Factors Influencing Mandibular Invasion, Lymph Node Metastasis and Extracapsular Spread in Squamous Cell Carcinoma of the Oral Cavity
Department of Oral and Maxillofacial Surgery, Faculty of Dental Sciences, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India
*
Author to whom correspondence should be addressed.
Craniomaxillofac. Trauma Reconstr. 2025, 18(3), 30; https://doi.org/10.3390/cmtr18030030
Submission received: 16 December 2024
/
Revised: 15 May 2025
/
Accepted: 19 May 2025
/
Published: 27 June 2025
Abstract
Background: A number of factors might affect survival in oral squamous cell carcinoma. Nodal status is one of the most important prognosticators affecting survival. Studies have shown that pattern of invasion is an important aspect related to survival. Study design: retrospective single-center study (original article). Objectives: Our study aimed at evaluating the factors affecting mandibular invasion, lymph node metastasis, and extracapsular spread in oral squamous cell carcinoma and the survival factors associated with it. Methods: Patient records were evaluated to identify factors influencing primary outcome and survival. Cox regression analysis and Kaplan Meir were applied to evaluate the outcomes. Youden’s index was used to determine a cut-off value for depth of invasion and lymph node size affecting outcome. A p value of <0.05 was considered statistically significant. Results: The study evaluated 162 patients with oral cancer. The cut-off value for DOI was 6.5 mm, significantly affecting mandibular invasion and cervical metastasis. The cut-off value for lymph node size was 2.95 cm, significantly affecting extracapsular spread and overall survival. An aggressive pattern of invasion significantly affects mandibular invasion, cervical metastasis, and survival. Conclusion: An aggressive pattern of invasion and depth of invasion are independent risk factors for cervical lymph node metastasis and mandibular invasion. The independent risk factor for extracapsular spread is lymph node size. Lymph node metastasis and nodal size, pattern of invasion, mandibular invasion, and extracapsular spread are independent risk factors affecting overall survival.
1. Introduction
Head and neck cancer is the third most common cancer in South Asia, and the majority of cases are oral squamous cell carcinomas [1]. The prognosis of oral squamous cell carcinoma (OSCC) is influenced by multiple factors, with the stage of the primary tumor and the nodal status being the most significant. Tumor size, grade, depth of invasion, perineural and lymphovascular invasion, tumor budding, worst pattern of invasion (WOPI), and lymphoid response are all risk factors for nodal metastasis [2,3]. Extracapsular spread (ECS) is one of the most important prognostic factors influencing survival in head and neck squamous cell carcinomas (HNSCCs). It may be present in up to 60% of patients with HNSCC, and microscopic ECS can be found in 10.5% to 25% of patients with a clinically N0 neck. Notably, ECS may also be present in metastatic lymph nodes measuring less than 2 mm in size. A number of factors might influence the presence of ECS: size and number of metastatic lymph nodes, contralateral neck metastasis, depth of invasion, size of primary tumor, etc. [4,5].
The POI can be divided into five categories; POI 1: pushing well-delineated infiltrative borders, POI 2: finger-like pushing pattern/infiltrative solid cords or bands and/or strands of cells, POI 3: small groups or cords of cells >15 cells, POI 4: small group of cells <15 or single cell, and POI 5: satellite tumor nodules >1 mm from the main tumor [6,7,8,9]. POI 5 was associated with poor prognosis in oral and oral pharyngeal cancers and in 2018 was added to the ICCR database as an obligatory element for reporting [10]. POI 5 has been reported to be an independent prognosticator associated with poor overall survival [11].
Bone invasion by oral squamous cell carcinoma (OSCC) is classified as T4a, indicating advanced head and neck cancer. The prognostic significance of mandibular invasion remains a subject of debate, possibly due to the lack of distinction between cortical and medullary involvement [12]. Mandibular involvement may be present in more than 50% of OSCC cases [13,14]. Marginal mandibulectomy is typically indicated when there is cortical erosion or periosteal involvement, whereas segmental mandibulectomy is preferred in cases of gross paramandibular spread or medullary invasion [15,16]. Our study aimed at evaluating the influence of various factors on mandibular invasion, lymph node metastasis, and extracapsular spread in oral squamous cell carcinoma.
2. Patients and Methods
2.1. Study Design and Setting
The following study was undertaken in a tertiary care center in an Indian institute of national importance, from January 2013 to December 2021. Ethical approval was obtained from the institute’s ethical committee (No. Dean/2021/EC/2696), and the study followed STROBE guidelines [17].
2.2. Participants
Medical records of the institute from January 2013 to December 2021 were evaluated. Patients who were operated on for OSCC and underwent mandibulectomy (marginal/segmental) were included in the study. Inadequate data and inability to review pathological reports or archive them were the exclusion criteria.
All records were evaluated by one senior surgeon, one pathologist, and one radiologist blinded to the outcome.
2.3. Evaluation and Outcome
From the medical records, data were obtained for clinical staging of the primary tumor, radiological investigations, histopathology, treatment of the neck, and adjuvant therapies. The clinical staging was performed on the basis of clinical examination, biopsy, CT/MRI, OPG for primary tumor, and CT/MRI/USG FNAC of the neck. Records obtained on the clinical staging of each patient were further updated according to the 8th edition of AJCC [9].
