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TRANSCRIPT
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Clinical
Paper
Head and Neck Oncology
Sentinel node biopsy in relationto survival in floor of the mouthcarcinoma§
J.
Alvarez,
A.
Bidaguren,
M.
McGurk,
G.
Diaz-Basterra,
J.
Brunsó , B. Andikoetxea,
J.
C.
Martı́n, L.
Barbier,
I.
Arteagoitia,
J.
A.
Santamarı́a:
Sentinel node biopsy in relation to survival in floor of the mouth carcinoma. Int. J. Oral Maxillofac. Surg. 2014; 43: 269–273. # 2013 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
J.
Alvareza,
A.
Bidagurena,M. McGurk b, G. Diaz-Basterraa,J.
Brunsó a,
B.
Andikoetxeaa,J.
C.
Martı́ na,
L.
Barbiera,I.
Arteagoitiaa,
J.
A.
Santamarı́ aa
aDepartment of Oral and MaxillofacialSurgery, BioCruces Health Research Institute,Hospital Universitario Cruces, University ofthe Basque Country, Spain; bDepartment of
Oral and Maxillofacial Surgery, Guy’s and StThomas’ Hospital, London, UK
Abstract. Promising results have been obtained with sentinel node biopsy (SNB) inearly 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
safetyof
SNB
by
comparing
survival
among
patients
with
early
stage
carcinoma
of
thefloor 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
ENDand 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
weresuccessfully
treated
by
salvage
surgery.
Disease-specific
survival
was
65.5%
for control patients and 85% for SNB patients; the difference was not statisticallysignificant. The use of SNB in the management of cancers of the FOM did notadversely
affect
survival
and
prevented
69.5%
of
patients
undergoing
unnecessaryneck
dissections,
while
clinical
progress
was
better
in
the
SNB
group
than
incontrols.
Keywords: head and neck neoplasms; sentinelnode biopsy; N0 neck; floor of the mouth.
Accepted for publication 24 October 2013Available online 2 December 2013
The assessment of metastatic disease inearly stage oral and oropharyngealtumours has not changed significantlyover the last three decades and with itthe debate as to the optimum treatment of the N0 neck. On the basis of evidence
available so far, it has not been possibleto decide between elective neck dissec-tion (END) and observation, as overallsurvival as well as disease-free survivalare similar using both of theseapproaches.1,2 Some authors championelective neck dissection,3 others a ‘waitand see’ policy.4 Various retrospectivestudies have been published, but there isno consensus in the resulting recommen-dations.
The challenge is to identify patientswith occult cervical metastasis at the timeof presentation. Current radiological tech-niques are not sufficiently sensitive todetect small tumour deposits, and at pre-sent the standard of care adopted world-wide is END.
If it were to be accepted that there islittle or no difference in survival betweenthe ‘wait and see’ approach and END, thenthere would be no intellectual reason not
Int. J. Oral Maxillofac. Surg. 2014; 43: 269–273http://dx.doi.org/10.1016/j.ijom.2013.10.022,
available online at http://www.sciencedirect.com
§ This
paper
was
presented
at
the
4th
Inter-national
Conference
on
Sentinel
Node
Biopsyin Mucosal
Head
and
Neck
Cancer,
Copenha-gen, Denmark, June 2010.
0901-5027/030269 + 05 $36.00/0 # 2013 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ijom.2013.10.022http://dx.doi.org/10.1016/j.ijom.2013.10.022http://dx.doi.org/10.1016/j.ijom.2013.10.022http://dx.doi.org/10.1016/j.ijom.2013.10.022
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to promote a conservative approach thatcautiously tries to limit the number of ENDs performed by using the techniqueof sentinel node biopsy (SNB). The latter is the most recent innovation in the iden-tification of micrometastatic disease aris-ing from primary carcinoma of the oralcavity and oropharynx. This minimally
invasive technique has improved func-tional outcomes compared to selectiveneck dissection.5
SNB is an accepted technique for themanagement of breast carcinoma and mel-anoma. Its application to carcinoma of thehead and neck is, however, still under research and needs to be validated. Largemulti-institutional clinical studies have been conducted at Canniesburn Hospital(UK)
6and by the American College of
Surgeons Oncology Group (ACOSOG),7
with two others still to be reported (theSentinel Node European Trial and the
Danish
Head
and
Neck
Cancer
Group
trial(DAHANCA 22)).
