Int. J. Oral Maxillofac. Surg.

2014; 43: 269273

http://dx.doi.org/10.1016/j.ijom.2013.10.022, available online at http://www.sciencedirect.com

Clinical Paper
Head and Neck Oncology

Sentinel node biopsy in relation

to survival in floor of the mouth

carcinoma

J. Alvareza, A. Bidagurena,
M. McGurkb, G. Diaz-Basterraa,
J. Brunsoa, B. Andikoetxeaa,
J. C. Martna, L. Barbiera,
I. Arteagoitiaa, J. A. Santamaraa
a

Department of Oral and Maxillofacial

Surgery, BioCruces Health Research Institute,
Hospital Universitario Cruces, University of
the Basque Country, Spain; bDepartment of
Oral and Maxillofacial Surgery, Guys and St
Thomas Hospital, London, UK

J. Alvarez, A. Bidaguren, M. McGurk, G. Diaz-Basterra, J. Brunso, B.

Andikoetxea, J. C. Martn, L. Barbier, I. Arteagoitia, J. A. Santamara: Sentinel
node biopsy in relation to survival in floor of the mouth carcinoma. Int. J. Oral
Maxillofac. Surg. 2014; 43: 269273. # 2013 International Association of Oral and
Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Abstract. Promising results have been obtained with sentinel node biopsy (SNB) in
early oral carcinoma, but the floor of the mouth remains a site at risk of
misdiagnosis. A retrospective and prospective study was designed to test the safety
of SNB by comparing survival among patients with early stage carcinoma of the
floor of the mouth (FOM) undergoing SNB, to a control group managed
traditionally by a combination of clinical observation and elective neck dissection
(END). A total of 63 patients with early stage carcinoma of the FOM were treated
between 1991 and 2005. In the control group, 26 patients were managed with END
and nine by close observation. In the test group, 28 patients were managed
prospectively with SNB. Regional recurrence occurred in 23% (8/35) of control
patients and 25% (7/28) of test patients. Approximately 25% of patients were
successfully treated by salvage surgery. Disease-specific survival was 65.5% for
control patients and 85% for SNB patients; the difference was not statistically
significant. The use of SNB in the management of cancers of the FOM did not
adversely affect survival and prevented 69.5% of patients undergoing unnecessary
neck dissections, while clinical progress was better in the SNB group than in
controls.

The assessment of metastatic disease in

early stage oral and oropharyngeal
tumours has not changed significantly
over the last three decades and with it
the debate as to the optimum treatment of
the N0 neck. On the basis of evidence

This paper was presented at the 4th International Conference on Sentinel Node Biopsy
in Mucosal Head and Neck Cancer, Copenhagen, Denmark, June 2010.

0901-5027/030269 + 05 $36.00/0

available so far, it has not been possible

to decide between elective neck dissection (END) and observation, as overall
survival as well as disease-free survival
are similar using both of these
approaches.1,2 Some authors champion
elective neck dissection,3 others a wait
and see policy.4 Various retrospective
studies have been published, but there is
no consensus in the resulting recommendations.

Keywords: head and neck neoplasms; sentinel

node biopsy; N0 neck; floor of the mouth.
Accepted for publication 24 October 2013
Available online 2 December 2013

The challenge is to identify patients

with occult cervical metastasis at the time
of presentation. Current radiological techniques are not sufficiently sensitive to
detect small tumour deposits, and at present the standard of care adopted worldwide is END.
If it were to be accepted that there is
little or no difference in survival between
the wait and see approach and END, then
there would be no intellectual reason not

# 2013 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

270

Alvarez et al.

