Predictors of recurrence in oral cavity cancer with clear surgical margins

Mansi Agrawal; Vidya Konduru; Amit Jiwan Tirkey; Riju Jeyashant; Philip George; Dona Maria Philip; Chandramohan Setty; Kiran Kumar Devarkonda

doi:10.4103/cmi.cmi_70_22

ORIGINAL ARTICLE

Year : 2023 | Volume : 21 | Issue : 2 | Page : 98-103

Predictors of recurrence in oral cavity cancer with clear surgical margins

Mansi Agrawal¹, Vidya Konduru¹, Amit Jiwan Tirkey¹, Riju Jeyashant², Philip George³, Dona Maria Philip⁴, Chandramohan Setty⁵, Kiran Kumar Devarkonda⁶
¹ Department of Head and Neck Surgery, Unit-2, Christian Medical College, Vellore, Tamil Nadu, India
² Department of Head and Neck Surgery, Unit-1, Christian Medical College, Vellore, Tamil Nadu, India
³ Department of ENT and Head and Neck Surgery, Mar Sleeva Medicity Palai, Puliyannoor, Kerala, India
⁴ Department of Biostatistics, Christian Medical College, Vellore, Tamil Nadu, India
⁵ Department of Head and Neck Surgery, Kidwai Hospital, Bengaluru, Karnataka, India
⁶ Department of Surgical Oncology, KIMS Hospital, Hyderabad, Telangana, India

Date of Submission	23-Jun-2022
Date of Decision	11-Nov-2022
Date of Acceptance	23-Nov-2022
Date of Web Publication	07-Apr-2023

Correspondence Address:
Dr. Vidya Konduru
Department of Head and Neck Surgery, Unit-2, 2^nd Floor, Paul Brand Building, Christian Medical College Hospital Campus, Vellore - 632 004, Tamil Nadu
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/cmi.cmi_70_22

Abstract

Introduction: Oral cancers recur in a significant proportion of patients, in spite of aggressive treatment strategies. The presence of a clear surgical margin is an important predictor of recurrent disease, among others. Since oral cancers often recur in the absence of compromised margins, there is a need to study the factors affecting recurrence and overall survival outcomes where clear surgical margins have been achieved during upfront surgery. This study attempts to identify the significant predictors of locoregional recurrence in oral squamous cell carcinoma (OSCC) with pathologically clear surgical margins. Methodology: This retrospective study was done to study the clinicopathological parameters associated with recurrence of oral cavity squamous cell carcinoma (SCC) in patients with clear surgical margins operated in our unit between January 2010 and December 2015. A total of 526 cases of oral cavity SCC were analyzed and records of 160 cases with clear surgical margins were reviewed for clinical details, histopathological data, and follow-up status. Age, gender, subsite, T–N clinical and pathological staging, tumor depth of invasion, grade of differentiation, lymphovascular invasion, perineural spread, adjuvant therapy, and recurrence details were analyzed. Results: Lymphovascular Invasion was found to be a significant predictor for local recurrence in OSCC in both univariate and multivariate analysis. Median recurrence-free survival was 53.6 months. Conclusion: Despite the best efforts of the surgeon in obtaining adequate tumor-free margins and the most comprehensive adjuvant treatment, recurrence patterns in oral cancers continue to defy accurate prediction. Lymphovascular invasion could be an important predictor of recurrence for oral cavity cancers in patients with clear surgical margins that require aggressive management.

Keywords: Clear margins, head-and-neck squamous cell carcinoma, oral squamous cell carcinoma, recurrence, surgical margins

How to cite this article:
Agrawal M, Konduru V, Tirkey AJ, Jeyashant R, George P, Philip DM, Setty C, Devarkonda KK. Predictors of recurrence in oral cavity cancer with clear surgical margins. Curr Med Issues 2023;21:98-103

How to cite this URL:
Agrawal M, Konduru V, Tirkey AJ, Jeyashant R, George P, Philip DM, Setty C, Devarkonda KK. Predictors of recurrence in oral cavity cancer with clear surgical margins. Curr Med Issues [serial online] 2023 [cited 2023 May 29];21:98-103. Available from: https://www.cmijournal.org/text.asp?2023/21/2/98/373758

