|Year : 2012 | Volume
| Issue : 1 | Page : 74-79
Cut margins and disease control in oral cancers
SR Priya, AK D'Cruz, PS Pai
Head and Neck Services, Tata Memorial Hospital, Mumbai, India
|Date of Web Publication||19-Apr-2012|
S R Priya
Head Neck Services, Tata Memorial Hospital, Dr E. Borges Marg, Parel, Mumbai - 400 012
Aim: This retrospective study was done to evaluate the impact of cut margins on disease-free survival in patients with previously untreated oral squamous cell cancers.
Materials and Methods: Records of 306 cases were reviewed for clinical details and status of margins at resection. The independent influence of margins on recurrence was analyzed. The impact of frozen section analysis on achieving free margins was also examined.
Results: 190 (62.1%) patients had negative margins of resection (≥5 mm), 102 (33.3%) patients had close margins (1-5 mm), while 14 (4.6%) patients had positive margins (≤1 mm). The median follow-up for the entire cohort was 26.5 months. There were 79 (25.8%) recurrences, of which, 46 (58.2%) were local, 9 (11.3%) were locoregional, 16 (20.2%) were regional, and 8 (10.1%) were distant metastasis. 42 (22.2%) cases with negative margins developed a recurrence as compared to 31 (30.4%) cases with close margins and 6 (42.8%) cases with positive margins (P value 0.01). Average time to recurrence in case of negative margins was 34.8 months, for close margins was 33.9 months, while in those with positive margins was 10.18 months (P value 0.002). Close and positive margins were found to be significantly associated with increased local recurrence (P values 0.01 and 0.03, respectively) and with overall recurrence (P values 0.003 and 0.003, respectively). Frozen section was seen to influence margins in 20.4% cases.
Conclusion: Margins are an important predictor of disease control. The surgeon must aim for adequate margins at initial resection.
Keywords: Frozen section margins, oral cancer, recurrence, resection margin
|How to cite this article:|
Priya S R, D'Cruz A K, Pai P S. Cut margins and disease control in oral cancers. J Can Res Ther 2012;8:74-9
| > Introduction|| |
The importance of margins of resection in oral cancers is known. A cut margin of 5 mm on the final histopathology has been accepted as adequate.  Besides margins, the T stage, differentiation , tumor thickness, and adjuvant treatment have been seen to influence outcome. We studied the factors affecting cut margins and evaluated the impact of cut margins independent of the rest of tumor and treatment factors on disease-free survival (DFS).
45.4% patients in our study presented at a late stage requiring extensive resection, with technical difficulties in achieving adequate margins. Chemotherapy - neoadjuvant or adjuvant - had not yet been adopted as standard treatment in 2003. Reconstruction with free flaps was also less routinely done at our institute at the time.
| > Materials and Methods|| |
306 patients with previously untreated squamous carcinomas of the oral cavity, including all subsites, who had been managed in our hospital in 2003 were studied.
Files were examined for patient characteristics, treatment details, histopathological data, and follow-up status. Margins were documented in both frozen section (FS) and histopathology report (HPR) as per the protocol followed at our institute - a resection margin of 5 mm or greater was taken as negative, a margin between 1 and 5 mm was close, while a margin of equal to or less than 1 mm were placed in the category of positive margin.
Follow-up was studied till present date for recurrence. Data were analyzed using Chi square tests for univariate analysis. Cox regression analysis using forward removal of variables was performed for multivariate analysis. Kaplan Meier curves were obtained for DFS.
| > Results|| |
Of the 306 patients, 237 (77.5%) were males and 69 (22.5%) were females. The mean age at presentation was 50 years (range of 19-80 years). Buccal mucosa was the site most frequently involved (33.3%), followed by oral tongue (24.5%) and lower alveolus (19.6%). 139 patients (45.4%) had advanced (stage T3 or T4) disease.
163 (53.3%) patients were N zero, 124 (40.5%) were N plus, and in 19 (6.2%) cases, nodal surgery was not done; therefore, pathologic N staging was not available.
173 (56.5%) patients had moderately differentiated carcinomas, 73 (23.9%) were poorly differentiated, and the rest 60 (19.6%) were well-differentiated squamous carcinomas.
Wide excision was done in 109 (35.6%) patients, the next most frequently done procedure being a hemimandibulectomy or segmental mandibulectomy in 110 (36%) cases.
Reconstruction with a pectoralis major (PMMC) was done most commonly where needed, followed by PMMC and DP (deltopectoral) flap. Free flaps were used in three cases.
