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Oral Oncology 50 (2014) 611–615

Contents lists available at ScienceDirect

Oral Oncology
journal homepage: www.elsevier.com/locate/oraloncology

Resection of early oral squamous cell carcinoma with positive or close
margins: Relevance of adjuvant treatment in relation to local recurrence
Margins of 3 mm as safe as 5 mm
Eric A. Dik a,⇑, Stefan M. Willems b, Norbertus A. Ipenburg a, Sven O. Adriaansens a,
Antoine J.W.P. Rosenberg a, Robert J.J. van Es a
a
b

Department of Oral and Maxillofacial Surgery, University Medical Centre Utrecht, Heidelberglaan 100, G.05.129, PO Box 85500, NL 3508 GA Utrecht, The Netherlands
Department of Pathology, University Medical Centre Utrecht, Heidelberglaan 100, PO Box 85500, NL 3508 GA Utrecht, The Netherlands

a r t i c l e

i n f o

Article history:
Received 3 December 2013
Received in revised form 16 February 2014
Accepted 20 February 2014
Available online 14 March 2014
Keywords:
Oral squamous cell carcinoma
Local recurrence
Re-resection
Post-operative radiotherapy
Pathological margin status
Head neck cancer

s u m m a r y
Objectives: The treatment strategy of early stage oral squamous cell carcinoma’s (OSCC) resected with
close or involved margins is a returning point of discussion. In this study we reviewed the consequences
of re-resection (RR), postoperative radiotherapy (PORT) or watchful waiting (WW).
Patients and methods: Two-hundred patients with a primary resected Stage 1–2 OSCC of the tongue, floor
of the mouth and cheek were included and retrospectively analysed. Local recurrence ratio was related to
margin status, unfavourable histological parameters (spidery infiltrative, peri-neural and vascular-invasive growth) and postoperative treatment modality. 3-year overall survival (OS) and disease-specific survival (DSS) was calculated in relation to margin status.
Results: Twenty-two of 200 (11%) patients had pathological positive margins (PM), 126 (63%) close margins (CM), and 52 (26%) free margins (FM). OS and DSS were not significantly different between these
groups. Nine of 200 (4.5%) patients developed local recurrent disease. Two (9.1%) had a PM, five (4.0%)
a CM and two (3.8%) a FM. Of the nine recurrences, five patients had undergone PORT, one a RR, and three
follow-up. Watchful waiting for CM P3 mm with 62 unfavourable histological parameters showed,
besides margin status no significant differences with the FM group.
Conclusion: With this treatment strategy, the local recurrence rate was 4.5%. No evidence was found for
local adjuvant treatment in case of close margins P3 mm with 62 unfavourable histological parameters.
Current data do not support the use of one treatment modality above any other.
Ó 2014 Elsevier Ltd. All rights reserved.

Introduction
For Stage 1–2 oral squamous cell carcinoma (OSCC) the preferred choice of treatment is complete surgical removal of the tumour. To achieve the best results in loco-regional control and
long-term disease-free survival, several authors believe that free
resection margins of at least 5 mm are essential [1–4], while others
disagree [5–7]. Complete removal should ideally be achieved at the
first surgical procedure [2]. However, in 5–13% of resected early
OSCCs, microscopic tumour is present in the resection margin,
known as a ‘‘positive’’ margin [2]. A positive margin carries a high

⇑ Corresponding author. Address: Department of Oral and Maxillofacial Surgery,
Maastricht University Medical Centre, P. Debyelaan 25, PO Box 5800, NL 6202 AZ
Maastricht, The Netherlands. Tel.: +31 433872010; fax: +31 433872020.
E-mail address: eric.dik@mumc.nl (E.A. Dik).
http://dx.doi.org/10.1016/j.oraloncology.2014.02.014
1368-8375/Ó 2014 Elsevier Ltd. All rights reserved.

risk of recurrence and is an indication for adjuvant treatment such
as irradiation or re-resection [2,8,9]. Another 15–42% of resected
OSCCs have a margin between 0 and 5 mm, known as a ‘‘close’’
margin [8,10]. In close margins, histological parameters of the tumour front such as spidery infiltrative growth, peri-neural and vascular invasive growth may influence the certainty whether or not
microscopic tumour is still present. Opinions vary about the impact of these parameters on local control and disease-free survival
and whether or not to implement adjuvant treatment [7,8,10–13].
If a margin is close, evidence in favour of either adjuvant treatment
or a policy of ‘‘watchful waiting’’, is lacking. In this retrospective
study, we review the treatment strategy of Stage 1–2 OSCC with
positive or close margins at our department. In case of close
margins, we compared surgical re-resection with adjuvant
radiotherapy and a watchful waiting policy. These results were
compared with those of resected early stage OSCC with margins
>5 mm, designated as ‘‘free’’ margins.

