CLINICAL REVIEW

David W. Eisele, MD, Section Editor

Advances in diagnostic modalities to detect occult lymph node metastases in head and
neck squamous cell carcinoma
Remco de Bree, MD, PhD,1* Robert P. Takes, MD, PhD,2 Jonas A. Castelijns, MD, PhD,3 Jesus E. Medina, MD,4 Sandro J. Stoeckli, MD,5
Anthony A. Mancuso, MD,6 Jennifer L. Hunt, MD,7 Juan P. Rodrigo, MD, PhD,8,9 Asterios Triantafyllou, FRCPath, PhD,10 Afshin Teymoortash, MD,11
Francisco J. Civantos, MD,12 Alessandra Rinaldo, MD, FRCSEd ad hominem, FRCS (Eng, Ir) ad eundem FRCSGlasg,13 Karen T. Pitman, MD,14
Marc Hamoir, MD,15 K. Thomas Robbins, MD, FRCSC,16 Carl E. Silver, MD,17 Otto S. Hoekstra, MD, PhD,3 Alfio Ferlito, MD, DLO, DPath, FRCSEd ad
hominem, FRCS (Eng, Glasg, Ir) ad eundem, FDSRCS ad eundem, FHKCORL, FRCPath, FASCP, IFCAP13
1

Department of OtolaryngologyHead and Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands, 2Department of OtolaryngologyHead and Neck Surgery,
Radboud University Medical Center, Nijmegen, The Netherlands, 3Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands,
4
Department of Otorhinolaryngology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, 5Department of OtorhinolaryngologyHead and Neck Surgery, Kantonsspital, St. Gallen, Switzerland, 6Department of Radiology, University of Florida College of Medicine, Gainesville, Florida, 7Department of Pathology, University of
Arkansas for Medical Sciences, Little Rock, Arkansas, 8Department of Otolaryngology, Hospital Universitario Central de Asturias, Oviedo, Spain, 9Instituto Universitario de
Oncologa del Principado de Asturias, Oviedo, Spain, 10Oral Pathology, School of Dentistry, University of Liverpool, Liverpool, United Kingdom, 11Department of Otolaryngology
Head and Neck Surgery, University of Marburg, Marburg, Germany, 12Department of OtolaryngologyHead and Neck Surgery, Sylvester Comprehensive Cancer Center, University
of Miami, Miami, Florida, 13University of Udine School of Medicine, Udine, Italy, 14Department of Surgery, Banner MD Anderson Cancer Center, Gilbert, Arizona, 15Department of
Head and Neck Surgery, Head and Neck Oncology Program, St. Luc University Hospital and Cancer Center, Brussels, Belgium, 16Division of OtolaryngologyHead and Neck Surgery, Southern Illinois University School of Medicine, Springfield, Illinois, 17Departments of Surgery and OtolaryngologyHead and Neck Surgery, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York.

Accepted 18 June 2014

Published online 26 September 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.23814

ABSTRACT: Regional metastasis is a prominent feature of head and

neck squamous cell carcinoma (HNSCC) and is an important prognostic
factor. The currently available imaging techniques for assessment of the
neck have limitations in accuracy; thus, elective neck dissection has
remained the usual choice of management of the clinically N0 neck
(cN0) for tumors with significant (20%) incidence of occult regional
metastasis. As a consequence, the majority of patients without regional
metastasis will undergo unnecessary treatment. The purpose of this
review was to discuss new developments in techniques that potentially
improve the accuracy of the assessment of the neck in patients with

HNSCC. Although imaging has improved in the last decades, a limitation

common to all imaging techniques is a lack of sensitivity for small tumor
deposits. Therefore, complementary to improvements in imaging techniques, developments in more invasive diagnostic procedures, such as
sentinel node biopsy (SNB) will add to the accuracy of diagnostic algoC 2014 Wiley Periodicals, Inc. Head
rithms for the staging of the neck. V
Neck 37: 18291839, 2015

INTRODUCTION

general agreement that elective treatment of the neck is

indicated when there is a high likelihood of occult (clinically and radiologically undetectable) lymph node metastasis, when the neck needs to be entered to resect the
primary tumor or reconstruct the surgical defect, or when
the feasibility of regular follow-up is questionable. The
risk of occult metastasis depends on site, stage, and other
tumor characteristics. Histopathological features of the
primary tumor, such as differentiation, growth pattern,
thickness, depth of invasion, lymphovascular or vascular
invasion, perineural invasion and degree of inflammatory
reaction surrounding the tumor, and numerous biomarkers
have been evaluated with regard to their relevance in predicting nodal disease. Unfortunately, all these features
have limited prognostic value.1,2 It may be anticipated
that, in the near future, molecular biological diagnostic
techniques will be useful for reliable prediction of
(occult) lymph node metastases. Gene expression profiles
of tumor biopsies assessed by microarray hybridization