According to the archived records, patients with clinically N0 staging underwent selective neck dissection (SND) I–III for all primary sites except for oral tongue, for which SND I–IV was undertaken. Modified radical neck dissection (MRND) sparing internal jugular vein IJV (IJV) and sternocleidomastoid was performed for node-positive necks. Bilateral neck dissection was performed for anterior tongue tumors and anterior floor of mouth tumors. Adjuvant radiotherapy was given to patients with pathological positive nodes, higher T stage (T3/T4), lymphovascular and perineural invasion, positive margins, and ECS. Adjuvant chemoradiation was given to patients with positive margins and ECS. As initially described, POI was divided into five categories and broadly classified into two major categories: POI (1,2,3)-cohesive pattern and POI (4,5)-aggressive pattern. The five broad categories were; I: broad tumor front, II: finger-like tumor front, III: tumor islands >15 cells, IV: tumor islands <15 cells, and V: tumor islands with <15 cells more than 1 mm apart. ECS was determined from histological records as either present or absent. No data could be obtained on either ECS being microscopic or macroscopic. ECS was considered positive when there was an extension of tumor >2 mm beyond the lymph node capsule with or without stromal reaction. Mandibular invasion data were obtained from radiological records (CT) for either no involvement or cortical or medullary involvement. Similar records were also obtained from histological reports. The pattern of invasion into the mandible was also recorded a serosive or infiltrative. For statistical purposes, the histological data on mandibular invasion were taken into consideration. Depth of invasion (DOI) was recorded in accordance with the final histopathological reports. It was measured by drawing a perpendicular line (plumb line) from the horizon of the basement membrane of the adjacent mucosa to the deepest point of tumor invasion and recorded in millimeters. Perineural invasion (PNI) was considered positive when nerve involvement was present irrespective of being intratumoral/extratumoral and/or focal/multifocal. Lymphovascular invasion (LVI) was defined as the presence of tumor epithelial cells within or attached to the vascular endothelial lining. For documenting lymph node (LN) size, the maximum diameter of the lymph node dissected was selected.
The predictor variables in our study included site, depth of invasion, pattern of invasion, LVI (lymphovascular invasion), PNI (perineural invasion), grading, and lymph node size. The primary outcome was the influence of these factors on mandibular invasion, lymph node metastasis, and extracapsular spread. Overall survival was considered as the secondary outcome of the study.
2.4. Statistical Analysis
The statistical analysis was performed using IBM SPSS software, version 22.0 (IBM, Armonk, NY, USA).The receiver operating characteristic (ROC) curve and Youden’s J statistic were used to determine the optimal cut-off point for LN size and DOI. For LN size and DOI, patients were hence categorized into groups below and above the cut-off point. The Kaplan–Meir method was used to evaluate OS, and the log rank test was used to compare the survival among groups. Cox regression analysis (univariate and multivariate) was used to evaluate the hazard ratio and identify the possible factors influencing risk of death and disease. Regression analysis was also performed to evaluate the effect of predictor variables on primary outcome. A p value of <0.05 was considered statistically significant at 95% confidence interval.
3. Results
This evaluation included 162 patients with biopsy-proven oral squamous cell carcinoma (OSCC) treated between January 2013 and December 2021. (Table 1) The mean age of the patients was 54.78±6.4 years, with a male-to-female ratio of 1:0.18. The majority of tumors were located in the buccal mucosa. Tumor staging revealed that 38.9% of patients were classified as T3, while 53.7% were in the T4 stage. Pathological nodal positivity was identified in 42% of cases. Histologically, mandibular involvement was observed in 53.1% of patients. An aggressive pattern of invasion was present in 43.2% of cases, whereas 56.8% demonstrated a cohesive pattern.
With respect to mandibular invasiveness, 67 patients exhibited medullary involvement, and 19 had cortical involvement. Among the 86 patients with mandibular invasion, 56 had an infiltrative variant, and 30 demonstrated an erosive tumor front. Of the 56 patients with infiltrative tumor fronts, 50 showed an aggressive pattern of invasion, while six had a cohesive pattern. The aggressive pattern was more commonly associated with the infiltrative variant, which, in turn, was more frequently linked to bone marrow (medullary) involvement. Adjuvant therapy was administered in 55.5% of patients.
Among the factors influencing mandibular invasion, depth of invasion (DOI) and the pattern of invasion were significantly associated with clinical outcomes. Receiver operating characteristic (ROC) analysis using Youden’s J statistic identified a DOI cut-off value of 6.5 mm, which was predictive of outcomes with a sensitivity of 63%, specificity of 82%, and a Youden’s index of 0.43. On multivariate analysis, both DOI and the pattern of invasion emerged as independent risk factors for mandibular invasion (Table 2). With regard to lymph node metastasis, a DOI greater than 6.5 mm and an aggressive pattern of invasion were significantly associated. These two variables were also found to be independent predictors of lymph node metastasis (Table 3).
Extracapsular spread was significantly and independently influenced only by lymph node size. ROC analysis established a cut-off lymph node size of 2.95 cm, demonstrating a sensitivity of 71.2%, specificity of 87.9%, and a Youden’s index of 0.59 (Table 4).
The median overall survival (OS) in our study was 33 months (range: 29–36 months). Patients with an aggressive pattern of invasion had a median OS of 28 months, compared to 34 months in those with a cohesive pattern. Patients with lymph node metastasis had a median OS of 26 months, whereas node-negative patients had a median OS of 49 months (Table 5).
On univariate regression analysis, the following factors were significantly associated with poorer overall survival: aggressive pattern of invasion, T4a and T4b tumors, moderately and poorly differentiated tumors, nodal positivity, mandibular invasion, perineural and lymphovascular invasion, extracapsular spread (ECS), depth of invasion (DOI) >6.5 mm, and lymph node size >2.95 cm (Table 6). Multivariate regression analysis identified the pattern of invasion, mandibular invasion, lymph node metastasis, lymph node size, and ECS as independent risk factors for reduced overall survival (Table 7, Figure 1, Figure 2, Figure 3, Figure 4 and Figure 5).
In our study, patients with nodal metastasis had a median OS of 26 months compared to 49 months in those with a pathologically node-negative neck. There was no statistically significant difference in survival among different tumor subsites. The presence of ECS significantly impacted survival, with a median OS of 28 months compared to 34 months in its absence. Similarly, mandibular invasion reduced the median OS to 27 months, versus 55 months in patients without bony involvement. Lymphnode size greater than 2.95 cm was associated with a median OS of 24 months, compared to 49 months in nodes ≤2.95 cm.
