Significance of Worst Pattern of Invasion 5 in Early-Stage Oral Cavity Squamous Cell Carcinoma

Significance of Worst Pattern of Invasion 5 in Early-Stage Oral Cavity Squamous Cell Carcinoma | 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 Significance of Worst Pattern of Invasion 5 in Early-Stage Oral Cavity Squamous Cell Carcinoma Shima Mohamed, Hadeel Jawad, Ryan O' Sullivan, Deirdre Callanan, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2935791/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background There is an ongoing need to identify pathologic prognosticators in early-stage oral cavity squamous cell carcinoma (OCSCC) to aid selection of patients who may benefit from adjuvant treatment. The objective of this study was to evaluate the prognostic ability of worst pattern of invasion 5 (WPOI-5) defined by the presence of satellite nodules, extratumoural perineural invasion (PNI) and/or extratumoural lymphovascular space invasion (LVI) in low-stage, node negative OCSCC. Methods Retrospective study of 160 patients with T1/T2N0 tumours staged using TNM7 treated surgically. Histologyof the primary tumour was re-reviewed as appropriate to assess for the presence of WPOI-5 parameters. Univariate and multivariate analysis assessing impact of pathological features on survival outcomes was performed Results On univariate analysis WPOI-5 and it’s 3 constituent components of satellite nodules, extratumoural PNI and extratumoural LVI were all significantly associated with disease-specific survival (DSS) and overall survival (OS). On multivariate analysis satellite nodules (odds ratio, 3.58, 95% CI 1.34, 9.55, p=0.01) and extratumoural LVI (odds ratio 10.94, CI 2.22, 53.79, p=0.003) were independently associated with OS. Postoperative radiotherapy was also significantly associated with OS on multivariate analysis (odds ratio 0.42, CI 0.19, 0.89, p=0.02). Conclusion Satellite nodules and extratumoural LVI correlated significantly with survival outcomes in our early-stage OSCC cohort. Further study is required to investigate the benefit of adjuvant treatment in these cases and to ascertain if worst pattern of invasion-5 parameters should be mandatory reporting data elements. Oral cancer Head and neck cancer Squamous cell carcinoma Prognosis. Figures Figure 1 Figure 2 Figure 3 Introduction Tumour stage at diagnosis is an important but imperfect prognosticator in oral cavity squamous cell carcinoma (OCSCC) [1]. A significant proportion of patients with small (T1-T2), node negative primaries categorised using TNM7 went on to develop local recurrence and/or nodal metastatic spread with reported disease specific mortality rates as high as 25% and 37% for stage I and II disease respectively [2]. In an attempt to improve the performance of the oral cavity cancer staging system the American Joint Committee on Cancer Control (AJCC) incorporated depth of invasion (DOI) into the T staging of the updated TNM 8th edition 2017 [3]. Multiple studies have demonstrated DOI to significantly predict for outcome in OCSCC [4–11] with 5mm and 10mm selected as the cut points for tumour upstaging based on a retrospective analysis undertaken by the International Consortium for Outcome Research in Head and Neck Cancer (ICOR) of 3149 patients treated at 11 cancer centres between 1990 and 2011 [11]. Even with the adoption of TNM8 there is an ongoing need to identify further robust pathologic prognosticators in early-stage OCSCC to aid selection of patients who may benefit from adjuvant radiotherapy. Margin status is proven to significantly predict for local recurrence [12–16]. Other parameters that have been shown to correlate with recurrence and survival outcomes in OCSCC include perineural invasion (PNI) [17–25], lymphovascular space invasion (LVI) [22,24,26–31] and pattern of invasion (POI) at the invasive tumour front [19,21,32–34]. PNI and LVI are regarded by both the Royal College of Pathologists (RCPath) and College of American Pathologists (CAP) to be core data elements for reporting [35,36]. In relation to POI, the CAP designates worst pattern of invasion (WPOI) as non-core and optional for reporting. Although 5 patterns of invasion are recognized, distinction of WPOI-5 (defined as dispersion of ≥ 1 mm between tumour satellites), from patterns 1 to 4 is most significant [19]. Of note extratumoural PNI and extratumoural LVI also qualify as WPOI-5 [36]. In contrast the RCPath classify POI using a two-tier system as cohesive versus non-cohesive and list it as a required data item. Of note non-cohesive invasive front includes both patterns 4 and 5 and no quantitative cut-off is explicitly specified in the RCPath dataset currently [35]. The primary aim of this study was to evaluate the prognostic ability of WPOI-5 including extratumoural PNI and extratumoural LVI in early-stage oral cavity squamous cell carcinoma (OCSCC). The patient cohort comprised of T1/T2N0 tumours staged using TNM7. Materials and Methods The study comprised a retrospective review of 160 patients with OCSCC who underwent definitive primary surgical treatment at the South Infirmary Victoria University Hospital, Cork, Ireland between the years 2000 and 2020. Ethical approval was granted by the Cork Clinical Research Ethics Committee. Inclusion criteria were patients with pT1/2N0 (TNM7) cancers undergoing primary surgical treatment. Exclusion criteria were patients with cervical or distant metastases; previous history of Head and Neck cancer or treatment with radiotherapy; or with synchronous primary Head and Neck cancers. Patients not undergoing neck dissection were included provided there was no clinical or radiological evidence of cervical metastases (cN0). Cases were identified and relevant clinical and pathological data extracted from our cancer database having been previously populated from review of medical charts, histological reports and/or slide review. Clinical data recorded included sex, site of cancer within the oral cavity, smoking status, medical comorbidity, administration of post-operative radiotherapy, and clinical outcome including recurrence, death due to cancer, death due to other causes, and further primary cancers. Pathological data recorded included depth of invasion, TNM8 T-stage and margin status. Of note depth of invasion (DOI) measurements were previously re-evaluated for all patients in our study cohort who underwent surgery prior to the issuance by the AJCC in 2017 of the clarified definition for this parameter [3]. Margin positivity was classified using both the RCPath definition of invasive carcinoma within 1mm of margin [35] and the CAP definition of invasive carcinoma or high-grade dysplasia present at margin [36]. In addition, haematoxylin and eosin (H&E)-stained slides of the primary tumour were re-reviewed in (1) cases reported as having a non-cohesive invasive front, to ascertain if satellite nodules fulfilling the definition for WPOI-5 were present; (2) all cases with PNI, to classify the location as intratumoural and/or extratumoural; and (3) all cases with LVI, to classify the location as intratumoural and/or extratumoural. Slide review