Triple threats in cancer of oral cavity: Navigating pathological risk factors

Triple threats in cancer of oral cavity: Navigating pathological risk factors | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Triple threats in cancer of oral cavity: Navigating pathological risk factors Pragyat Thakur, Deepander S Rathore, Priyanka Goel, Alok Goel, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8101509/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract Background: Despite multimodal treatment, oral cavity cancer (OCC) outcomes remain poor due to frequent presentation at advanced stages. Identifying reliable prognostic markers is crucial for improving outcomes. Lymphovascular invasion (LVI), perineural invasion (PNI), and depth of invasion (DOI) are key pathological features linked to aggressive tumor behavior. While each factor is associated with worse outcomes, their combined prognostic value remains underexplored. This study evaluates the combined prognostic value of LVI, PNI, and DOI on overall survival (OS) and recurrence-free survival (RFS) in OCC patients treated with curative intent. Methods: This retrospective study included 342 OCC cases treated from January 2017 to December 2021. Patients were stratified into six subgroups based on LVI (±), PNI (±), and DOI (> 1 cm or ≤ 1 cm). Survival outcomes were analyzed using Kaplan-Meier and log-rank tests. Independent prognostic factors were identified using Cox regression. A p-value 1 cm were present in 29.8%, 48.8%, and 43.3% of cases, respectively. Significant differences in OS and RFS were observed among the six subgroups. The worst outcomes were seen when all three risk factors were present, with a nearly fivefold higher risk of death. Shallower tumors (< 1 cm) were associated with improved survival, even in the presence of LVI or PNI. When both LVI and PNI were absent, OS and RFS differed significantly for deeper versus shallower tumours. Conclusion: Combined assessment of LVI, PNI, and DOI enables effective risk stratification in OCC and can guide forpersonalized patient treatment. Oral cavity cancer lymphovascular invasion Perineural invasion Depth of invasion Chemoradiation Overall survival Figures Figure 1 Figure 2 Figure 3 Background Oral cavity cancer (OCC) remains a significant public health challenge, particularly in lower and lower-middleincome countries, where it ranks among the most prevalent malignancies due to high rates of tobacco use, betel quid chewing and limited access to early screening. Despite advancements in multimodality treatments, including surgery, radiotherapy and chemotherapy, the prognosis for OCC remains suboptimal as majority of patients present in locally advanced stage [ 1 , 2 , 3 ]. This complicates treatment planning and contributes to high rates of recurrence and mortality. To improve outcomes, researchers have focused on identifying pathological markers that can predict prognosis and guide treatment decisions. Lymphovascular invasion (LVI) is defined as infiltration of tumour cells into lymphatic or vascular endothelium-lined spaces. Tumour can spread indirectly through lymphatics or lymphatic vein exchange channels or directly through blood vessels. LVIhas been found to be associated with aggressive tumour behavior and poor survival outcomes [ 4 ].OCC is considered a neurotropic malignancy as tumour cells and associated stroma show strong affinity to surrounding nerves and neural invasion, also known as perineural invasion (PNI), through molecular mediators. Tumourcellsshow directional movement such that these spread beyond the primary lesion and can be missed during resection thereby, contributing to increased chances of local recurrence. Recently, PNI has been classified on the basis of extent of invasion into unifocal and multifocal; with multifocality being associated with increased local failure. However, some studies have also shown varied results for LVI and PNI; therefore, they have not yet been incorporated into tumour staging[ 5 ]. Depth of invasion(DOI), measured as distance from the normal mucosal basement membrane to the deepest point of tumour invasion, is a critical indicator of tumour aggressiveness. Unlike tumour thickness, which measures the distance from tumour surface to its deepest point, DOI provides a more precise assessment of tumour invasiveness and has been incorporated into American Joint Committee on Cancer (AJCC) tumour-node-metastasis (TNM) 8th edition staging system. Current evidence supports DOI as a prognostic factor for overall survival (OS), recurrence-free survival (RFS) and nodal metastasis, reflecting its role in local tumourspread and systemic progression [ 6 ]. While LVI, PNI and DOI are individually associated with adverse outcomes, their combined prognostic impact remains underexplored. Literature reports conflicting results regarding the significance of LVI and PNI[ 5 ].DOI, while established as a staging criterion, requires further investigation to understand its interaction with other pathological features. Comparative analyses of clinical trials have identified high-risk features, such as positive surgical margins or extranodal extension(ENE) that necessitate aggressive treatment with concurrent chemoradiotherapy.[ 4 ] However, the synergistic effect of multiple risk factors, such as LVI, PNI and DOIis not well-defined, leaving a gap in the ability to stratify patients for personalized treatment. This study aims to evaluate the combined effect of LVI, PNI, and DOI (stratified at 1cm) on OS and RFS in patients with OCC treated with curative intent. These three factors were selected to avoid overlap with other pathological characteristics, which may result in confounded results, eg. DOI would have overlap with tumour size and primary tumour stage, since it is included in staging whereas LVI isa significant predictor of presence of cervical lymph node metastasis at presentation,independent of other known prognostic factors and would have overlap with nodal stage [ 7 ]. Moreover, LVI, PNI and DOI represent distinct mechanisms of tumour spread—hematogenous/ lymphatic, neurotropic and local invasion, respectively—making them ideal candidates for assessing their cumulative prognostic impact. By stratifying patients into subgroups based on these factors, we sought to identify high-risk cohorts that may benefit from intensified treatment regimens and low-risk groups suitable for de-escalation or surveillance, ultimately contributing to more tailored therapeutic strategies. Methods This retrospective study included 342 patients diagnosed with OCC and treated with curative intent at a tertiary oncology center in India from January 2017 to December 2021. To ensure a homogeneous cohort, patients with metastatic or recurrent tumours, prior chemotherapy or radiotherapy, incomplete or revision surgeriesand non-squamous histology were excluded. Demographic, clinical, and pathological data were retrieved from medical records to provide a comprehensive dataset for analysis. AJCC TNM 8th editionwas used for tumour staging, based on radiological records, including contrast-enhanced computed tomography or magnetic resonance imaging of face and neck, to accurately characterize the primary tumour and nodal involvement. Treatment plans for all patients were finalized through consensus in multidisciplinary tumour board, ensuring standardized and evidence-based treatment plan. All patients underwent surgical excision of primary tumour and nodal dissection, followed by adjuvant radiotherapy using external beam radiation therapy or concurrent chemoradiotherapy, depending on the presence of high-risk pathological features. Patients were classified into six subgroups based on the presence or absence of LVI and PNI along with DOI stratified at 1cm: Subgroup A: Positive LVI, positive PNI, DOI > 1cm Subgroup B: Either positive LVI or positive PNI, DOI > 1cm Subgroup C: Negative LVI, negative PNI, DOI > 1cm Subgroup D: Positive LVI, positive PNI, DOI < 1cm Subgroup E: Either positive LVI or positive PNI, DOI < 1cm Subgroup F: Negative LVI, negative PNI, DOI < 1cm Data analysis was conducted using IBM SPSS Statistics version 23.0 (IBM Corp., Armonk, NY, USA). Descriptive statistics were employed to summarize demographic and tumourcharacteristics, providing a clear overview of the cohort’s profile across subgroups. Chi-square tests were used to evaluate differences in clinical and pathological features among the six subgroups, ensuring robust comparisons of tumour behavior and patient characteristics. OS, defined as the time from diagnosis to death from any cause, and RFS, defined as the time to tumour recurrence or death, were calculated to assess long-term outcomes. Pearson’s chi-square test was used to assess correlation between clinico-pathological features and OS. Survival outcomes were analyzed using Kaplan-Meier curves, with differences between subgroups evaluated using log-rank tests to determine statistical significance. Patients lost to follow-up were censored to maintain the integrity of the survival analysis. To estimate the independent prognostic impact of the subgroups, Cox proportional hazard models were applied, with hazard ratios (HR) and 95% confidence intervals (CI) calculated to quantify the magnitude and strength of associations. A p-value less than 0.05 was considered statistically significant for all analyses, ensuring rigorous interpretation of the results. Results The study cohort comprised 342 patients with a median age of 55 years (range: 28–86 years), of whom 85% were male, reflecting the typical demographic profile of OCC in high-incidence regions. LVI was positive in 29.8% (102 cases), PNI in 48.8% (167 cases), and DOI > 1cm in 43.3% (148 cases), highlighting the prevalence of these adverse pathological features in the cohort. Subgroup distribution was as follows: Subgroup A: 14.3% (49 patients) Subgroup B: 25.1% (86 patients) Subgroup C: 17.25% (59 patients) Subgroup D: 7% (24 patients) Subgroup E: 10.08% (37 patients) Subgroup F: 25.4% (87 patients) Comparison of demographic and clinico-pathological details for each subgroup is summarised in Table 1 . Subgroup F, with no risk factors, exhibited the lowest incidence of adverse features, serving as the reference group. Tumours with DOI > 1cm were predominantly poorly differentiated (83.3%), with frequent