4. Discussion
4.1. Interpretation
Two primary patterns of mandibular invasion have been described: the erosive and the infiltrative patterns. In the erosive pattern, the tumor advances with a broad front, separated from the bone by intervening connective tissue and active osteoclastic resorption—referred to as the osteoclast-dependent phase. In contrast, the infiltrative pattern is characterized by the absence of an intervening connective tissue layer, minimal osteoclastic activity, and the presence of tumor cell islands and projections extending directly into the medullary bone.
A third, mixed pattern of invasion may also be observed wherein tumors transition from an osteoclast-dependent to an osteoclast-independent phase, depending on the extent of invasion. The pattern of mandibular invasion is also influenced by both the depth and width of tumor infiltration, with the likelihood of bone invasion increasing proportionally with greater depth and width [18,19,20,21]. A 2002 systematic review reported that mandibular invasion is associated with poor overall survival (OS). Specifically, medullary invasion was linked to significantly worse OS, whereas cortical invasion showed no clear correlation with survival outcomes. Additionally, medullary involvement was associated with reduced disease-specific survival. Importantly, invasion of the medullary portion of the mandible was identified as a poor prognostic factor, regardless of tumor size [12,22].
The pattern of invasion (POI) has been identified as a potential indicator of lymph node metastasis [3,23,24]. In a study conducted by Chatterjee et al., 47 out of 48 patients with confirmed lymphatic metastasis exhibited an aggressive invasion pattern. Their findings further established POI as an independent risk factor for cervical lymph node involvement [3]. However, conflicting evidence exists, as some studies have reported no significant correlation between POI and lymphatic spread [25,26]. Mair et al. demonstrated a strong association between extracapsular spread (ECS) and specific tumor characteristics, including a depth of invasion (DOI) exceeding 5 mm, metastatic lymph nodes larger than 15 mm, and the presence of multiple involved neck nodes [5]. To refine ECS risk stratification, Lewis et al. proposed a grading system: Grade 0 (tumor confined within the lymph node), Grade 1 (tumor extending to the nodal capsule with capsular thickening), Grade 2 (perinodal extension ≤1 mm beyond the capsule), Grade 3 (extension >1 mm beyond the capsule), and Grade 4 (soft tissue metastasis with no residual nodal tissue). While Grade 4 ECS correlated with worse clinical outcomes, its prognostic impact was not independent of other variables [27]. The mechanism of ECS involves progressive tumor infiltration: metastatic cells initially invade the subcapsular sinuses, followed by interfollicular and medullary sinuses, ultimately disrupting the nodal architecture and breaching the capsule. In larger nodes, mechanical expansion of the tumor mass may precipitate ECS, whereas in smaller nodes, tumor emboli lodged within the capsular sinuses can cause focal disruption, leading to extracapsular extension [28]. Toker [29] classified carcinomatous growth within cervical lymph nodes into four distinct patterns:
- Subcapsular Sinus Invasion: Tumor cells initially proliferate in the subcapsular sinus, progressively replacing the nodal architecture. Extracapsular spread (ECS) arises either through direct capsular penetration or via tumor emboli trapped in adjacent capsular and juxtacapsular lymphatics.
- Lymphatic Sinus Infiltration: Widespread tumor infiltration of the lymphatic sinuses occurs while sparing germinal centers and trabeculae. ECS may develop through mechanisms similar to those described above.
- Concurrent Intra- and Extranodal Proliferation: Tumor cells exhibit simultaneous and proportional growth both inside the lymph node and in surrounding tissues.
- Extranodal Embolic Growth: Tumor emboli proliferate without significant intranodal involvement, potentially leading to early ECS in the disease course.
Extracapsular spread (ECS) is influenced by a constellation of clinicopathological variables, including advanced nodal stage, metastatic lymph node dimensions, primary tumor location, histopathological characteristics, tumor thickness, multiplicity of involved nodes, midline-crossing tumors, and contralateral cervical metastases [4,28]. A pronounced correlation exists between nodal staging and ECS prevalence, with documented rates of 35% in N1 disease, 55% in N2, and 74% in N3 classifications. Notably, ECS incidence exhibits a size-dependent escalation: 60–100% in nodes exceeding 3 cm, 39–59% in nodes measuring 1–3 cm, and a modest 23% in subcentimetric nodal metastases [4]. The therapeutic approach to mandibular involvement in oral carcinoma is dictated by multifactorial considerations. Key determinants of resection strategy encompass tumor dimensions, depth of soft tissue infiltration, dentition status, and the extent of osseous invasion [20]. Neoplastic infiltration typically initiates at the tumor–mandible interface, with an erosive invasion pattern often warranting marginal resection to achieve oncological clearance [27].
4.2. Limitations
- Prior radiotherapy and secondary tumors exhibit different POI, which was not taken into consideration in our study.
- Several other factors like comorbidities, lifestyle, and patient physical status might impact survival. Further studies are necessary to evaluate the combined effects of each of these factors on survival.
- In our study, the pattern of invasion was determined histologically. Various imaging modalities have been shown to determine the pattern of invasion, comparison of which was not performed in our study.
- Smaller sample size and retrospective nature of the study.
5. Conclusions
Aggressive pattern of invasion and depth of invasion are independent risk factors for cervical lymph node metastasis and mandibular invasion. The only independent risk factor for extracapsular spread is lymph node size. Aggressive tumors preferentially show an infiltrative pattern of invasion into the mandible, necessitating segmental resection. Lymph node metastasis and nodal size, pattern of invasion, mandibular invasion, and extracapsular spread are independent risk factors affecting overall survival.
Further research and clinical trials are necessary in this regard for better description and identification of risk factors for early cervical metastasis and bone invasion.