In 106 (34.7%) patients, surgery was the sole treatment modality. 200 (65.3%) patients received adjuvant radiotherapy.
On final HPR, there were 14 cases (4.6%) of positive margins and 102 cases (33.3%) with close margins. The rest 190 (62.1%) cases had negative or free margins.
Follow-up and recurrence: The median follow-up time was 26.5 months.
146 (47.7%) patients had a follow-up of more than 36 months. Patients with advanced cancers (T3 and T4) followed up for an average of 30.48 months (0.33-81 months). Patients with early cancers (T1 and T2) followed up for an average of 36.5 months (0.2-77.5 months).
At the end of study period, there were 79 (25.8%) recurrences, of which 46 (58.2%) were local, 16 (20.2%) were regional, 9 (11.3%) were locoregional, and 8 (10.1%) were distant metastasis.
24 patients died of disease and 16 died of other causes.
Of the total number of cases that were disease free (227), the number of cases with negative margins was 148 (65.2%), the number of cases with close margins was 71 (31.3%), and that of positive margins was 8 (3.5%).
Looking at all patterns of recurrence, 42 of 190 (22.2%) of cases with negative margins recurred, 31 of 102 (30.4%) cases with close margins, and 6 of 14 (42.8%) of those with positive margins recurred [Table 1].
Looking at local recurrence alone, 31 (16.3%) of cases with negative margins, 20 (19.6%) cases with close margins, and 4 (28.6%) cases of positive margins recurred [Table 1].
Factors affecting resection margins
T stage vs. Margins: Cases were grouped into early (T1-2) and advanced (T3-4). T stage did not have a statistically significant impact on margins (P value 0.193). Though advanced tumors had a higher probability of having soft-tissue margins close or positive, the association was not statistically significant (P value 0.5) [Table 2].
Subsite vs. Margins: The major subsites affected were the buccal mucosa, the oral tongue, and the mandibular alveolus. The rates of inadequate (close or positive) margins in these were 38% in buccal mucosa, 29.3% in tongue, and 37.2% in mandibular alveolus.
In retromolar trigone lesions, there were insufficient margins in 41% cases. In certain subsites viz. upper alveolus, upper and lower GB sulcus, upper and lower lip, and hard palate, we found a higher rate of close/positive margins [Table 3].
However, the number of patients in these subsites was small and no correlation could be made.
Differentiation vs. Margins: The rates of positive margins were 3.3%, 4.7%, and 5.5%, respectively, for well-differentiated, moderately, and poorly differentiated cancers, respectively. However, the overall correlation of differentiation versus margin status was not statistically significant (P = 0.5).
Factors influencing DFS - Univariate analysis
Margin status: Margins were significant when close and positive were clubbed together (P value 0.05) as regards overall and local recurrence. However, when the margins were taken separately, there was no statistical significance (P value 0.1).
T stage: 13.7% of early T-staged (T1 and T2) tumors and 29.9% of advanced tumors (T3 and T4) recurred locally (P value 0.036). Overall recurrence rate for early T tumors was 19.7% and for advanced was 33% (P value 0.008).
N stage: 19.8% of N zero and 34.7% of N plus patients recurred overall (P value 0.03). 14.8% of N zero and 22.6% N plus patients recurred locally (P value 0.08).
Differentiation: It was not significantly associated with either overall recurrence (P 0.195) or with local recurrence (P 0.21).
Tumor thickness: Lesions were arbitrarily divided into less than and more than 5 mm thickness. Maximum tumor thickness was not significant for overall and local recurrences, P value 0.072 and 0.076, respectively, although it did show a trend toward increased overall recurrence (28% of thicker tumors recurred as compared to 18% of tumors less than 5 mm) and local recurrence (20.3% and 11.1%, respectively).
Influence of adjuvant treatment: As seen in the [Table 4], cases with close and positive margins recurred more often, even after adjuvant therapy. However, this was not significant statistically (P value 0.35).
Factors influencing DFS - Multivariate analysis
Margin status, T stage, N stage, subsite, adjuvant treatment, differentiation, and tumor thickness were correlated with local recurrence alone and with overall recurrence.
For overall recurrence, margins, differentiation, thickness, T stage, N stage were significantly associated. The P values were as follows - close margins 0.003, positive margins 0.039, differentiation 0.05, T stage 0.022, and N stage 0.003. The subsite of origin and adjuvant treatment did not significantly impact overall recurrence.
For local recurrence alone, margins, differentiation, thickness, and adjuvant treatment achieved significance statistically. The P value were - close margins 0.001, positive margins 0.037, differentiation 0.03, thickness 0.015, and adjuvant treatment 0.024. T stage had a P value of 0.08. Nodal status and subsite did not have statistical significance.