Introduction

Oral cavity squamous cell carcinoma (SCC) is the sixth most common cancer in the world, highly prevalent in Southeast Asia and some European countries. Oral cancer is more common in males, who are usually present in the sixth and seventh decade, although there is an increasing trend in young males.^[1] The two main etiological factors resulting in oral cancers are the use of tobacco and alcohol. Around 50% of oral cancers develop recurrence, most commonly at the primary site. Various well-defined clinical, pathological, and patient factors alter the risk of recurrence and the overall prognosis of these patients. The surgical margin is the only prognostic factor under the surgeon's control. Pathological tumor-free margin of 5 mm is considered to be adequate. Approximately 35% of cancers, despite a negative surgical margin (R0 resection), develop disease recurrence. Recurrence often correlates strongly with poor prognosis and incurability. The presence of other adverse factors such as lymph node metastasis, extranodal extension (ENE), lymphovascular invasion (LVI), perineural invasion (PNI), and depth of invasion (DOI) affect the rate of recurrence, even when the surgical margins are adequate. The aim of this study was to analyze the influence of established adverse factors on recurrence rates in the presence of clear surgical margins among patients with previously untreated oral cavity SSC.

Methodology

Study site

This study was conducted in the Department of Head and Neck Surgery, Christian Medical College, Vellore.

Study population

The study population included all patients who were newly diagnosed and were previously untreated with oral SCC (OSCC) and underwent surgery in the Department of Head and Neck Surgery Unit-2 and obtained clear surgical margins in their histopathological reports.

Study design

This is a retrospective analysis of data collected from the records of the above-mentioned patients.

Time frame for the study

The data were collected for patients who underwent surgery for OSCC between January 2010 and December 2015.

Inclusion criteria

Newly diagnosed and previously untreated cases of OSCC who underwent treatment in our Department of Head and Neck Surgery Unit 2
All patients who had surgically clear margins in the histopathology.

Exclusion criteria

All patients who were previously treated outside for Oral squamous cell carcinoma and then presented to the outpatient department
Patients with close or positive margins in the histopathology
Patients who underwent treatment in other surgical departments of the institute.

All patients were staged according to the American joint committee on cancer (AJCC) Cancer Staging Manual, 7^th Edition as per the guidelines. They were operated and received adjuvant therapy according to the best possible evidence of the time, as decided by the multidisciplinary tumor board. The patients were followed up by tracking patient records and through telephonic interviews. In patients with clear surgical margins (defined as pathological tumor-free margin of 5 mm or more), clinical and pathological data pertaining to established prognostic factors, and the occurrence of recurrent, second primary, and metastatic disease was noted. Data of a total of 526 patients were collected, of which 160 had clear surgical margins in all dimensions, 30 of whom were lost to follow-up. Out of the remaining 130 patients, 45 had recurrent disease and their data were analyzed in further detail.

Ethical considerations

The study was approved by the Institutional Review Board and Ethics Committee, approval reference no.IRB Min.No. 12844 (Retro) IRB Min. No. 12844 [Retro] dated: 01.05.2020. All patients signed the consent form before surgery which stated that their data will be used for research purposes, maintaining their confidentiality.

Statistical analysis

Categorical variables were summarized using numbers and percentages. Continuous variables were reported using the mean and standard deviation or median and interquartile range. To check an association between two categorical variables, the Chi-square test or Fisher's exact test was reported. P ≤ 0.05 was considered statistically significant. All analyses were done using SPSS 21.0: IBM Corp. Released 2012. IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp.

Recurrence in OSCC was considered the outcome of interest. The overall probability of the event occurrence at different periods was estimated using the probabilities estimated from each interval. Survival probabilities, standard error, and mean and median survival time have been calculated.