Clinical Implication: The current study has elaborated the causative and predictor factors for lymph node metastasis, extracapsular spread, and mandibular invasion. Though individual studies exist, a thorough comprehensive study is lacking. Currently, only the primary site and depth of invasion are considered important prognostic factors for lymph node metastasis. Future studies should consider biologic behavior of the tumor. ECS hampers survival. Our study has shown that only the size of the metastatic lymph node is an independent risk factor, not the biologic behavior of the primary tumor. Tumor biology is an independent risk factor for mandibular invasion, necessitating aggressive management in cases of mandible involvement.
Author Contributions
Conceptualization, R.N.B.; writing, R.N.B.; formatting, R.N.B.; analysis, R.N.B.; investigation, R.N.B.; visualization, R.T.; supervision, R.T., data curation, R.T. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of Banaras Hindu University (protocol code No. Dean 2021/EC/2696 and date of approval 23 June 2021).
Informed Consent Statement
Not applicable.
Data Availability Statement
The original contributions presented in this study are included in the article. Further inquiries can be directed to the corresponding author.
Conflicts of Interest
The authors declare no conflicts of interest.
References
- Sarode, G.; Maniyar, N.; Sarode, S.C.; Jafer, M.; Patil, S.; Awan, K.H. Epidemiologic aspects of oral cancer. Dis. Mon. 2020, 66, 100988. [Google Scholar] [CrossRef]
- Montero, P.H.; Patel, S.G. Cancer of the oral cavity. Surg. Oncol. Clin. N. Am. 2015, 24, 491–508. [Google Scholar] [CrossRef]
- Arora, A.; Husain, N.; Bansal, A.; Neyaz, A.; Jaiswal, R.; Jain, K.; Chaturvedi, A.; Anand, N.; Malhotra, K.; Shukla, S. Development of a New Outcome Prediction Model in Early-stage Squamous Cell Carcinoma of the Oral Cavity Based on Histopathologic Parameters With Multivariate Analysis: The Aditi-Nuzhat Lymph-node Prediction Score (ANLPS) System. Am. J. Surg. Pathol. 2017, 41, 950–960. [Google Scholar] [CrossRef] [PubMed]
- Mermod, M.; Tolstonog, G.; Simon, C.; Monnier, Y. Extracapsular spread in head and neck squamous cell carcinoma: A systematic review and meta-analysis. Oral. Oncol. 2016, 62, 60–71. [Google Scholar] [CrossRef] [PubMed]
- Mair, M.D.; Shetty, R.; Nair, D.; Mathur, Y.; Nair, S.; Deshmukh, A.; Thiagarajan, S.; Pantvaidya, G.; Lashkar, S.; Prabhash, K.; et al. Depth of invasion, size and number of metastatic nodes predicts extracapsular spread in early oral cancers with occult metastases. Oral. Oncol. 2018, 81, 95–99. [Google Scholar] [CrossRef] [PubMed]
- Jakobsson, P.A.; Eneroth, C.M.; Killander, D.; Moberger, G.; Mårtensson, B. Histologic classification and grading of malignancy in carcinoma of the larynx. Acta Radiol. Ther. Phys. Biol. 1973, 12, 1–8. [Google Scholar] [CrossRef]
- Bryne, M.; Koppang, H.S.; Lilleng, R.; Kjaerheim, A. Malignancy grading of the deep invasive margins of oral squamous cell carcinomas has high prognostic value. J. Pathol. 1992, 166, 375–381. [Google Scholar] [CrossRef]
- Anneroth, G.; Batsakis, J.; Luna, M. Review of the literature and a recommended system of malignancy grading in oral squamous cell carcinomas. Scand. J. Dent. Res. 1987, 95, 229–249. [Google Scholar] [CrossRef]
- Brandwein-Gensler, M.; Teixeira, M.S.; Lewis, C.M.; Lee, B.; Rolnitzky, L.; Hille, J.J.; Genden, E.; Urken, M.L.; Wang, B.Y. Oral squamous cell carcinoma: Histologic risk assessment, but not margin status, is strongly predictive of local disease-free and overall survival. Am. J. Surg. Pathol. 2005, 29, 167–178. [Google Scholar] [CrossRef]
- Müller, S.; Boy, S.C.; Day, T.A.; Magliocca, K.R.; Richardson, M.S.; Sloan, P.; Tilakaratne, W.M.; Zain, R.B.; Thompson, L.D.R. Data set for the reporting of oral cavity carcinomas: Explanations and recommendations of the guidelines from the International Collaboration of Cancer Reporting. Arch. Pathol. Lab. Med. 2019, 143, 439–446. [Google Scholar] [CrossRef]
- Xu, B.; Salama, A.M.; Valero, C.; Yuan, A.; Khimraj, A.; Saliba, M.; Zanoni, D.K.; Ganly, I.; Patel, S.G.; Katabi, N.; et al. The prognostic role of histologic grade, worst pattern of invasion, and tumor budding in early oral tongue squamous cell carcinoma: A comparative study. Virchows Arch. 2021, 479, 597–606. [Google Scholar] [CrossRef] [PubMed]