was undertaken by 2 pathologists at a multiheaded microscope and consensus results recorded. In cases with PNI and LVI reported, this was re-confirmed by the 2 reviewing pathologists by agreement. There was some re-categorisation of cases from PNI/LVI positive to negative and vice versa, which was expected due to interobserver variability. Extratumoural PNI and extratumoural LVI were defined as PNI or LVI present ≥ 1 mm beyond the invasive tumour front respectively. Cases not fulfilling the criterion for extratumoural in location were classified as intratumoural. WPOI-5 was defined as dispersed satellite nodule(s) ≥ 1 mm from the main tumour or next closest satellite (Fig. 1). In addition, extratumoural PNI and extratumoural LVI were also classified as WPOI-5. Therefore, 3 categories of WPOI-5 were recognized, which were evaluated both separately and collectively when statistical analysis was performed. XLSTAT (Addinsoft, France, version 2015.1.03) was utilised for statistical analysis. Survival was calculated from time of surgery to time of death or last clinic follow-up. Patients dying with recurrence or uncontrolled cancer were regarded to have died from disease. Patients dying from medical complications in the first month after surgery were also classified as having died due to cancer. Survival estimates were performed using the Kaplan–Meier method. Univariate and multivariate analysis assessing impact of pathological features on survival outcomes was performed using Cox proportional hazards modelling. A p-value of 0.05 was regarded to be significant. Results The study population comprised of 160 patients. Clinicopathological and demographic details are presented in Table 1 . In total 11 cases were re-classified on review: 3 cases from PNI positive to negative, 3 cases PNI negative to positive, 2 cases LVI positive to negative and 3 cases cohesive to non-cohesive POI. Table 1 Clinicopathological and demographic features of study population Number % Sex Male 101 63.1 Female 59 36.9 Primary site Tongue 79 49.4 Floor of mouth 43 26.9 Buccal 13 8.1 Alveolus / RMT / palate 18 11.3 Lip 7 4.4 T-classification (AJCC 8th edition) T1 67 41.9 T2 75 46.9 T3 18 11.3 Depth of invasion 5mm, 10mm 28 17.5 Involved margins (RCPath) Yes 31 19.4 Involved margins (CAP) Yes 17 10.6 WPOI-5 Yes 15 9.4 Satellite nodules Yes 13 8.1 Perineural invasion Any 34 21.3 Intratumoural 33 20.6 Extratumoural 5 3.1 Lymphovascular space invasion Any 9 5.6 Intratumoural 8 5.0 Extratumoural 3 1.9 Postoperative radiotherapy (RT) No 116 72.5 RT alone 38 23.8 Chemoradiotherapy 6 3.8 Fifteen patients (9.4%) were identified as having WPOI-5, of whom 13 (8.1%) had satellite nodules, 5 (3.1%) had extratumoural PNI and 3 (1.9%) had extratumoural LVI. 6 (3.8%) were positive for 2 of the 3 WPOI-5 parameters, but none for all 3. Mean (median) follow-up for all patients was 61 (55) months (range 1-168 months). 32 patients (20%) developed recurrent disease. 58 patients (36.25%) died, of whom 15 (9.4%) died from cancer, and 43 (26.9%) from other causes. On univariate analysis WPOI-5 (odds ratio 22.68, 95% CI 6.54, 78.68, p = < 0.0001) and its 3 constituent components of satellite nodules (odds ratio 18.32, 95% CI 5.53, 60.67, p = < 0.0001), extratumoural PNI (odds ratio 14.46, 95% CI 3.69, 56.70, p = 0.0001) and extratumoural LVI (odds ratio 73.50, 95% CI 14.61, 369.80, p = 10mm (odds ratio 3.04, 95% CI 1.03, 8.97, p = 0.04), non-cohesive POI (odds ratio 4.22, 95% CI 1.48, 12.09, p = 0.007), any PNI (odds ratio 10.23, 95% CI 3.29, 31.84, p = < 0.0001), intratumoural PNI (odds ratio 7.62, 95% CI 2.55, 22.75, p = 0.0001) and any LVI (odds ratio 16.18, 95% CI 4.88, 53.65, p = < 0.0001). On univariate analysis OS was also significantly associated with WPOI-5 (odds ratio 5.31, 95% CI 2.64, 10.65, p = < 0.0001) and its subcategories of satellite nodules (odds ratio 5.45, 95% CI 2.66, 11.15, p = < 0.0001), extratumoural PNI (odds ratio 5.30, 95% CI 1.84, 15.22, p = 0.002) and extratumoural LVI (odds ratio 22.65, 95% CI 6.17, 83.1, p = < 0.0001). Other parameters which were significant for OS included any PNI (odds ratio 1.97, 95% CI 1.06, 3.66, p = 0.03) and postoperative radiotherapy (odds ratio 0.41, 95% CI 0.02, 0.85, p = 0.02). See Table 2 for full results of univariate analysis of impact of pathological features and postoperative radiotherapy on DSS and OS. See Figs. 2 and 3 and supplementary Figs. 1 and 2 for Kaplan-Meier survival curves for PNI, LVI, satellite nodules and WPOI-5 respectively. Table 2 Univariate analysis of impact of pathological features and postoperative radiotherapy on DSS and OS DSS OR (95% CI) DSS p-value OS OR (95% CI) OS p-value > 5mm depth of invasion 2.26 (0.72, 7.09) 0.16 0.91 (0.54, 1.53) 0.71 > 10mm depth of invasion 3.04 (1.03, 8.97) 0.04 1.18 (0.58, 2.41) 0.65 > 20mm diameter 2.14 (0.76, 6.05) 0.15 1.27 (0.71, 2.26) 0.42 Non-cohesive pattern of invasion 4.22 (1.48, 12.09) 0.007 1.62 (0.94, 2.79) 0.08 Involved margins (RCPath) 0.80 (0.22, 2.87) 0.73 0.50 (0.23, 1.06) 0.07 Involved margins (CAP) 0.46 (0.06, 3.56) 0.46 0.49 (0.18, 1.36) 0.17 Any PNI 10.23 (3.29, 31.84) < 0.0001 1.97 (1.06, 3.66) 0.03 Extratumoral PNI 14.46 (3.69, 56.70) 0.0001 5.30 (1.84, 15.22) 0.002 Intratumoral PNI 7.62 (2.55, 22.75) 0.0001 1.81 (0.96, 3.43) 0.07 Any LVI 4.73 (1.33, 16.79) 0.02 1.88 (0.75, 4.72) 0.18 Extratumoral LVI 73.50 (14.61, 369.80) < 0.0001 22.65 (6.17, 83.1) < 0.0001 Intratumoral LVI 2.93 (0.66, 13.01) 0.16 1.48 (0.54, 4.10) 0.45 Satellite nodules 18.32 (5.53, 60.67) < 0.0001 5.45 (2.66, 11.15) < 0.0001 WPOI-5 22.68 (6.54, 78.68) < 0.0001 5.31 (2.64, 10.65) < 0.0001 Postoperative radiotherapy 0.37 (0.08, 1.65) 0.19 0.41 (0.20, 0.85) 0.02 On multivariate analysis, satellite nodules (odds ratio, 3.58, 95% CI 1.34, 9.55, p = 0.01) and extratumoural LVI (odds ratio 10.94, CI 2.22, 53.79, p = 0.003) were independently associated with OS. In addition, post-operative radiotherapy significantly correlated with OS on multivariate analysis (odds ratio 0.42, CI 0.19, 0.89, p = 0.02). DSS was not assessed as part of the multivariate analysis due to the small number of events. Table 3 shows results of multivariate analysis of impact of pathological features and postoperative radiotherapy on OS. Variables that did show any independent effect are not presented. Table 3 Multivariate analysis of impact of pathological features and postoperative radiotherapy on OS OS OR (95% CI) OS p-value Extratumoral PNI 2.35 (0.66, 8.30) 0.19 Intratumoral PNI 0.15 (0.02, 1.32) 0.09 Extratumoral LVI 10.94 (2.22, 53.79) 0.003 Satellite nodules 3.58 (1.34, 9.55) 0.01 Margins (RCPath) 1.71 (0.78, 3.73) 0.18 Postoperative radiotherapy 0.42 (0.19, 0.89) 0.02 Discussion Depth of invasion was incorporated into the T staging of oral cavity SCC in TNM8 to enable clinicians to more accurately discriminate higher risk early-stage cancers, which may benefit from adjuvant radiotherapy [1]. However, there is still an imperative to identify additional adverse prognosticators in stage I/II disease. Worst pattern of invasion at the invasive tumour front is one such potential high-risk feature. WPOI has been found