Oral Oncology 50 (2014) 611615

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 carcinomas (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 12 OSCC of the tongue, oor
of the mouth and cheek were included and retrospectively analysed. Local recurrence ratio was related to
margin status, unfavourable histological parameters (spidery inltrative, peri-neural and vascular-invasive growth) and postoperative treatment modality. 3-year overall survival (OS) and disease-specic 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 signicantly different between these
groups. Nine of 200 (4.5%) patients developed local recurrent disease. Two (9.1%) had a PM, ve (4.0%)
a CM and two (3.8%) a FM. Of the nine recurrences, ve 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 signicant 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.
2014 Elsevier Ltd. All rights reserved.

Introduction
For Stage 12 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 [14], while others
disagree [57]. Complete removal should ideally be achieved at the
rst surgical procedure [2]. However, in 513% 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/ 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 1542% 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 inltrative growth, peri-neural and vascular invasive growth may inuence 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 [7,8,1013].
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 12 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.

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E.A. Dik et al. / Oral Oncology 50 (2014) 611615

Patients and methods

Between 2004 and 2010, 226 patients had primary surgery for a
Stage 12 OSCC of the tongue, the oor of the mouth or the cheek
mucosa. Patient charts were analysed retrospectively. Twenty-six
patients were excluded: 21 because they had been treated for a
previous head and neck malignancy and ve because they underwent both re-resection and radiotherapy for the same tumour. A
total of 200 patients were included in this study.
Before treatment, a multidisciplinary team, consisting of a head
and neck surgeon, pathologist, radiologist and radiation oncologist,
discussed every patient. The trans-oral excision included a macroscopic safety margin of 10 mm. In 125 patients, a selective neck
dissection (levels IIII) was performed. All operations were performed by one of four experienced head and neck surgeons. A dedicated head and neck pathologist assessed all resected specimen.
The margin status, tumour diameter, tumour thickness, and the
histological parameters of the tumour front, i.e. spidery inltrative
growth, peri-neural and vascular invasive growth, were determined. The latter three characteristics were dened as unfavourable histological parameters. If margins were positive or close the
location of the closest margin deep or mucosal was determined.
Based on resection margin status, we created three groups: a
pathologically positive margin (PM), close margin (CM) and free
margin (FM) group (Table 1).
After resection, the choice of whether to implement adjuvant
treatment was based on the pathological ndings and tumour
characteristics of the resection specimen. There were three options
for further patient management:
Re-resection (RR) was dened as a repeat resection at the primary tumour site during a second intervention. RR was chosen in
patients with a PM or CM situated mainly at the mucosal resection
border. Margins had to be locatable by a pathologist and surgically
resectable. The acceptable number of unfavourable histological
parameters was generally 62.
Postoperative Radiotherapy (PORT) was dened as local irradiation of the primary resection site. 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.
Regional radiotherapy of the neck in case of lymph node metastasis
was labelled differently and excluded from this analysis.
Watchful Waiting (WW) was dened as a close follow up
(every 12 months for three years postoperatively) without adjuvant treatment. This policy was generally chosen in cases of a
CM P3 mm with 62 unfavourable histological parameters.
Patients in the PM group received adjuvant treatment. This
comprised either radiotherapy (66 Gy) or re-resection at the primary tumour site. One patient with PM received no adjuvant treatment for unknown reasons. Patients in the CM group were either
allocated to RR, PORT (56 Gy) or WW. Patients in the FM group received no adjuvant therapy.
Results were analysed according to the incidence of local recurrence during follow-up, classied as the recurrence of OSCC at, or
adjacent to, the primary site within three years of the incidence
date of the rst tumour. The distribution of recurrences over the
three groups (i.e. PM, CM and FM) and the various treatment

Table 1
Denition of patient groups based on pathological margin status.
Group

Denition

n (%)

PM

Positive margins, microscopically tumour cells

present in the resection border
Close resection margins >05 mm
Free resection margins >5 mm

22 (11)

