1. Margin Status in Oral Cancer: Requirement for Reassessment
Sandhya Gokavarapu. MDS.
Registrar
Basavatarakam Indo American Cancer Hospital and Research Centre
Hyderabad, Andhra Pradesh , pin – India

2. Introduction
Surgery is treatment of choice in oral cancer considering better treatment outcomes with surgery and morbidity associated with primary radiotherapy.
Among all prognostic factors, margin status is the only factor under the clinician’s control. Other risk factors include tumor staging and grading, lymph vascular spread, perineural spread and perinodal spread of regional disease.

3. Introduction
Current consensus for margin status describes cut margin greater than 5mm on histology as clear, 1-5mm as close and less than 1 mm as involved1.
Margin status less than 1mm from tumor is considered as positive margin1.

4. Pitfalls of current consensus
Wide distance of 1-5mm is considered as close margin- considering a 10mm clinical margin has a maximum of 50% shrinkage,2 would result in 5mm histological margin which is a close margin despite adequate initial resection.
Implication of premalignant change in the margin such as dysplasia is not clear.
There is no apparent difference in the outlook of margins three dimensionally- deep margin vs mucosal margin in tongue cancer.
What happens to the margin when revised? Is it considered as close? Clear or positive?

5. A retrospective data of a large volume tertiary cancer institute is analyzed
Historical cohorts of patients treated between Jan 2010 to Dec 2011 at tertiary cancer hospital were investigated, patients with primary squamous cell carcinomas of oral cavity were only analyzed.
The prognostic factors that were analyzed are age, gender, tumor stage and grade, perineural spread, lymphovascular invasion, depth of tumor, margin status.
The variables that yielded p value of less than 0.1 in univariate log rank test were tested in multivariate cox regression model.

6. Problem no 1
What does close margins signify on recurrence or survival compared to clear margins.
Stage I and Stage II primary squamous cell carcinoma of oral cavity with margin status of close and clear margins were analyzed in multivariate logistic regression model for locoregional recurrences and cox regression for overall survival.

7. results
A total of 104 patients fulfilled the above mentioned criteria, of whom 36 were “clear margin” and 68 were “close margin”. the median period of follow up was 39 months.
There was no significant difference in Locoregional recurrence (p value: ) and survival (p value: ) among ‘close margin’ and ‘clear margin’ patients.
published in IJSO
Gokavarapu, Sandhya, et al. “Close margins in oral cancers: Implication of close margin status in recurrence and survival of PT1N0 and pT2N0 oral cancers.“ International Journal of surgical oncology; November 2014.

8. Problem no 2 What distance is adequate for oral cancer resection?
Methodology: Stage I and Stage II primary oral cancer were analyzed with current protocol, patients with margin dysplasia were excluded, further patients belonging to “close margin” group were split depending on the distance from tumor to cut margin at which prognosis varied considerably. Patients were grouped into Group A : margin less than 1mm, Group B: 1mm to 3mm , Group C: >3mm up to 5mm, Group D: >5mm.

9. results
In the univariate log-rank test, the factors responsible for mortality were margin status (p = 0.004), perineural invasion (p = 0.005) and locoregional recurrence (p < ).
The risk of death remain almost same in patients whose margin status fell in Group C with that of Group D, though patients in Group A significantly experienced more risk of death (p = 0.004)
Published in Oral Oncology
Gokavarapu, Sandhya, et al. "Margin status in oral cancer: Requirement for Reassessment." Oral oncology (2014).

10. Problem no 3 What is the significance of dysplasia at the margin?
Methodology
Authors investigated DFS in primary oral cancer patients with margin dysplasia as an independent variable in a multivariate cox regression model.(n=240) median follow up period: 37 months.
Patients with severe dysplasia at margin and positive margins were not included since they often undergo adjuvant therapy.

