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An official publication of the Middle-Eastern Association for Cancer Research
Clinical Cancer Investigation Journal
ISSN Print: 2278-1668, Online: 2278-0513
Year: 2019   |   Volume: 8   |   Issue: 2   |   Page: 47-51     View issue
Surgical margins and nodal metastasis are prognostic factors in oral squamous cell carcinoma: A meta-analysis
Mohammad Akheel, Rinku George, Amit Jain, Qutubuddin Chahwala, Ashmi Wadhwania

Background: To find out whether surgical margins and nodal metastasis are prognostic factors in oral squamous cell carcinoma (OSCC). Materials and Methods: PubMed search was done to look for studies done on surgical margins and nodal metastasis of OSCC from 2008 to 2018. Results: Fixed effects meta-analysis showed a pooled estimate absolute risk reduction of −3% (95% confidence interval [CI] [−8, 2.5%]). P =0.2819 from the fixed margin model shows no statistically significant difference between close margins with cases of deaths due to recurrence or metastasis. The pooled odds ratio was 0.87 (95% CI 0.63–1.99, P = 0.3928) for the comparison between clear and closed margins for estimating the odds. It should be noted that the mean unweighted local recurrence rate for margins 5 mm or greater was 4.9% with 95% CI as −10.7%, 0.8%. Conclusion: The study shows that close surgical margins with nodal metastasis have a poor prognosis in OSCC; however, no statistical significance was seen in this meta-analysis.

Nodal metastasis, prognosis, squamous cell carcinoma, surgical margins


According to the World Health Organization (WHO), oral squamous cell carcinomas (OSCCs) are the most frequent head-and-neck malignancies with 390,000 new cases are reported every year.[1],[2],[3] In India, OSCCs are the sixth-most frequent malignancies among males (9.2% of cases) and the seventh-most frequent in females (3.6% of cases) not including skin cancers.[2] In total, these malignancies are 6.7% of all cancer cases. Estimates for 2007 had suggested that there would be 10.91 new cases of OSCCs for each 100,000 males and 3.58 new cases for each 100,000 females.[3],[4],[5],[6] The incidence rate is increasing and the WHO foresees further increase in the next decades. Around 95% of oral cancers are OSCCs; the remaining 5% are sarcomas, lymphomas, and salivary gland tumors.[7],[8]

The prognosis of oral cancer remains unfavorable with high mortality rates, notwithstanding advances in diagnosis and therapy, including radical surgery, novel chemotherapy, and hyper fractionated/conformational radiotherapy. Mortality rates have ranged from 2.16 to 2.96 for each 100,000 males and 0.48 to 0.70 for each 100,000 females between 1979 and 1998 in Brazil; the mortality rate has increased at an annual 0.72% rate. According to Sessions et al.,[9] the 5-year survival rate remains low at about 48% (overall survival) and 57% (disease-specific survival). The biological behavior of OSCC is uncertain; many of these tumors have an aggressive biological behavior at initial stages with early regional metastases and death.[10],[11],[12] On the other hand, advanced tumors may metastasize slowly, and these patients may remain disease free for long periods after surgery. This uncertainty in tumor progression has led researchers to seek factors that might alter the prognosis.[13],[14],[15] Such factors may be related to patients (age, sex, race, social and economic status, and habits such as smoking and alcohol intake), to the tumor (site, stage, tumor thickness, histopathology, and expression of certain molecular markers), and to the treatment (type of treatment and adjuvant therapy). Investigation of these factors aims to learn more about the biological behavior of the tumor and hence that specific strategies may be applied individually; thus, aggressive therapy may be given to patients with the worst prognosis.

The presence of the neck nodal metastases is the most important prognostic factor for OSCCs. Survival rates reduce by 50%, if there is any nodal metastasis. Tumor node-metastasis (TNM) staging, the histological grade, and safety margins are other factors with unknown roles which reduces the survival rates.[15],[16],[17] Many studies have suggested that TNM staging cannot predict individual tumor biological behavior. The prognostic value of the histological grade is controversial in this tumor; studies have suggested that poorly differentiated carcinomas tend to metastasize and to have involved margins more often.[18],[19] These tumors are associated with decreased survival rates. There is still controversy in the literature about surgical margin status.

