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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 6  |  Issue : 2  |  Page : 86-92

Oral cancer in the young with no tobacco exposure: A distinct epidemiological subset?


1 Department of Head and Neck Oncology, Mazumdar Shaw Medical Centre, Narayana Health, Bengaluru, Karnataka, India
2 Department of Head and Neck Oncology, Amrita Institute of Medical Sciences, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
3 Department of Head and Neck Oncology, Global Gleneagles Hospital, Bengaluru, Karnataka, India

Date of Web Publication14-Jan-2019

Correspondence Address:
Deepak Balasubramanian
Department of Head and Neck Oncology, Amrita Institute of Medical Sciences, Amrita Vishwa Vidyapeetham, Kochi, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2347-8128.208524

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  Abstract 


Objectives: To describe oral squamous cell carcinoma (OSCC) in the young (<45 years) with no tobacco exposure and identify the determinants of locoregional control and survival. Materials and Methods: This is a retrospective analysis of 82 young patients of OSCC with no tobacco exposure treated with surgery and adjuvant therapy. Survival analysis was performed, and determinants of control and survival were identified by Cox proportional hazards regression model. Results: Overall 67% were male, and the median age was 40 years. Survival was excellent: for Stages I, II, III, and IV, 5-year overall survival was 97%, 95%, 75%, and 64% and disease-free survival (DFS) was 84%, 79%, 57%, and 59%, respectively. On multivariable analysis, perineural invasion (PNI) predicted DFS and local and distant control. Conclusion: This cohort had excellent survival when treated appropriately with adjuvant therapy. PNI may represent the need for treatment escalation. Further study is required to identify if this is a biologically distinct cohort.


How to cite this article:
Subramaniam N, Balasubramanian D, Murthy S, Vidhyadharan S, Thankappan K, Iyer S. Oral cancer in the young with no tobacco exposure: A distinct epidemiological subset?. J Head Neck Physicians Surg 2018;6:86-92

How to cite this URL:
Subramaniam N, Balasubramanian D, Murthy S, Vidhyadharan S, Thankappan K, Iyer S. Oral cancer in the young with no tobacco exposure: A distinct epidemiological subset?. J Head Neck Physicians Surg [serial online] 2018 [cited 2019 Jun 18];6:86-92. Available from: http://www.jhnps.org/text.asp?2018/6/2/86/208524




  Introduction Top


Oral squamous cell carcinoma (OSCC) contributes significantly to the global cancer burden, with an estimated annual incidence of 300,000 cases.[1] The predominant causative factor associated with these cancers has been the use of tobacco; it has been estimated that tobacco use in conjunction with alcohol abuse and poor diet is responsible for over 90% of all cases.[2] The incidence of OSCC occurring in patients with no history of tobacco exposure has been low; literature reports it anywhere between 5%[3] and 13%,[4] with a majority of these patients having no demonstrable risk factor for carcinogenesis.

OSCC has been typically described as a disease afflicting those between the fifth and eighth decades of life.[5] With no standardized definition for “young,” various arbitrary cutoffs have been used, such as 30 years, 40 years, and 45 years.[6] The incidence of OSCC in the young has been quoted as 1%–8%,[7] but recent studies have shown an increase in incidence by up to 60%.[8] This has been attributed to genetic alterations and the incidence of human papillomavirus infections; however, no conclusive evidence exists to support these claims.

OSCC in the young with no history of tobacco use is a rare occurrence in literature. Assumed to have an underlying genetic component, very little is known on outcomes and prognostic determinants in this cohort of patients. To describe this cohort, we studied the characteristics of all patients below 45 years with no history of tobacco use treated at our institution during a 10-year period to ascertain oncological outcomes and their determinants.


  Materials and Methods Top


From a prospectively maintained database of nearly 700 patients treated at our institution, we identified 82 patients of OSCC (tongue and buccal mucosa) below 45 years of age with no history of previous or current tobacco exposure (smoking, chewing tobacco, snuff, or other forms) treated between 2004 and 2014. Patients with any previous history of tobacco use, irrespective of quantity, were excluded from the study. No other known predisposing factors for malignancy were noted (chronic dental trauma, immunosuppressive medications, alcohol abuse, etc.). All staging were as per the American Joint Committee on Cancer (AJCC) 8th edition.[9] Only patients who underwent surgical resection with curative intent in our institution were included in our analysis. All patients were treated with a wide excision of the tongue lesion (a gross margin of 1–1.5 cm aiming for a minimum microscopic margin of 5 mm) and ipsilateral selective neck dissection, with appropriate reconstruction. Contralateral neck dissection was performed for clinically or radiologically positive nodes, lesions crossing the midline, or lesions with extensive floor of mouth involvement. Adjuvant radiotherapy was administered for advanced stage (III/IV), any nodal disease, or more than one adverse pathological feature (perineural invasion [PNI], lymphovascular invasion [LVI], or poor differentiation). Adjuvant chemoradiotherapy was administered for positive/close margins or extranodal extension (ENE). Clinical and pathological information for these patients was extracted.