in multiple studies to predict for poor outcome in OSCC, with WPOI-5 versus patterns 1–4 representing the key significant cut-point [19,21,32–34]. WPOI-5 is defined as tumour dispersion of ≥ 1 mm between satellite foci and includes extratumoural PNI and LVI. Of note WPOI has previously been validated as a prognosticator specifically in early stage OCSCC. Li et al found WPOI-5 to significantly correlate with both locoregional recurrence and disease specific survival on multivariate analysis in a stage I/II cohort. When WPOI-5 was present the probability of developing locoregional recurrence was 42% [21]. We also found WPOI-5 to be significantly associated with survival on univariate analysis. In our multivariate model, where we included WPOI-5, as well as its components, the subcategories of satellite nodules and extratumoural LVI were found to be independently predictive of OS, whereas overall WPOI-5 was not significant. Perineural invasion is a well-recognized adverse prognosticator in OCSCC including in early-stage node negative cases. It has been shown to correlate with locoregional recurrence, nodal metastatic spread and reduced disease specific and overall survival [17–25]. Furthermore, the National Comprehensive Cancer Network (NCCN) recommends adjuvant radiotherapy for surgically resected T1/T2 N0 oral cavity cancers with adverse risk features such as PNI [37]. An additional emerging data element is the location of PNI. Miller et al reported a trend toward reduced disease-free survival (DFS) with extratumoural PNI [38]. More recently Park et al demonstrated worse DFS on multivariate analysis in cases with this feature [39]. On univariate analysis we demonstrated a significant correlation between all categories of PNI and reduced DSS. Any PNI and extratumoural PNI also predicted for worse OS. However, all 3 PNI groupings lost significance on multivariate analysis. This may be secondary to the impact of postoperative radiotherapy (PORT), or interaction with other factors such as satellite nodules and lymphovascular invasion in the multivariate model. Lymphovascular space invasion (LVI) have been linked to an increased risk of nodal metastases, locoregional recurrence and reduced survival outcomes in OCSCC [22,24, 26–31]. Similar to PNI it is listed by the NCCN as an indication for postoperative radiotherapy in early-stage disease [37]. A recently published meta-analysis investigating the impact of LVI in OCSCC demonstrated a significant association between presence of LVI and reduced DSS and OS. In addition, a positive correlation between cervical nodal metastasis and LVI was found in low-stage disease and therefore it could be used as a criterion to select patients for neck dissection [30]. We found extratumoural LVI, but not intratumoural LVI to significantly predict for OS on multivariate analysis. The main limitations of this study are its retrospective nature, and the small number of patients dying from cancer precluding multivariate analysis of disease specific survival. On the other hand, strengths include restriction of the study cohort to TNM7 T1-T2N0 cases but with inclusion of DOI as a variable, consensus slide review by 2 pathologists to assess for WPOI-5 criteria and re-categorisation of PNI and LVI status of cases if appropriate. Furthermore, DOI measurements were previously re-evaluated for all patients in our study cohort who underwent surgery prior to the publication by the AJCC of the clarified DOI definition in 2017. Conclusion WPOI-5 predicts survival in early oral cancer, with the subcategories of satellite nodules and extratumoural LVI independent prognosticators of OS in our cohort, along with PORT. Our results support the NCCN recommendation that adjuvant therapy be considered for surgically resected T1/T2 N0 oral cavity cancers with PNI and LVI [37] and suggest that satellite nodules should also be regarded as an adverse risk factor in this patient cohort. Further study is recommended to assess the benefits of adjuvant treatment for patients with satellite nodules. Declarations Authorship contributions: Shima Mohamed, Hadeel Jawad, Ryan O’ Sullivan, Deirdre Callanan: Acquisition of data. Patrick Sheahan: Conception and design, acquisition of data, analysis and interpretation of data, revising of article. Linda Feeley: Conception and design, acquisition of data, interpretation of data, drafting of article. Acknowledgements: This work was supported by the Head and Neck Oncology Fund, South Infirmary Victoria University Hospital (payment of salary of Research Assistant). Conflict of Interest Statement: None declared. No funding was received for conducting this study. 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Supplementary Files supplementaryfigure1.pptx Supplementary Fig. 1 DSS and OS according to satellite nodules (absent, blue line; present, green line) supplementaryfigure2.pptx Supplementary Fig. 2 DSS and OS according to WPOI-5 (absent, blue line; present, green line) Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major revision 30 May, 2023 Reviews received at journal 25 May, 2023 Reviewers agreed at journal 15 May, 2023 Reviewers invited by journal 15 May, 2023 Editor assigned by journal 15 May, 2023 Submission checks completed at journal 15 May, 2023 First submitted to journal 15 May, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2935791","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":200465253,"identity":"d20d93b4-b782-44ad-ad14-0cdec3bfbcf9","order_by":0,"name":"Shima Mohamed","email":"","orcid":"","institution":"Cork University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shima","middleName":"","lastName":"Mohamed","suffix":""},{"id":200465254,"identity":"97e6775f-0794-41a0-a518-93f2a8192c6f","order_by":1,"name":"Hadeel Jawad","email":"","orcid":"","institution":"Cork University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hadeel","middleName":"","lastName":"Jawad","suffix":""},{"id":200465255,"identity":"99bbb2e6-0228-4add-ae09-0dd7c6698f62","order_by":2,"name":"Ryan O' Sullivan","email":"","orcid":"","institution":"South Infirmary Victoria University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ryan","middleName":"O'","lastName":"Sullivan","suffix":""},{"id":200465256,"identity":"9c668aed-c4c8-4536-9c72-8a477170667f","order_by":3,"name":"Deirdre Callanan","email":"","orcid":"","institution":"South Infirmary Victoria University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Deirdre","middleName":"","lastName":"Callanan","suffix":""},{"id":200465257,"identity":"3db595a0-c0a9-4d6d-ac6c-faf5e0726300","order_by":4,"name":"Patrick Sheahan","email":"","orcid":"","institution":"South Infirmary Victoria University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Patrick","middleName":"","lastName":"Sheahan","suffix":""},{"id":200465258,"identity":"361c80f1-d01f-4b79-a590-c6274153a616","order_by":5,"name":"Linda Feeley","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6ElEQVRIiWNgGAWjYBACA2YGBgkGBjkGBnYg72MDkGAmTosxWCXjTKK0MCBpYeZtIMZh7LwHb/xgMJDjZ2Y+Jm27o06OgZ35AAGH8SVb9jAYGEs2s6VJ5545bMzAzJZAQAuPmQQPw5/EDYd5zKRz2w4kNjDzGBDUIvmHwaB+/2H+b9KWbXX1Dcz8HwhqkeZhMEgAMtikGduYExiYefDqAGkxtpYxMDCccZjN2LK37bBhGzMbfofZ958xvPmmwkCev7354Y2fbXXy/PyHH+C3BmIXmGSRAJFsRKiHA2b83h4Fo2AUjIIRCwDiCjP7YbJmbQAAAABJRU5ErkJggg==","orcid":"","institution":"Cork University Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Linda","middleName":"","lastName":"Feeley","suffix":""}],"badges":[],"createdAt":"2023-05-15 06:59:31","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2935791/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2935791/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":37149270,"identity":"40879abf-98f8-43f2-8c58-bbb23526b6fb","added_by":"auto","created_at":"2023-05-17 18:03:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":11885533,"visible":true,"origin":"","legend":"\u003cp\u003eLow power (1.5x) H\u0026amp;E image showing main tumour bottom right and a satellite focus \u0026gt;1mm away at the black arrow\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-2935791/v1/64a84005b3883635a974d2c0.png"},{"id":37149842,"identity":"53cfe876-2aee-411d-b695-2e2d957c2043","added_by":"auto","created_at":"2023-05-17 18:11:47","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":58087,"visible":true,"origin":"","legend":"\u003cp\u003eDSS and OS according to PNI (absent, solid line; intratumoural dotted line; extratumoural, dashed line)\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-2935791/v1/b47178974eb5e8aafc45e330.png"},{"id":37149843,"identity":"00adbc84-7d09-414f-9a17-023831eebabf","added_by":"auto","created_at":"2023-05-17 18:11:48","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":49764,"visible":true,"origin":"","legend":"\u003cp\u003eDSS and OS according to LVI (absent, solid line; intratumoural dotted line; extratumoural, dashed line)\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-2935791/v1/e80b4ab21e37e4cec51dcab6.png"},{"id":37150830,"identity":"363d2bad-1205-4bcd-8022-c0777ea58ef2","added_by":"auto","created_at":"2023-05-17 18:19:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3297373,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2935791/v1/6dd8413f-46bc-4930-846d-3c080576f2c4.pdf"},{"id":37149266,"identity":"771521c0-da88-46e9-b731-d296edcc4e2a","added_by":"auto","created_at":"2023-05-17 18:03:47","extension":"pptx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":48948,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Fig. 1\u003c/strong\u003e DSS and OS according to satellite nodules (absent, blue line; present, green line)\u003c/p\u003e","description":"","filename":"supplementaryfigure1.pptx","url":"https://assets-eu.researchsquare.com/files/rs-2935791/v1/c7f1c2156cc30a82e52699c8.pptx"},{"id":37149268,"identity":"23cd9293-0dab-4620-811c-3943460c33d6","added_by":"auto","created_at":"2023-05-17 18:03:47","extension":"pptx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":48917,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Fig. 2\u003c/strong\u003e DSS and OS according to WPOI-5 (absent, blue line; present, green line)\u003c/p\u003e","description":"","filename":"supplementaryfigure2.pptx","url":"https://assets-eu.researchsquare.com/files/rs-2935791/v1/0a100776557c0a7912bee7aa.pptx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Significance of Worst Pattern of Invasion 5 in Early-Stage Oral Cavity Squamous Cell Carcinoma","fulltext":[{"header":"Introduction","content":"\u003cp\u003eTumour stage at diagnosis is an important but imperfect prognosticator in oral cavity squamous cell carcinoma (OCSCC) [1]. A significant proportion of patients with small (T1-T2), node negative primaries categorised using TNM7 went on to develop local recurrence and/or nodal metastatic spread with reported disease specific mortality rates as high as 25% and 37% for stage I and II disease respectively [2]. In an attempt to improve the performance of the oral cavity cancer staging system the American Joint Committee on Cancer Control (AJCC) incorporated depth of invasion (DOI) into the T staging of the updated TNM 8th edition 2017 [3]. Multiple studies have demonstrated DOI to significantly predict for outcome in OCSCC [4\u0026ndash;11] with 5mm and 10mm selected as the cut points for tumour upstaging based on a retrospective analysis undertaken by the International Consortium for Outcome Research in Head and Neck Cancer (ICOR) of 3149 patients treated at 11 cancer centres between 1990 and 2011 [11].\u003c/p\u003e \u003cp\u003eEven with the adoption of TNM8 there is an ongoing need to identify further robust pathologic prognosticators in early-stage OCSCC to aid selection of patients who may benefit from adjuvant radiotherapy. Margin status is proven to significantly predict for local recurrence [12\u0026ndash;16]. Other parameters that have been shown to correlate with recurrence and survival outcomes in OCSCC include perineural invasion (PNI) [17\u0026ndash;25], lymphovascular space invasion (LVI) [22,24,26\u0026ndash;31] and pattern of invasion (POI) at the invasive tumour front [19,21,32\u0026ndash;34]. PNI and LVI are regarded by both the Royal College of Pathologists (RCPath) and College of American Pathologists (CAP) to be core data elements for reporting [35,36]. In relation to POI, the CAP designates worst pattern of invasion (WPOI) as non-core and optional for reporting. Although 5 patterns of invasion are recognized, distinction of WPOI-5 (defined as dispersion of \u0026ge;\u0026thinsp;1 mm between tumour satellites), from patterns 1 to 4 is most significant [19]. Of note extratumoural PNI and extratumoural LVI also qualify as WPOI-5 [36]. In contrast the RCPath classify POI using a two-tier system as cohesive versus non-cohesive and list it as a required data item. Of note non-cohesive invasive front includes both patterns 4 and 5 and no quantitative cut-off is explicitly specified in the RCPath dataset currently [35].\u003c/p\u003e \u003cp\u003eThe primary aim of this study was to evaluate the prognostic ability of WPOI-5 including extratumoural PNI and extratumoural LVI in early-stage oral cavity squamous cell carcinoma (OCSCC). The patient cohort comprised of T1/T2N0 tumours staged using TNM7.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e The study comprised a retrospective review of 160 patients with OCSCC who underwent definitive primary surgical treatment at the South Infirmary Victoria University Hospital, Cork, Ireland between the years 2000 and 2020. Ethical approval was granted by the Cork Clinical Research Ethics Committee. Inclusion criteria were patients with pT1/2N0 (TNM7) cancers undergoing primary surgical treatment. Exclusion criteria were patients with cervical or distant metastases; previous history of Head and Neck cancer or treatment with radiotherapy; or with synchronous primary Head and Neck cancers. Patients not undergoing neck dissection were included provided there was no clinical or radiological evidence of cervical metastases (cN0). Cases were identified and relevant clinical and pathological data extracted from our cancer database having been previously populated from review of medical charts, histological reports and/or slide review.