Patient charts were analysed retrospectively. 87% (95% CI 80–92%) in group CM and 87% (95% CI 74–93%) in group FM (p = 0. and the significance level was set at p < 0. All operations were performed by one of four experienced head and neck surgeons. SPSS Inc. One-way ANOVA was used for hypotheses testing of normally distributed continuous data and Mann–Whitney U test and Kruskal–Wallis test for continuous data that were not normally distributed.005 and p = 0. a selective neck dissection (levels I–III) was performed. College Station. TX: StataCorp LP) All other analyses were performed with the use of Statistical Package for the Social Sciences (SPSS for windows.3%) in the WW and 2/52 (3. classified as the recurrence of OSCC at. Nine out of 200 (4. discussed every patient. one a RR. Also. Continuous variables are presented as mean (SD) when normally distributed or median (range) when not. Patients in the PM group received adjuvant treatment. consisting of a head and neck surgeon. In 125 patients. illustrated by Kaplan–Meier plots. Before treatment.e.7%) and inside the cheek in 1/ 22 (4. Three-year overall survival (OS). tumour thickness. Watchful Waiting (WW) was defined as a close follow up (every 1–2 months for three years postoperatively) without adjuvant treatment. / Oral Oncology 50 (2014) 611–615 Patients and methods Between 2004 and 2010. Characteristics of the patients are reported as frequency (percentage) for categorical variables. Using life table techniques. a significant difference in margin status (p < 0. the floor of the mouth or the cheek mucosa. Results In the total cohort of 200 patients. Also unfavourable histological parameters. i.001) with a median resection margin of 3. a multidisciplinary team. Fig. This policy was generally chosen in cases of a CM P3 mm with 62 unfavourable histological parameters. If margins were positive or close the location of the closest margin – deep or mucosal – was determined. This comprised either radiotherapy (66 Gy) or re-resection at the primary tumour site. close margin (CM) and free margin (FM) group (Table 1).1%). peri-neural and vascular invasive growth. PORT (56 Gy) or WW. radiologist and radiation oncologist.0 2011.0. 126(63%) a CM. gender or age. Margins had to be locatable by a pathologist and surgically resectable. pathologist. The three-year OS was 91% (95% CI 68–98%) in group PM. Patients in the CM group were either allocated to RR. the choice of whether to implement adjuvant treatment was based on the pathological findings and tumour characteristics of the resection specimen. microscopically tumour cells present in the resection border Close resection margins >0–5 mm Free resection margins >5 mm 22 (11) CM FM 126 (63) 52 (26) modalities (i. 226 patients had primary surgery for a Stage 1–2 OSCC of the tongue. five patients had undergone PORT. five (4. being 1/77(1.). and 90% (95% CI . A total of 200 patients were included in this study. For the groups PM. A dedicated head and neck pathologist assessed all resected specimen. Comparison of patients in the WW group (n = 77) with those of the FM group (n = 52) showed. thickness and diameter were not significantly different between these groups (Table 5). patients’ habits. Survival analyses were performed with Stata Statistical Software (Release 12. Patients in the WW group (with CM) were compared to patients in the FM group. release 20. and the histological parameters of the tumour front. PORT and WW) were determined. respectively two (9. no significant difference in development of local recurrence was encountered. RR.0 mm (range 5. RR was chosen in patients with a PM or CM situated mainly at the mucosal resection border. However. Of all nine recurrences.e.86). The three patient groups did not differ regarding tumour site. Patients and tumour characteristics in relation to the margin status and the type of adjuvant treatment were analysed and compared. For DSS-rates censoring occurred at the date of death from causes other than OSCC or at the end of the follow-up period. Gaussian distribution was confirmed by visual analysis of the histograms. and 52(26%) a FM. The acceptable number of unfavourable histological parameters was generally 62. and three developed during WW (Tables 3 and 4. After resection.e.and DSS-rates were determined for these two groups as well. or adjacent to. whichever came first. One patient with PM received no adjuvant treatment for unknown reasons. The trans-oral excision included a macroscopic safety margin of 10 mm. the primary site within three years of the incidence date of the first tumour. CM and FM groups. Twenty-six patients were excluded: 21 because they had been treated for a previous head and neck malignancy and five because they underwent both re-resection and radiotherapy for the same tumour.612 E. the floor of mouth in 2/75(2.002 respectively): in the CM group. Regional radiotherapy of the neck in case of lymph node metastasis was labelled differently and excluded from this analysis. Recurrences were located at the tongue in 6/105 (5. Patients in the FM group received no adjuvant therapy. 91% (95% CI 84–95%) in group CM. DSS-rates and OS-rates were calculated. In the PM. as expected due to selection. Of the five local recurrences in the CM group. Results were analysed according to the incidence of local recurrence during follow-up. Table 2 shows all relevant data of the 200 patients included in the study. A significant difference was found with relation to tumour diameter and thickness (p = 0. Of the two patients with local recurrence in the PM group. spidery infiltrative growth. we created three groups: a pathologically positive margin (PM).05.1–10) in the FM group.5%). For categorical data P-values were calculated with the use of Fisher’s exact tests.0 mm (range 1–5) in the CM group and 6. tumour diameter. PM. Three-year OS. one had undergone a RR and one PORT. Distribution over the different sub-sites is shown in Table 4. The distribution of recurrences over the three groups (i. CM and FM survival curves were calculated. Dik et al. Postoperative Radiotherapy (PORT) was defined as ‘local irradiation of the primary resection site’. 1). were determined.A. There were three options for further patient management: Re-resection (RR) was defined as a repeat resection at the primary tumour site during a second intervention. Group Definition n (%) PM Positive margins. 22(11%) had a PM. The latter three characteristics were defined as ‘‘unfavourable histological parameters’’.5%) patients developed recurrent disease at the primary site. CM and FM) and the various treatment Table 1 Definition of patient groups based on pathological margin status. Q–Q plots and the Shapiro–Wilk test. All test statistics were two tailed. The three-year DSS was 95% (95% CI 72–99%) in group PM. PORT was the treatment of choice in patients with a PM or CM situated mainly at the deep resection margin and P2 unfavourable histological parameters.0%) and two (3. Covariates were compared with the log-rank test.8%) in de FM group.8%) patients had local recurrent disease. there were no differences in the unfavourable histological parameters. Based on resection margin status.7%). tumours were bigger than those in the PM and FM group. The margin status. four had received PORT and one was selected for WW. The three-year disease-specific survival (DSS) was the secondary outcome. was calculated from the date of first histological confirmation of OSCC to the date of death from any cause.