SNB is an operator-sensitive techniqueand the floor of the mouth (FOM) is ananatomical area for which there is a highrisk of false-negative results. This isattributed to radiation ‘shine-through’.In this situation, the first echelon nodeslie in such close proximity to the primarytumour that the radiation from the colloid injected around the primary lesionobscuresthe radiation signal emitted fromfirst-order lymph nodes.
8–10Conse-
quently, the rate of false-negatives
reported
in
other
series for tumours inthe FOM is relatively high.6,7,10 Theobjective of the present study was totarget our patients with squamous cellcarcinoma of the FOM and establishwhether the SNB technique is safe at thissite and produces comparable outcomesto those in historical controls. In particu-lar, the results would indicate whether SNB has an adverse effect on outcomesin this specific at-risk population.
Materials and methods
The two study cohorts, one a retrospectivegroup and the other consisting of patientsmanaged prospectively, were selected from the records of the maxillofacialdepartment. Before commencing thestudy, local research ethics committeeapproval was obtained.
In the period 1991–2000, a total of 200consecutive patients with histologicallyconfirmed T1–T2 N0 M0 squamous cellcarcinoma of the oral cavity received definitive curative treatment. The primarycarcinoma was located in the FOM in 35of these patients and they represent the
historical control group for the presentstudy. These patients were treated by widelocal excision and either clinical observa-tion of the neck (n = 9) or elective neck dissection (n = 26).
The second group comprised 60 patients, again all with T1–T2 N0 M0 oralsquamous 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 theyrepresent 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 sur-gery underwent SNB. In the event thatthe sentinel node was negative, the neck was simply observed; if it was positive,the patient went on to have a therapeuticneck dissection (i.e., as treatment rather than elective surgery). The technique of
SNB
used
has
been reported before8–11
;in brief, 0.2 ml of a radionuclide marker (Nanocoll labelled with Tc-99, 40– 50 MBq) is injected around the peripheryof the tumour, 0.5–1 cm from the mar-gins, and lymphatic mapping is per-formed by preoperative dynamiclymphoscintigraphy (LSG). All imagingwas carried out within 24 h before sur-gery. We considered the first node on thelymphatic 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
aGeiger counter, and the site was marked on the patient’s skin. We used patent blueV dye and malleable lead blocks to assistlocation in the shine-through level I area.In the case of tumours within 2 cm of themidline, contralateral lymph nodes (aswell as the ipsilateral ones) were consid-ered for study.
The retrieved sentinel nodes wereexamined in detail by serial sectioningand dual-staining immunohistochemistrywith haematoxylin and eosin (H&E) and cytokeratin.6–11 Most of our sentinel node patients wer e r ecruited in a multi-institu-tional study,10 and the protocol for theselection and evaluation of sentinel nodeswas defined at that time. In brief, no frozensections were allowed and formalin-fixed specimens were examined using H&E and cytokeratin staining, as described in d etailin the report of the previous study.10 Therecruitment of that study started in 1998and finished in 2002; at that time, a pro-tocol was submitted to the European Orga-nisation for Research and Treatment of Cancer (EORTC) culminating in the Sen-tinel Node European Trial, and the two
studies had similar protocols: when the SNwas positive for occult disease, neck dis-section 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 beenconfirmed. The neck dissection nodes
were examined first by direct inspectionand then further investigated by conven-tional H&E staining.
The use of immunocytochemistry for cytokeratin has allowed larger numbersof positive sentinel nodes to bedetected.10,12 On the other hand, the mean-ing of these findings has not yet beenestablished 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
Kaplan–Meier
method
and
the
log
rank test was used to assess differences insurvival between groups. A result wasconsidered significant when the P-valuewas less than 0.05.