- Li, C.; Lin, J.; Men, Y.; Yang, W.; Mi, F.; Li, L. Does Medullary Versus Cortical Invasion of the Mandible Affect Prognosis in Patients With Oral Squamous Cell Carcinoma? J. Oral Maxillofac. Surg. 2017, 75, 403–415. [Google Scholar] [CrossRef] [PubMed]
- Rao, L.P.; Das, S.R.; Mathews, A.; Naik, B.R.; Chacko, E.; Pandey, M. Mandibular invasion in oral squamous cell carcinoma: Investigation by clinical examination and orthopantomogram. Int. J. Oral Maxillofac. Surg. 2004, 33, 454–457. [Google Scholar] [CrossRef]
- Tsue, T.T.; McCulloch, T.M.; Girod, D.A.; Couper, D.J.; Weymuller, E.A., Jr.; Glenn, M.G. Predictors of carcinomatous invasion of the mandible. Head Neck 1994, 16, 116–126. [Google Scholar] [CrossRef]
- Gou, L.; Yang, W.; Qiao, X.; Ye, L.; Yan, K.; Li, L.; Li, C. Marginal or segmental mandibulectomy: Treatment modality selection for oral cancer: A systematic review and meta-analysis. Int. J. Oral Maxillofac. Surg. 2018, 47, 1–10. [Google Scholar] [CrossRef]
- Rao, L.P.; Shukla, M.; Sharma, V.; Pandey, M. Mandibular conservation in oral cancer. Surg. Oncol. 2012, 21, 109–118. [Google Scholar] [CrossRef]
- Vandenbroucke, J.P.; von Elm, E.; Altman, D.G.; Gøtzsche, P.C.; Mulrow, C.D.; Pocock, S.J.; Poole, C.; Schlesselman, J.J.; Egger, M.; Strobe Initiative. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): Explanation and elaboration. PLoS Med. 2007, 4, e297. [Google Scholar] [CrossRef] [PubMed]
- Brown, J. Mechanisms of cancer invasion of the mandible. Curr. Opin. Otolaryngol. Head. Neck Surg. 2003, 11, 96–102. [Google Scholar] [CrossRef]
- Carter, R.L.; Tsao, S.W.; Burman, J.F.; Pittam, M.R.; Clifford, P.; Shaw, H.J. Patterns and mechanisms of bone invasion by squamous carcinomas of the head and neck. Am. J. Surg. 1983, 146, 451–455. [Google Scholar] [CrossRef]
- Brown, J.S.; Browne, R.M. Factors influencing the patterns of invasion of the mandible by oral squamous cell carcinoma. Int. J. Oral. Maxillofac. Surg. 1995, 24, 417–426. [Google Scholar] [CrossRef]
- Brown, J.S.; Lowe, D.; Kalavrezos, N.; D’Souza, J.; Magennis, P.; Woolgar, J. Patterns of invasion and routes of tumor entry into the mandible by oral squamous cell carcinoma. Head Neck 2002, 24, 370–383. [Google Scholar] [CrossRef]
- Fives, C.; Nae, A.; Roche, P.; O’Leary, G.; Fitzgerald, B.; Feeley, L.; Sheahan, P. Impact of mandibular invasion on prognosis in oral squamous cell carcinoma four centimeters or less in size. Laryngoscope 2017, 127, 849–854. [Google Scholar] [CrossRef] [PubMed]
- Khwaja, T.; Tayaar, A.S.; Acharya, S.; Bhushan, J.; Muddapur, M.V. Pattern of invasion as a factor in determining lymph node metastasis in oral squamous cell carcinoma. J. Cancer Res. Ther. 2018, 14, 382–387. [Google Scholar] [CrossRef] [PubMed]
- Chatterjee, D.; Bansal, V.; Malik, V.; Bhagat, R.; Punia, R.S.; Handa, U.; Gupta, A.; Dass, A. Tumor Budding and Worse Pattern of Invasion Can Predict Nodal Metastasis in Oral Cancers and Associated with Poor Survival in Early-Stage Tumors. Ear Nose Throat J. 2019, 98, E112–E119. [Google Scholar] [CrossRef] [PubMed]
- Lundqvist, L.; Stenlund, H.; Laurell, G.; Nylander, K. The importance of stromal inflammation in squamous cell carcinoma of the tongue. J. Oral Pathol. Med. 2012, 41, 379–383. [Google Scholar] [CrossRef]
- Kane, S.V.; Gupta, M.; Kakade, A.C.; D’ Cruz, A. Depth of invasion is the most significant histological predictor of subclinical cervical lymph node metastasis in early squamous carcinomas of the oral cavity. Eur. J. Surg. Oncol. 2006, 32, 795–803. [Google Scholar] [CrossRef]
- Lewis, J.S., Jr.; Carpenter, D.H.; Thorstad, W.L.; Zhang, Q.; Haughey, B.H. Extracapsular extension is a poor predictor of disease recurrence in surgically treated oropharyngeal squamous cell carcinoma. Mod. Pathol. 2011, 24, 1413–1420. [Google Scholar] [CrossRef]
- Puri, S.K.; Fan, C.Y.; Hanna, E. Significance of extracapsular lymph node metastases in patients with head and neck squamous cell carcinoma. Curr. Opin. Otolaryngol. Head. Neck Surg. 2003, 11, 119–123. [Google Scholar] [CrossRef]
- Tokerc, C. Some observations on the deposition of metastatic carcinoma within cervical lymph nodes. Cancer 1963, 16, 364–374. [Google Scholar] [CrossRef]
Figure 1.
Pattern of invasion as a predictor of overall survival.
Figure 2.
Mandibular invasion as a predictor of overall survival.
Figure 3.
Lymph node metastasis as a predictor of overall survival.
Figure 4.
Lymph node size as a predictor of overall survival.
Figure 5.
Extracapsular spread as a predictor of overall survival.
Table 1.
Study characteristics.