Head and neck squamous cell carcinoma (HNSCC) has a

high propensity to metastasize through lymphatics to
regional lymph nodes rather than to spread hematogenously. Moreover, regional metastasis at the time of diagnosis is one of the most important prognostic factors.
Patients with multiple, contralateral, or bilateral metastases in the neck have a markedly reduced survival. It is
universally accepted that the neck has to be addressed by
either surgery with or without adjuvant (chemo)radiation
or by primary (chemo)radiation in case of overt lymph
node metastases. However, management of the clinically
negative neck (cN0) is still a controversial issue. There is

*Corresponding author: R. de Bree, Department of OtolaryngologyHead and

Neck Surgery, VU University Medical Center, De Boelelaan 1117, 1081 HV
Amsterdam, PO Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail:
r.bree@vumc.nl

KEY WORDS: head and neck, squamous cell carcinoma, lymph node
metastasis, occult, diagnostic techniques

HEAD & NECKDOI 10.1002/HED

DECEMBER 2015

1829

DE

BREE ET AL.

have already proven their potential value for N classification as evidenced in a Dutch multicenter study of 101
early (cN0) oral squamous cell carcinomas (OSCC) in
which a negative predictive value of 89% was achieved.
Unfortunately, because of the positive predictive value of
only 37%, a substantial percentage of patients would
undergo unnecessary treatment of the neck if decisionmaking would have been based on this gene expression
profile.3
The rationale for elective treatment is based on the following assumptions. First, occult metastases will inevitably develop into clinically manifest disease. Second, even
with watchful waiting some patients will develop extensive or even inoperable disease in the neck with a wait
and see policy. Finally, if left untreated, disease in the
neck may be associated with a higher incidence of distant
metastases, developing while the undetected lymph node
metastasis is growing to a clinically detectable size. However, a causal relationship is speculative as the potential
for distant metastasis may also be considered a feature of
the primary tumor.4 The arguments against elective treatment of the neck are as follows. First, a large proportion
of patients are subjected to the morbidity (eg, shoulder
dysfunction5) and costs of unnecessary treatment. Second,
such treatment could alter a route of cancer spread in
case of local recurrence or second primary tumor. However, selective neck dissections may have a low incidence
of surgical complications and acceptable functional and
esthetic results.6
If the cN0 is not treated electively, close follow-up
with the obligatory use of diagnostic techniques, such as
ultrasound-guided fine-needle aspiration cytology (FNAC)
is an option in selected patients in order to detect occult
metastases at an early stage.79 With such strategies,
unnecessary elective neck dissections can be avoided in
the majority of patients without compromise of regional
control of the neck and survival. However, among those
patients who eventually need a (salvage) neck dissection
for delayed metastases, treatment of the neck will be
more extensive and associated with a higher morbidity
(eg, modified radical neck dissection with or without chemoradiotherapy instead of elective selective neck
dissection).9
Therefore, pretreatment identification of lymph node
metastasis is of utmost importance. Only reliable detection or exclusion of lymph node metastases can replace
elective neck treatment.
The purpose of this review was to discuss new developments in techniques that potentially improve the accuracy
of the assessment of the neck in patients with HNSCC.

Selection of patients and reference standards

In analyzing the potential of diagnostic modalities to
detect occult lymph node metastasis, it is important to
realize that the criteria to define the N0 neck may vary
among the different studies. The validity of clinical N0
classification is dependent on the diagnostic methods
used: studies that apply negative palpation to define the
N0 neck are likely to report higher sensitivity of a prospective staging technique than those that apply more
sophisticated assessments to define the N0 status. According to the Union for International Cancer Control TNM
1830