Results

A total of 526 patients who underwent surgical treatment for OSCC were included in the study. Clear surgical margins were achieved in 160, of which 30 were lost to follow-up. Data of the 130 remaining patients were collected and analyzed. The median duration of follow-up was 30 months (range 12–86). This group was male predominant (n = 89, 68.4%) and the mean age at the time of diagnosis was 53.5 years. Sixty-seven patients had tongue primary (51.5%), 36 patients had buccal mucosa cancer as their primary subsite (27.7%), and the remaining 27 patients had primary in the other subsites of the oral cavity such as floor of the mouth, gingivobuccal sulci, and hard palate [Figure 1]. Among the pathological factors that were studied, a total of 20 patients had LVI and 46 patients had PNI-positive primaries. There were seven patients with only LVI as the risk factor and all of them underwent adjuvant radiation therapy. The majority of the primary cancers were early stage with DOI <5 mm (54.6%). Among early-stage cases, there were 10 patients with both LVI and PNI positivity, seven had only LVI and 27 had PNI-positive primaries. Node positivity upstages the disease to either Stages III or IV, and in our study, a total of 27 patients had pathologically positive nodes. The criteria for adjuvant therapy that are used in our institute are based on the National comprehensive cancer network (NCCN) Clinical Practice Guidelines in oncology for head-and-neck cancers, which include the presence of T3 or T4 disease, positive nodes, presence of LVI and/or PNI, and presence of extracapsular extension in nodes. In our study, there were a total of 70 patients who received adjuvant therapy according to these criteria, and 48 among them were early-stage disease. Recurrent disease was noted in 45 of these patients (34.6%), of which 14 had early-stage cancers. The most common site of recurrence was local (28, 62.2%), followed by regional (9, 20%), distant (6, 13.3%), and locoregional (2, 4%). Of all the oral cavity subsites affected by the index tumor, the oral tongue had the most number of recurrences (n = 17, 43.5%), followed by buccal mucosa (n = 12, 39%). It was also noted that the majority of recurrences with clear surgical margins occurred in the early T stages, clinical T2 (n = 14), and pathological T1 (n = 21). Of the 45 recurrences, 12 patients had LVI, whereas 16 had PNI-positive disease. Fourteen cases among the recurrences had a node-positive disease. Adjuvant therapy was defaulted by 10 patients, although indicated [Table 1]. It was observed that the mean duration of occurrence of recurrence was 53.67 months (95% confidence interval: 41.262, 66.07).

Figure 1: Flowchart of the study protocol.

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Table 1: Univariate analysis of clinical and pathological variables in patients with clear surgical margins (n=130) and their correlation with recurrent oral squamous cell carcinoma

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Univariate and multivariate analysis

Univariate analysis of clinical and pathological factors in the 130 patients with clear surgical margins had shown LVI, lymph node positivity, and requiring adjuvant therapy as significant factors in predicting recurrence at all sites. However, multivariate analysis showed only LVI as a significant variable.

Discussion

There are many well-described adverse prognostic factors which can determine the risk of recurrent disease after appropriate treatment of OSCC. Notable among these are tumor factors such as an advanced T stage, close or positive surgical margins, LVI, PNI, and nodal factors like ENE. The surgical margin on the pathological specimen is a strong independent predictor of both locoregional recurrence (LR) and overall survival (OS).^[2],[3] It is the only adverse factor under the control of the surgeon.

Pathological tumor-free margin of 5 mm or more is considered an adequate or clear margin.

The presence of severe dysplasia at the margin can also have a significant impact on local recurrence. In a study by Kurita et al., the hazard ratio for recurrence was 3 with a close and 7.89 with an involved margin.^[2] Buchakjian et al. studied independent predictors of LR such as nodal involvement, histologic grade, and the permanent margin status on the specimen. The presence of a positive or <1 mm/carcinoma – in situ margin on the main specimen was an independent predictor of LR, whereas intraoperative tumor bed margins were not predictive of LR on multivariate analysis.^[4] Increased survival is predicted with each millimeter of the clear surgical margin. A margin of 5 mm or more has shown higher survival rates compared to the <5 mm group.^[5]

In spite of obtaining clear margins, many cases of OSCC recur locally and regionally. Only few studies have looked at independent predictors of recurrence when all surgical margins are clear. The presence of LVI and non-T4 muscle invasion were found to be independent predictors of recurrence in early-stage OSCC with clear surgical margins in a study by Huang et al.^[6] Another study which retrospectively analyzed 296 patients with pT1-2 N0 OSCC showed PNI and moderate/poor differentiation (MD/PD) as significant predictors in Stage I and DOI and PNI in Stage II. Combined MD/PD and PNI were associated with worse locoregional control (LRC) than either feature individually.^[7]

The presence of LVI was also found to be a significant prognostic factor for oral and oropharyngeal SCC in a study by Carrillo et al., along with surgical margins, perineural and perivascular invasion, lymphocytic infiltration, and infiltrative patterns of tumor invasion. LVI was associated with poor survival at the late stage, especially with subsites tongue and buccal mucosa.^[8] In our study, we included early and advanced-stage OSCC and found that the presence of LVI, node positivity, and adjuvant therapy were found to be significant prognostic factors in univariate analysis. However, multivariate analysis showed LVI as a significant factor, with an odds ratio of 3.96, thereby establishing the presence of LVI as a strong predictor of recurrence in the presence of clear surgical margins.