to promote a conservative approach that

cautiously tries to limit the number of
ENDs performed by using the technique
of sentinel node biopsy (SNB). The latter
is the most recent innovation in the identification of micrometastatic disease arising from primary carcinoma of the oral
cavity and oropharynx. This minimally
invasive technique has improved functional outcomes compared to selective
neck dissection.5
SNB is an accepted technique for the
management of breast carcinoma and melanoma. Its application to carcinoma of the
head and neck is, however, still under
research and needs to be validated. Large
multi-institutional clinical studies have
been conducted at Canniesburn Hospital
(UK)6 and by the American College of
Surgeons Oncology Group (ACOSOG),7
with two others still to be reported (the
Sentinel Node European Trial and the
Danish Head and Neck Cancer Group trial
(DAHANCA 22)).
SNB is an operator-sensitive technique
and the floor of the mouth (FOM) is an
anatomical area for which there is a high
risk of false-negative results. This is
attributed to radiation shine-through.
In this situation, the first echelon nodes
lie in such close proximity to the primary
tumour that the radiation from the colloid
injected around the primary lesion
obscures the radiation signal emitted from
first-order lymph nodes.810 Consequently, the rate of false-negatives
reported in other series for tumours in
the FOM is relatively high.6,7,10 The
objective of the present study was to
target our patients with squamous cell
carcinoma of the FOM and establish
whether the SNB technique is safe at this
site and produces comparable outcomes
to those in historical controls. In particular, the results would indicate whether
SNB has an adverse effect on outcomes
in this specific at-risk population.
Materials and methods

The two study cohorts, one a retrospective

group and the other consisting of patients
managed prospectively, were selected
from the records of the maxillofacial
department. Before commencing the
study, local research ethics committee
approval was obtained.
In the period 19912000, a total of 200
consecutive patients with histologically
confirmed T1T2 N0 M0 squamous cell
carcinoma of the oral cavity received
definitive curative treatment. The primary
carcinoma was located in the FOM in 35
of these patients and they represent the

historical control group for the present

study. These patients were treated by wide
local excision and either clinical observation of the neck (n = 9) or elective neck
dissection (n = 26).
The second group comprised 60
patients, again all with T1T2 N0 M0 oral
squamous cell carcinoma, who were part
of a prospective sentinel node trial (2001
2005). Within this group, there were 28
patients with cancer of the FOM and they
represent the test population.
The test group was treated in a similar
way to the traditional treatment cohort,
namely by wide local excision of the
primary tumour, but at the time of surgery underwent SNB. In the event that
the sentinel node was negative, the neck
was simply observed; if it was positive,
the patient went on to have a therapeutic
neck dissection (i.e., as treatment rather
than elective surgery). The technique of
SNB used has been reported before811;
in brief, 0.2 ml of a radionuclide marker
(Nanocoll labelled with Tc-99, 40
50 MBq) is injected around the periphery
of the tumour, 0.51 cm from the margins, and lymphatic mapping is performed by preoperative dynamic
lymphoscintigraphy (LSG). All imaging
was carried out within 24 h before surgery. We considered the first node on the
lymphatic drainage pathway from the
primary tumour to be the sentinel node.
Prior to surgery, a hand-held gamma
probe was used to identify the sentinel
node by detecting the radiation with a
Geiger counter, and the site was marked
on the patients skin. We used patent blue
V dye and malleable lead blocks to assist
location in the shine-through level I area.
In the case of tumours within 2 cm of the
midline, contralateral lymph nodes (as
well as the ipsilateral ones) were considered for study.
The retrieved sentinel nodes were
examined in detail by serial sectioning
and dual-staining immunohistochemistry
with haematoxylin and eosin (H&E) and
cytokeratin.611 Most of our sentinel node
patients were recruited in a multi-institutional study,10 and the protocol for the
selection and evaluation of sentinel nodes
was defined at that time. In brief, no frozen
sections were allowed and formalin-fixed
specimens were examined using H&E and
cytokeratin staining, as described in detail
in the report of the previous study.10 The
recruitment of that study started in 1998
and finished in 2002; at that time, a protocol was submitted to the European Organisation for Research and Treatment of
Cancer (EORTC) culminating in the Sentinel Node European Trial, and the two

studies had similar protocols: when the SN

was positive for occult disease, neck dissection was undertaken within 3 weeks of
the original surgery. Type III modified
radical neck dissections were performed,
as in the Canniesburn trial,8 being carried
out once a positive sentinel node had been
confirmed. The neck dissection nodes
were examined first by direct inspection
and then further investigated by conventional H&E staining.
The use of immunocytochemistry for
cytokeratin has allowed larger numbers
of positive sentinel nodes to be
detected.10,12 On the other hand, the meaning of these findings has not yet been
established for the head and neck.
The follow-up period was >5 years for
both the test and historical control groups.
The statistical analysis was performed
with SPSS 16.0 (SPSS Inc., Chicago, IL,
USA). The survival rate was calculated by
KaplanMeier method and the log rank
test was used to assess differences in
survival between groups. A result was
considered significant when the P-value
was less than 0.05.
Results