skin and bone invasion, suggesting aggressive local behavior. Nodal metastasis was 10 times more common in subgroup A and 3 times more common in subgroup B compared to subgroup F. Incidence of ENE was 3 times higher in subgroup A and 1.7 times higher in subgroup B, with reduced risk in subgroup C. Notably, subgroup D, characterized by positive LVI and PNI with DOI less than 1cm, showed a 3-fold higher ENE risk. Advanced pathological T and N stages and occult nodal disease were most prevalent in subgroup A. No early-stage (I or II) cases were observed in subgroups A or D, while cases insubgroup F predominantly presented in early stages. Recurrence rates exceeded 50% in subgroup A and were elevated in subgroup D, correlating with the presence of multiple adverse factors. This indicates positivity of both LVI and PNI portends an aggressive disease with poor prognosis independent of DOI status, although presence of DOI > 1cm makes it worse. Table 1 Patient demographics and clinical characteristics of OCC patients across sub-groups Characteristics Sub-group A Sub-group B Sub-group C Sub-group D Sub-group E Sub-group F χ2 p-value LVI (+), PNI (+), DOI > 1cm LVI or PNI (+), DOI > 1cm LVI (-), PNI (-), DOI > 1cm LVI (+), PNI (+), DOI < 1cm LVI or PNI (+), DOI < 1cm LVI (-), PNI (-), DOI < 1cm Gender M F 38 10 73 13 56 2 21 3 32 5 72 15 8.06 0.153 Differentiation WD MD PD 1 46 0 4 78 4 4 54 1 0 24 0 4 32 1 15 69 0 23.3 0.009 pT 1 2 3 4a 0 0 14 34 0 1 29 56 0 1 20 38 0 8 4 12 5 20 2 10 25 39 12 9 204.5 < 0.0001 pN 0 1 2a 2b 2c 3a 3b 4 5 6 1 0 0 33 23 4 15 3 0 0 41 35 8 3 3 0 0 10 2 2 6 1 1 0 12 17 2 3 3 0 1 11 62 9 1 2 0 0 11 133.2 < 0.0001 Group stage I II III IVA IVB 0 0 4 11 33 0 0 10 35 40 1 1 14 33 10 0 0 2 10 12 4 10 4 8 11 23 23 17 11 11 179.3 4cm No Yes 25 24 35 40 31 21 14 8 28 4 66 9 40.6 < 0.0001 Skin Y N 7 39 15 71 9 50 4 20 4 32 1 83 19.7 0.031 Bone Y N 22 24 23 63 26 33 10 14 9 27 9 75 36.3 < 0.0001 Nodal status Neg Pos 4 45 23 63 35 24 2 22 17 20 64 23 85.2 < 0.0001 ENE Yes No 38 11 53 31 12 44 18 6 12 24 12 71 86.9 < 0.0001 Recurrence Yes No 18 17 23 41 19 31 11 10 5 29 17 61 30.5 0.01 OS at 3 years was calculated, which varied significantly based on subgroups (Fig. 1 ). Patients in subgroup A had the poorest 3 year OS at 31.5% which improved to 43.6% for patients in subgroup B. Interestingly, within subgroup B, presence of LVI alone had more detrimental effect on 3year OS than PNI alone in tumours with DOI > 1cm (23.1% vs 48.6%). The 3 year OS further improved to 62.4% for patients in subgroup C when both LVI and PNI were absent with DOI > 1cm. Despite DOI < 1cm in subgroup D, worse outcome with 3 year OS of 30.4% was observed. In contrast, 3 year OS was 77.6% for subgroup E and was the highest in subgroup F with no risk factors at 78.8% (Fig. 2 ). A similar trend was observed for RFS (Fig. 3 ) and is summarised in Table 2 . Table 2 Distribution of 3-year OS and 3-year RFS across subgroups based on LVI, PNI and DOI Subgroups Factor combination 3 yrs OS 3 yrs RFS A LVI (+), PNI (+), DOI > 1cm (n = 49) 31.5% 31.5% B LVI or PNI (+), DOI > 1cm (n = 86) 43.6% 40.2% C LVI (-), PNI (-), DOI > 1cm (n = 59) 62.4% 55.4% D LVI (+), PNI (+), DOI < 1cm (n = 24) 30.4% 26.1% E LVI or PNI (+), DOI < 1cm (n = 37) 77.6% 72.4% F LVI (-), PNI (-), DOI < 1cm (n = 87) 78.8% 75.6% Median OS for whole cohort was 54 months but differed significantly among subgroups [Table 3 ]. Lowest outcome was observed for subgroup A (17 months, 95% CI − 11.1 to 22.8 months). However, in subgroup D with DOI 1cm and median was not reached with DOI < 1cm. Absence of LVI and PNI in subgroup C improved median OS to 46 months (95% CI − 30.4 to 61.5 months). Median was not reached in subgroup F where all the risk factors were absent (mean OS − 68 months, 95% CI − 61.7 to 75.1 months). Similarly, trend was observed for RFS and values are summarized in Table 3 . Table 3 Median OS and RFS across subgroups with log rank test p- value Subgroups Factor OS ± S.E. (95%CI) (months) χ2 log rank p-value RFS ± S.E. (95%CI) (months) χ2 log rank p-value A LVI (+), PNI (+), DOI > 1cm 17 ± 2.9 (11.1 to 22.8) 16 1cm 25 ± 6.7 (11.7 to 38.3) 8.5 0.003 22 ± 6.7 (8.7 to 35.2) 6.73 0.009 C LVI (-), PNI (-), DOI > 1cm 46 ± 7.9 (30.4 to 61.5) 0.013 0.9 43 ± 7.3 (28.5 to 57.4) 0.12 0.72 D LVI (+), PNI (+), DOI < 1cm 21 ± 0.79 (19.4 to 22.5) 7.6 0.006 12 ± 1.1 (9.6 to 14.3) 7.6 0.006 E LVI or PNI (+), DOI < 1cm 67.2 ± 5.1 (57.1 to 77.4) (Mean) (Median not reached) 7.1 0.007 64.8 ± 5.6 (53.8 to 75.8) (Mean) (Median not reached) 6.9 0.008 F LVI (-), PNI (-), DOI < 1cm 68.4 ± 3.4 (61.7 to 75.1) (Mean) (Median not reached) 21.8 < 0.0001 65 ± 3.7 (57.7 to 72.4) (Mean) (Median not reached) 21.3 < 0.0001 Multivariate analysis confirmed the above findings. Patients in all subgroups were compared to subgroup F. Subgroup A had the worst outcome with the highest HR for both OS (HR 4.8, p < 0.0001) and RFS (HR 4.29, p < 0.0001). Similarly, subgroups B and D also had significantly worse outcomes and recurrences, with multivariate HRs for OS of 3.5 and 4.4 respectively. Even with DOI < 1cm, presence of both LVI and PNI led to poor outcomes as observed in subgroup D. Subgroup C was not found significant in univariate analysis (HR ~ 1), but became significant in multivariate analysis (OS HR 2.3, RFS HR 2.4). Subgroup E showed relatively better outcomes in univariate analysis (HR -0.4), but these were not significant in multivariate analysis, indicating that either LVI or PNI with DOI < 1cm may not independently affect prognosis[Table 4 ]. To confirm the independent prognostic value of these subgroups, a multivariate Cox regression analysis was done. After adjusting for ENE, nodal status, bone and skin invasion, tumour size and group stage, the subgroups based on LVI, PNI and DOI were independent and significant predictors of OS (p = 0.015, B = 0.15, HR = 0.85, 95% CI − 0.75 to 0.97). Table 4 Univariate and Multivariate Cox Regression for OS and RFS Subgroup Factor Overall survival Recurrence Free Survival Univariate analysis Multivariate analysis Univariate analysis Multivariate analysis HR (95% CI) p-value HR (95% CI) p-value HR (95% CI) p-value HR (95% CI) p-value A LVI (+), PNI (+), DOI > 1cm 2.26 (1.49 to 3.43) 0.0001 4.8 (2.69 to 8.8) < 0.0001 2.11 (1.4 to 3.16) 0.0002 4.29 (2.44 to 7.5) 1cm 1.68 (1.17 to 2.4) 0.004 3.5 (2.05 to 6.16) < 0.0001 1.5 (1.1 to 2.1) 0.011 3.13 (1.8 to 5.2) 1cm 0.97 (0.62 to 1.52) 0.91 2.3 (1.2 to 4.4) 0.006 1.07 (0.71 to 1.63) 0.73 2.4 (1.35 to 4.2) 0.003 D LVI (+), PNI (+), DOI < 1cm 1.95 (1.20 to 3.16) 0.007 4.4 (2.3 to 8.4) < 0.0001 1.92 (1.19 to 3.12) 0.007 4.11 (2.2 to 7.6) < 0.0001 E LVI or PNI (+), DOI < 1cm 0.41 (0.21 to 0.81) 0.01 1.08 (0.48 to 2.4) 0.84 0.43 (0.23 to 0.83) 0.011 1.06 (0.49 to 2.2) 0.87 F LVI (-), PNI (-), DOI < 1cm reference - reference - reference - reference - Discussion This study provides a comprehensive analysis of the combined prognostic impact of LVI, PNI and DOI in 342 patients with OCC, offering insights into their synergistic effects on survival outcomes. LVI was observed in 29.8% of cases, aligning with rates reported by Matsushita et al. (23.6%) [ 8 ]and Choi et al. (21.7%) [ 9 ], though some studies reported higher rates ranging from 33–35%[ 7 , 10 ].In our cohort, PNI was present in 48.8%, consistent with ranges of 37–50% in the literature, potentially reflecting advanced-stage presentations common in our cohort, where patients often seek care at later stages and hence, have a higher propensity of high risk features[ 11 , 12 ].DOI > 1cm was noted in 43.3% of tumours, underscoring its prevalence in aggressive disease and its relevance as a staging criterion. Prognostic significance of these factors has been established individually in prior studies. Huang et al.’s [ 13 ] meta-analysis reported LVI as a predictor of poor OS(HR: 1.55, 95% CI: 1.43–1.69) but not DFS (HR = 1.20; 95% CI- 0.89–1.62; p = 0.24). Cheng et al. [ 14 ] identified PNI as an independent OS predictor (HR: 1.37, 95% CI: 1.02–1.83). Dolens et al.’s [ 15 ] meta-analysis confirmed impact of DOI on OS (HR: 1.94, 95% CI: 1.54–2.44) and DFS (HR: 1.53, 95% CI: 1.29–1.81). However, the combined effect of these factors has been underexplored, making this study a critical contribution to understanding their interplay in OCC. Significant differences were observed across subgroups for tumour size, nodal metastasis, skin and bone invasion, ENE, pathological stage, and group stage. No significant differences were noted for age, gender, addiction history, or tumour subsite, indicating that prognostic impact of the subgroups was driven by pathological rather than demographic factors. Pathologically, DOI > 1cm was associated with poorly differentiated tumours and frequent skin and bone invasion, indicating aggressive local behavior that complicates surgical management. LVI and PNI significantly influenced nodal metastasis and ENE, with subgroup A showing a 10-fold higher nodal metastasis rate than subgroup F. The absence of early-stage cases in subgroups A and D highlights their aggressive nature, while subgroup F’s predominance in early stages reflects its favorable prognosis. High recurrence rates in subgroups A (over 50%) and D further emphasize the need for tailored interventions to address these high-risk cohorts. Stratification into six subgroups revealed stark survival differences. Subgroup A, with all three risk factors, exhibited the worst outcomes (3-year OS: 31.5%; RFS: 11 months), highlighting the synergistic detrimental effect of LVI, PNI and DOI > 1cm. Subgroup D, with positive LVI and PNI but DOI < 1cm, also showed poor outcomes (3-year OS: 30.4%; RFS: 12 months), indicating that LVI and PNI significantly impact prognosis even in shallower tumours. On further analysis in subgroup B, LVI had a more pronounced effect than PNI (3-year OS: 23.1% vs. 48.6%), suggesting that LVI may contribute more significantly to tumour aggressiveness in deeper tumours. Subgroup C, with negative LVI and PNI but DOI > 1cm, had improved outcomes (3-year OS: 62.4%; RFS: 43 months), but multivariate analysis confirmed DOI as an independent predictor of poor prognosis (OS HR: 2.3). Subgroup F, with no risk factors, exhibited the best outcomes (3-year OS: 78.8%; RFS: 65 months), underscoring the favorable prognosis of tumours lacking these adverse features. Previous