Results
The combined study group included 63 patients with carcinoma of the FOM whowere treated with curative intent. Themean age of the combined traditional con-trol and sentinel node patients was 61.21years (range 41–87 years), with 89% of
patients
being
men.
The
position
of
thetumour 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 sen-tinel node group (n = 28), occult diseasewas present in 39% of the patients (posi-tive SNB 7/28; false-negatives 4/28).
Of the 28 SNB cases, the midline wasaffected in eight cases, which could cor-respond to 36 neck dissections. In these patients, no contralateral necks were
involved;
there
were
seven
positive
nodesand four false-negatives. Overall, thiscould mean the percentage of unnecessaryneck dissections avoided by SNB in our series was 69.5%.
Patients in both groups received postoperative radiotherapy: traditional
270 Alvarez et al.
Table 1. Midline affected by groups.
Treatment
group
Midline
Lateral
T1
T2
Traditional
9
26
15
20SNB 9 19 21 7
SNB,
sentinel
node
biopsy.
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treatment group 57% vs. sentinel nodegroup 25%.
Recurrent disease was observed in 44%
of cases,
and
the
distribution
of
recurrence by site for the two groups is shown inTable 2. The shortest time to recurrencewas 2 months and the longest 48 months,with a median disease-free interval of 13.7months (standard deviation 12.3 months).
The 5-year crude survival rate was63.1% in both groups. Disease-specificand disease-free survival rates were65.5% and 39.4%, respectively, withthe traditional approach, and 85% and 62.5%, respectively, in the SNB group(Table 3). A total of six patients were lostto follow-up.
Group comparisons with the log rank test indicated that the difference in thesurvival rate between the traditional treat-ment group and the prospective sentinelnode group was not significant ( P = 0.17).
Discussion
The prevalence of cervical metastasisfrom early carcinoma of the mouth isrelatively high (20–30%).13–20 The opti-mum management of the N0 neck remainscontroversial; a ‘wait and see’ policy has been advocated by some groups,
1,10,11
while others have suggested that there isa poorer outcome with this approach.21
Data obtained from prospective rando-mized trials are limited and at presentthere is insufficient evidence to concludethat END im proves survival over closeobservation.22 Further, a recent Cochranereview23 concluded that there was no
evidence that END increased overall or disease-free survival compared to a ther-apeutic neck dissection.
SNB is a new diagnostic tool thatallows microscopic deposits of tumour to be detected in cervical lymph nodes.6,7,12
The advantage of this approach is thattreatment is tailored to the individual patientwith only those who have positive sentinelnode(s) going forward to a therapeutic neck dissection and the remaining 69.5% beingspared this procedure. It is, however, wellestablished that false-negative results occur with SNB, and in melanoma patients the
false-negative rate is a similar figure to thatin oral cancer.
The Canniesburn study,6,8 ACOSOG7
study, and Sentinel Node European Trial(in press) have found false-negative ratesof 5%, 7.1%, and 13%, respectively. In thecurrent study of FOM cancer, in which onemight expect a high level of false-nega-
tives, 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 traditionaltreatment group. The literature and our results suggest that patients with false-negative results are not disadvantaged by a late therapeutic neck dissection. Itwould, nevertheless, be prudent whenmanaging FOM cancers by SNB to under-take a careful exploration of level Inodes.
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 toresults in the literature (Table 4). Theregional control of disease after neck recurrence in the control group was 25%and in the sentinel node group 29%; thisdifference is not statistically significant.Recently, an unexpectedly high rate of neck failure (40%) has been reported inearly T1–T2 N0 tongue tumours with 33%of regional control,24 related to the depthof the invasion (which may be a patholo-gic factor to be aware of after the use of thesentinel node technique) and apparently
Sentinel node biopsy in floor of mouth carcinoma 271
Table
4.
Comparison
of
results
between
series.