HEAD & NECKDOI 10.1002/HED

DECEMBER 2015

classification of malignant tumors, assessment of the neck

by physical examination and appropriate imaging is mandatory for staging of the neck. Apart from the fact that
palpation alone should not be considered sufficient for
appropriate staging of the neck, it is crucial that such
clinical studies accurately describe their definition of the
clinically or radiologically negative neck as different
(imaging) modalities have different diagnostic accuracies.10 Unfortunately, the cN0 is frequently not defined.
Histopathological examination of a neck dissection
specimen is often considered to be the best reference
(gold standard) to rule out metastases. However, routine
histopathological examination can miss minimal disease,
whereas step-serial sectioning and immunohistochemistry
can increase the yield by as much as 15.2%.11 Therefore,
by using routine histopathology as the reference standard,
some false-negative findings may be incorrectly scored as
true-negative. Therefore, long-term observation of the
untreated neck is the best reference standard to determine
the value of diagnostic techniques for detection of occult
lymph node metastasis. It is important to appreciate that
sensitivity of a diagnostic technique depends on the
applied reference standard.12

Diagnostic techniques to detect lymph node metastasis

Before performing studies on the detection of occult
lymph node metastasis, one must understand the potential
of new diagnostic techniques to detect clinically apparent
lymph node metastasis. For some diagnostic techniques,
results are limited or not yet available for cN0 and therefore studies also including clinically positive necks are
discussed in this review. If a new technique is capable of
demonstrating these lymph node metastases, it should
then be tested in the cN0 and be compared with standard
detection techniques. Moreover, applicability, availability,
and costs should be taken into account before considering
the new technique as an addition to the diagnostic workup
in routine clinical practice. Not all new techniques will be
universally available. For example, a relatively new technique, like diffusion weighted and especially perfusion
magnetic resonance imaging (MRI), are not universally
available at a sufficient high level. Obviously, before clinical introduction, strict criteria for test positivity are
required as well as high interobserver (or interoperator)
agreement.
To be implemented in clinical practice, diagnostic techniques should also be cost-effective. Consequently, sometimes new techniques show promising results but are
unlikely to be incorporated in routine clinical practice.
Radioimmunodiagnosis
using
radiolabeled
tumorassociated monoclonal antibodies seemed to have similar
accuracy for the detection of lymph node metastasis as
computed tomography (CT) and MRI, even using gamma
camera techniques.13 Although the performance of positron emission tomography (PET)-CT using monoclonal
antibodies labeled with 89-Zirconium is likely to be better
than single photon emission CT (SPECT) using antibodies
labeled with 99m-Technetium,14 it is unlikely that this
technique will be used routinely in cN0 patients as the
test will add too little to the diagnostic accuracy to justify
its additional costs and efforts.

DIAGNOSTIC

CT and MRI
Because of their superior anatomic resolution, CT and
MRI are now routinely used in the preoperative assessment of the primary tumor. If performed for evaluation of
the primary tumor, contrast-enhanced CT and MRI can
also be used to assess the lymph node status. Criteria for
recognition of lymph nodes as suspicious of containing
metastasis on conventional CT and MRI are mainly based
on the size of the node, contrast enhancement, and the
presence of central necrosis or extranodal extension.
Unfortunately, test positivity criteria were heterogeneous
in studies or have been described in insufficient detail to
allow for accurate meta-analysis. Depending on whether
specificity or sensitivity of a test is more desirable, different criteria may be used.
The following criteria for defining positive lymph node
disease were proposed by van den Brekel et al15: a minimal axial diameter of 10 mm (for level II, 11 mm),
groups of 3 or more borderline nodes and central radiolucency. Others have used different measurements (eg,
maximal axial diameter) for size criteria and also include
shape and internal abnormalities.16,17 Stoeckli et al18 used
the following criteria: nodes of any size with clear evidence of non-fat low density on contrast-enhanced CT;
more than 15 mm (greatest diameter) for nodes level II
and >10 mm for nodes located in other levels or maximum longitudinal/short axis diameter <2.0; spherical
shape (a supportive criterion in borderline sizes); and
groups of 3 or more borderline nodes.18
A recent meta-analysis on the detection of lymph node
metastasis in different body regions by ultra-small superparamagnetic iron oxide (USPIO)-enhanced MRI showed
that the diagnostic performance is higher than with conventional MRI, and that it is sensitive and specific for the
detection of lymph node metastases.19 Although the specificity of USPIO-MRI was better than that of precontrast
MRI, its potential contribution still remains limited by
technical problems regarding motion and susceptibility
artifacts as well as spatial resolution.20 Because of these
technical problems, it can be anticipated that USPIO-MRI
will not be reliable enough to detect occult lymph node
metastases in patients with HNSCC.