which was based on margin status.17].0 1–40 0. Fig. (%) Site of recurrence – no. Table 5 Recurrence and pathological characteristics of group WW (with CM) and FM. 78–96%) in group FM (p = 0. (%) Yes No Angio invasive growth – no. Dik et al. .49). / Oral Oncology 50 (2014) 611–615 Table 2 Patient characteristics. 2 shows the Kaplan Meier survival curves of the mentioned groups.8) 0 0 0.6 23–90 61. (%) Yes No 9 (41) 13 (59) 67 (53) 59 (47) 26 (50) 26 (50) 0.0) 2 (3.7%).21 a 0. P values were determined by Kruskal–Wallis test.1 11.57 44 (57) 33 (43) 28 (44) 24 (56) a a 0.23 4.9 12. (%) Spidery Peri-neural Angio-invasive 16(73) 7 (32) 3 (14) 81 (64) 36 (29) 12 (10) 28(54) 7 (13) 2 (4) 0.3 12.5%) and floor of the mouth (2.2) 1 (0. as it resulted in only 4. (%) Yes No 12 (55) 10 (45) 73 (58) 53 (42) 30 (58) 22 (42) Site – no. An explanation could be our group distribution.0 1–16 5.8 1–30 4.0 13. In group WW with CM the threeyear OS was 91% (95% CI 82–96% p = 0.613 E. type of treatment and recurrence rate.5% local recurrences. These results are similar to those reported by others [12.7%) followed by the cheek (4.0 1–30 4.76).33 a b b P values were determined by Fisher’s exact test.0 1–20 0. 0.A.14. (%) Yes No Peri neural growth – no.07 0.5 1–40 12.0 1–20 Growth pattern – no. Flowchart of patient groups.72 a 13 (17) 64 (83) 7 (14) 45 (87) 0.10].26 0.8) 0 1 (4. Italic: The amount of patients with local recurrence in relation to margin status and treatment modality. P values were determined by one-way ANOVA.8) 0 2 (3. (%) Tongue Floor of mouth Cheek 2 (9.8 31–83 63.1) 5 (4.4 36–86 Smoker – no.0 2–36 17.005 c Tumour thickness (mm) Median Range 3.41) and the three-year DSS was 93% (95% CI 85–97% p = 0. which concurs with the lower limit of percentages mentioned in the literature ranging from 4% to 22% [7.0 1–40 0. P values were determined by Mann–Whitney U test. As our margins between 0 and 5 mm are classified as close and others consider margins 61 mm or more WW (with CM) n = 77 CM 126 FM 52 RR 16 PORT 5 WW 1 RR 15 PORT 34 WW 77 RR 0 PORT 0 WW 52 1 1 0 0 4 1 0 0 2 Figure 1.14–16]. Table 3 Adjuvant therapy in relation to patient groups and recurrences. Variables (n = 200) Gender – no. (%) 2 9 0 0 2 1 (3) 5 (13) 3 (2) Bold: The amount of patients in relation to margin status and treatment modality.81 4 (5) 73 (95) 2 (4) 50 (96) 1.5) 1 (4. (%) Tongue (n = 105) Floor of mouth (n = 73) Cheek (n = 22) 11 (50) 9 (41) 2 (9) 67 (53) 46 (37) 13 (10) 27 (52) 18 (35) 7 (13) Tumour diameter (mm) Median Range a Table 4 Distribution of recurrence in relation to margin status. (%) Yes No Tumour diameter (mm) Median Range Tumour thickness (mm) Median Range 0. Sixty-three percent of the OSCC’s was resected with close margins. a b FM n = 52 P value 1 (1) 76 (99) 2 (4) 50 (96) 0.30 P values were determined by Fisher’s exact test. (%) Male Female b c PM n = 22 CM n = 126 FM n = 52 13 (59) 9 (41) 72 (57) 54 (43) 28(54) 24 (46) P-value Variables (n = 200) PM n = 22 CM n = 126 FM n = 52 a Recurrence – no.96 c 11.57 a Alcohol – no.5) 4 (3. Total 200 PM 22 Discussion Our current strategy in treating early stage OSCC is effective. In literature this percentage ranges between 15% and 42% [8.0 1–40 12.95 Variable (n = 129) a Local recurrence Yes No Spidery growth – no.91 b Age – yr Mean SD Range 58. Variables (n = 200) PM n = 22 Recurrence RR n = 31 PORT n = 39 WW n = 130 CM n = 126 2 16 5 1 1 1 0 FM n = 52 5 15 34 77 0 4 1 0 0 52 Total recurrence no. Most recurrences are located at the tongue (5.002 a 0.