| Characteristics | Frequency | ||
|---|---|---|---|
| No. of Patients | Percentage | ||
| Mean Age M:F ratio | 54.78 ± 6.4 years 1:0.18 | ||
| Site of primary tumor | Buccal mucosa | 40 | 24.70% |
| Tongue | 33 | 20.40% | |
| Floor of mouth | 35 | 21.60% | |
| Mandibular alveolus | 32 | 19.80% | |
| Retro molar trigone | 22 | 13.60% | |
| pT stage: | T2 | 12 | 7.4% |
| T3 | 63 | 38.90% | |
| T4a | 76 | 46.90% | |
| T4b | 11 | 6.8% | |
| pN stage: | N0 | 94 | 58.02% |
| N+ | 68 | 42% | |
| Mandibular Invasion: Histopathology | No involvement | 76 | 46.9% |
| Cortical involvement | 19 | 11.73% | |
| Medullary involvement | 67 | 41.40% | |
| Erosive | 30 | 34.88% | |
| Infiltrative | 56 | 65.11% | |
| Grading. | Well | 72 | 44.40% |
| Moderate | 47 | 29.0% | |
| Poor | 43 | 26.5% | |
| LVI | Absent | 101 | 62.3% |
| Present | 61 | 37.7% | |
| PNI | Absent | 115 | 71% |
| Present | 47 | 29% | |
| Pattern of invasion | Cohesive | 92 | 56.8% |
| Aggressive | 70 | 43.2% | |
| DOI (mm) | ≤6.5 | 95 | 58.6% |
| >6.5 | 67 | 41.4% | |
| ECS | Absent | 122 | 75.3% |
| Present | 40 | 24.7% | |
| Lymph node size (cm) | ≤2.95 | 116 | 71.6% |
| >2.95 | 46 | 28.4% | |
| Mandibulectomy: | Marginal | 42 | 25.9% |
| Segmental | 120 | 74.1% | |
| Management of neck: | Ipsilateral SND | 130 | 80.24% |
| Ipsilateral MRND | 28 | 17.3% | |
| Ipsilateral MRND + contralateral SND | 4 | 2.5% | |
| Adjuvant treatment: | No adjuvant therapy | 72 | 44.4% |
| Radiotherapy | 70 | 43.2% | |
| Chemoradiation | 20 | 12.3% | |
LVI: lymphovascular invasion, PNI: perineural invasion, ECS: extracapsular spread, DOI: depth of invasion, SND: selective neck dissection, MRND: modified radical neck dissection.
Table 2.
Factors influencing mandibular invasion.
| Univariate Regression | OR | 95% C.I. | p Value | OR | 95% C.I | p Value | ||||
|---|---|---|---|---|---|---|---|---|---|---|
| Lower | Upper | Lower | Upper | |||||||
| BM | multivariate regression | Site | 0.830 | 0.639 | 1.079 | 0.165 | ||||
| FOM | 2.746 | 0.782 | 9.643 | 0.115 | size | 0.940 | 0.537 | 1.645 | 0.828 | |
| Mn alveolus | 1.701 | 0.501 | 5.782 | 0.395 | DOI | 2.810 | 1.200 | 6.580 | 0.017 | |
| RMT | 1.266 | 0.295 | 5.439 | 0.751 | GRADING | 1.353 | 0.854 | 2.141 | 0.197 | |
| TONGUE | 0.359 | 0.101 | 1.276 | 0.114 | LVI | 0.865 | 0.273 | 2.738 | 0.805 | |
| pT 2 | PNI | 2.162 | 0.607 | 7.706 | 0.234 | |||||
| pT 3 | 1.140 | 0.199 | 6.544 | 0.883 | PATTERN | 8.870 | 3.825 | 20.570 | 0.000 | |
| pT4 | 0.788 | 0.141 | 4.409 | 0.787 | LN size | 1.907 | 0.573 | 6.352 | 0.293 | |
| DOI ≤ 6.5 | ||||||||||
| DOI > 6.5 mm | 3.273 | 1.283 | 8.348 | 0.013 | ||||||
| Well differentiated | ||||||||||
| Moderate | 0.702 | 0.253 | 1.946 | 0.496 | ||||||
| Poor | 1.843 | 0.700 | 4.853 | 0.216 | ||||||
| LVI absent | ||||||||||
| LVI present | 0.810 | 0.237 | 2.772 | 0.738 | ||||||
| PNI absent | ||||||||||
| PNI present | 2.955 | 0.738 | 11.830 | 0.126 | ||||||
| Cohesive pattern | ||||||||||
| Aggressive pattern | 10.748 | 4.222 | 27.357 | <0.001 | ||||||
| LN size ≤ 2.95 | ||||||||||
| LN size > 2.95 cm | 3.544 | 0.917 | 13.705 | 0.067 | ||||||
Table 3.
Factors influencing lymph node metastasis.
| Univariate Regression | OR | 95% C.I. | p Value | OR | 95% C.I. | p Value | ||||
|---|---|---|---|---|---|---|---|---|---|---|
| Lower | Upper | Lower | Upper | |||||||
| BM | multivariate regression | Site | 0.804 | 0.604 | 1.071 | 0.136 | ||||
| FOM | 1.586 | 0.431 | 5.842 | 0.488 | pT | 1.525 | 0.797 | 2.917 | 0.203 | |
| Mn alveolus | 0.767 | 0.199 | 2.956 | 0.700 | DOI | 6.486 | 2.453 | 17.144 | <0.001 | |
| Tongue | 0.916 | 0.159 | 5.288 | 0.922 | GRADING | 1.455 | 0.860 | 2.461 | 0.162 | |
| Site_1(4) | 0.492 | 0.139 | 1.743 | 0.272 | LVI | 2.156 | 0.591 | 7.864 | 0.245 | |
| pT2 | 0.753 | PNI | 1.419 | 0.326 | 6.173 | 0.641 | ||||
| pT3 | 0.946 | 0.131 | 6.827 | 0.956 | PATTERN | 11.448 | 4.414 | 29.693 | <0.001 | |
| pT4a | 1.504 | 0.223 | 10.145 | 0.675 | ||||||
| pT4b | 2.319 | 0.138 | 38.897 | 0.559 | ||||||
| DOI ≤ 6.5 | ||||||||||
| DOI > 6.5 | 7.155 | 2.547 | 20.099 | <0.001 | ||||||
| Well differentiated | ||||||||||
| Moderate | 1.866 | 0.635 | 5.483 | 0.257 | ||||||
| Poor | 1.993 | 0.682 | 5.823 | 0.207 | ||||||
| LVI absent | ||||||||||
| LVI present | 2.109 | 0.569 | 7.820 | 0.265 | ||||||
| PNI absent | ||||||||||
| PNI present | 1.475 | 0.324 | 6.711 | 0.615 | ||||||
| Cohesive pattern | ||||||||||
| Aggressive pattern | 11.516 | 4.332 | 30.611 | <0.001 | ||||||
Table 4.