Ultrasound and ultrasound-guided FNAC

For ultrasound studies, besides the size of the node, the
following additional criteria have been used to distinguish
between normal nodes and those suspicious of containing
metastases: absence of an echogenic hilus, presence of
cystic or coagulation necrosis, presence of abnormal vessels, presence of eccentric cortical hypertrophy, and hypoechoic sonomorphology.18,21
Ultrasound-guided FNAC has the advantage of providing cytological evidence of the presence of metastatic
cells in lymph node metastasis. Specificity of the procedure is approximately 100% as false-positive results of
cytology are exceedingly rare. However, the sensitivity
and resulting overall accuracy of ultrasound-guided
FNAC for the neck is dependent on the criteria used to
select lymph nodes for cytological aspiration. It should be
noted that the aforementioned ultrasound criteria,
although valid, are rarely applicable for small lymph

MODALITIES FOR DETECTION OF LYMPH NODE METASTASIS

nodes (ie, those with an axial diameter of less than 7

8 mm).22 Currently, the most reliable criterion for assessing the nature of a lymph node and the selection of a
lymph node for aspiration is its size, measured as the
minimal axial diameter. Based on previous studies, lymph
nodes with a minimal axial diameter larger than 4 mm in
level II, and 3 mm in other levels of the neck should be
selected for ultrasound-guided FNAC in order to obtain
optimal sensitivity.23 Although sensitivity as high as 73%
for ultrasound-guided FNAC has been reported in patients
with HNSCC with a clinically (palpably) negative neck,24
2 multicenter studies have reported sensitivity of only
48% and 50% in N0 necks on palpation.25,26 These findings suggest that the results of ultrasound-guided FNAC
are highly dependent on the skills of the physicians performing the procedure.7 Ultrasound-guided FNAC, when
used in the initial diagnostic workup of early OSCC, was
demonstrated to decrease the risk of occult lymph node
metastasis to 21% as this was the percentage of patients
that developed regional metastasis in follow-up in a wait
and scan strategy of the cN0 neck after ultrasoundguided FNAC.8 In summary, advantages of ultrasoundguided FNAC are its relatively low cost, lack of radiation
exposure, low-threshold availability, and the possibility of
confirmation of sonographic findings by cytology. The
main drawbacks of ultrasound-guided FNAC are the limitation in detection of micrometastasis (because of sampling error of the aspirate), dependence on the experience
of the ultrasonographer and the cytologist, and the inaccessibility of retropharyngeal, paratracheal, and mediastinal lymph nodes.

PET
PET imaging with 18F-fluorodeoxyglucose (FDG) is a
functional modality that has been used increasingly for
staging of HNSCC. Combining PET and CT in modern
imaging equipment unites both anatomic and functional
imaging, providing more accurate diagnosis and improved
patient management compared with PET-only scanners.
Most scanners can provide state-of-the-art contrastenhanced CT and not just the low-dose CT required for
attenuation correction of the PET signals in a single scan
session. In tonsillar carcinomas, contrast-enhanced 18FFDG-PET-CT has been shown to perform better than
non-enhanced 18F-FDG-PET-CT in differentiating
between N0 and N1 necks, probably because of the high
prevalence of cystic lymph node metastases frequently
found in human papillomavirus-associated tonsillar carcinomas.27 Criteria for PET positivity are generally poorly
defined.
A meta-analysis conducted by Kyzas et al28 showed
that the use of 18F-FDG-PET only in pretreatment evaluation has good accuracy for assessment of lymph node
metastases in untreated patients with HNSSC, with a
pooled sensitivity of 79% (95% confidence interval
CI 5 72% to 85%) and pooled specificity of 86% (95%
CI 5 83% to 89%). In studies with head-to-head comparison of both 18F-FDG-PET and conventional diagnostic
tests like CT and MRI, sensitivity and specificity of 18FFDG-PET were 80% (95% CI 5 72% to 87%) and 86%
(95% CI 5 82% to 90%), respectively, whereas for the
HEAD & NECKDOI 10.1002/HED

DECEMBER 2015

1831

DE

BREE ET AL.