\u003c/p\u003e \u003cp\u003eClinical data recorded included sex, site of cancer within the oral cavity, smoking status, medical comorbidity, administration of post-operative radiotherapy, and clinical outcome including recurrence, death due to cancer, death due to other causes, and further primary cancers. Pathological data recorded included depth of invasion, TNM8 T-stage and margin status. Of note depth of invasion (DOI) measurements were previously re-evaluated for all patients in our study cohort who underwent surgery prior to the issuance by the AJCC in 2017 of the clarified definition for this parameter [3]. Margin positivity was classified using both the RCPath definition of invasive carcinoma within 1mm of margin [35] and the CAP definition of invasive carcinoma or high-grade dysplasia present at margin [36]. In addition, haematoxylin and eosin (H\u0026amp;E)-stained slides of the primary tumour were re-reviewed in (1) cases reported as having a non-cohesive invasive front, to ascertain if satellite nodules fulfilling the definition for WPOI-5 were present; (2) all cases with PNI, to classify the location as intratumoural and/or extratumoural; and (3) all cases with LVI, to classify the location as intratumoural and/or extratumoural.\u003c/p\u003e \u003cp\u003eSlide review was undertaken by 2 pathologists at a multiheaded microscope and consensus results recorded. In cases with PNI and LVI reported, this was re-confirmed by the 2 reviewing pathologists by agreement. There was some re-categorisation of cases from PNI/LVI positive to negative and vice versa, which was expected due to interobserver variability. Extratumoural PNI and extratumoural LVI were defined as PNI or LVI present\u0026thinsp;\u0026ge;\u0026thinsp;1 mm beyond the invasive tumour front respectively. Cases not fulfilling the criterion for extratumoural in location were classified as intratumoural. WPOI-5 was defined as dispersed satellite nodule(s)\u0026thinsp;\u0026ge;\u0026thinsp;1 mm from the main tumour or next closest satellite (Fig.\u0026nbsp;1). In addition, extratumoural PNI and extratumoural LVI were also classified as WPOI-5. Therefore, 3 categories of WPOI-5 were recognized, which were evaluated both separately and collectively when statistical analysis was performed.\u003c/p\u003e \u003cp\u003eXLSTAT (Addinsoft, France, version 2015.1.03) was utilised for statistical analysis. Survival was calculated from time of surgery to time of death or last clinic follow-up. Patients dying with recurrence or uncontrolled cancer were regarded to have died from disease. Patients dying from medical complications in the first month after surgery were also classified as having died due to cancer. Survival estimates were performed using the Kaplan\u0026ndash;Meier method. Univariate and multivariate analysis assessing impact of pathological features on survival outcomes was performed using Cox proportional hazards modelling. A p-value of 0.05 was regarded to be significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe study population comprised of 160 patients. Clinicopathological and demographic details are presented in Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. In total 11 cases were re-classified on review: 3 cases from PNI positive to negative, 3 cases PNI negative to positive, 2 cases LVI positive to negative and 3 cases cohesive to non-cohesive POI.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinicopathological and demographic features of study population\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNumber\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e101\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e63.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e36.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary site\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTongue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e49.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFloor of mouth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e26.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBuccal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAlveolus / RMT / palate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLip\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT-classification (AJCC 8th edition)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e41.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e46.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDepth of invasion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;/=5mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e46.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;5mm, \u0026lt;/=10mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e35.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;10mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e17.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInvolved margins (RCPath)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e19.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInvolved margins (CAP)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWPOI-5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSatellite nodules\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePerineural invasion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAny\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e21.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIntratumoural\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e20.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eExtratumoural\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphovascular space invasion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAny\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIntratumoural\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eExtratumoural\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePostoperative radiotherapy (RT)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e116\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e72.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRT alone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e23.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChemoradiotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFifteen patients (9.4%) were identified as having WPOI-5, of whom 13 (8.1%) had satellite nodules, 5 (3.1%) had extratumoural PNI and 3 (1.9%) had extratumoural LVI. 6 (3.8%) were positive for 2 of the 3 WPOI-5 parameters, but none for all 3.\u003c/p\u003e \u003cp\u003eMean (median) follow-up for all patients was 61 (55) months (range 1-168 months). 32 patients (20%) developed recurrent disease. 58 patients (36.25%) died, of whom 15 (9.4%) died from cancer, and 43 (26.9%) from other causes.