CM
FM

126 (63)
52 (26)

modalities (i.e. RR, PORT and WW) were determined. For the
groups PM, CM and FM survival curves were calculated. Three-year
overall survival (OS), was calculated from the date of rst histological conrmation of OSCC to the date of death from any cause. The
three-year disease-specic survival (DSS) was the secondary outcome. For DSS-rates censoring occurred at the date of death from
causes other than OSCC or at the end of the follow-up period,
whichever came rst.
Patients and tumour characteristics in relation to the margin
status and the type of adjuvant treatment were analysed and compared. Patients in the WW group (with CM) were compared to patients in the FM group. Three-year OS- and DSS-rates were
determined for these two groups as well. Characteristics of the patients are reported as frequency (percentage) for categorical variables. Continuous variables are presented as mean (SD) when
normally distributed or median (range) when not. Gaussian distribution was conrmed by visual analysis of the histograms, QQ
plots and the ShapiroWilk test. One-way ANOVA was used for
hypotheses testing of normally distributed continuous data and
MannWhitney U test and KruskalWallis test for continuous data
that were not normally distributed. For categorical data P-values
were calculated with the use of Fishers exact tests. Using life table
techniques, DSS-rates and OS-rates were calculated, illustrated by
KaplanMeier plots. Covariates were compared with the log-rank
test. All test statistics were two tailed, and the signicance level
was set at p < 0.05. Survival analyses were performed with Stata
Statistical Software (Release 12. College Station, TX: StataCorp
LP) All other analyses were performed with the use of Statistical
Package for the Social Sciences (SPSS for windows, release 20.0.0
2011, SPSS Inc.).

Results
In the total cohort of 200 patients, 22(11%) had a PM, 126(63%)
a CM, and 52(26%) a FM. The three patient groups did not differ
regarding tumour site, patients habits, gender or age. Also, there
were no differences in the unfavourable histological parameters.
A signicant difference was found with relation to tumour diameter and thickness (p = 0.005 and p = 0.002 respectively): in the CM
group, tumours were bigger than those in the PM and FM group.
Table 2 shows all relevant data of the 200 patients included in
the study. Nine out of 200 (4.5%) patients developed recurrent disease at the primary site. Distribution over the different sub-sites is
shown in Table 4. Recurrences were located at the tongue in 6/105
(5.7%), the oor of mouth in 2/75(2.7%) and inside the cheek in 1/
22 (4.5%). In the PM, CM and FM groups, respectively two (9.1%),
ve (4.0%) and two (3.8%) patients had local recurrent disease. Of
the two patients with local recurrence in the PM group, one had
undergone a RR and one PORT. Of the ve local recurrences in
the CM group, four had received PORT and one was selected for
WW. Of all nine recurrences, ve patients had undergone PORT,
one a RR, and three developed during WW (Tables 3 and 4, Fig. 1).
Comparison of patients in the WW group (n = 77) with those of
the FM group (n = 52) showed, as expected due to selection, a signicant difference in margin status (p < 0.001) with a median
resection margin of 3.0 mm (range 15) in the CM group and
6.0 mm (range 5.110) in the FM group. However, no signicant
difference in development of local recurrence was encountered,
being 1/77(1.3%) in the WW and 2/52 (3.8%) in de FM group. Also
unfavourable histological parameters, thickness and diameter
were not signicantly different between these groups (Table 5).
The three-year OS was 91% (95% CI 6898%) in group PM, 87%
(95% CI 8092%) in group CM and 87% (95% CI 7493%) in group
FM (p = 0.86). The three-year DSS was 95% (95% CI 7299%) in
group PM, 91% (95% CI 8495%) in group CM, and 90% (95% CI

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E.A. Dik et al. / Oral Oncology 50 (2014) 611615

Table 2
Patient characteristics.
Variables (n = 200)
Gender no. (%)
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

Recurrence no. (%)

Site of recurrence no. (%)
Tongue
Floor of mouth
Cheek

2 (9.1)

5 (4.0)

2 (3.8)

0
1 (4.5)
1 (4.5)

4 (3.2)
1 (0.8)
0

2 (3.8)
0
0

0.91
b

Age yr
Mean
SD
Range

58.9
12.8
3183

63.3
12.6
2390

61.1
11.4
3686

Smoker no. (%)

Yes
No

9 (41)
13 (59)

67 (53)
59 (47)

26 (50)
26 (50)

0.21

0.57
a

Alcohol no. (%)

Yes
No

12 (55)
10 (45)

73 (58)
53 (42)

30 (58)
22 (42)

Site no. (%)

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

Table 4
Distribution of recurrence in relation to margin status.