Recurrent disease was defined as any proven local, regional, or distant disease occurring at least 3 months after the completion of treatment. Overall survival (OS) was defined as time from initial surgery to date of death or last follow-up evaluation.

Statistical analysis

Statistical analysis was performed using SPSS version 20 (IBM, New York, USA) and Microsoft Excel version 2010 (Microsoft, Redmond, WA, USA). The endpoints for analysis were OS, disease-free survival (DFS), local recurrence-free survival (LRFS), nodal RFS (NRFS), and distant RFS (DRFS). Survival curves were generated using the Kaplan–Meier method and log rank test. Multivariable analysis was performed using the Cox proportional hazards model. All statistics were two sided, and P < 0.05 was considered statistically significant.


  Results Top


Patient and disease characteristics

A total of 82 patients were included in our analysis, with a median follow-up of 31 months (range: 6–108 months). The median age was 40 years (range: 17–44 years). A majority of the patients (67%) were males [Table 1]. The subsite was predominantly oral tongue (80%), with the remainder being buccal mucosa. pT3 was the most common T-stage (39%), followed by pT2 (30%). pT4a was rare (10%), and all of these were buccal cancers with cortical invasion of the lower alveolus. Majority of the patients were pN0 (57%), followed by pN2a (29%). Of the 35 node-positive patients, 24 (69%) had ENE. LVI was noted in 27 (33%) and PNI was noted in 33 (40%) patients. Moderate or poor differentiation was noted in 42 (51%) patients. Majority received surgery alone (59%), followed by surgery with adjuvant chemoradiotherapy (29%) and surgery with adjuvant radiotherapy (12%). The most common TNM stage was III (38%), followed by II (24%).
Table 1: Patient and tumor characteristics and impact on overall survival and disease-free survival

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Survival outcomes

Five-year OS based on stage was 97% for Stage I, 95% for Stage II, 75% for Stage III, and 64% for Stage IV [Figure 1]. On univariate analysis, the factors found to impact OS were nodal status (P = 0.02), ENE (P = 0.003), and PNI (P = 0.003). Method of treatment was also observed to correlate with survival, reflecting the adverse features associated with adjuvant therapy administration (P = 1.007).
Figure 1: Overall survival in years by American Joint Committee on Cancer 8th edition tumor node metastasis staging

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Five-year DFS based on stage was 84% for Stage I, 79% for Stage II, 57% for Stage III, and 59% for Stage IV. On univariate analysis, only PNI was found to strongly impact DFS (P < 0.001). To identify the patterns of failure in this cohort and their clinical course, we considered the determinants of LRFS, NRFS, and DRFS [Table 2]. On univariate analysis, PNI was a predictor of LRFS (P = 0.008) and DRFS (P = 0.010), and ENE was a predictor of NRFS (P = 0.009) and DRFS (P = 0.048).
Table 2: Factors predicting local recurrence-free survival, nodal recurrence-free survival, and distant recurrence-free survival

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On multivariate analysis, no factors were found to be significant for OS, whereas for DFS, PNI was found to be statistically significant (P = 0.002, hazard ratio [HR]: 2.4, 95% confidence interval [CI]: 0.08–0.566) [Table 3] and [Figure 2]. For LRFS, PNI was statistically significant (P = 0.006, HR: 1.3, 95% CI: 0.57–1.23); for NRFS, ENE was statistically significant (P = 0.045, HR: 1.85, 95% CI: 0.775–1.175); and for DRFS, PNI was statistically significant (P = 0.048, HR: 1.8, 95% CI: 0.39–1.83) [Table 4].
Table 3: Multivariable analysis for overall survival and disease-free survival

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Figure 2: Disease-free survival in years based on the presence of perineural invasion: Those with perineural invasion (1) and those without (0)

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Table 4: Multivariable analysis for local recurrence-free survival, nodal recurrence-free survival, and distant recurrence-free survival

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  Discussion Top


OSCC in the young with no history of tobacco use is a rare entity;[8],[12] it is estimated that over 90% of OSCC is associated with self-reported tobacco use.[13],[14] The role of tobacco exposure in OSCC in the young is controversial; some hypothesize that the exposure to carcinogens is of insufficient duration to warrant malignant transformation, suggesting that young users of tobacco with OSCC have a genetic predisposition or that carcinogen exposure at a younger age has a more profound impact on malignant transformation.[15],[16] It has also been shown that younger patients have an altered metabolism of carcinogens and pro-carcinogens,[17] supporting the theory that OSCC in the young may be biologically distinct from that in the elderly. However, literature still remains divided, with some authors suggesting that OSCC in the young represents more biologically aggressive disease,[18],[19],[20] with the majority of authors having concluded that younger patients have similar or improved outcomes when compared to their older counterparts.[10],[12],[20],[21],[22] Given that tobacco exposure may have an altered effect on younger patients, it was our intention in this study to evaluate if younger patients of OSCC with no tobacco exposure had favorable outcomes.