conventional diagnostic tests these figures were 75%

(95% CI 5 65% to 83%) and 79% (95% CI 5 72% to
85%), respectively.28 Roh et al29 compared preoperative
PET or PET-CT (only low-dose CT) with CT or MRI for
the detection of (occult and evident) lymph node metastases in 167 patients and reported a sensitivity of 90% to
91% and 76% to 77% and a specificity of 87% to 88%
and 81% to 83%, respectively, with similar accuracy of
PET only and PET-CT.29
Despite these promising results in an unselected (clinically node-positive and negative) population, a subgroup
meta-analysis showed that for cN0 patients sensitivity of
18F-FDG PET was only 50% (95% CI 5 37% to 63%),
which is similar to the figures found for ultrasoundguided FNAC in a population staged cN0 by palpation
alone, whereas specificity was 87% (95% CI 5 76% to
93%), which is inferior to ultrasound-guided FNAC; thus
emphasizing the inability of this imaging modality to
detect microscopic metastatic disease. Because the prevalence of the disease affects the predictive value of a test,
additional analyses were made. At lymph node tumor positivity, prevalences of 10%, 20%, 30%, 40%, 50%, 60%,
70%, and 80% in cN0 patients, negative predictive values
were 94%, 87%, 80%, 72%, 64%, 53%, 43%, and 30%,
respectively.28
In 18F-FDG-PET studies addressing patients with
HNSCC with cN0, reported sensitivity and specificity are
quite variable. Krabbe et al30 studied the accuracy of
18F-FDG-PET in 38 patients with OSCC and oropharyngeal SCC, clinically classified as N0 after physical examination. Using neck dissection specimens or follow-up as a
reference standard, a sensitivity of 50%, specificity of
97%, negative predictive value of 88%, and positive predictive value of 80% were found.30
Brouwer et al31 showed that PET studies applying routine histopathological evaluation reported much higher
sensitivities for detection of occult lymph node metastases
than those using step-serial sectioning and immunohistochemistry as the reference standard (67% to 100% vs 0%
to 40%).31 The difference between those groups is likely
to be explained by the fact that with the use of routine
histopathological examination as the reference standard,
small metastatic deposits are still missed resulting in
overrating of the sensitivity of the PET. An additional
explanation may be the differences in patient selection
and inclusion criteria: not unexpectedly, studies reporting
a low sensitivity included patients with both clinically
and ultrasonographically negative necks, whereas higher
sensitivities are reported if patients were included with a
negative neck on physical examination only.32 Several
studies have been conducted combining PET with (combinations of) other modalities in an attempt to increase
diagnostic accuracy.
Jeong et al33 showed that PET-CT (low-dose CT) was
more accurate than PET alone and contrast-enhanced CT
in the evaluation of the cervical lymph nodes in 47
patients with HNSCC with and without clinically apparent
lymph node metastases who were scheduled to undergo
neck dissection(s). The authors reported sensitivities of
91.8%, 80.3%, and 90.2%, and specificities of 98.8%,
92.8%, and 93.9%, respectively. Although low-dose CT is
used for attenuation correction, contrast-enhanced CT
1832

HEAD & NECKDOI 10.1002/HED

DECEMBER 2015

may be helpful for localization of increased 18F-FDG

uptake, thus differentiating between uptake in lymph
nodes and brown fat and increasing 18F-FDG-PET specificity.33 Ng et al34 showed that, for the detection of subclinical lymph node metastases, the visual correlation of
18F-FDG-PET with contrast-enhanced CT/MRI was more
accurate than 18F-FDG-PET alone. In 134 patients with
OSCC with a palpably negative neck, they found a sensitivity of 51.4%, which increased to 57.1% after visual
correlation with CT or MRI. This increment stemmed
from the correction of false-negative 18F-FDG-PET
results caused by necrotic nodes.34 Ozer et al35 reported a
sensitivity of 57% and specificity of 82% for the detection of occult metastasis by 18F-FDG-PET-CT in 112
patients with clinically negative necks on physical examination, CT, and/or MRI.35 Cetin et al36 recently reported
on the detection of occult lymph node metastasis by 18FFDG-PET low-dose CT using routine histopathological
examination of the neck dissection specimen as the reference standard in 17 patients with HNSCC with radiologically N0 neck (as defined by CT and MRI criteria15). A
sensitivity of 84.2% and a specificity of 76.5% were
found.
Lee et al37 performed 18F-FDG-PET-CT, CT, MRI,
and ultrasound in 114 patients with HNSCC. Lymph
nodes that were positive only on PET-CT were found at
48 levels in 33 patients and were correlated with the routine histopathological examination of the lymph node
level as the reference standard. A false-negative rate of
27% and a false-positive rate of 73% were found. The
authors suggest that lymph nodes that were positive only
on PET should be considered negative, especially in the
N0 neck and in the contralateral side of the neck.
Gilbert et al38 retrospectively analyzed the results of
PET-CT in 15 patients with cN0 on physical examination
who underwent salvage laryngectomy. Using routine histopathological examination of the neck dissection specimen as the reference standard a sensitivity of 70%,
specificity of 100%, positive predictive value of 100%,
and negative predictive value of 63% were found. The
authors consider the false-negative rate too high to warrant deferring neck dissection based on negative PET-CT.
More advanced PET-CT techniques include dual timepoint PET imaging (repeated PET within a few hours
after single 18F-FDG injection, exploiting the assumption
that 18F-FDG uptake in malignant tissue increases over
time and not with inflammation, the main source of falsepositive PET readings). Carlson et al39 examined dynamic
PET-CT imaging using 9 time points post-injection of
18F-FDG. Metastatic lymph nodes were defined as those
that showed an increase greater than or equal to 10%
over the baseline (90 minutes after injection) standardized
uptake values. Further analysis was performed on 119
lymph nodes, which show increased uptake at baseline
imaging. Using histopathological examination of each of
these lymph nodes as a reference standard, they reported
a sensitivity of 60.3% and a specificity of 70.5%.
Based on the evidence cited, the use of 18F-FDGPET(-CT) for detecting occult lymph node metastases is
currently not sufficiently reliable to avoid elective treatment of the neck.