\u003c/p\u003e \u003cp\u003eOn univariate analysis WPOI-5 (odds ratio 22.68, 95% CI 6.54, 78.68, p\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and its 3 constituent components of satellite nodules (odds ratio 18.32, 95% CI 5.53, 60.67, p\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), extratumoural PNI (odds ratio 14.46, 95% CI 3.69, 56.70, p\u0026thinsp;=\u0026thinsp;0.0001) and extratumoural LVI (odds ratio 73.50, 95% CI 14.61, 369.80, p\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) were all significantly associated with disease-specific survival (DSS). Other parameters which significantly predicted reduced DSS on univariate analysis included DOI\u0026thinsp;\u0026gt;\u0026thinsp;10mm (odds ratio 3.04, 95% CI 1.03, 8.97, p\u0026thinsp;=\u0026thinsp;0.04), non-cohesive POI (odds ratio 4.22, 95% CI 1.48, 12.09, p\u0026thinsp;=\u0026thinsp;0.007), any PNI (odds ratio 10.23, 95% CI 3.29, 31.84, p\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), intratumoural PNI (odds ratio 7.62, 95% CI 2.55, 22.75, p\u0026thinsp;=\u0026thinsp;0.0001) and any LVI (odds ratio 16.18, 95% CI 4.88, 53.65, p\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.0001).\u003c/p\u003e \u003cp\u003eOn univariate analysis OS was also significantly associated with WPOI-5 (odds ratio 5.31, 95% CI 2.64, 10.65, p\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and its subcategories of satellite nodules (odds ratio 5.45, 95% CI 2.66, 11.15, p\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), extratumoural PNI (odds ratio 5.30, 95% CI 1.84, 15.22, p\u0026thinsp;=\u0026thinsp;0.002) and extratumoural LVI (odds ratio 22.65, 95% CI 6.17, 83.1, p\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Other parameters which were significant for OS included any PNI (odds ratio 1.97, 95% CI 1.06, 3.66, p\u0026thinsp;=\u0026thinsp;0.03) and postoperative radiotherapy (odds ratio 0.41, 95% CI 0.02, 0.85, p\u0026thinsp;=\u0026thinsp;0.02). See Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e for full results of univariate analysis of impact of pathological features and postoperative radiotherapy on DSS and OS. See Figs.\u0026nbsp;2 and 3 and supplementary Figs.\u0026nbsp;1 and 2 for Kaplan-Meier survival curves for PNI, LVI, satellite nodules and WPOI-5 respectively.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate analysis of impact of pathological features and postoperative radiotherapy on DSS and OS\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDSS OR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDSS p-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOS OR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOS p-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;5mm depth of invasion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.26 (0.72, 7.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.91 (0.54, 1.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.71\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;10mm depth of invasion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.04 (1.03, 8.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.18 (0.58, 2.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.65\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;20mm diameter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.14 (0.76, 6.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.27 (0.71, 2.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.42\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-cohesive pattern of invasion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.22 (1.48, 12.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.62 (0.94, 2.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInvolved margins (RCPath)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.80 (0.22, 2.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.50 (0.23, 1.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInvolved margins (CAP)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.46 (0.06, 3.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.49 (0.18, 1.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny PNI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10.23 (3.29, 31.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.97 (1.06, 3.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtratumoral PNI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14.46 (3.69, 56.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.0001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.30 (1.84, 15.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntratumoral PNI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7.62 (2.55, 22.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.0001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.81 (0.96, 3.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny LVI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.73 (1.33, 16.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.88 (0.75, 4.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtratumoral LVI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e73.50 (14.61, 369.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e22.65 (6.17, 83.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntratumoral LVI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.93 (0.66, 13.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.48 (0.54, 4.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSatellite nodules\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e18.32 (5.53, 60.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.45 (2.66, 11.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWPOI-5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22.68 (6.54, 78.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.31 (2.64, 10.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePostoperative radiotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.37 (0.08, 1.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.41 (0.20, 0.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eOn multivariate analysis, satellite nodules (odds ratio, 3.58, 95% CI 1.34, 9.55, p\u0026thinsp;=\u0026thinsp;0.01) and extratumoural LVI (odds ratio 10.94, CI 2.22, 53.79, p\u0026thinsp;=\u0026thinsp;0.003) were independently associated with OS. In addition, post-operative radiotherapy significantly correlated with OS on multivariate analysis (odds ratio 0.42, CI 0.19, 0.89, p\u0026thinsp;=\u0026thinsp;0.02). DSS was not assessed as part of the multivariate analysis due to the small number of events. Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows results of multivariate analysis of impact of pathological features and postoperative radiotherapy on OS. Variables that did show any independent effect are not presented.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariate analysis of impact of pathological features and postoperative radiotherapy on OS\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOS OR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOS p-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtratumoral PNI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.35 (0.66, 8.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntratumoral PNI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.15 (0.02, 1.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtratumoral LVI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10.94 (2.22, 53.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSatellite nodules\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.58 (1.34, 9.