Materials and Methods

The meta-analysis was undertaken in accordance with 2009 PRIMSA guidelines in PubMed search from 2008 to 2018. Terms searched were “OSCCs,” “nodal metastasis,” “surgical margins,” and “prognosis.” A total of 14 studies were reviewed and only nine studies were included in meta-analysis considering the following inclusion criteria: studies with primary surgery and postadjuvant radiation, studies with recurrences/death postsurgery, studies where the follow-up was >2 years, and studies in which surgical margins had viewed pathologically and classified with clear/close margins. Exclusion criteria were studies which had patients with salvage surgery or palliative surgery and studies which had other subsites of head and neck.

Statistical analysis

Data extracted from the nine studies were as follows: total number of patients in the study, cutoff margins classified as clear/close margins in each study, follow-up of the patients, nodal metastasis, and death of the patients. Data used for statistical analysis were based on the percentage of overall local recurrence rate in clear/close margins with 95% confidence intervals (CIs) and P values calculated to indicate the size of the difference between close and clear margins.

Meta-analysis was done with review manager 5.0. Heterogeneity was assessed using Cochrans Q, τ2, and I2 statistics, and the results are tabulated as below.


The summarized data for individual studies are tabulated in [Table 1]. The studies tabulated in this meta-analysis were the proposed cutoff, number of patients in the study, followup months, death due to nodal metastasis/recurrence, nodal metastasis, and percentage with death due to recurrence/ metastasis; however, in one of the study conducted by Hicks et al.[20] margin cutoff was 10 mm. Number and percentages of clear and close margins according to the individual study are given, along with the number and percentage of cases by death or local recurrences for each margin group. CIs and P values were calculated using a Chi-squared test whether surgical margins and cases by deaths or recurrence and nodal metastasis are prognostic factors for survival in OSCC in each study.{Table 1}

These results are shown graphically in [Figure 1]. Rates of local recurrence and death differ between studies; however, in major proportion, there is a trend toward increased recurrence and deaths in groups with smaller margin size. In the majority of the studies, the local recurrence rate with a 10-mm margin cutoff was lower in both groups. [Table 2] shows tests to measure data heterogeneity were performed for eight studies except one study with a clear margin ≥10 mm. Cochran's Q was 14.91, P = 0.0372, τ2 = 0.00844; I2= 53.04%. Fixed effect modeling was performed to obtain the pooled estimates for meta-analysis. Fixed effects meta-analysis showed a pooled estimate absolute risk reduction of −3% (95% CI [−8, 2.5%]). P = 0.2819 from the fixed margin model shows no statistically significant difference between close margins with cases of deaths due to recurrence or metastasis. The pooled odds ratio was 0.87 (95% CI 0.63–1.99, P = 0.3928) for the comparison between clear and closed margins for estimating the odds. It should be noted that the mean unweighted local recurrence rate for margins 5 mm or greater was 4.9% with 95% CI as −10.7%, 0.8%.{Figure 1}{Table 2}


The efficiency of the surgery is assessed by its adequate pathological margins which are a major consideration in determining the need of further adjuvant treatment. Pathological margins are microscopically assessed margins after tissue shrinkage and tumor extension. The amount of shrinkage noted is 9.2%–75% according to the literature.[21] The classification of surgical margins according to the Royal College of Pathologists UK: <1 mm as involved margins, 1–5 mm margin are close margins, and >5 mm margin are free margins.[13] These parameters are important in the prognosis of the patient; however, studies have not shown statistically significance in terms of recurrence.