Table 5
Recurrence and pathological characteristics of group WW (with CM) and FM.

0.95

Variable (n = 129)

Local recurrence
Yes
No
Spidery growth no. (%)
Yes
No
Peri neural growth no. (%)
Yes
No
Angio invasive growth no. (%)
Yes
No
Tumour diameter (mm)
Median
Range
Tumour thickness (mm)
Median
Range

0.96

11.0
236

17.5
140

12.0
140

0.005
c

Tumour thickness (mm)

Median
Range

3.0
116

5.8
130

4.0
120

Growth pattern no. (%)

Spidery
Peri-neural
Angio-invasive

16(73)
7 (32)
3 (14)

81 (64)
36 (29)
12 (10)

28(54)
7 (13)
2 (4)

0.002
a

0.26
0.07
0.30

P values were determined by Fishers exact test.

P values were determined by one-way ANOVA.
P values were determined by KruskalWallis test.

a
b

FM
n = 52

P value

1 (1)
76 (99)

2 (4)
50 (96)

0.57

44 (57)
33 (43)

28 (44)
24 (56)

0.72
a

13 (17)
64 (83)

7 (14)
45 (87)

0.81

4 (5)
73 (95)

2 (4)
50 (96)

1.0

13.0
140

12.0
140

0.23

4.0
130

4.0
120

0.33

P values were determined by Fishers exact test.

P values were determined by MannWhitney U test.

7896%) in group FM (p = 0.76). In group WW with CM the threeyear OS was 91% (95% CI 8296% p = 0.41) and the three-year DSS
was 93% (95% CI 8597% p = 0.49).
Fig. 2 shows the Kaplan Meier survival curves of the mentioned
groups.

Total
200
PM
22

Discussion
Our current strategy in treating early stage OSCC is effective, as
it resulted in only 4.5% local recurrences, which concurs with the
lower limit of percentages mentioned in the literature ranging
from 4% to 22% [7,1416]. Most recurrences are located at the tongue (5.7%) followed by the cheek (4.5%) and oor of the mouth
(2.7%).
These results are similar to those reported by others [12,14,17].
Sixty-three percent of the OSCCs was resected with close margins.
In literature this percentage ranges between 15% and 42% [8,10].
An explanation could be our group distribution, which was based
on margin status. As our margins between 0 and 5 mm are
classied as close and others consider margins 61 mm or more

WW (with CM)
n = 77

CM
126

FM
52

RR
16

PORT

WW
1

RR
15

PORT

34

WW
77

RR
0

PORT

WW
52

Figure 1. Flowchart of patient groups, type of treatment and recurrence rate.

Table 3
Adjuvant therapy in relation to patient groups and recurrences.
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. (%)

2

0
0
2

1 (3)
5 (13)
3 (2)

Bold: The amount of patients in relation to margin status and treatment modality. Italic: The amount of patients with local recurrence in relation to margin status and
treatment modality.

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E.A. Dik et al. / Oral Oncology 50 (2014) 611615

Figure 2. Kaplan Meier survival curves of group PM, CM, FM and group WW with CM.