studies provide context for these findings. Liao et al. found no significant benefit of adjuvant radiation in PNI-positive tumours without other risk factors, possibly due to higher DOI ( ≥ 10mm)concealing the advantage offered with adjuvant RT [ 16 ]. Fan et al. reported 3-year RFS of 45% with three or more risk factors. It was slightly better than our 31.5% in subgroup A that was likely due to their lower LVI rate (3.6%) [ 17 ]. Hinerman et al. identified ENE, PNI, and advanced T-stage as predictors of locoregional control, with less emphasis on LVI, contrasting our findings where LVI significantly impacted outcomes [ 18 ]. These discrepancies highlight the variability in the prognostic impact of individual risk factors across different cohorts and underscore the importance of evaluating their combined effects. The results of our study suggest that current treatment paradigms may be insufficient for patients with multiple risk factors. The interplay of LVI, PNI and DOI amplifies their prognostic impact, necessitating risk stratification to guide treatment decisions. High-risk subgroups (A and D) may benefit from intensified regimens, such as concurrent chemoradiation, to improve locoregional control and survival. For instance, patients in subgroup A, with all three risk factors, exhibited HR of 4.8 for OS, indicating a need for aggressive therapeutic approaches to address their poor prognosis. Conversely, low-risk subgroup F, with no risk factors, could be considered for treatment de-escalation or surveillance to reduce treatment-related morbidity without compromising outcomes. There are a few limitations to this study. First, it is a retrospective analysis conducted in a single institute and has its associated limitations includingunequaldistribution of patients in subsets. Due to classification of cases of the whole cohort into 6 subgroups, number of cases in each subgroup has reduced. This may limit statistical power and may not completely correlate in general population. Conclusion This study underscores the critical importance of the combined prognostic impact of LVI, PNI and DOI in OCC. The significant survival variations observed across six subgroups highlight the potential of risk stratification to identify high-risk patients who may benefit from aggressive treatment intensification and low-risk patients suitable for reduced-intensity follow-up or surveillance. These findings advocate for personalized therapeutic approaches to improve outcomes in OCC. However, prospective, multi-institutional studies are needed to confirm the applicability of this risk stratification model and to optimize clinical management strategies for patients with varying risk profiles. Abbreviations OCC Oral cavity cancer LVI Lymphovascular invasion PNI Perineural invasion DOI Depth of Invasion AJCC American Joint Committee on Cancer TNM Tumour-node-metastasis ENE Extra-nodal extension OS Overall Survival RFS Recurrence-Free Survival HR Hazard Ratio CI Confidence Interval Declarations Ethics approval and consent to participate - All procedures were performed in compliance with the Declaration of Helsinki. This work is a retrospective subset analysis derived from a previously approved retrospective study titled “Comparison of the seventh and eighth editions of American Joint Committee Cancer Classification system in oral cavity squamous cell cancers and their prognostic implication”, which had obtained full approval from the Institutional Ethics Committee, Homi Bhabha Cancer Hospital, Sangrur, Punjab (Institutional Ethics Committee Approval No. - EC/NEW/2024/PB/501, dated 29.8.25). For the present manuscript, no new data were collected, no patient contact or intervention was performed, and the analysis was conducted exclusively on existing, fully de-identified records from the parent retrospective dataset. Therefore, at the time of conducting this subset analysis, a separate IEC approval was not sought, as the dataset was already covered under the primary IEC approval. Written informed consent was obtained from all participants prior to inclusion. Consent for publication – Not applicable Availability of data and materials - The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. Competing interests - The authors declare no competing interests. Funding – None Authors' contributions – PT: Study design, data analysis and preparing manuscript, DSR: Reviewed radiology and manuscript, PG: Data collection and Data analysis, AG: Managed chemotherapy and its complication, SS: Meticulous reporting of all histopathology, AS: Managed surgical aspects of data, TKD: Supervised manuscript, AG: Supervised overall manuscript. All authors reviewed the manuscript. Acknowledgements – Not applicable References National Cancer Institute. Head and Neck Cancers [Internet]. Bethesda (MD): National Cancer Institute; [cited 2025 May 29]. Available from: https://www.cancer.gov/types/head-and-neck/head-neck-fact-sheet Ferlay J, Ervik M, Lam F, Laversanne M, Colombet M, Mery L et al. Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for Research on Cancer; 2024 [cited 2025 May 29]. Available from: https://gco.iarc.who.int/today Ferlay J, Ervik M, Lam F, Laversanne M, Colombet M, Mery L et al. Global Cancer Observatory: Cancer Today – India Fact Sheet. Lyon, France: International Agency for Research on Cancer; 2024 [cited 2025 May 29]. Available from: https://gco.iarc.who.int/media/globocan/factsheets/populations/356-india-fact-sheet.pdf Huang Q, Huang Y, Chen C, Zhang Y, Zhou J, Xie C, et al. Prognostic impact of lymphovascular and perineural invasion in squamous cell carcinoma of the tongue. Sci Rep. 2023;13:3828. 10.1038/s41598-023-30939-8 . Cheng HW, Lin LH, Lin HP, Liu CJ. Perineural invasion unveiled: Deciphering the prognostic impact of diameter and quantity subcategories in oral cancer. J Otolaryngol Head Neck Surg. 2024;54(1):1–14. 10.1177/191602/6251316219 . 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Impact of lymphovascular invasion in oral squamous cell carcinoma: A meta-analysis. Oral MaxillofacPathol. 2021;131(3):319–28. 10.1016/j.oooo.2020.10.026 . Cheng HW, Lin LH, Lin HP, Liu CJ. Perineural invasion unveiled: Deciphering the prognostic impact of diameter and quantity subcategories in oral cancer. J Otolaryngol Head Neck Surg. 2024;54(1):1–14. 10.1177/191602/62513/6219 . Dolens ES, Dourado MR, Almangush A, Salo TA, Rocha CAG, da Silva SD, et al. The impact of histopathological features on the prognosis of oral squamous cell carcinoma: A comprehensive review and meta-analysis. Front Oncol. 2021;11:784924. 10.3389/fonc.2021.784924 . Liao CT, Chang JT, Wang HM, Ng SH, Hsueh C, Lee LY, et al. Does adjuvant radiation therapy improve outcomes in pT1-3N0 oral cavity cancer with tumor- free margins and perineural invasion? Int J RadiatOncolBiolPhys. 2008;71:371–6. Fan KH, Wang HM, Kang CJ, Lee LY, Huang SF, Lin CY, et al. Treatment results of postoperative radiotherapy on squamous cell carcinoma of the oral cavity: coexistence of multiple minor risk factors results in higher recurrence rates. Int J RadiatOncolBiolPhys. 2010;77:1024–9. Hinerman RW, Mendenhall WM, Morris CG, et al. Postoperative irradiation for squamous cell carcinoma of the oral cavity: 35-year experience. Head Neck. 2004;26:984–94. Additional Declarations No competing interests reported. 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1","display":"","copyAsset":false,"role":"figure","size":131012,"visible":true,"origin":"","legend":"\u003cp\u003eOS and RFS analysis in OCC: Kaplan Meier Curves depicting OS and comparing subgroups based on LVI, PNI and DOI\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8101509/v1/a41b8db7702a2a98499459ca.jpg"},{"id":100012336,"identity":"a8f1a5bf-20ab-44ba-b907-b089b71ca468","added_by":"auto","created_at":"2026-01-12 06:13:39","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":165371,"visible":true,"origin":"","legend":"\u003cp\u003eOS in OCC subgroups based on LVI, PNI and DOI: a) LVI (+), PNI (+), DOI \u0026gt;1cm; b) LVI or PNI (+), DOI \u0026gt;1cm; c) LVI (-), PNI (-), DOI \u0026gt;1cm; d) LVI (+), PNI (+), DOI \u0026lt;1cm; e) LVI or PNI (+), DOI \u0026lt;1cm; f) LVI (-), PNI (-), DOI \u0026lt;1cm.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8101509/v1/1861fe6f7d6b60262ade759d.jpg"},{"id":100362116,"identity":"4e7491e0-6dc2-495d-afbe-cb8e02f617e6","added_by":"auto","created_at":"2026-01-16 07:46:12","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":162421,"visible":true,"origin":"","legend":"\u003cp\u003eRFS in OCC subgroups based on LVI, PNI and DOI: a) LVI (+), PNI (+), DOI \u0026gt;1cm; b) LVI or PNI (+), DOI \u0026gt;1cm; c) LVI (-), PNI (-), DOI \u0026gt;1cm; d) LVI (+), PNI (+), DOI \u0026lt;1cm; e) LVI or PNI (+), DOI \u0026lt;1cm; f) LVI (-), PNI (-), DOI \u0026lt;1cm.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8101509/v1/786429aae2fc1d2f6631e77a.jpg"},{"id":100380898,"identity":"5fd7e163-9974-44c0-bfae-49c352c24c41","added_by":"auto","created_at":"2026-01-16 10:36:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1600820,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8101509/v1/0eb4455d-576c-41cb-a9f1-29bea6d31794.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Triple threats in cancer of oral cavity: Navigating pathological risk factors","fulltext":[{"header":"Background","content":"\u003cp\u003eOral cavity cancer (OCC) remains a significant public health challenge, particularly in lower and lower-middleincome countries, where it ranks among the most prevalent malignancies due to high rates of tobacco use, betel quid chewing and limited access to early screening. Despite advancements in multimodality treatments, including surgery, radiotherapy and chemotherapy, the prognosis for OCC remains suboptimal as majority of patients present in locally advanced stage [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. This complicates treatment planning and contributes to high rates of recurrence and mortality.