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMargins (RCPath)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.71 (0.78, 3.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePostoperative radiotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.42 (0.19, 0.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eDepth of invasion was incorporated into the T staging of oral cavity SCC in TNM8 to enable clinicians to more accurately discriminate higher risk early-stage cancers, which may benefit from adjuvant radiotherapy [1]. However, there is still an imperative to identify additional adverse prognosticators in stage I/II disease. Worst pattern of invasion at the invasive tumour front is one such potential high-risk feature. WPOI has been found in multiple studies to predict for poor outcome in OSCC, with WPOI-5 versus patterns 1\u0026ndash;4 representing the key significant cut-point [19,21,32\u0026ndash;34]. WPOI-5 is defined as tumour dispersion of \u0026ge;\u0026thinsp;1 mm between satellite foci and includes extratumoural PNI and LVI. Of note WPOI has previously been validated as a prognosticator specifically in early stage OCSCC. Li et al found WPOI-5 to significantly correlate with both locoregional recurrence and disease specific survival on multivariate analysis in a stage I/II cohort. When WPOI-5 was present the probability of developing locoregional recurrence was 42% [21]. We also found WPOI-5 to be significantly associated with survival on univariate analysis. In our multivariate model, where we included WPOI-5, as well as its components, the subcategories of satellite nodules and extratumoural LVI were found to be independently predictive of OS, whereas overall WPOI-5 was not significant.\u003c/p\u003e \u003cp\u003ePerineural invasion is a well-recognized adverse prognosticator in OCSCC including in early-stage node negative cases. It has been shown to correlate with locoregional recurrence, nodal metastatic spread and reduced disease specific and overall survival [17\u0026ndash;25]. Furthermore, the National Comprehensive Cancer Network (NCCN) recommends adjuvant radiotherapy for surgically resected T1/T2 N0 oral cavity cancers with adverse risk features such as PNI [37]. An additional emerging data element is the location of PNI. Miller et al reported a trend toward reduced disease-free survival (DFS) with extratumoural PNI [38]. More recently Park et al demonstrated worse DFS on multivariate analysis in cases with this feature [39]. On univariate analysis we demonstrated a significant correlation between all categories of PNI and reduced DSS. Any PNI and extratumoural PNI also predicted for worse OS. However, all 3 PNI groupings lost significance on multivariate analysis. This may be secondary to the impact of postoperative radiotherapy (PORT), or interaction with other factors such as satellite nodules and lymphovascular invasion in the multivariate model.\u003c/p\u003e \u003cp\u003eLymphovascular space invasion (LVI) have been linked to an increased risk of nodal metastases, locoregional recurrence and reduced survival outcomes in OCSCC [22,24, 26\u0026ndash;31]. Similar to PNI it is listed by the NCCN as an indication for postoperative radiotherapy in early-stage disease [37]. A recently published meta-analysis investigating the impact of LVI in OCSCC demonstrated a significant association between presence of LVI and reduced DSS and OS. In addition, a positive correlation between cervical nodal metastasis and LVI was found in low-stage disease and therefore it could be used as a criterion to select patients for neck dissection [30]. We found extratumoural LVI, but not intratumoural LVI to significantly predict for OS on multivariate analysis.\u003c/p\u003e \u003cp\u003eThe main limitations of this study are its retrospective nature, and the small number of patients dying from cancer precluding multivariate analysis of disease specific survival. On the other hand, strengths include restriction of the study cohort to TNM7 T1-T2N0 cases but with inclusion of DOI as a variable, consensus slide review by 2 pathologists to assess for WPOI-5 criteria and re-categorisation of PNI and LVI status of cases if appropriate. Furthermore, DOI measurements were previously re-evaluated for all patients in our study cohort who underwent surgery prior to the publication by the AJCC of the clarified DOI definition in 2017.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWPOI-5 predicts survival in early oral cancer, with the subcategories of satellite nodules and extratumoural LVI independent prognosticators of OS in our cohort, along with PORT. Our results support the NCCN recommendation that adjuvant therapy be considered for surgically resected T1/T2 N0 oral cavity cancers with PNI and LVI [37] and suggest that satellite nodules should also be regarded as an adverse risk factor in this patient cohort. Further study is recommended to assess the benefits of adjuvant treatment for patients with satellite nodules.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAuthorship contributions:\u003c/p\u003e\n\u003cp\u003eShima Mohamed, Hadeel Jawad, Ryan O\u0026rsquo; Sullivan, Deirdre Callanan: Acquisition of data.\u003c/p\u003e\n\u003cp\u003ePatrick Sheahan: Conception and design, acquisition of data, analysis and interpretation of data, revising of article.\u003c/p\u003e\n\u003cp\u003eLinda Feeley: Conception and design, acquisition of data, interpretation of data, drafting of article.\u003c/p\u003e\n\u003cp\u003eAcknowledgements: This work was supported by the Head and Neck Oncology Fund, South Infirmary Victoria University Hospital (payment of salary of Research Assistant).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Statement:\u003c/strong\u003e None declared. No funding was received for conducting this study. The authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLydiatt WM, Patel SG, O\u0026apos;Sullivan B, Brandwein MS, Ridge JA, Migliacci JC, et al. Head and Neck cancers-major changes in the American Joint Committee on cancer eighth edition cancer staging manual. CA Cancer J Clin 2017;67(2):122-37.\u003c/li\u003e\n\u003cli\u003eSessions DG, Spector GJ, Lenox J, Haughey B, Chao C, Marks J. Analysis of treatment results for oral tongue cancer. Laryngoscope 2002;112(4):616-25.\u003c/li\u003e\n\u003cli\u003eRidge JA, Lydiatt WM, Patel SG, Glastonbury CM, Brandwein-Gensler M, Ghossein RA, et al. Lip and oral cavity. In: Amin MB, Greene FL, Byrd DR, Brookland RK, Washington MK, editors. AJCC Cancer Staging Manual. 8th ed. New York: Springer;2017.\u003c/li\u003e\n\u003cli\u003eYuen AP, Lam KY, Wei WI, Lam KY, Ho CM, Chow TL, et al. A comparison of the prognostic significance of tumor diameter, length, width, thickness, area, volume, and clinicopathological features of oral tongue carcinoma. Am J Surg 2000;180(2):139-43.\u003c/li\u003e\n\u003cli\u003eGonzalez-Moles MA, Esteban F, Rodriguez-Archilla A, Ruiz-Avila I, Gonzalez-Moles S. Importance of tumour thickness measurement in prognosis of tongue cancer. Oral Oncol 2002;38(4):394-7.