Factors influencing extracapsular spread.
| Univariate Regression | OR | 95% C.I. | p Value | Multivariate Regression | OR | 95% C.I. | p Value | ||
|---|---|---|---|---|---|---|---|---|---|
| Lower | Upper | Lower | Upper | ||||||
| BM | Site | 0.318 | 0.073 | 1.383 | 0.127 | ||||
| FOM | 0.371 | 0.091 | 1.510 | 0.166 | pT | 1.120 | 0.592 | 2.118 | 0.728 |
| Mn alveolus | 0.296 | 0.067 | 1.311 | 0.109 | DOI | 0.845 | 0.357 | 2.005 | 0.703 |
| RMT | 0.955 | 0.193 | 4.723 | 0.955 | GRADING | 0.858 | 0.533 | 1.381 | 0.528 |
| Tongue | 3.684 | 0.908 | 14.941 | 0.068 | LVI | 1.503 | 0.483 | 4.674 | 0.481 |
| pT2 | PNI | 0.575 | 0.153 | 2.158 | 0.412 | ||||
| pT3 | 8.302 | 0.490 | 140.752 | 0.143 | PATTERN | 1.293 | 0.406 | 4.120 | 0.663 |
| pT4a | 9.276 | 0.558 | 154.324 | 0.120 | LN size | 19.152 | 5.827 | 62.946 | <0.001 |
| pT4b | 5.540 | 0.217 | 141.512 | 0.300 | |||||
| DOI ≤ 6.5 | |||||||||
| DOI > 6.5 | 0.563 | 0.215 | 1.478 | 0.244 | |||||
| Well differentiated | |||||||||
| Moderate | 1.317 | 0.344 | 5.041 | 0.688 | |||||
| Poor | 0.977 | 0.338 | 2.829 | 0.966 | |||||
| LVI absent | |||||||||
| LVI present | 1.491 | 0.433 | 5.140 | 0.527 | |||||
| PNI absent | |||||||||
| PNI present | 0.703 | 0.165 | 3.003 | 0.634 | |||||
| Cohesive pattern | |||||||||
| Aggressive pattern | 1.689 | 0.471 | 6.053 | 0.421 | |||||
| LN size ≤ 2.95 | |||||||||
| LN size > 2.95 | 27.795 | 6.953 | 111.119 | 0.000 | |||||
Table 5.
Mean and median overall survival of the study population.
| Mean and Median Survival Time (in Months) | ||||||||
|---|---|---|---|---|---|---|---|---|
| PATTERN | Mean | Median | ||||||
| Estimate | Std. Error | 95% Confidence Interval | Estimate | Std. Error | 95% Confidence Interval | |||
| Lower Bound | Upper Bound | Lower Bound | Upper Bound | |||||
| Cohesive | 40.521 | 2.057 | 36.489 | 44.553 | 34.000 | 3.294 | 27.544 | 40.456 |
| Aggressive | 34.430 | 2.472 | 29.585 | 39.275 | 28.000 | 2.564 | 22.974 | 33.026 |
| pT | ||||||||
| T2 | 47.932 | 5.165 | 37.808 | 58.056 | ||||
| T3 | 38.072 | 2.559 | 33.057 | 43.086 | 34.000 | 8.772 | 16.808 | 51.192 |
| T4a | 37.629 | 2.344 | 33.034 | 42.223 | 33.000 | 0.581 | 31.862 | 34.138 |
| T4b | 26.364 | 3.718 | 19.077 | 33.651 | 24.000 | 2.752 | 18.605 | 29.395 |
| GRADING | ||||||||
| Well | 51.016 | 2.214 | 46.676 | 55.356 | ||||
| Moderate | 34.065 | 2.353 | 29.452 | 38.677 | 33.000 | 1.301 | 30.450 | 35.550 |
| Poor | 26.022 | 2.362 | 21.391 | 30.652 | 21.000 | 1.634 | 17.798 | 24.202 |
| LVI | ||||||||
| Absent | 41.337 | 2.117 | 37.188 | 45.487 | 41.000 | 8.703 | 23.943 | 58.057 |
| Present | 33.374 | 2.359 | 28.751 | 37.997 | 30.000 | 2.279 | 25.533 | 34.467 |
| PNI | ||||||||
| Absent | 40.710 | 1.959 | 36.871 | 44.549 | 40.000 | 6.489 | 27.281 | 52.719 |
| Present | 31.908 | 2.657 | 26.701 | 37.115 | 28.000 | 1.424 | 25.209 | 30.791 |
| MANDIBULAR INVASION | ||||||||
| Absent | 45.664 | 2.298 | 41.160 | 50.169 | 55.000 | 4.125 | 46.914 | 63.086 |
| Present | 31.279 | 1.879 | 27.596 | 34.962 | 27.000 | 1.845 | 23.383 | 30.617 |
| LYMPH NODE METASTASIS | ||||||||
| Absent | 44.089 | 2.146 | 39.883 | 48.296 | 49.000 | 9.114 | 31.136 | 66.864 |
| Present | 30.720 | 2.140 | 26.526 | 34.914 | 26.000 | 2.087 | 21.909 | 30.091 |
| ECS | ||||||||
| Absent | 40.082 | 2.066 | 36.032 | 44.132 | 34.000 | 3.486 | 27.168 | 40.832 |
| Present | 34.337 | 2.624 | 29.193 | 39.481 | 28.000 | 2.703 | 22.702 | 33.298 |
| DOI_1 | ||||||||
| ≤6.5 | 44.898 | 2.160 | 40.664 | 49.132 | ||||
| >6.5 | 30.123 | 1.989 | 26.225 | 34.020 | 26.000 | 2.237 | 21.615 | 30.385 |
| LN_size | ||||||||
| ≤2.95 | 42.952 | 1.878 | 39.271 | 46.633 | 49.000 | 6.286 | 36.680 | 61.320 |
| >2.95 | 26.657 | 2.263 | 22.221 | 31.092 | 24.000 | 1.270 | 21.512 | 26.488 |
| Site | ||||||||
| BM | 35.459 | 2.904 | 29.767 | 41.151 | 30.000 | 3.839 | 22.475 | 37.525 |
| FOM | 39.326 | 3.498 | 32.469 | 46.182 | 49.000 | 14.004 | 21.553 | 76.447 |
| Mandibular alveolus | 38.319 | 4.182 | 30.122 | 46.515 | 36.000 | 8.472 | 19.395 | 52.605 |
| RMT | 36.857 | 3.409 | 30.176 | 43.538 | 33.000 | 2.455 | 28.188 | 37.812 |
| TONGUE | 39.126 | 3.635 | 32.002 | 46.250 | 34.000 | 6.270 | 21.711 | 46.289 |
| Overall | 37.918 | 1.604 | 34.774 | 41.063 | 33.000 | 1.982 | 29.116 | 36.884 |
Table 6.