\u003c/p\u003e \u003cp\u003eTo improve outcomes, researchers have focused on identifying pathological markers that can predict prognosis and guide treatment decisions. Lymphovascular invasion (LVI) is defined as infiltration of tumour cells into lymphatic or vascular endothelium-lined spaces. Tumour can spread indirectly through lymphatics or lymphatic vein exchange channels or directly through blood vessels. LVIhas been found to be associated with aggressive tumour behavior and poor survival outcomes [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].OCC is considered a neurotropic malignancy as tumour cells and associated stroma show strong affinity to surrounding nerves and neural invasion, also known as perineural invasion (PNI), through molecular mediators. Tumourcellsshow directional movement such that these spread beyond the primary lesion and can be missed during resection thereby, contributing to increased chances of local recurrence. Recently, PNI has been classified on the basis of extent of invasion into unifocal and multifocal; with multifocality being associated with increased local failure. However, some studies have also shown varied results for LVI and PNI; therefore, they have not yet been incorporated into tumour staging[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDepth of invasion(DOI), measured as distance from the normal mucosal basement membrane to the deepest point of tumour invasion, is a critical indicator of tumour aggressiveness. Unlike tumour thickness, which measures the distance from tumour surface to its deepest point, DOI provides a more precise assessment of tumour invasiveness and has been incorporated into American Joint Committee on Cancer (AJCC) tumour-node-metastasis (TNM) 8th edition staging system. Current evidence supports DOI as a prognostic factor for overall survival (OS), recurrence-free survival (RFS) and nodal metastasis, reflecting its role in local tumourspread and systemic progression [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhile LVI, PNI and DOI are individually associated with adverse outcomes, their combined prognostic impact remains underexplored. Literature reports conflicting results regarding the significance of LVI and PNI[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].DOI, while established as a staging criterion, requires further investigation to understand its interaction with other pathological features. Comparative analyses of clinical trials have identified high-risk features, such as positive surgical margins or extranodal extension(ENE) that necessitate aggressive treatment with concurrent chemoradiotherapy.[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] However, the synergistic effect of multiple risk factors, such as LVI, PNI and DOIis not well-defined, leaving a gap in the ability to stratify patients for personalized treatment.\u003c/p\u003e \u003cp\u003eThis study aims to evaluate the combined effect of LVI, PNI, and DOI (stratified at 1cm) on OS and RFS in patients with OCC treated with curative intent. These three factors were selected to avoid overlap with other pathological characteristics, which may result in confounded results, eg. DOI would have overlap with tumour size and primary tumour stage, since it is included in staging whereas LVI isa significant predictor of presence of cervical lymph node metastasis at presentation,independent of other known prognostic factors and would have overlap with nodal stage [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Moreover, LVI, PNI and DOI represent distinct mechanisms of tumour spread\u0026mdash;hematogenous/ lymphatic, neurotropic and local invasion, respectively\u0026mdash;making them ideal candidates for assessing their cumulative prognostic impact. By stratifying patients into subgroups based on these factors, we sought to identify high-risk cohorts that may benefit from intensified treatment regimens and low-risk groups suitable for de-escalation or surveillance, ultimately contributing to more tailored therapeutic strategies.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis retrospective study included 342 patients diagnosed with OCC and treated with curative intent at a tertiary oncology center in India from January 2017 to December 2021. To ensure a homogeneous cohort, patients with metastatic or recurrent tumours, prior chemotherapy or radiotherapy, incomplete or revision surgeriesand non-squamous histology were excluded. Demographic, clinical, and pathological data were retrieved from medical records to provide a comprehensive dataset for analysis. AJCC TNM 8th editionwas used for tumour staging, based on radiological records, including contrast-enhanced computed tomography or magnetic resonance imaging of face and neck, to accurately characterize the primary tumour and nodal involvement. Treatment plans for all patients were finalized through consensus in multidisciplinary tumour board, ensuring standardized and evidence-based treatment plan. All patients underwent surgical excision of primary tumour and nodal dissection, followed by adjuvant radiotherapy using external beam radiation therapy or concurrent chemoradiotherapy, depending on the presence of high-risk pathological features.\u003c/p\u003e\n\u003cp\u003ePatients were classified into six subgroups based on the presence or absence of LVI and PNI along with DOI stratified at 1cm:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\n \u003cp\u003eSubgroup A: Positive LVI, positive PNI, DOI\u0026thinsp;\u0026gt;\u0026thinsp;1cm\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eSubgroup B: Either positive LVI or positive PNI, DOI\u0026thinsp;\u0026gt;\u0026thinsp;1cm\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eSubgroup C: Negative LVI, negative PNI, DOI\u0026thinsp;\u0026gt;\u0026thinsp;1cm\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eSubgroup D: Positive LVI, positive PNI, DOI\u0026thinsp;\u0026lt;\u0026thinsp;1cm\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eSubgroup E: Either positive LVI or positive PNI, DOI\u0026thinsp;\u0026lt;\u0026thinsp;1cm\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eSubgroup F: Negative LVI, negative PNI, DOI\u0026thinsp;\u0026lt;\u0026thinsp;1cm\u003c/p\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eData analysis was conducted using IBM SPSS Statistics version 23.0 (IBM Corp., Armonk, NY, USA). Descriptive statistics were employed to summarize demographic and tumourcharacteristics, providing a clear overview of the cohort\u0026rsquo;s profile across subgroups. Chi-square tests were used to evaluate differences in clinical and pathological features among the six subgroups, ensuring robust comparisons of tumour behavior and patient characteristics. OS, defined as the time from diagnosis to death from any cause, and RFS, defined as the time to tumour recurrence or death, were calculated to assess long-term outcomes. Pearson\u0026rsquo;s chi-square test was used to assess correlation between clinico-pathological features and OS. Survival outcomes were analyzed using Kaplan-Meier curves, with differences between subgroups evaluated using log-rank tests to determine statistical significance. Patients lost to follow-up were censored to maintain the integrity of the survival analysis. To estimate the independent prognostic impact of the subgroups, Cox proportional hazard models were applied, with hazard ratios (HR) and 95% confidence intervals (CI) calculated to quantify the magnitude and strength of associations. A p-value less than 0.05 was considered statistically significant for all analyses, ensuring rigorous interpretation of the results.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe study cohort comprised 342 patients with a median age of 55 years (range: 28\u0026ndash;86 years), of whom 85% were male, reflecting the typical demographic profile of OCC in high-incidence regions. LVI was positive in 29.8% (102 cases), PNI in 48.8% (167 cases), and DOI\u0026thinsp;\u0026gt;\u0026thinsp;1cm in 43.3% (148 cases), highlighting the prevalence of these adverse pathological features in the cohort.\u003c/p\u003e\n\u003cp\u003eSubgroup distribution was as follows:\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003e\n\u003cp\u003eSubgroup A: 14.3% (49 patients)\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eSubgroup B: 25.1% (86 patients)\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eSubgroup C: 17.25% (59 patients)\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eSubgroup D: 7% (24 patients)\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eSubgroup E: 10.08% (37 patients)\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eSubgroup F: 25.4% (87 patients)\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eComparison of demographic and clinico-pathological details for each subgroup is summarised in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Subgroup F, with no risk factors, exhibited the lowest incidence of adverse features, serving as the reference group. Tumours with DOI\u0026thinsp;\u0026gt;\u0026thinsp;1cm were predominantly poorly differentiated (83.3%), with frequent skin and bone invasion, suggesting aggressive local behavior. Nodal metastasis was 10 times more common in subgroup A and 3 times more common in subgroup B compared to subgroup F. Incidence of ENE was 3 times higher in subgroup A and 1.7 times higher in subgroup B, with reduced risk in subgroup C. Notably, subgroup D, characterized by positive LVI and PNI with DOI less than 1cm, showed a 3-fold higher ENE risk. Advanced pathological T and N stages and occult nodal disease were most prevalent in subgroup A. No early-stage (I or II) cases were observed in subgroups A or D, while cases insubgroup F predominantly presented in early stages. Recurrence rates exceeded 50% in subgroup A and were elevated in subgroup D, correlating with the presence of multiple adverse factors. This indicates positivity of both LVI and PNI portends an aggressive disease with poor prognosis independent of DOI status, although presence of DOI\u0026thinsp;\u0026gt;\u0026thinsp;1cm makes it worse.