This is a first meta-analysis done with total of 1333 patients which was a reasonable number to find a conclusion regarding the two prognostic parameters. Although this study could not prove statistical significance to find margins and nodal metastasis as a prognosticator in OSCC, it highlights the areas of lacunae which needed high-quality research with multicentric trials. This analysis clearly indicates that margins of 5 mm are required to have a good prognosis of the patients and prevent local recurrences/death. Clinicians must concentrate on the surgical margins of at least 1–1.5 cm macroscopically to gain 5 mm clear microscopic pathological-free margins considering the shrinkage and tumor extent. The finding of 22% local recurrence for 5 mm or greater margins is in accordance to 25% reported by Brandwein-Gensler et al.[22] which showed histological factors, in general, were responsible for local recurrence. A detailed pathological study needs to be done at the margins close to the tumor: dysplasia, carcinoma in situ, or invasive carcinoma and needed to study the prognosis of these patients. In this meta-analysis, any of these were considered as involved margins. This meta-analysis reviewed most of the subsites in the oral cavity, while Sadeghi et al.[23] and Loree and Strong[24] included all subsites, with the majority of tumors on the tongue or floor of the mouth. The other articles focused on just one or two subsites which can be the reason for the bias in the respective study.[25],[26],[27] Sieczka et al.[28] studied on buccal mucosa alone which showed the highest recurrence rates for both involved and clear margins. All the subsites behave differently than each other due to the tumor biology and are not very understood; however, a 5-mm cutoff is required in all subsites for good prognosis along with no neck nodes.[29],[30] This meta-analysis shows the other histopathological parameters such as depth, differentiation, perineural, and lymphovascular invasion, and pattern of invasion also affects the prognosis of the patient which is in accordance with other pathological studies of the literature.[31],[32] There are few articles considering all parameters in terms for adjuvant therapy although they are not proven statistically significant.[33],[34],[35] In spite of these studies, it is still a question that surgical margins and nodal metastasis in isolation can affect the prognosis of the patients of OSCC. This meta-analysis of 1333 patients was unable to prove statistically significance; however, there is a slight risk of increased recurrence in close margins with a decrease in survival rate with neck node metastasis. There has to be multicentric study and comparison for two groups: clear margins and close margins to find the prognosis of the patients.


The study shows that surgical margins <5 mm with nodal metastasis have poor prognosis in OSCC; however, no statistical significance was seen in this meta-analysis when compared to clear margins. Further research is needed in a large scale to understand the relationship between isolated surgical margins with prognosis and isolated neck nodal metastasis with local recurrence to increase the effectiveness of the surgery as a primary treatment and need for adjuvant therapy.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359-86.

Mourad M, Jetmore T, Jategaonkar AA, Moubayed S, Moshier E, Urken ML. Epidemiological trends of head and neck cancer in the United States: A SEER population study. J Oral Maxillofac Surg 2017;75:2562-72.

Mifsud M, Eskander A, Irish J, Gullane P, Gilbert R, Brown D, et al. Evolving trends in head and neck cancer epidemiology: Ontario, Canada 1993-2010. Head Neck 2017;39:1770-8.

Marur S, Forastiere AA. Update on role of chemotherapy in head and neck squamous cell cancer. Indian J Surg Oncol 2010;1:85-95.

Baddour HM Jr., Magliocca KR, Chen AY. The importance of margins in head and neck cancer. J Surg Oncol 2016;113:248-55.

Haque R, Contreras R, McNicoll MP, Eckberg EC, Petitti DB. Surgical margins and survival after head and neck cancer surgery. BMC Ear Nose Throat Disord 2006;6:2.

Ribeiro KC, Kowalski LP, Latorre MR. Impact of comorbidity, symptoms, and patients' characteristics on the prognosis of oral carcinomas. Arch Otolaryngol Head Neck Surg 2000;126:1079-85.

Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol 2009;45:309-16.

Sessions DG, Spector GJ, Lenox J, Haughey B, Chao C, Marks J. Analysis of treatment results for oral tongue cancer. Laryngoscope 2002;112:616-25.

Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64:9-29.

Mistry M, Parkin DM, Ahmad AS, Sasieni P. Cancer incidence in the United Kingdom: Projections to the year 2030. Br J Cancer 2011;105:1795-803.

Ward EC, Van As-Brooks CJ. Head and neck cancer: Treatment, rehabilitation, and outcomes. Plural Publishing; 2014.

Brown JS, Shaw RJ, Bekiroglu F, Rogers SN. Systematic review of the current evidence in the use of postoperative radiotherapy for oral squamous cell carcinoma. Br J Oral Maxillofac Surg 2012;50:481-9.

Furness S, Glenny AM, Worthington HV, Pavitt S, Oliver R, Clarkson JE, et al. Interventions for the treatment of oral cavity and oropharyngeal cancer: chemotherapy. Cochrane Database of Systematic Reviews 2011;(4):CD006386.

Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350:1937-44.

Glenny AM, Furness S, Worthington HV, Conway DI, Oliver R, Clarkson JE, et al. Interventions for the treatment of oral cavity and oropharyngeal cancer: radiotherapy. Cochrane Database of Systematic Reviews 2010;(12):CD006387.