11. results
There was no significant difference in DFS among the patients with mild and moderate dysplasia to patients without dysplasia in univariate analysis (p value=0.949). In the multivariable Cox- regression model,
increased dysplasia from mild to moderate had an insignificant effect on DFS; HR: 1.47 (95% CI: 0.72, 3.01), (p = 0.293).
Under review

12. Problem no 4
How effective is the revision and what should be a revised margin considered: clear; close or positive?
Methodology
Patients with consecutive primary pT1, pT2 oral squamous cell carcinoma, in whom initial resection resulted in involved margin were included in the study.
outcome of patients with successful revision under frozen section control were compared to patients who had false negative result on frozen section.

13. results
There were 68 patients reported with involved margin on initial resection; of whom 42(68%) were successfully revised under frozen control (Group 1) and 26(38.2%) patients had false negative result on frozen section, these patients were not further revised (Group 2). Median period of follow up was 24 months.
Statistical analysis revealed that the local recurrences were more frequent in Group 2 although not statistically significant (p value-0.076). The risk of death was greater in patients with local recurrence, HR: 4.74 (95% CI: 1.79, ) (p = 0.002). However; the overall survival (p value-0.730), loco regional recurrences (p value-0.59) or neck recurrence (p value-1.000) were not significantly different among the groups.
Under review

14. Discussion
There was no significant difference in the outcome of patients with close margin to clear margin. 3mm appears to be the cut off point for close margin.
Patients with 4mm and 5mm margin showed parallel outcome to the patients with >5mm. The studies by Barrya et al4. and Nason et al.5 parallel our findings.
Dysplasia in the margin specially mild and moderate dysplasia did not show significant difference in the DFS to patients without margin dysplasia. Discontinuance of tobacco use post surgery might have some significance in this regard. , Larsson, Åke et al6 had reported reversal of dysplasia in such instances; however; our findings do not parallel the studies by Sopka et al7; we observe difference in demographics and difference in type of tobacco use in our population to other studies.
There was a borderline significance for local recurrence when involved margins were revised under frozen control, however; overall survival did not change significantly. Infiltrating growth pattern of some tumors and difficulty of relocation of the tumor for re-excision might be the major determinant.
Kerawala and Ong 8 showed that an error of a centimeter was present in 32% of cases on revisiting the tumor site. Lee et al9. recommended re excision, however; authors observed that only 50% of re excised specimen contained tumor.

15. conclusion
Definition of margin status in oral cancer needs reassessment.
It is advisable to consider margin status on initial resection as the final margin irrespective of revision when further therapy is planned.
Presence of dysplastic margin may not signify inadequate resection; rather it might be the presentation of preconditioned epithelium to carcinogens based on the concept of field cancerization by slaughter et al.

16. References
Helliwell T, Woolgar JA. Standards and minimum datasets for reporting cancers. Dataset for histopathologic reports on head and neck carcinomas and salivary neoplasms. 2nd ed. London: Royal College of Pathologists; 2005.
Batsakis, John G. "Surgical excision margins: a pathologist's perspective."Advances in anatomic pathology 6.3 (1999):
Johnson, Robert E., et al. "Quantification of surgical margin shrinkage in the oral cavity." Head & neck 19.4 (1997):
Barry, Conor, et al. "OP081: Evidence to support: A 3mm margin as oncologically safe in early oral SCC." Oral Oncology 49 (2013): S37.
Nason, Richard W., et al. "What is the adequate margin of surgical resection in oral cancer?." Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology 107.5 (2009):
Larsson, Åke, Tony Axéll, and Gunilla Andersson. Reversibility of snuff dippers' lesion in Swedish moist snuff users: a clinical and histologic follow‐up study. J Oral Path Med ; 20.6:
Sopka, Dennis M., et al. Dysplasia at the margin? Investigating the case for subsequent therapy in ‘Low-Risk’squamous cell carcinoma of the oral tongue.Oral Oncol. 2013; 49.11:
Kerawala C J, & Ong T K. Relocating the site of frozen sections—Is there room for improvement?.  Head Neck 2001; 23.3:
Lee J G. Detection of residual carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx: a study of surgical margins. Trans Am Acad Ophthalmol Oto laryngol 1974; 78.1: 49.

17. Thank you
Any questions?