The stage at presentation was balanced, with roughly half of the patients presenting with early-stage disease (I/II) and the remaining half presenting with advanced-stage disease (III/IV). Roughly a third of the patients were female. Western studies have usually shown that female patients account for a smaller proportion of OSCC and are less likely to be associated with tobacco use;[11],[23],[24],[25] however, our data are consistent with other data from the subcontinent, showing that female patients account for approximately a third of OSCC and are just as likely as male patients to have tobacco exposure.[26],[27],[28] Recent data from the subcontinent have also shown a larger proportion of OSCC not being attributed to tobacco exposure.[29],[30],[31]

The survival outcomes in this cohort were excellent: for TNM Stages I, II, III, and IV, the 5-year OS was 97%, 95%, 75%, and 64% and the 5-year DFS was 84%, 79%, 57%, and 59%, respectively. On comparison, the OS in OSCC for Stages I–IV in a large series had been reported to be in the range of 85%, 75%, 60%, and 50%, respectively.[32],[33],[34] Pathological T-stage was not found to be a predictor of OS or DFS. This may be because our patients of pT4a had uncharacteristically good outcomes, with an OS of 82% and a DFS of 50%. This most likely reflects a previously described anomaly in the AJCC staging, where tumors with bone invasion (pT4a) having a diameter of 4 cm or less have outcomes similar to pT2 tumors;[35] all the eight pT4a patients in our cohort had buccal cancers with a diameter of 4 cm or less, having cortical mandible invasion.

The subsite of OSCC involved was predominantly oral tongue (81%), with buccal cancers forming the remainder. We had no young patients without tobacco exposure having alveolus or floor of mouth as the involved subsite in our database of nearly 700 patients. Interestingly, these subsites were involved only in elderly patients with or without tobacco exposure. This concurs with other literatures which show the oral tongue as the most commonly involved subsite in patients of OSCC having no tobacco exposure, followed by buccal cancers.[4] This is potentially relevant as some of the potential causative factors associated with OSCC in the absence of tobacco include poor dental hygiene,[13] chronic trauma from sharp teeth or ill-fitting dentures,[36] human papillomavirus,[37],[38] and chemical exposure,[39],[40] which may impact OSCC subsites differently.

The role of PNI on locoregional control and survival was profound. PNI was found to impact DFS and local and distant recurrences on multivariate analysis. The 5-year DFS in patients without PNI was 77% compared to 42% in those with PNI, suggesting that these patients require treatment escalation when possible and that PNI may help better prognosticate patients in this cohort. Whether PNI is a marker of biological disease aggression in these patients is a potential area of future study.

ENE was common in this cohort, with 68% of patients with nodal disease having ENE. All patients with ENE in our cohort received adjuvant chemoradiotherapy. Surprisingly, the patients with ENE in our cohort had good survival outcomes (5-year OS and DFS of 60% and 56%, respectively) when compared with contemporary literature, showing an OS of 45% or less.[41],[42],[43] ENE was a significant predictor of OS, NRFS, and DRFS on univariate analysis and of NRFS on multivariate analysis in our cohort; however, when treated with appropriate adjuvant therapy, still had acceptable survival outcomes and locoregional control rates.


  Conclusion Top


Literature would suggest that OSCC in the young with no history of tobacco exposure is an increasingly common trend in the Indian subcontinent. When appropriately treated with adjuvant, this cohort has excellent survival. PNI is an important prognostic determinant in this cohort and may require treatment escalation. Further study is required to identify potential etiological agents, biological basis, and markers of aggression in this potentially distinct subset of patients.


  Summary Top


  • OSCC in patients <45 years is a relatively rare occurrence in literature; however, recent studies show an increasing trend
  • Survival in this cohort has been similar to older patients in literature; however, majority of these tumors are associated with tobacco use; very limited data exist on OSCC in young patients without tobacco exposure
  • Our study showed excellent survival in patients <45 years with no tobacco exposure with OSCC, even in the presence of high-risk features such as ENE
  • PNI was an independent predictor of overall survival in this cohort and may indicate biological aggression.


Acknowledgments

No further acknowledgments beyond those credited with authorship.

Financial support and sponsorship

This study has not been funded by any funding agency or sponsor. It was conducted without any financial interest.

Conflict of interest

All authors declare that they have no conflict of interest.

Disclosure

This material has never been published and is not currently under evaluation in any other peer reviewed publication.

Ethical approval

The permission was taken from Institutional Ethics Committee prior to starting the project. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.



 
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