FOM
series
Year StageT1–T2
Occultmetastases,stage
I–II
Localrecurrence,I–IV
Regionalfailure,I–IV
Loco-regionalfailure,
I–IV
5-year survival,I–II
Sessions
et
al.13
(n = 280)2000
74
–
41.2%
18.5%
9.2%
72.4–62.8%
Hicks
et
al.14
(n = 99)1997
52
21–62%
19%(I–II)a
26%
–
95–86%
McGuirt et al.19
(n = 129)1995 116 31.5–37.2% 3% 31–30.5%
(I–II)32% 96–85% b
Cole
et
al.16
(n
=
70)c1994
40
24–33%(I–II)
77–70%
Steinhart and Kleinsasser 20
(n = 56) (surgery)
1992 55.8% 57% 43% -
80–50%(T1–T2)
Nason
et
al.15
(n = 209)1989
105
29%(I–IV)
28%
59%
21.9%
69–64%
Shaha
et
al.18
(n = 320)1984
155
17%(I–IV)
21%
37%
29%
88–80%
Ildstad
et
al.17
(n = 163)1983
93
17–20%(I–II)
17%(I)
20%(II)
64–61%
Our
seriesd –
63
38.2%
14.3%(I–II)
23.8%(I–II)
4.8%(I–II)
73.5%
FOM,
floor
of
the
mouth
carcinoma.aPatients
treated
with
surgery
alone. bSurvival
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%).
Table 3. Crude, disease-specific, and disease-free
survival
in
the
two
study
groups.
Studygroup
Crude(%)
Disease-specific
(%)Disease-free
(%)
Traditional
57.6
65.5
39.4SNB
70.8
85
62.5Total
63.1
73.5
49.1
SNB,
sentinel
node
biopsy.
Table 2. Distribution of recurrence in the twostudy
groups.
Treatmentgroup
LocalLoco-regional
Regional
Traditional
9
1
8SNB 1 2 7
SNB,
sentinel
node
biopsy.
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not related to the presence of micrometas-tases.
In FOM cancer, poor outcome has beenattributed to failure to control the primarylesion. In our study, this factor was respon-sible for a third of deaths in the controlgroup and a fifth in the sentinel nodegroup. The rates of patients with localand loco-regional recurrence in both the
control
and
test
groups
(10/35,
29%
and
3/28, 11%, respectively) are similar to fig-ures reported in other series.
12,14,17
In the sentinel group, the 5-year disease-specific survival was 85%, with a meanfollow-up of 80 months (95% confidenceinterval 67–92 months) (Fig. 1), which iscompar able to the outcomes in other ser-ies12–20 (Table 4). This disease-specificsurvival is very high, which suggests thatthe technique is able to identify patientsat risk, meaning that it would enable usto use a more aggressive therapeuticapproach in such cases.
The current study does not provide sta-tistically significant evidence of a better prognosis when using the sentinel nodetechnique, rather it confirms that the pre-sence of neck disease (either macroscopicor microscopic) has a negative impact onsurvival.12,23 Specifically, there was a positive association between the presenceof occult disease, neck recurrence, and lower survival, whereas other authors havenot found any association between the presence of micrometastases and neck recurrence.
24On the other hand, our
results do indicate that the use of SNB
in the at-risk population with the primarycancer in the FOM does not adverselyaffect outcomes when compared to histor-ical controls. It is as safe as END, yetspares 69.5% of patients from an END.Accordingly, it can be recommended for use in patients with early stage FOMtumours.
Funding
No source of funding for this research.
Competing interests
No conflict of interest.
Ethical
approval
Ethical approval was given by the hospitalethics committee.
Acknowledgement. We thank the nuclear
medicine and pathology departments for their contributions to this study.
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272 Alvarez et al.
Fig. 1. Survival by study group.
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Corresponding
author
at: Department
of
Oral
and
MaxillofacialSurgery
BioCruces
Health
Research
Institute Hospital
Universitario
CrucesUniversity of the Basque CountryPlaza
de
Cruces
s/n Barakaldo
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Sentinel node biopsy in floor of mouth carcinoma 273
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