Disease-free survival: The average interval to overall recurrence in our study was 34.8 months in case of negative margins, 33.9 for close margins, while it was 10.18 months for positive margins [Figure 1]. The log rank P value was significant for positive margins (P value 0.00).
|Figure 1: Kaplan Meier graph for disease recurrence (all patterns) showing significant difference in outcome of the three margin categories, especially of cases with positive margins (log rank P value 0.00)|
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[Figure 2] shows all events including the second primaries, defined as lesions seen after 5 years. It again shows the impact of positive margins on DFS (P value 0.002). The dipping of the line representing negative margins at more than 5 years interval is due to the development of second primaries.
|Figure 2: Kaplan Meier graph for disease recurrence (all patterns, including second primaries) showing signifi cant difference in outcome of the three margin categories, especially of cases with positive margins (log rank P value 0.002). The dipping of the line representing negative margins at more than 5 years interval is due to the development of second primaries|
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For local recurrence alone, the average interval was 11.4 months for negative margins, 13.7 months for close margins, and 5.4 months for positive margins. The log rank for positive margins was 0.023, as shown in [Figure 3].
|Figure 3: Kaplan Meier graph for local disease recurrence showing significant difference in outcome of cases with positive margins (log rank P value 0.023)|
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Second primary: 10 second primaries were seen, all in the oral cavity. All 10 developed in patients who had had negative margins on original resection. Mean interval to the development of a second primary lesion was 55 months, with a minimum of 39 months and a maximum of 65 months. 7 of the 10 patients had received adjuvant radiotherapy. There was no correlation with subsite or T stage with the development of the same.
Correlation of FS and final histopathology:
The resected specimen was sent for FS analysis in 264 patients (86.2%) patients. FS was reported as negative (≥5 mm) in 148 (56.1%) cases, as close (between 1 and 5 mm) in 87 (32.9%) cases , and as positive(≤1 mm) in 11 (4.16%) cases. Complete data on FS analysis were not available in 18 cases (6.18%).
80% of margins predicted to be close on frozen were confirmed as close on histopathology. The sensitivity of frozen in this study was 88% and the specificity was 82% [Table 5].
There was good agreement between the frozen and HPRs as regards the diagnosis of a particular margin as close or positive (weighted kappa value 0.648).
Revision of margins was done in 10 out of the 11 cases when they were reported as positive on FS and in 22 out of the 87 cases reported as close. Of these, 13 cases had negative margins on HPR. The difference in outcome is not significant (P value 0.42), that is, adjuvant treatment, in this study, was not able to affect difference in outcome of revised margins.
The FS was positive and close, respectively, in two cases for the soft-tissue margin - the revised margin both of which cases were reported likewise in the histopathology, despite revision. 12 out of 18 cases in which soft tissue was positive or close also had one or more other margin positive or close, so the independent association of soft tissue could not be ascertained vis-a-vis recurrences.
In 42 cases, the FS was not asked for and resection was completed on the basis of clinical judgment. In these cases, the final cut margins were reported as follows:
Negative 29 (69%), close 10 (23.8%), and positive 3 (7.1%), which is not very disparate from the overall rates of margins are negative 62%, close 33%, and positive 4%.
Impact of FS: Out of the 98 cases when the FS was reported as positive or close, the margins were revised in 32. Of these, in five cases, the final margin status remained the same (close or positive as the case may be). In seven cases, some other margin was reported as close or positive in the final HPR. In 66 cases, the margins were not revised - a possible reason being that the close margin was a soft-tissue margin which was not amenable to correction, or the margins were possibly thought sufficient as per the surgeon's clinical judgement. Thus, the FS report was utilized in 32 out of 98 cases (25.5%) cases. Further, FS was unable to influence margin control in 12 out of 98 (12.2%) cases and was useful in 20 out of 98 cases (20.4%).
The 12 cases where revision did not give us a free margin demonstrate the fact that, one, it is not always possible to revise accurately and, two, sampling errors can occur as regards the margins which the pathologist samples or the surgeon marks.
The number of patients who did and who did not have FS was not comparable; hence, no survival analysis was made.
| > Discussion|| |
Curative surgery for tumors of head and neck must ensure that an adequate margin of uninvolved tissue be resected around the tumor in all three dimensions. There are guidelines on defining margin width.  However, margins of 2 cm have been advocated by some. , It is also an accepted practice to go as wide as is possible, keeping in mind the issues of reconstruction and of functional impairment.