The combined study group included 63

patients with carcinoma of the FOM who
were treated with curative intent. The
mean age of the combined traditional control and sentinel node patients was 61.21
years (range 4187 years), with 89% of
patients being men. The position of the
tumour and stage distribution in each of
the groups is shown in Table 1.
In the retrospective group (n = 35),
occult metastasis was detected in 40%
of cases (clinical observation 4/9; neck
dissection 10/26). In the prospective sentinel node group (n = 28), occult disease
was present in 39% of the patients (positive SNB 7/28; false-negatives 4/28).
Of the 28 SNB cases, the midline was
affected in eight cases, which could correspond to 36 neck dissections. In these
patients, no contralateral necks were
involved; there were seven positive nodes
and four false-negatives. Overall, this
could mean the percentage of unnecessary
neck dissections avoided by SNB in our
series was 69.5%.
Patients in both groups received
postoperative radiotherapy: traditional
Table 1. Midline affected by groups.
Treatment group Midline Lateral T1 T2
Traditional
SNB

9
9

SNB, sentinel node biopsy.

26
19

15 20
21 7

Sentinel node biopsy in floor of mouth carcinoma

Table 2. Distribution of recurrence in the two
study groups.
Treatment
group

Local

Locoregional

Regional

Traditional
SNB

9
1

1
2

8
7

SNB, sentinel node biopsy.

Discussion

Table 3. Crude, disease-specific, and diseasefree survival in the two study groups.
Study
group
Traditional
SNB
Total

Crude
(%)
57.6
70.8
63.1

Group comparisons with the log rank

test indicated that the difference in the
survival rate between the traditional treatment group and the prospective sentinel
node group was not significant (P = 0.17).

Diseasespecific (%)
65.5
85
73.5

Diseasefree (%)
39.4
62.5
49.1

SNB, sentinel node biopsy.

treatment group 57% vs. sentinel node

group 25%.
Recurrent disease was observed in 44%
of cases, and the distribution of recurrence
by site for the two groups is shown in
Table 2. The shortest time to recurrence
was 2 months and the longest 48 months,
with a median disease-free interval of 13.7
months (standard deviation 12.3 months).
The 5-year crude survival rate was
63.1% in both groups. Disease-specific
and disease-free survival rates were
65.5% and 39.4%, respectively, with
the traditional approach, and 85% and
62.5%, respectively, in the SNB group
(Table 3). A total of six patients were lost
to follow-up.

The prevalence of cervical metastasis

from early carcinoma of the mouth is
relatively high (2030%).1320 The optimum management of the N0 neck remains
controversial; a wait and see policy has
been advocated by some groups,1,10,11
while others have suggested that there is
a poorer outcome with this approach.21
Data obtained from prospective randomized trials are limited and at present
there is insufficient evidence to conclude
that END improves survival over close
observation.22 Further, a recent Cochrane
review23 concluded that there was no
evidence that END increased overall or
disease-free survival compared to a therapeutic neck dissection.
SNB is a new diagnostic tool that
allows microscopic deposits of tumour to
be detected in cervical lymph nodes.6,7,12
The advantage of this approach is that
treatment is tailored to the individual patient
with only those who have positive sentinel
node(s) going forward to a therapeutic neck
dissection and the remaining 69.5% being
spared this procedure. It is, however, well
established that false-negative results occur
with SNB, and in melanoma patients the

271

false-negative rate is a similar figure to that

in oral cancer.
The Canniesburn study,6,8 ACOSOG7
study, and Sentinel Node European Trial
(in press) have found false-negative rates
of 5%, 7.1%, and 13%, respectively. In the
current study of FOM cancer, in which one
might expect a high level of false-negatives, the rate was still only 14% (4/28).
On reflection, these false-negative cases
mimic the management of patients treated
by a wait and see policy in the traditional
treatment group. The literature and our
results suggest that patients with falsenegative results are not disadvantaged
by a late therapeutic neck dissection. It
would, nevertheless, be prudent when
managing FOM cancers by SNB to undertake a careful exploration of level I
nodes.10,12
The rates of regional failure (alone) for
the prospective sentinel node and control
groups were 25% (7/28) and 23% (8/35),
respectively, which is comparable to
results in the literature (Table 4). The
regional control of disease after neck
recurrence in the control group was 25%
and in the sentinel node group 29%; this
difference is not statistically significant.
Recently, an unexpectedly high rate of
neck failure (40%) has been reported in
early T1T2 N0 tongue tumours with 33%
of regional control,24 related to the depth
of the invasion (which may be a pathologic factor to be aware of after the use of the
sentinel node technique) and apparently

Table 4. Comparison of results between series.