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003ePatient demographics and clinical characteristics of OCC patients across sub-groups\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCharacteristics\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSub-group A\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSub-group B\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSub-group C\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSub-group D\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSub-group E\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSub-group F\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u0026chi;2\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ep-value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eLVI (+), PNI (+), DOI\u0026thinsp;\u0026gt;\u0026thinsp;1cm\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eLVI or PNI (+), DOI\u0026thinsp;\u0026gt;\u0026thinsp;1cm\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eLVI (-), PNI (-), DOI\u0026thinsp;\u0026gt;\u0026thinsp;1cm\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eLVI (+), PNI (+), DOI\u0026thinsp;\u0026lt;\u0026thinsp;1cm\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eLVI or PNI (+), DOI\u0026thinsp;\u0026lt;\u0026thinsp;1cm\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eLVI (-), PNI (-), DOI\u0026thinsp;\u0026lt;\u0026thinsp;1cm\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eGender\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eM\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eF\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e38\u003c/p\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e73\u003c/p\u003e\n\u003cp\u003e13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e56\u003c/p\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e21\u003c/p\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e32\u003c/p\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e72\u003c/p\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e8.06\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.153\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eDifferentiation\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eWD\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMD\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePD\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003cp\u003e46\u003c/p\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003cp\u003e78\u003c/p\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003cp\u003e54\u003c/p\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003cp\u003e24\u003c/p\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003cp\u003e32\u003c/p\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003cp\u003e69\u003c/p\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e23.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.009\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003epT\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4a\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003cp\u003e14\u003c/p\u003e\n\u003cp\u003e34\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003cp\u003e29\u003c/p\u003e\n\u003cp\u003e56\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003cp\u003e20\u003c/p\u003e\n\u003cp\u003e38\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003cp\u003e20\u003c/p\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e25\u003c/p\u003e\n\u003cp\u003e39\u003c/p\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e204.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003epN\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2a\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2b\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2c\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3a\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3b\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003cp\u003e33\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e23\u003c/p\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003cp\u003e41\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e35\u003c/p\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e17\u003c/p\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e62\u003c/p\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e133.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eGroup stage\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eI\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eII\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIII\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIVA\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIVB\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003cp\u003e33\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003cp\u003e35\u003c/p\u003e\n\u003cp\u003e40\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003cp\u003e14\u003c/p\u003e\n\u003cp\u003e33\u003c/p\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e23\u003c/p\u003e\n\u003cp\u003e23\u003c/p\u003e\n\u003cp\u003e17\u003c/p\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e179.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eOccult node\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eNo\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eYes\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e13\u003c/p\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e16\u003c/p\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e51\u003c/p\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e20.14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eTumour size\u0026thinsp;\u0026gt;\u0026thinsp;4cm\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eNo\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eYes\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e25\u003c/p\u003e\n\u003cp\u003e24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e35\u003c/p\u003e\n\u003cp\u003e40\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e31\u003c/p\u003e\n\u003cp\u003e21\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e14\u003c/p\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e28\u003c/p\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e66\u003c/p\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e40.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eSkin\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eN\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003cp\u003e39\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003cp\u003e71\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003cp\u003e50\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003cp\u003e20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003cp\u003e32\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003cp\u003e83\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e19.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.031\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBone\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eY\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eN\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e22\u003c/p\u003e\n\u003cp\u003e24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e23\u003c/p\u003e\n\u003cp\u003e63\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e26\u003c/p\u003e\n\u003cp\u003e33\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003cp\u003e14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003cp\u003e27\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003cp\u003e75\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e36.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eNodal status\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eNeg\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePos\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003cp\u003e45\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e23\u003c/p\u003e\n\u003cp\u003e63\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e35\u003c/p\u003e\n\u003cp\u003e24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003cp\u003e22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e17\u003c/p\u003e\n\u003cp\u003e20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e64\u003c/p\u003e\n\u003cp\u003e23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e85.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eENE\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eYes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNo\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e38\u003c/p\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e53\u003c/p\u003e\n\u003cp\u003e31\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003cp\u003e44\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e18\u003c/p\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003cp\u003e24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003cp\u003e71\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e86.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eRecurrence\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eYes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNo\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e18\u003c/p\u003e\n\u003cp\u003e17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e23\u003c/p\u003e\n\u003cp\u003e41\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e19\u003c/p\u003e\n\u003cp\u003e31\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003cp\u003e29\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e17\u003c/p\u003e\n\u003cp\u003e61\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e30.