The inevitability of margins being close has also been written about the range in various studies being unto 42%. ,,
Just as the presence of negative margins does not predict cure, the presence of positive margins does not predict recurrence. In a study by Brandwein-Gensler et al.,  12 patients with T1 carcinomas that were resected with more than 5 mm margins developed local and/or regional recurrence. Looser et al. found an overall local recurrence rate of 17% in patients with T1-2 N0 lesions and in 20% of patients with T3-4N0 lesions treated with surgery alone with margins greater than 5 mm.
The percentage of close or positive margins in sites such as lip and retromolar trigone was, in our study, higher than that of other subsites. The mucosal margin was seen to be most often positive, especially in lower stage tumors. Adjuvant treatment when seen individually for lip alone did not have significant impact on control. Hence, care must be taken about disease clearance, besides cosmesis. This was also the conclusion in a study by Sieczka et al. who questioned the assumption that early staged tumors with negative margins implies good local control.
Impact of Adjuvant Radiotherapy: Kovacs  found the 3-year survival rate to be 85% in cases of free margins and 31% in close margins when adjuvant chemoradiotherapy was given. When only surgery was done, the two respective rates were 56% and 41%. However, Binahmed et al. did not find beneficial effect of adjuvant treatment on survival when margins were inadequate. Loree and Strong  found that local recurrence rates in patients with positive margins who underwent radiotherapy was greater than that in comparable patients with negative margins not receiving radiotherapy.
The average interval to recurrence in our study was 34.3 months in case of negative or close margins, while it was 10.18 months for positive margins. Sadeghi et al. also found that positive margin patients had earlier recurrence (8 months vs. 11 months).
In the study by Chen et al.,  cases with negative margins had 39% DFS at five years, versus 7% for those where margins were not free. Local recurrence rate for positive margins was 100% and that for negative margins was 17%.
Byers et al. found that the surgeon was able to obtain free margins on the first instance in 67% cases. In our study also, in 69% cases, where we did not ask for FS for margins, the final histopathology showed negative margins.
Kerawala and Ong  showed that there was an error of more than a centimeter in relocating the possible site for revising margins in 32% cases. They inferred that even a re-excision of a 2-cm cuff would not ensure adequate clearance in such a situation.
DinNardo et al. found that 5% of patients in their study benefited from frozen by virtue of immediate margin revision. They found that 40% of positive and 100% of close margins were missed by FS. In a study by Pathak et al. these two rates were 15.4% and 14.2%. Also they found that the accuracy rate of frozen in predicting clear margin status was 70.4%, while the rate of clinical judgement was 67.4% in achieving clear margins. Ribeiro et al.,  in a study of 82 patients with oral cavity cancer, reported frozen to have a sensitivity of 92.8% and a specificity of 99.8% and an accuracy rate of 99.5%. Still, there was failure to achieve adequate clearance of invasive tumor in 15% patient with its use of frozen. Lee  found that 13% patients with close margins in their study developed local recurrence. He has recommended FS and intraoperative re-excision; however, he found only 50% of re-excision samples to contain tumor. Sutton et al. and Ord et al. have determined frozen to be of little accuracy in adequacy of resection. Our study determined that FS was ultimately useful for margin control in 20.4% cases only.
In the study by Ribeiro et al.,  revision of involved margins was done in nine patients, out of whom one patient developed local recurrence and three developed neck recurrence. The overall rate of local recurrence in their study was 13% in those with close margins. Their inference was that though FS had good overall accuracy, and it improves the prospect of clearance, they do not influence the outcome of patients with close margins.
Scholl et al. found that the rate of initially negative margins was significantly lower than that of those with ultimately negative group, when there has been microscopic cut through during resection. In their opinion, if routine use of radiotherapy is done in all cases of insufficient margins, routine use of FS may not be justified.
The status of the surgical margin is an important predictor of disease control. It is the one prognostic factor which is in the surgeon's control. A 5-mm margin has been accepted as adequate for tumor clearance. Margins lesser than this, in oral cavity cancers, were seen in this study to have a significant effect on DFS. This holds good even for small tumors in "minor" subsites like the lip. We also established that FS may be unable to correctly predict which margin is close, especially for soft-tissue clearance. Microscopic cut through negatively impacts upon disease control, this is not completely remediable with revision of margins. Patients with initial negative margins had lower recurrence rates and longer interval to recurrence than those with close or positive margins.
In conclusion, control of cut margins is crucial, the surgeon must keep in mind all the caveats of use of FS and must aim for complete clearance without need for revision.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]