Distinct Second Primary Tumor Phenotypes in Oral Squamous Cell Carcinoma According to Exposure Status and Immune Background

TL;DR

This study finds that second primary tumors in oral cancer patients differ based on lifestyle factors and immune conditions, suggesting tailored surveillance strategies.

Contribution

The study identifies distinct second primary tumor phenotypes in oral squamous cell carcinoma linked to exposure status and immune background.

Findings

Smoking/drinking patients more frequently develop extra-oral second primary tumors.

Non-smoking/non-drinking patients with immune conditions like oral lichen planus are more likely to have multifocal oral SCC.

Oral lichen planus strongly predicts multifocal oral SCC in non-smoking/non-drinking patients.

Abstract

Background: Second primary tumors (SPTs) are a major survivorship challenge in oral squamous cell carcinoma (OSCC), yet their biological phenotypes may differ according to exposure status and immune background. Methods: In this retrospective cohort (2011–2020), 242 surgically treated primary OSCC patients were classified as non-smoking, non-drinking (NSND; never smokers/never drinkers) or smoking and/or drinking (SD; any history of smoking and/or alcohol consumption). SPTs were categorized as extra-oral SPTs (eoSPTs) or multifocal oral SCC (mOSCC), with mOSCC (≥3) denoting ≥3 oral primaries. Immune background was assessed by documenting immune-modulating conditions (including oral lichen planus as an immune-mediated mucosal disorder). Multivariable logistic regression was used to evaluate predictors of eoSPTs and mOSCC. Results: SPT occurred in 82/242 (33.9%), comprising 54 eoSPT (22.3%) and 28 mOSCC (11.6%). Overall SPT prevalence was similar in NSND and SD patients (29.8% vs. 36.1%), but phenotype composition differed significantly (chi-square p = 0.004): eoSPTs were more common in SD (27.8% vs. 11.9%), whereas mOSCC was more common in NSND (17.9% vs. 8.2%); mOSCC (≥3) occurred in 10.7% of NSND versus 1.3% of SD patients. Immune-modulating conditions were associated with mOSCC but not eoSPTs. Within the immune-modulating spectrum, OLP showed strong phenotype specificity (0/20 eoSPTs; mOSCC in 7/20 [35.0%), particularly among NSND patients (38.9% with OLP vs. 12.1% without). In adjusted models, NSND status was associated with lower odds of eoSPT (OR 0.37, 95% CI 0.15–0.96), while OLP independently predicted mOSCC (OR 3.47, 95% CI 1.04–11.52). Conclusions: SPTs in OSCC comprise distinct phenotypes: SD patients predominantly develop eoSPTs consistent with carcinogen-associated aerodigestive field effects, whereas NSND patients exhibit an immune-associated, oral-restricted pattern with frequent mOSCC, supporting phenotype-tailored surveillance.

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