucci  7 , Kelsey E Hirotsu  8 , Shlomo A Koyfman  9 , Aaron R Mangold  10 , Fabio Muradás Girardi  11 , Kathryn T Shahwan  5 , Divya Srivastava  12 , Allison T Vidimos  13 , Tyler J Willenbrink  3 , Ashley Wysong  14 , Emily S Ruiz  1
Affiliations
Multicenter Study

Risk Factor Number and Recurrence, Metastasis, and Disease-Related Death in Cutaneous Squamous Cell Carcinoma

Nina A Ran et al. JAMA Dermatol. .

Abstract

Importance: 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: To determine how RF number is associated with the risk of recurrence, metastasis, and disease-related death.

Design, setting, and participants: 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: 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: Five-year cumulative incidences of local recurrence, nodal metastasis, distant metastasis, and disease-specific death.

Results: 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: 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Cañueto reported grants from Sanofi/Regeneron and Castle-Biosciences; honoraria from Sanofi, Almirall, AbbVie, Regeneron, and Sun Pharma; payment for expert testimony from Sanofi, Regeneron, and Almirall; travel support from Pfizer, Almirall, Lilly, and Castle-Biosciences; advisory board service for Almirall, Sanofi, Regeneron, Kyowa, Roche, and InflaRx; and research support from the Gerencia Regional de Salud de Castilla y León (GRS2549/A/22) and Instituto de Salud Carlos III (PI21/01207), which was cofinanced by European Union. Dr Carr reported being an investigator for Regeneron outside the submitted work. Dr Carucci reported grants from Regeneron during the conduct of the study. Dr Koyfman reported personal fees from Merck, BMS, Regeneron, Galera Therapeutics, Varian Medical Systems, and UpToDate as well as grants from Castle Biosciences outside the submitted work. Dr Mangold reported personal fees from Regeneron and grants from Regeneron during the conduct of the study as well as personal fees from Phlecs BV, Kyowa, Eli Lilly, Momenta, UCB, Regeneron, Incyte, Soligenix, Clarivate, Argenyx, Bristol Myers Squibb, PPD, Nuvig, Tourmaline Bio, Janssen; grants from Kyowa, Miragen, Regeneron, Corbus, Pfizer, Incyte, Eli Lilly, Argenyx, Palvella, AbbVie, Priovant, Bristol Myers Squibb, and Merck; and patents for machine-learning models for tumor grading using rank-aware contextual reasoning on whole slide images and methods and materials for assessing and treating cutaneous squamous cell carcinoma outside the submitted work. Dr Girardi reported grants from the American College of Mohs Surgery Foundation during the conduct of the study. Dr Wysong reported grants from the American College of Mohs Surgery during the conduct of the study and grants from Castle Biosciences outside the submitted work. No other disclosures were reported.

References

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