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.01\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eOS at 3 years was calculated, which varied significantly based on subgroups (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Patients in subgroup A had the poorest 3 year OS at 31.5% which improved to 43.6% for patients in subgroup B. Interestingly, within subgroup B, presence of LVI alone had more detrimental effect on 3year OS than PNI alone in tumours with DOI\u0026thinsp;\u0026gt;\u0026thinsp;1cm (23.1% vs 48.6%). The 3 year OS further improved to 62.4% for patients in subgroup C when both LVI and PNI were absent with DOI\u0026thinsp;\u0026gt;\u0026thinsp;1cm. Despite DOI\u0026thinsp;\u0026lt;\u0026thinsp;1cm in subgroup D, worse outcome with 3 year OS of 30.4% was observed. In contrast, 3 year OS was 77.6% for subgroup E and was the highest in subgroup F with no risk factors at 78.8% (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). A similar trend was observed for RFS (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e) and is summarised in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eDistribution of 3-year OS and 3-year RFS across subgroups based on LVI, PNI and DOI\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSubgroups\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eFactor combination\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e3 yrs OS\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e3 yrs RFS\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eA\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLVI (+), PNI (+), DOI\u0026thinsp;\u0026gt;\u0026thinsp;1cm (n\u0026thinsp;=\u0026thinsp;49)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e31.5%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e31.5%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eB\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLVI or PNI (+), DOI\u0026thinsp;\u0026gt;\u0026thinsp;1cm (n\u0026thinsp;=\u0026thinsp;86)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e43.6%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e40.2%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eC\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLVI (-), PNI (-), DOI\u0026thinsp;\u0026gt;\u0026thinsp;1cm (n\u0026thinsp;=\u0026thinsp;59)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e62.4%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e55.4%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eD\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLVI (+), PNI (+), DOI\u0026thinsp;\u0026lt;\u0026thinsp;1cm (n\u0026thinsp;=\u0026thinsp;24)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e30.4%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e26.1%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eE\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLVI or PNI (+), DOI\u0026thinsp;\u0026lt;\u0026thinsp;1cm (n\u0026thinsp;=\u0026thinsp;37)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e77.6%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e72.4%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eF\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLVI (-), PNI (-), DOI\u0026thinsp;\u0026lt;\u0026thinsp;1cm (n\u0026thinsp;=\u0026thinsp;87)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e78.8%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e75.6%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eMedian OS for whole cohort was 54 months but differed significantly among subgroups [Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e]. Lowest outcome was observed for subgroup A (17 months, 95% CI \u0026minus;\u0026thinsp;11.1 to 22.8 months). However, in subgroup D with DOI\u0026thinsp;\u0026lt;\u0026thinsp;1cm, median OS improved to 21 months (95% CI \u0026minus;\u0026thinsp;19.4 to 22.5 months). In presence of either of LVI or PNI, OS was 25 months (95% CI \u0026minus;\u0026thinsp;11.7 to 38.3 months) if DOI\u0026thinsp;\u0026gt;\u0026thinsp;1cm and median was not reached with DOI\u0026thinsp;\u0026lt;\u0026thinsp;1cm. Absence of LVI and PNI in subgroup C improved median OS to 46 months (95% CI \u0026minus;\u0026thinsp;30.4 to 61.5 months). Median was not reached in subgroup F where all the risk factors were absent (mean OS \u0026minus;\u0026thinsp;68 months, 95% CI \u0026minus;\u0026thinsp;61.7 to 75.1 months). Similarly, trend was observed for RFS and values are summarized in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eMedian OS and RFS across subgroups with log rank test p- value\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSubgroups\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eFactor\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eOS\u0026thinsp;\u003cspan class=\"Underline\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;S.E. (95%CI) (months)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u0026chi;2\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003elog rank p-value\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eRFS\u0026thinsp;\u003cspan class=\"Underline\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;S.E. (95%CI) (months)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u0026chi;2\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003elog rank p-value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eA\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLVI (+), PNI (+), DOI\u0026thinsp;\u0026gt;\u0026thinsp;1cm\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17\u0026thinsp;\u003cspan class=\"Underline\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;2.9 (11.1 to 22.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11\u0026thinsp;\u003cspan class=\"Underline\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;2.2 (6.5 to 15.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e14.05\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eB\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLVI or PNI (+), DOI\u0026thinsp;\u0026gt;\u0026thinsp;1cm\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25\u0026thinsp;\u003cspan class=\"Underline\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;6.7 (11.7 to 38.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.003\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22\u0026thinsp;\u003cspan class=\"Underline\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;6.7 (8.7 to 35.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e6.73\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.009\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eC\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLVI (-), PNI (-), DOI\u0026thinsp;\u0026gt;\u0026thinsp;1cm\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e46\u0026thinsp;\u003cspan class=\"Underline\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;7.9 (30.4 to 61.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.013\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e43\u0026thinsp;\u003cspan class=\"Underline\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;7.3 (28.5 to 57.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.72\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eD\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLVI (+), PNI (+), DOI\u0026thinsp;\u0026lt;\u0026thinsp;1cm\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21\u0026thinsp;\u003cspan class=\"Underline\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;0.79 (19.4 to 22.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.006\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12\u0026thinsp;\u003cspan class=\"Underline\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;1.1 (9.6 to 14.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e7.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.006\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eE\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLVI or PNI (+), DOI\u0026thinsp;\u0026lt;\u0026thinsp;1cm\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e67.2\u0026thinsp;\u003cspan class=\"Underline\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;5.1 (57.1 to 77.4)\u003c/p\u003e\n\u003cp\u003e(Mean)\u003c/p\u003e\n\u003cp\u003e(Median not reached)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.007\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e64.8\u0026thinsp;\u003cspan class=\"Underline\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;5.6 (53.8 to 75.8)\u003c/p\u003e\n\u003cp\u003e(Mean)\u003c/p\u003e\n\u003cp\u003e(Median not reached)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e6.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.008\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eF\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLVI (-), PNI (-), DOI\u0026thinsp;\u0026lt;\u0026thinsp;1cm\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e68.4\u0026thinsp;\u003cspan class=\"Underline\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;3.4 (61.7 to 75.1)\u003c/p\u003e\n\u003cp\u003e(Mean)\u003c/p\u003e\n\u003cp\u003e(Median not reached)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e65\u0026thinsp;\u003cspan class=\"Underline\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;3.7 (57.7 to 72.4)\u003c/p\u003e\n\u003cp\u003e(Mean)\u003c/p\u003e\n\u003cp\u003e(Median not reached)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e21.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eMultivariate analysis confirmed the above findings. Patients in all subgroups were compared to subgroup F. Subgroup A had the worst outcome with the highest HR for both OS (HR 4.8, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and RFS (HR 4.29, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Similarly, subgroups B and D also had significantly worse outcomes and recurrences, with multivariate HRs for OS of 3.5 and 4.4 respectively. Even with DOI\u0026thinsp;\u0026lt;\u0026thinsp;1cm, presence of both LVI and PNI led to poor outcomes as observed in subgroup D. Subgroup C was not found significant in univariate analysis (HR\u0026thinsp;~\u0026thinsp;1), but became significant in multivariate analysis (OS HR 2.3, RFS HR 2.4). Subgroup E showed relatively better outcomes in univariate analysis (HR -0.4), but these were not significant in multivariate analysis, indicating that either LVI or PNI with DOI\u0026thinsp;\u0026lt;\u0026thinsp;1cm may not independently affect prognosis[Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e]. To confirm the independent prognostic value of these subgroups, a multivariate Cox regression analysis was done. After adjusting for ENE, nodal status, bone and skin invasion, tumour size and group stage, the subgroups based on LVI, PNI and DOI were independent and significant predictors of OS (p\u0026thinsp;=\u0026thinsp;0.015, B\u0026thinsp;=\u0026thinsp;0.15, HR\u0026thinsp;=\u0026thinsp;0.85, 95% CI \u0026minus;\u0026thinsp;0.75 to 0.97).