Wong LS, McMahon J, Devine J, McLellan D, Thompson E, Farrow A, et al. Influence of close resection margins on local recurrence and disease-specific survival in oral and oropharyngeal carcinoma. Br J Oral Maxillofac Surg 2012;50:102-8.

Kurita H, Nakanishi Y, Nishizawa R, Xiao T, Kamata T, Koike T, et al. Impact of different surgical margin conditions on local recurrence of oral squamous cell carcinoma. Oral Oncol 2010;46:814-7.

Brodland DG, Zitelli JA. Surgical margins for excision of primary cutaneous squamous cell carcinoma. J Am Acad Dermatol 1992;27:241-8.

Hicks WL Jr., North JH Jr., Loree TR, Maamoun S, Mullins A, Orner JB, et al. Surgery as a single modality therapy for squamous cell carcinoma of the oral tongue. Am J Otolaryngol 1998;19:24-8.

Motley R, Kersey P, Lawrence C; British Association of Dermatologists, British Association of Plastic Surgeons, Royal College of Radiologists, Faculty of Clinical Oncology. Multiprofessional guidelines for the management of the patient with primary cutaneous squamous cell carcinoma. Br J Dermatol 2002;146:18-25.

Brandwein-Gensler M, Teixeira MS, Lewis CM, Lee B, Rolnitzky L, Hille JJ, et al. 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;29:167-78.

Sadeghi A, McLaren J, Grist WL, Tran L, Kuisk H. Value of radiation therapy in addition to surgery for cancer of the head and neck. Otolaryngol Head Neck Surg 1986;94:601-4.

Loree TR, Strong EW. Significance of positive margins in oral cavity squamous carcinoma. Am J Surg 1990;160:410-4.

Mistry RC, Qureshi SS, Kumaran C. Post-resection mucosal margin shrinkage in oral cancer: Quantification and significance. J Surg Oncol 2005;91:131-3.

Cheng A, Cox D, Schmidt BL. Oral squamous cell carcinoma margin discrepancy after resection and pathologic processing. J Oral Maxillofac Surg 2008;66:523-9.

Helliwell T, Woolgar J. Dataset for Histopathology Reporting of Mucosal Malignancies of the Oral Cavity. London: Royal College of Pathologists; 2011.

Sieczka E, Datta R, Singh A, Loree T, Rigual N, Orner J, et al. Cancer of the buccal mucosa: Are margins and T-stage accurate predictors of local control? Am J Otolaryngol 2001;22:395-9.

Sutton DN, Brown JS, Rogers SN, Vaughan ED, Woolgar JA. The prognostic implications of the surgical margin in oral squamous cell carcinoma. Int J Oral Maxillofac Surg 2003;32:30-4.

Oliver R, Clarkson JE, Conway D, Glenny AM, Macluskey M, Pavitt S, et al. Interventions for the treatment of oral and oropharyngeal cancers: surgical treatment. Cochrane Database of Systematic Reviews 2007;(4):CD006205.

Dixit S, Vyas RK, Toparani RB, Baboo HA, Patel DD. Surgery versus surgery and postoperative radiotherapy in squamous cell carcinoma of the buccal mucosa: A comparative study. Ann Surg Oncol 1998;5:502-10.

Hinni ML, Ferlito A, Brandwein-Gensler MS, Takes RP, Silver CE, Westra WH, et al. Surgical margins in head and neck cancer: A contemporary review. Head Neck 2013;35:1362-70.

Alicandri-Ciufelli M, Bonali M, Piccinini A, Marra L, Ghidini A, Cunsolo EM, et al. Surgical margins in head and neck squamous cell carcinoma: What is 'close'? Eur Arch Otorhinolaryngol 2013;270:2603-9.

Liao CT, Chang JT, Wang HM, Ng SH, Hsueh C, Lee LY, et al. Analysis of risk factors of predictive local tumor control in oral cavity cancer. Ann Surg Oncol 2008;15:915-22.

Weijers M, Snow GB, Bezemer PD, van der Wal JE, van der Waal I. The clinical relevance of epithelial dysplasia in the surgical margins of tongue and floor of mouth squamous cell carcinoma: An analysis of 37 patients. J Oral Pathol Med 2002;31:11-5.

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ISSN Print: 2278-1668, Online: 2278-0513