OS and DSS between these groups were seen. As. 15/ 126 (12%). There is no consensus about which adjuvant treatment modality to use in case of a positive margin [1–4.11. underwent RR and 77/126 (61%) received no adjuvant therapy at all (Table 3). A substantial proportion of the CM group may have undergone PORT or RR without evident necessity or benefit while causing extra morbidity and expenses [22.8. showing a local recurrence of 1.12].18].3% and 3. which probably led to a bigger proportion of OSCC’s resected with close margins.4.11].20. significant conclusions are often impossible to draw [11. As positive margins have an adverse effect on local control. The management of positive or close margins is a recurring point of discussion among clinicians. as positive [4]. However. FM and group WW with CM.28]. Dik et al.19]. 9% of the resected OSCC with a PM recurred locally compared with 4. In case of close margins.9.614 E. it can be concluded that where local recurrence risk is concerned.12.7.8% in the FM group. Many authors suggest that histological parameters such as depth of tumour infiltration [14. at least a free margin of 3 mm is just as safe as one of 6 mm.8% respectively (not significant). OS and DSS in the CM and FM groups. .7].19.A.21] and because of the low numbers of local recurrences. this may have resulted in a shift of patients form the positive margin to the close margin group.27]. Most studies have a retrospective design [8. apart from resection margins averaging 3 mm in the WW group and 6 mm in the FM group. We found a similar level of recurrence. Some authors suggest RR [2. only a comparison between the WW group with CM and FM groups is justified (Table 5).23]. which suggests that free margin status is irrelevant. Therefore the ‘‘close margin concept’’ introduced a decade ago seems irrelevant in making decisions on adjuvant treatment for Stage 1–2 oral cancers [10. as has previously been demonstrated [5. this treatment strategy did not alter the risk of local recurrence [7]. recurrence risk is extremely low. no significant differences in pathological parameters. no consensus about the necessity of adjuvant treatment exists. a multivariate analysis of pathological parameters was not possible due to the small recurrence numbers. Some authors state close margins between 0 and 5 mm are strongly related to local control [3. / Oral Oncology 50 (2014) 611–615 Figure 2. while others refute this [5. Margins were measured in millimetres with 1 decimal accuracy and were not rounded.9. Our study underscores this statement. Kaplan Meier survival curves of group PM. many authors state adjuvant treatment is justified [1– 4. the CM group is an inhomogeneous group: 34/126 (27%) patients received PORT.24–26].9].20. local adjuvant treatment is performed in a considerably proportion of the cases. peri-neural ingrowth vasoinvasive growth and spidery growth are also related to poor local control [2.0% in the CM group and 3.12. Another explanation is our pathological analysis. Even despite adjuvant treatment.10. In comparison to our 1985–1994 cohort of Stage 1–2 oral cancers. in which no adjuvant treatment for CM was given.18]. No prospective randomised clinical trials are available to answer this question. and hence indicate adjuvant treatment.18. Our study could not endorse that statement. Also in this study.19. In case of PM or CM. Others suggest postoperative radiotherapy [5.3.12.14].12. CM. Therefore. it could be argued that the whole concept of using a free margin status is irrelevant in early oral cancer: once resection margins are clear. Indeed.

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