Stage
T1T2

Occult
metastases,
stage III

Local
recurrence,
IIV

Regional
failure,
IIV

Loco-regional
failure, IIV

5-year
survival,
III

FOM series

Year

Sessions et al.13
(n = 280)
Hicks et al.14
(n = 99)
McGuirt et al.19
(n = 129)
Cole et al.16
(n = 70)c
Steinhart and
Kleinsasser20
(n = 56) (surgery)
Nason et al.15
(n = 209)
Shaha et al.18
(n = 320)
Ildstad et al.17
(n = 163)
Our seriesd

2000

74

41.2%

18.5%

9.2%

72.462.8%

1997

52

2162%

26%

9586%

1995

116

19%
(III)a
3%

3130.5%
(III)

32%

9685%b

1994

40

2433%
(III)

7770%

1992
1989

105

1984

155

1983

93

63

31.537.2%

55.8%

57%

43%

29%
(IIV)
17%
(IIV)

28%

59%

21.9%

6964%

21%

37%

29%

8880%

1720%
(III)
14.3%
(III)

17%
(I)
23.8%
(III)

20%
(II)
4.8%
(III)

6461%

38.2%

FOM, floor of the mouth carcinoma.

a
Patients treated with surgery alone.
b
Survival elective neck dissection vs. observation (stages I, II, III, and IV).
c
70/183 patients had surgery  radiotherapy.
d
Regional recurrence by groups (elective neck dissection and observation 33.33%, SNB group 25%).

8050%
(T1T2)

73.5%

272

Alvarez et al.

Fig. 1. Survival by study group.

not related to the presence of micrometastases.

In FOM cancer, poor outcome has been
attributed to failure to control the primary
lesion. In our study, this factor was responsible for a third of deaths in the control
group and a fifth in the sentinel node
group. The rates of patients with local
and loco-regional recurrence in both the
control and test groups (10/35, 29% and 3/
28, 11%, respectively) are similar to figures reported in other series.12,14,17
In the sentinel group, the 5-year diseasespecific survival was 85%, with a mean
follow-up of 80 months (95% confidence
interval 6792 months) (Fig. 1), which is
comparable to the outcomes in other series1220 (Table 4). This disease-specific
survival is very high, which suggests that
the technique is able to identify patients
at risk, meaning that it would enable us
to use a more aggressive therapeutic
approach in such cases.
The current study does not provide statistically significant evidence of a better
prognosis when using the sentinel node
technique, rather it confirms that the presence of neck disease (either macroscopic
or microscopic) has a negative impact on
survival.12,23 Specifically, there was a
positive association between the presence
of occult disease, neck recurrence, and
lower survival, whereas other authors have
not found any association between the
presence of micrometastases and neck
recurrence.24 On the other hand, our
results do indicate that the use of SNB

in the at-risk population with the primary

cancer in the FOM does not adversely
affect outcomes when compared to historical controls. It is as safe as END, yet
spares 69.5% of patients from an END.
Accordingly, it can be recommended for
use in patients with early stage FOM
tumours.

3.

4.

Funding

No source of funding for this research.

5.

Competing interests

No conflict of interest.
6.

Ethical approval

Ethical approval was given by the hospital

ethics committee.
7.

Acknowledgement. We thank the nuclear

medicine and pathology departments for
their contributions to this study.

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Corresponding author at:

Department of Oral and Maxillofacial
Surgery
BioCruces Health Research Institute
Hospital Universitario Cruces
University of the Basque Country
Plaza de Cruces s/n
Barakaldo 48903
Spain
Tel.: +34 94 6006469
E-mail: jalvarezamezaga@telefonica.net