as positive [4], this may have resulted in a shift of patients form the
positive margin to the close margin group. Another explanation is
our pathological analysis. Margins were measured in millimetres
with 1 decimal accuracy and were not rounded, which probably
led to a bigger proportion of OSCCs resected with close margins.
The management of positive or close margins is a recurring
point of discussion among clinicians. There is no consensus about
which adjuvant treatment modality to use in case of a positive
margin [14,9]. As positive margins have an adverse effect on local
control, many authors state adjuvant treatment is justied [1
4,9,12,18]. Our study underscores this statement. Even despite
adjuvant treatment, 9% of the resected OSCC with a PM recurred
locally compared with 4.0% in the CM group and 3.8% in the FM
group.
In case of close margins, no consensus about the necessity of
adjuvant treatment exists. Some authors state close margins between 0 and 5 mm are strongly related to local control
[3,4,12,18], while others refute this [5,7,19]. No prospective randomised clinical trials are available to answer this question. Most
studies have a retrospective design [8,11,12,20,21] and because
of the low numbers of local recurrences, signicant conclusions
are often impossible to draw [11,12]. We found a similar level of
recurrence, OS and DSS in the CM and FM groups, which suggests
that free margin status is irrelevant. However, the CM group is an
inhomogeneous group: 34/126 (27%) patients received PORT, 15/
126 (12%), underwent RR and 77/126 (61%) received no adjuvant
therapy at all (Table 3). Therefore, only a comparison between
the WW group with CM and FM groups is justied (Table 5),

showing a local recurrence of 1.3% and 3.8% respectively (not signicant). As, apart from resection margins averaging 3 mm in the
WW group and 6 mm in the FM group, no signicant differences
in pathological parameters, OS and DSS between these groups were
seen, it can be concluded that where local recurrence risk is concerned, at least a free margin of 3 mm is just as safe as one of
6 mm. Indeed, 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, recurrence risk is extremely low, as has previously been demonstrated [5,7]. A substantial proportion of the
CM group may have undergone PORT or RR without evident necessity or benet while causing extra morbidity and expenses [22,23].
In comparison to our 19851994 cohort of Stage 12 oral cancers,
in which no adjuvant treatment for CM was given, this treatment
strategy did not alter the risk of local recurrence [7]. Therefore
the close margin concept introduced a decade ago seems irrelevant in making decisions on adjuvant treatment for Stage 12 oral
cancers [10,11].
Many authors suggest that histological parameters such as
depth of tumour inltration [14,18,2426], peri-neural ingrowth
vasoinvasive growth and spidery growth are also related to poor
local control [2,10,12,19,20,27], and hence indicate adjuvant treatment. Our study could not endorse that statement. Also in this
study, a multivariate analysis of pathological parameters was not
possible due to the small recurrence numbers.
In case of PM or CM, local adjuvant treatment is performed in a
considerably proportion of the cases. Some authors suggest RR
[2,3,8,14]. Others suggest postoperative radiotherapy [5,9,19,28],

E.A. Dik et al. / Oral Oncology 50 (2014) 611615

while accepting its adverse side-effects [22,23]. Most recurrences

occurred in the PORT group with 13% compared to 3% in the RR
group. This suggests RR to be the type of treatment to choose in
case of positive or close margins <3 mm, locatable by a pathologist
and reachable for resection. To check whether our non-signicant
results were due to a lack of statistical power, a post hoc power
analysis was conducted using Stata Statistical Software (Release
12. College Station, TX: StataCorp LP), with power (1-b) set at
0.80 and a at .05, two-tailed. The post hoc power analysis (RR vs
PORT) revealed that with a recurrence rate of 3% in the re-resection
group and 13% in the PORT group, at least 145 patients in both
groups would be needed to reach signicance. This implies that
at least 5 times as many patients should be included in each treatment group. In total, over a thousand early OSCCs should be included to reach signicance. Thus, due to the low number of
recurrences and the consequential impossibility to reach signicance, the preference for a local RR, PORT or WW could not be estimated on this material. Another important factor is the selection
bias. OSSCs with deep margin involvement not reachable for a
re-resection and P2 unfavourable histological parameters were
treated with PORT. The more unfavourable OSCCs are in this
group, which probably explains the higher amount of recurrences.
In conclusion, this study demonstrates that, what local recurrence is concerned, there is no evidence for local adjuvant treatment in case of resection margins P3 mm with 62 unfavourable
histological parameters. A meta-analysis of available literature
could contribute to answer the question in which cases what type
of local adjuvant treatment is relevant for incompletely removed
early oral cancers.
Conict of interest statement
None declared.
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