# Non-Smoking, Non-Drinking Oral Squamous Cell Carcinoma Is Associated with an Immune-Modulated Clinical Phenotype

## TL;DR

Non-smoking, non-drinking oral cancer patients show a unique pattern linked to immune-related factors, including different tumor locations and better survival trends.

## Contribution

This study identifies a distinct immune-modulated clinical phenotype in non-smoking, non-drinking oral squamous cell carcinoma patients.

## Key findings

- Non-smoking, non-drinking patients had more tumors on the tongue and buccal mucosa and fewer on the floor of the mouth.
- These patients had immune-modulating conditions and showed lower systemic inflammatory indices.
- Non-smoking, non-drinking patients showed a trend toward better overall survival.

## Abstract

Oral cancer is generally associated with smoking and alcohol use, but some patients develop oral squamous cell carcinoma without these exposures. Because these patients do not match the typical risk profile, diagnosis may be delayed. We analyzed 243 treated patients, comparing those who neither smoked nor drank with those who smoked and/or drank. Non-smoking, non-drinking patients were more often women and showed a distinct pattern of tumor sites, with more tumors on the tongue and buccal mucosa and very few on the floor of the mouth. They also more frequently had medical conditions affecting immune function, including autoimmune diseases, especially in patients older than 50 years, and showed inflammatory patterns in blood tests. Overall survival tended to be better, but outcomes were determined by tumor stage and key pathological risk factors. These findings may help clinicians refine risk assessment and follow-up and support research into immune-associated pathways.

Background: Non-smoking, non-drinking (NSND) oral squamous cell carcinoma (OSCC) is increasingly recognized, yet its clinicopathologic and immune-related correlates remain incompletely defined. Methods: We retrospectively studied 243 surgically treated patients with previously untreated primary OSCC (2011–2020). Patients were classified as NSND or smoking and/or drinking (SD). Immune-modulating conditions and preoperative systemic immune–inflammatory indices (NLR, LMR, SIRI, AISI) were assessed, and overall (OS) and disease-specific survival (DSS) were analyzed. Results: Eighty-five patients (35.0%) were NSND. NSND patients were more often female (58.8% vs. 12.7%) and slightly older (median 54 vs. 50 years). Subsite distribution differed (p < 0.001): tongue (52.9%), buccal mucosa (15.3%), and floor of mouth (3.5%) in NSND versus a predominance of floor of mouth tumors in SD (34.8%). NSND tumors showed smaller diameter, lower depth of invasion, less perineural invasion (40.5% vs. 55.1%), and more frequent inflammatory infiltrate (73.8% vs. 60.1%). Immune-modulating conditions were enriched in NSND (67.1% vs. 17.7%; p < 0.001; adjusted OR 6.25, 95% CI 3.23–12.11), particularly among NSND patients >50 years (79.2%). NSND patients showed lower NLR (p = 0.01), lower SIRI and AISI (p < 0.001), and higher LMR (p < 0.001). Median OS was 81.2 months; NSND showed a trend toward improved OS (p = 0.083) and improved OS after age/sex adjustment (HR 0.64, 95% CI 0.42–0.98), but not after full clinicopathologic adjustment; DSS did not differ (p = 0.59). Conclusions: NSND OSCC exhibits a distinct clinicopathologic presentation and is strongly associated with immune-modulating comorbidity and lower tumor-associated systemic inflammatory indices, consistent with an immune-modulated clinical phenotype.