\u003c/li\u003e\n\u003cli\u003eO\u0026apos;Brien CJ, Lauer CS, Fredricks S, Clifford AR, McNeil EB, Bagia JS, et al. Tumor thickness influences prognosis of T1 and T2 oral cavity cancer--but what thickness? Head Neck 2003;25(11):937-45.\u003c/li\u003e\n\u003cli\u003eBonnardot L, Bardet E, Steichen O, Cassagnau E, Piot B, Salam AP, et al L. Prognostic factors for T1-T2 squamous cell carcinomas of the mobile tongue: A retrospective cohort study. Head Neck 2011;33(7):928-34.\u003c/li\u003e\n\u003cli\u003eLiao CT, Lin CY, Fan KH, Wang HM, Ng SH, Lee LY, et al. Identification of a high-risk group among patients with oral cavity squamous cell carcinoma and pT1-2N0 disease. Int J Radiat Oncol Biol Phys 2012;82(1):284-90.\u003c/li\u003e\n\u003cli\u003eLing W, Mijiti A, Moming A. Survival pattern and prognostic factors of patients with squamous cell carcinoma of the tongue: a retrospective analysis of 210 cases. J Oral Maxillofac Surg 2013;71(4):775-85.\u003c/li\u003e\n\u003cli\u003eAlmangush A, Bello IO, Keski-S\u0026auml;ntti H, M\u0026auml;kinen LK, Kauppila JH, Pukkila M, et al. Depth of invasion, tumor budding, and worst pattern of invasion: prognostic indicators in early-stage oral tongue cancer. Head Neck 2014;36(6):811-8.\u003c/li\u003e\n\u003cli\u003eEbrahimi A, Gil Z, Amit M, Yen TC, Liao CT, Chaturvedi P, et al. Primary tumor staging for oral cancer and a proposed modification incorporating depth of invasion: an international multicenter retrospective study. JAMA Otolaryngol Head Neck Surg 2014;140(12):1138-48.\u003c/li\u003e\n\u003cli\u003eSlootweg PJ, Hordijk GJ, Schade Y, van Es RJJ, Koole R. Treatment failure and margin status in head and neck cancer. A critical view on the potential value of molecular pathology. Oral Oncol 2002;38(5):500-3.\u003c/li\u003e\n\u003cli\u003eGhosh Laskar S, Agarwal JP, Srinivas C, Dinshaw KA. Radiotherapeutic management of locally advanced head and neck cancer. Expert Rev Anticancer Ther 2006;6(3):405-17.\u003c/li\u003e\n\u003cli\u003eBradley PJ, MacLennan K, Brakenhoff RH, Leemans CR. Status of primary tumour surgical margins in squamous head and neck cancer: prognostic implications. Curr Opin Otolaryngol Head Neck Surg 2007;15(2):74-81.\u003c/li\u003e\n\u003cli\u003eLangendijk JA, Ferlito A, Takes RP, Rodrigo JP, Su\u0026aacute;rez C, P. Strojan P, et al. Postoperative strategies after primary surgery for squamous cell carcinoma of the head and neck. 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Retrieved 19/2/22 from https://www.nccn.org/login?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf.\u003c/li\u003e\n\u003cli\u003eMiller ME, Palla B, Chen Q, Elashoff DA, Abemayor E, St John MA, et al. A novel classification system for perineural invasion in noncutaneous head and neck squamous cell carcinoma: histologic subcategories and patient outcomes. Am J Otolaryngol 2012:33(2):212-5.\u003c/li\u003e\n\u003cli\u003ePark J, Megow A, Swalling A, Hodge JC, Foreman A, Boase S, et al. Prognosis of oral squamous cell carcinoma with perineural invasion: A comparative study of classification types. Clin Otolaryngol 2020;45(1):99-105.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"head-and-neck-pathology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Head and Neck Pathology](https://www.springer.com/journal/12105)","snPcode":"12105","submissionUrl":"https://submission.springernature.com/new-submission/12105/3","title":"Head and Neck Pathology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Oral cancer, Head and neck cancer, Squamous cell carcinoma, Prognosis.","lastPublishedDoi":"10.21203/rs.3.rs-2935791/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2935791/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere is an ongoing need to identify pathologic prognosticators in early-stage oral cavity squamous cell carcinoma (OCSCC) to aid selection of patients who may benefit from adjuvant treatment. The objective of this study was to evaluate the prognostic ability of worst pattern of invasion 5 (WPOI-5) defined by the presence of satellite nodules, extratumoural perineural invasion (PNI) and/or extratumoural lymphovascular space invasion (LVI) in low-stage, node negative OCSCC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRetrospective study of 160 patients with T1/T2N0 tumours staged using TNM7 treated surgically. Histologyof the primary tumour was re-reviewed as appropriate to assess for the presence of WPOI-5 parameters. Univariate and multivariate analysis assessing impact of pathological features on survival outcomes was performed\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOn univariate analysis WPOI-5 and it’s 3 constituent components of satellite nodules, extratumoural PNI and extratumoural LVI were all significantly associated with disease-specific survival (DSS) and overall survival (OS). On multivariate analysis satellite nodules (odds ratio, 3.58, 95% CI 1.34, 9.55, p=0.01) and extratumoural LVI (odds ratio 10.94, CI 2.22, 53.79, p=0.003) were independently associated with OS. Postoperative radiotherapy was also significantly associated with OS on multivariate analysis (odds ratio 0.42, CI 0.19, 0.89, p=0.02).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSatellite nodules and extratumoural LVI correlated significantly with survival outcomes in our early-stage OSCC cohort. Further study is required to investigate the benefit of adjuvant treatment in these cases and to ascertain if worst pattern of invasion-5 parameters should be mandatory reporting data elements.\u003c/p\u003e","manuscriptTitle":"Significance of Worst Pattern of Invasion 5 in Early-Stage Oral Cavity Squamous Cell Carcinoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-05-17 18:03:43","doi":"10.21203/rs.3.rs-2935791/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2023-05-30T19:34:28+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-05-25T17:13:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"117458eb-a80c-4873-8843-c3d3a1554185","date":"2023-05-15T20:08:35+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-05-15T19:32:19+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-05-15T19:26:22+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-05-15T07:15:16+00:00","index":"","fulltext":""},{"type":"submitted","content":"Head and Neck Pathology","date":"2023-05-15T06:54:21+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"head-and-neck-pathology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Head and Neck Pathology](https://www.springer.com/journal/12105)","snPcode":"12105","submissionUrl":"https://submission.springernature.com/new-submission/12105/3","title":"Head and Neck Pathology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"d9abb4bc-ef31-4f17-a78f-d875ca6ebe7e","owner":[],"postedDate":"May 17th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2023-07-05T19:59:11+00:00","versionOfRecord":[],"versionCreatedAt":"2023-05-17 18:03:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2935791","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2935791","identity":"rs-2935791","version":["v1"]},"buildId":"cBFmMYwuxLRRLfASyISRj","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}