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab4\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eUnivariate and Multivariate Cox Regression for OS and RFS\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSubgroup\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eFactor\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003eOverall survival\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003eRecurrence Free Survival\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eUnivariate analysis\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMultivariate analysis\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eUnivariate analysis\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMultivariate analysis\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eHR (95% CI)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ep-value\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eHR (95% CI)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ep-value\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eHR (95% CI)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ep-value\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eHR (95% CI)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ep-value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eA\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLVI (+), PNI (+), DOI\u0026thinsp;\u0026gt;\u0026thinsp;1cm\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.26 (1.49 to 3.43)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.8 (2.69 to 8.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.11 (1.4 to 3.16)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.0002\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.29 (2.44 to 7.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eB\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLVI or PNI (+), DOI\u0026thinsp;\u0026gt;\u0026thinsp;1cm\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.68 (1.17 to 2.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.004\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.5 (2.05 to 6.16)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.5 (1.1 to 2.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.011\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.13 (1.8 to 5.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eC\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLVI (-), PNI (-), DOI\u0026thinsp;\u0026gt;\u0026thinsp;1cm\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.97 (0.62 to 1.52)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.91\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.3 (1.2 to 4.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.006\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.07 (0.71 to 1.63)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.73\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.4 (1.35 to 4.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.003\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eD\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLVI (+), PNI (+), DOI\u0026thinsp;\u0026lt;\u0026thinsp;1cm\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.95 (1.20 to 3.16)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.007\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.4 (2.3 to 8.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.92 (1.19 to 3.12)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.007\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.11 (2.2 to 7.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eE\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLVI or PNI (+), DOI\u0026thinsp;\u0026lt;\u0026thinsp;1cm\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.41 (0.21 to 0.81)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.01\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.08 (0.48 to 2.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.84\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.43 (0.23 to 0.83)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.011\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.06 (0.49 to 2.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.87\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eF\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLVI (-), PNI (-), DOI\u0026thinsp;\u0026lt;\u0026thinsp;1cm\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ereference\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ereference\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ereference\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ereference\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study provides a comprehensive analysis of the combined prognostic impact of LVI, PNI and DOI in 342 patients with OCC, offering insights into their synergistic effects on survival outcomes. LVI was observed in 29.8% of cases, aligning with rates reported by Matsushita et al. (23.6%) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]and Choi et al. (21.7%) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], though some studies reported higher rates ranging from 33\u0026ndash;35%[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].In our cohort, PNI was present in 48.8%, consistent with ranges of 37\u0026ndash;50% in the literature, potentially reflecting advanced-stage presentations common in our cohort, where patients often seek care at later stages and hence, have a higher propensity of high risk features[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].DOI\u0026thinsp;\u0026gt;\u0026thinsp;1cm was noted in 43.3% of tumours, underscoring its prevalence in aggressive disease and its relevance as a staging criterion.\u003c/p\u003e \u003cp\u003ePrognostic significance of these factors has been established individually in prior studies. Huang et al.\u0026rsquo;s [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] meta-analysis reported LVI as a predictor of poor OS(HR: 1.55, 95% CI: 1.43\u0026ndash;1.69) but not DFS (HR\u0026thinsp;=\u0026thinsp;1.20; 95% CI- 0.89\u0026ndash;1.62; p\u0026thinsp;=\u0026thinsp;0.24). Cheng et al. [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] identified PNI as an independent OS predictor (HR: 1.37, 95% CI: 1.02\u0026ndash;1.83). Dolens et al.\u0026rsquo;s [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] meta-analysis confirmed impact of DOI on OS (HR: 1.94, 95% CI: 1.54\u0026ndash;2.44) and DFS (HR: 1.53, 95% CI: 1.29\u0026ndash;1.81). However, the combined effect of these factors has been underexplored, making this study a critical contribution to understanding their interplay in OCC.\u003c/p\u003e \u003cp\u003eSignificant differences were observed across subgroups for tumour size, nodal metastasis, skin and bone invasion, ENE, pathological stage, and group stage. No significant differences were noted for age, gender, addiction history, or tumour subsite, indicating that prognostic impact of the subgroups was driven by pathological rather than demographic factors.\u003c/p\u003e \u003cp\u003ePathologically, DOI\u0026thinsp;\u0026gt;\u0026thinsp;1cm was associated with poorly differentiated tumours and frequent skin and bone invasion, indicating aggressive local behavior that complicates surgical management. LVI and PNI significantly influenced nodal metastasis and ENE, with subgroup A showing a 10-fold higher nodal metastasis rate than subgroup F. The absence of early-stage cases in subgroups A and D highlights their aggressive nature, while subgroup F\u0026rsquo;s predominance in early stages reflects its favorable prognosis. High recurrence rates in subgroups A (over 50%) and D further emphasize the need for tailored interventions to address these high-risk cohorts.\u003c/p\u003e \u003cp\u003eStratification into six subgroups revealed stark survival differences. Subgroup A, with all three risk factors, exhibited the worst outcomes (3-year OS: 31.5%; RFS: 11 months), highlighting the synergistic detrimental effect of LVI, PNI and DOI\u0026thinsp;\u0026gt;\u0026thinsp;1cm. Subgroup D, with positive LVI and PNI but DOI\u0026thinsp;\u0026lt;\u0026thinsp;1cm, also showed poor outcomes (3-year OS: 30.4%; RFS: 12 months), indicating that LVI and PNI significantly impact prognosis even in shallower tumours. On further analysis in subgroup B, LVI had a more pronounced effect than PNI (3-year OS: 23.1% vs. 48.6%), suggesting that LVI may contribute more significantly to tumour aggressiveness in deeper tumours. Subgroup C, with negative LVI and PNI but DOI\u0026thinsp;\u0026gt;\u0026thinsp;1cm, had improved outcomes (3-year OS: 62.4%; RFS: 43 months), but multivariate analysis confirmed DOI as an independent predictor of poor prognosis (OS HR: 2.3). Subgroup F, with no risk factors, exhibited the best outcomes (3-year OS: 78.8%; RFS: 65 months), underscoring the favorable prognosis of tumours lacking these adverse features.\u003c/p\u003e \u003cp\u003ePrevious studies provide context for these findings. Liao et al. found no significant benefit of adjuvant radiation in PNI-positive tumours without other risk factors, possibly due to higher DOI (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;10mm)concealing the advantage offered with adjuvant RT [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Fan et al. reported 3-year RFS of 45% with three or more risk factors. It was slightly better than our 31.5% in subgroup A that was likely due to their lower LVI rate (3.6%) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Hinerman et al. identified ENE, PNI, and advanced T-stage as predictors of locoregional control, with less emphasis on LVI, contrasting our findings where LVI significantly impacted outcomes [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. These discrepancies highlight the variability in the prognostic impact of individual risk factors across different cohorts and underscore the importance of evaluating their combined effects.\u003c/p\u003e \u003cp\u003eThe results of our study suggest that current treatment paradigms may be insufficient for patients with multiple risk factors. The interplay of LVI, PNI and DOI amplifies their prognostic impact, necessitating risk stratification to guide treatment decisions. High-risk subgroups (A and D) may benefit from intensified regimens, such as concurrent chemoradiation, to improve locoregional control and survival. For instance, patients in subgroup A, with all three risk factors, exhibited HR of 4.8 for OS, indicating a need for aggressive therapeutic approaches to address their poor prognosis. Conversely, low-risk subgroup F, with no risk factors, could be considered for treatment de-escalation or surveillance to reduce treatment-related morbidity without compromising outcomes.\u003c/p\u003e \u003cp\u003eThere are a few limitations to this study. First, it is a retrospective analysis conducted in a single institute and has its associated limitations includingunequaldistribution of patients in subsets. Due to classification of cases of the whole cohort into 6 subgroups, number of cases in each subgroup has reduced. This may limit statistical power and may not completely correlate in general population.