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Multicenter Study
. 2025 Aug;93(2):368-377.
doi: 10.1016/j.jaad.2025.04.029. Epub 2025 Apr 17.

Lymphovascular invasion is an independent predictor of metastasis and disease-specific death in cutaneous squamous cell carcinoma: A multicenter retrospective study

Kelsey E Hirotsu  1 , Sumaira Z Aasi  1 , Kaeli K Samson  2 , Cheng Zheng  2 , Jaron R Nazaroff  1 , Lindsey M Voller  1 , Emily S Ruiz  3 , Nina A Ran  3 , Emily E Granger  4 , Shlomo A Koyfman  5 , Allison T Vidimos  6 , David R Carr  7 , Kathryn T Shahwan  7 , John A Carucci  8 , Joi B Carter  9 , Javier Cañueto  10 , Fábio Muradás Girardi  11 , Aaron R Mangold  12 , Divya Srivastava  13 , David G Brodland  14 , John A Zitelli  14 , Tyler J Willenbrink  14 , Ashley Wysong  15
Affiliations
Multicenter Study

Lymphovascular invasion is an independent predictor of metastasis and disease-specific death in cutaneous squamous cell carcinoma: A multicenter retrospective study

Kelsey E Hirotsu et al. J Am Acad Dermatol. 2025 Aug.

Abstract

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 < .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 = 1.82; P = .002). Notably, LVI+ low-stage Brigham and Women's Hospital (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 < .001).

Limitations: 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.

Keywords: cutaneous squamous cell carcinoma; lymphovascular invasion; metastasis; nonmelanoma skin cancer; oncology; outcomes; recurrence.

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Conflict of interest statement

Conflicts of interest Dr Ruiz serves as a consultant for Regeneron Inc, Checkpoint Therapeutic, Feldan Pharmaceuticals, and Merck Pharmaceuticals. She serves as a Principal Investigator/Co-Investigator for the following companies: Regeneron (PI/Co-I), Merck (Co-I), and Castle Biosciences (PI/Co-I). She is on the Board of Directors of Skin Cancer Outcomes Consortium (SCOUT). Dr Carr serves as an investigator for Regeneron, no direct funds. Dr Cañueto receives grants to institution from Sanofi/Regeneron, Castle Biosciences; lectures honoraria from Sanofi, Almirall, Abbvie, Regeneron, and Sun Pharma; payment for expert testimony from Sanofi, Regeneron, and Almirall; support for attending meetings from Pfizer, Almirall, Lilly, and Castle Biosciences; advisory board from Almirall, Sanofi, Regeneron, Kyowa, Roche, and InflaRx; funding support by the Gerencia Regional de Salud de Castilla y León (GRS2549/A/22) and by the Instituto de Salud Carlos III (PI21/01207), cofinanced by European Union. Dr Mangold reports relevant disclosures patent Methods and Materials for assessing and treating cutaneous squamous cell carcinoma (provisional PCT/US2023/078902) and Regeneron Consulting with payments to the institution. He has consulted for Phelecs BV, Kyowa, Eli Lilly, Momenta, UCB, and Regeneron in the past, greater than 24 months ago. He has consulted for Incyte, Soligenix, Clarivate, Argenyx, and Bristol Myers Squibb in the past, less than 12 months ago. He consults for Nuvig, Tourmaline Bio, Janssen, and Boehringer Ingelheim currently. He consults for Pfizer currently with payments to the institution. He has grant support from Kyowa, Miragen, Regeneron, Corbus, Pfizer, Incyte, Eli Lilly, Argenx, Palvella, Abbvie, Priovant, and Merck in the last 24 months. Beyond 24 months, grant support has come from Sun Pharma, Elorac, Novartis, and Janssen. His current patents include Use of Oral Jaki in Lichen Planus- PCT/US2024/020149; and Topical Ruxolitinib in Lichen Planus-PCT/US2021/053149, 2023-520085, and 21805700.8, respectively. Dr Carucci receives funding for investigator initiated basic science research from Regeneron and is a PI for a clinical trial sponsored by Regeneron. Dr Koyfman serves on the advisory board (paid) of Merck, BMS, Regeneron, Galera Therapeutics; advisory board (unpaid) of Castle Biosciences; receives research support from Castle Biosciences, Merck, BMS, and Regeneron; honoraria from UpToDate. Dr Vidimo receives research support from Castle; serves on the advisory board from Inhibitor Therapeutics; receives honoraria from Up to Date. Dr Wysong receives institutional research grant from Castle Biosciences. Drs Hirotsu, Aasi, Samson, Zheng, Nazaroff, Voller, Granger, Ran, Girardi, Srivastava, Carter, Shahwan, Brodland, Zitelli, and Willenbrink have no conflicts of interest to disclose.

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