The degree of differentiation is another important factor which needs to be studied more extensively. Poorly differentiated tumors are known to have poor prognosis. Bo Liu et al. studied the recurrence and survival pattern in 275 cases of OSCC. PN stage, T stage, and degree of differentiation were independent predictors of recurrence (P < 0.001).^{[9],[10],[11]} Our study had more cases with MD/PD in the recurrence group.

Depth of invasion is a widely studied prognostic factor in OSCC, with a significant implication on the prognosis. This has led to the inclusion of DOI in the latest 8^th Edition of AJCC cancer staging manual.^[12],[13] According to the newest staging system, DOI can upstage the T category, even if the tumor is smaller in size. A study by Liao et al. identified a high-risk group in early OSCC with a combination of PD and 4 mm or greater tumor depth. This group had shown poor outcomes in neck control and survival.^[14] Almangush, et al. concluded that poor prognosis was noted in tongue SCC cases with tumor budding (≥5 clusters at the invasive front of the tumor) and DOI (≥4 mm).^[15] In our study, we did not find DOI statistically significant in this patient subgroup with clear surgical margins (P = 0.177).

The presence of PNI has been found to independently predict poor disease-specific survival and higher distant recurrence rates.^{[16],[17],[18]} Jardim, et al. studied the significance of LVI and PNI in advanced stages of oral cancers who underwent radical surgery and adjuvant therapy.^[16] The presence of PNI had a significantly poorer effect on survival. The incidence of cervical nodal metastasis has been found to have been less in cases with intratumoral and peritumoral lymphoplasmacytic infiltration. Nevertheless, aggressive management of the primary and the neck is essential in the presence of PNI, along with a low threshold for adjuvant therapy.^[18]

According to Liao et al.,^[19] there are significant differences in the failure pattern of tongue and buccal carcinomas in terms of regional control and distant metastasis, but in our study, we could not find a significance.

Nodal positivity decreases the OS of patients with OSCC by 50%. There were 13 patients with positive nodes out of the 45 recurrent cases in our study. Regional recurrences were found to be higher in the N0 group compared to the node-positive group. This could be because these patients may not have received adjuvant therapy if there were no other adverse factors present. Default of adjuvant therapy when indicated had also contributed to a proportion of these cases.

Adjuvant therapy is usually reserved for advanced cancers and for early cancers with adverse features in histopathology, which are more predictive of recurrence. The advanced T stage is a consistent predictor of recurrence in most studies. In our study, however, more recurrences were noted in patients with early T stages. Around 20 cases each were recurred in pT1 and pT2 groups [Table 1]. Out of the 28 cases of local recurrences, 13 were in pT2 and 11 in pT1 groups [Table 2] and [Table 3]. A total of 19 patients who developed recurrence with clear margins had received adjuvant therapy. Univariate analysis had shown the need for adjuvant therapy as a significant predictor, but multivariate analysis did not show any significance. This might reflect the importance of reconsidering the selection criteria and implementing a lower threshold for adjuvant therapy, even for early-stage oral cancers.

Table 2: Multivariate analysis of clinical and pathological variables in patients with clear surgical margins (n=130) and their correlation with recurrent oral squamous cell carcinoma

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Table 3: Sites of recurrence on follow-up of 130 patients with clear surgical margins (n=45)

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Although this was a retrospective analysis and all risk factors which are currently followed were not reported, as part of the standard protocol (such as the pattern of invasion and ENE) and hence could not be included in the study, this study showed that there are other adverse factors that have yet to be incorporated into the present tumor, node, and metastasis staging system, including worst pattern of invasion, lymph node density, lymphocytic host response, and a host of molecular factors, that might be contributory to poor LRC and OS. Further studies with a larger sample size done over a larger time frame would be helpful in prognosticating such patients as it is important to individualize treatment for each patient and perhaps amend our present criteria for selecting treatment modalities for patients with OSCC.

Conclusion

Despite the best efforts of the surgeon in obtaining adequate tumor-free margins and the most comprehensive adjuvant treatment, recurrence patterns in oral cancers continue to defy accurate prediction. Lymphovascular invasion could be an important predictor of recurrence for oral cavity cancers in patients with clear surgical margins that require aggressive management.

Research quality and ethics statement

The institutional ethics committee at our institute reviewed this study design, data collection instruments, consent forms, and patient information sheets as part of the required procedure. The research proposal was approved on May 01, 2020, through IRB Min.No. 12844 (Retro) dated: 01.05.2020.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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