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study underscores the critical importance of the combined prognostic impact of LVI, PNI and DOI in OCC. The significant survival variations observed across six subgroups highlight the potential of risk stratification to identify high-risk patients who may benefit from aggressive treatment intensification and low-risk patients suitable for reduced-intensity follow-up or surveillance. These findings advocate for personalized therapeutic approaches to improve outcomes in OCC. However, prospective, multi-institutional studies are needed to confirm the applicability of this risk stratification model and to optimize clinical management strategies for patients with varying risk profiles.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOCC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eOral cavity cancer\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLVI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLymphovascular invasion\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePNI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePerineural invasion\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDOI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDepth of Invasion\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAJCC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAmerican Joint Committee on Cancer\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTNM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTumour-node-metastasis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eENE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eExtra-nodal extension\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eOverall Survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRFS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRecurrence-Free Survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHazard Ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eConfidence Interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e - All procedures were performed in compliance with the Declaration of Helsinki.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eThis work is a retrospective subset analysis derived from a previously approved retrospective study titled “Comparison of the seventh and eighth editions of American Joint Committee Cancer Classification system in oral cavity squamous cell cancers and their prognostic implication”, which had obtained full approval from the Institutional Ethics Committee, Homi Bhabha Cancer Hospital, Sangrur, Punjab (Institutional Ethics Committee Approval No. - EC/NEW/2024/PB/501, dated 29.8.25).\u003c/li\u003e\n \u003cli\u003eFor the present manuscript, no new data were collected, no patient contact or intervention was performed, and the analysis was conducted exclusively on existing, fully de-identified records from the parent retrospective dataset. Therefore, at the time of conducting this subset analysis, a separate IEC approval was not sought, as the dataset was already covered under the primary IEC approval. Written informed consent was obtained from all participants prior to inclusion.\u003c/li\u003e\n \u003cli\u003eConsent for publication – Not applicable\u003c/li\u003e\n \u003cli\u003eAvailability of data and materials - The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.\u003c/li\u003e\n \u003cli\u003eCompeting interests - The authors declare no competing interests.\u003c/li\u003e\n \u003cli\u003eFunding – None\u003c/li\u003e\n \u003cli\u003eAuthors' contributions – PT: Study design, data analysis and preparing manuscript, DSR: Reviewed radiology and manuscript, PG: Data collection and Data analysis, AG: Managed chemotherapy and its complication, SS: Meticulous reporting of all histopathology, AS: Managed surgical aspects of data, TKD: Supervised manuscript, AG: Supervised overall manuscript. All authors reviewed the manuscript.\u003c/li\u003e\n \u003cli\u003eAcknowledgements – Not applicable\u003cbr\u003e\u0026nbsp;\u003cbr\u003e\u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNational Cancer Institute. Head and Neck Cancers [Internet]. Bethesda (MD): National Cancer Institute; [cited 2025 May 29]. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.cancer.gov/types/head-and-neck/head-neck-fact-sheet\u003c/span\u003e\u003cspan address=\"https://www.cancer.gov/types/head-and-neck/head-neck-fact-sheet\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFerlay J, Ervik M, Lam F, Laversanne M, Colombet M, Mery L et al. Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for Research on Cancer; 2024 [cited 2025 May 29]. 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Impact of lymphovascular invasion in oral squamous cell carcinoma: A meta-analysis. Oral MaxillofacPathol. 2021;131(3):319\u0026ndash;28. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.oooo.2020.10.026\u003c/span\u003e\u003cspan address=\"10.1016/j.oooo.2020.10.026\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheng HW, Lin LH, Lin HP, Liu CJ. Perineural invasion unveiled: Deciphering the prognostic impact of diameter and quantity subcategories in oral cancer. J Otolaryngol Head Neck Surg. 2024;54(1):1\u0026ndash;14. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1177/191602/62513/6219\u003c/span\u003e\u003cspan address=\"10.1177/191602/62513/6219\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDolens ES, Dourado MR, Almangush A, Salo TA, Rocha CAG, da Silva SD, et al. The impact of histopathological features on the prognosis of oral squamous cell carcinoma: A comprehensive review and meta-analysis. Front Oncol. 2021;11:784924. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fonc.2021.784924\u003c/span\u003e\u003cspan address=\"10.3389/fonc.2021.784924\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiao CT, Chang JT, Wang HM, Ng SH, Hsueh C, Lee LY, et al. Does adjuvant radiation therapy improve outcomes in pT1-3N0 oral cavity cancer with tumor- free margins and perineural invasion? Int J RadiatOncolBiolPhys. 2008;71:371\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFan KH, Wang HM, Kang CJ, Lee LY, Huang SF, Lin CY, et al. Treatment results of postoperative radiotherapy on squamous cell carcinoma of the oral cavity: coexistence of multiple minor risk factors results in higher recurrence rates. Int J RadiatOncolBiolPhys. 2010;77:1024\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHinerman RW, Mendenhall WM, Morris CG, et al. Postoperative irradiation for squamous cell carcinoma of the oral cavity: 35-year experience. Head Neck. 2004;26:984\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Oral cavity cancer, lymphovascular invasion, Perineural invasion, Depth of invasion, Chemoradiation, Overall survival","lastPublishedDoi":"10.21203/rs.3.rs-8101509/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8101509/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e \u003cp\u003eDespite multimodal treatment, oral cavity cancer (OCC) outcomes remain poor due to frequent presentation at advanced stages. Identifying reliable prognostic markers is crucial for improving outcomes. Lymphovascular invasion (LVI), perineural invasion (PNI), and depth of invasion (DOI) are key pathological features linked to aggressive tumor behavior. While each factor is associated with worse outcomes, their combined prognostic value remains underexplored. This study evaluates the combined prognostic value of LVI, PNI, and DOI on overall survival (OS) and recurrence-free survival (RFS) in OCC patients treated with curative intent.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e \u003cp\u003eThis retrospective study included 342 OCC cases treated from January 2017 to December 2021. Patients were stratified into six subgroups based on LVI (\u0026plusmn;), PNI (\u0026plusmn;), and DOI (\u0026gt;\u0026thinsp;1 cm or \u0026le;\u0026thinsp;1 cm). Survival outcomes were analyzed using Kaplan-Meier and log-rank tests. Independent prognostic factors were identified using Cox regression. A p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered significant.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e \u003cp\u003eLVI, PNI, and DOI\u0026thinsp;\u0026gt;\u0026thinsp;1 cm were present in 29.8%, 48.8%, and 43.3% of cases, respectively. Significant differences in OS and RFS were observed among the six subgroups. The worst outcomes were seen when all three risk factors were present, with a nearly fivefold higher risk of death. Shallower tumors (\u0026lt;\u0026thinsp;1 cm) were associated with improved survival, even in the presence of LVI or PNI. When both LVI and PNI were absent, OS and RFS differed significantly for deeper versus shallower tumours.\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e \u003cp\u003eCombined assessment of LVI, PNI, and DOI enables effective risk stratification in OCC and can guide forpersonalized patient treatment.\u003c/p\u003e","manuscriptTitle":"Triple threats in cancer of oral cavity: Navigating pathological risk factors","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-12 06:13:34","doi":"10.21203/rs.3.rs-8101509/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-01-09T07:10:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"272629844624349476601576023243555033222","date":"2026-01-08T01:43:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"261901674939420361551985521438264259072","date":"2026-01-07T11:54:32+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-07T10:56:22+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-05T07:43:46+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-12T09:52:20+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-12T06:13:07+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2025-12-12T06:05:33+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cfc4bfcc-38bc-49c2-9299-cb93b69e11b2","owner":[],"postedDate":"January 12th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-01-12T06:13:34+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-12 06:13:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8101509","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8101509","identity":"rs-8101509","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}