Univariate regression analysis of factors influencing survival.
| PATTERN | Frequency | p Value | OR | Lower 95% CI | Upper 95% CI |
|---|---|---|---|---|---|
| Cohesive | 92 | ||||
| Aggressive | 70 | 0.046 | 1.560 | 1.008 | 2.414 |
| pT | |||||
| T2 | 12 | ||||
| T3 | 63 | 0.063 | 3.915 | 0.928 | 16.511 |
| T4a | 76 | 0.048 | 4.207 | 1.014 | 17.451 |
| T4b | 11 | 0.004 | 9.407 | 2.074 | 42.659 |
| GRADING | |||||
| Well | 72 | ||||
| Moderate | 47 | <0.001 | 3.902 | 1.983 | 7.680 |
| Poor | 43 | <0.001 | 7.629 | 3.987 | 14.598 |
| LVI | |||||
| Absent | 101 | ||||
| Present | 61 | 0.019 | 1.688 | 1.091 | 2.610 |
| PNI | |||||
| Absent | 115 | ||||
| Present | 47 | 0.008 | 1.816 | 1.165 | 2.831 |
| MANDIBULAR INVASION | |||||
| Absent | 76 | ||||
| Present | 86 | <0.001 | 8.467 | 4.234 | 16.934 |
| LYMPH NODE METASTASIS | |||||
| Absent | 94 | ||||
| Present | 68 | <0.001 | 12.172 | 5.596 | 26.475 |
| ECS | |||||
| Absent | 122 | ||||
| Present | 40 | <0.001 | 8.411 | 3.862 | 18.317 |
| DOI | |||||
| ≤6.5 | 95 | ||||
| >6.5 | 67 | <0.001 | 2.924 | 1.860 | 4.597 |
| LN size | |||||
| ≤2.95 | 116 | ||||
| >2.95 | 46 | <0.001 | 4.476 | 2.838 | 7.058 |
| SITE | |||||
| BM | 40 | ||||
| FOM | 35 | 0.478 | 0.793 | 0.419 | 1.503 |
| Mandibular alveolus | 32 | 0.901 | 0.959 | 0.493 | 1.864 |
| RMT | 22 | 0.832 | 0.928 | 0.464 | 1.856 |
| TONGUE | 33 | 0.514 | 0.798 | 0.405 | 1.571 |
| Total | 162 |
Table 7.
Multivariate regression analysis of factors influencing survival.
| OR | 95.0% CI for Exp(B) | p Value | ||
|---|---|---|---|---|
| Lower | Upper | |||
| DOI | 0.987 | 0.565 | 1.722 | 0.963 |
| GRADING | 1.284 | 0.889 | 1.853 | 0.182 |
| LVI | 0.834 | 0.392 | 1.776 | 0.638 |
| PNI | 0.730 | 0.337 | 1.581 | 0.425 |
| pT | 1.213 | 0.882 | 1.668 | 0.235 |
| MANDIBULAR INVASION | 2.274 | 1.006 | 5.144 | 0.048 |
| ECS | 2.762 | 1.106 | 6.898 | 0.030 |
| PATTERN | 2.065 | 1.152 | 3.703 | 0.015 |
| LN size | 1.903 | 1.037 | 3.491 | 0.038 |
| LYMPHNODE METASTASIS | 2.790 | 1.056 | 7.367 | 0.038 |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2025 by the authors. Published by MDPI on behalf of the AO Foundation. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
MDPI and ACS Style
Bera, R.N.; Tripathi, R. Factors Influencing Mandibular Invasion, Lymph Node Metastasis and Extracapsular Spread in Squamous Cell Carcinoma of the Oral Cavity. Craniomaxillofac. Trauma Reconstr. 2025, 18, 30. https://doi.org/10.3390/cmtr18030030
AMA Style
Bera RN, Tripathi R. Factors Influencing Mandibular Invasion, Lymph Node Metastasis and Extracapsular Spread in Squamous Cell Carcinoma of the Oral Cavity. Craniomaxillofacial Trauma & Reconstruction. 2025; 18(3):30. https://doi.org/10.3390/cmtr18030030
Chicago/Turabian StyleBera, Rathindra Nath, and Richik Tripathi. 2025. "Factors Influencing Mandibular Invasion, Lymph Node Metastasis and Extracapsular Spread in Squamous Cell Carcinoma of the Oral Cavity" Craniomaxillofacial Trauma & Reconstruction 18, no. 3: 30. https://doi.org/10.3390/cmtr18030030
APA StyleBera, R. N., & Tripathi, R. (2025). Factors Influencing Mandibular Invasion, Lymph Node Metastasis and Extracapsular Spread in Squamous Cell Carcinoma of the Oral Cavity. Craniomaxillofacial Trauma & Reconstruction, 18(3), 30. https://doi.org/10.3390/cmtr18030030