DIAGNOSTIC

Sentinel node biopsy (SNB)

In an attempt to reliably select the lymph nodes that
contain metastases, the concept of analyzing the sentinel
lymph nodes has been introduced. Although not a new
technique, its application in the staging of the neck in
HNSCC, particularly OSCC, is relatively recent. The
procedure aims to identify the first echelon of draining
lymph node(s), the sentinel lymph node(s), which is
most likely to harbor metastasis. SNB is a diagnostic
staging procedure that is applied in a variety of tumor
types, including OSCC. The histopathologic status of the
sentinel lymph node should determine whether additional
treatment of the nodal basin should be performed in
case of metastatic involvement of the sentinel lymph
node. A negative sentinel lymph node, on the other
hand, justifies observation of the nodal basin. In short,
the routine sentinel lymph node procedure consists of
preoperative peritumoral injections of a 99mTc-labeled
colloid followed by lymphoscintigraphy using planar
and/or SPECT/CT imaging. Based on the preoperative
lymphoscintigraphy, the position of the sentinel lymph
node is marked on the skin and intraoperative detection
is possible by tumor injection of blue dye (coloration)
and by using a portable gamma probe (radionuclide
detection). After surgical removal, this sentinel lymph
node is investigated by histopathological examination
using step-serial sectioning and immunohistochemistry.40
SNB is a reliable diagnostic procedure for staging the
cN0 neck and identifying patients with occult nodal metastatic disease.
A recent meta-analysis showed a pooled sensitivity of
93% in HNSCC. The vast majority of the studies included
were performed in patients with early OSCCs. The diagnostic workup before considering a neck clinically negative varied substantially. The negative predictive value
ranged from 80% to 100%.41 In some institutions that
treat the majority of pharyngeal and laryngeal cancers
endoscopically, SNBs have been performed for these sites
as well. When this modality is used in clinical practice,
patients found to have positive SNBs undergo subsequent
neck dissection, whereas patients with a negative SNB
are carefully observed and are thus spared unnecessary
and more extensive surgery of the neck. Therefore, SNB
is considered to be more precise than imaging procedures
and less invasive than elective neck dissection. Moreover,
it is associated with significantly less postoperative morbidity and better shoulder function as compared to elective neck dissection.42 Current best practice guidelines
have been put forth, which provide a framework for the
evolving recommendations for the use of SNB in patients
with OSCC.40
A recent cost-effectiveness study in which 5 different
strategies for management of the cN0 (defined as N0
after imaging and ultrasound-guided FNAC) in patients
with OSCC were compared, predicted that the SNB followed by neck dissection (if positive) or watchful waiting
(if negative) is more cost-effective than elective neck dissection, watchful waiting, gene expression profiling
(GEP) followed by neck dissection (if high risk) and
GEP and sentinel lymph node procedure (in case of highrisk GEP) followed by neck dissection or watchful
waiting.43

MODALITIES FOR DETECTION OF LYMPH NODE METASTASIS

The findings of the aforementioned meta-analysis of

generally small studies may be confirmed by recent large
multicenter studies of which long-term follow-up data are
pending. A single center study of 79 patients with clinically (after ultrasound-guided FNAC) N0 early oral cancer found a sentinel lymph node detection rate of 99%, a
sensitivity of 91%, and a negative predictive value of
90%.44 This study showed evidence that the previously
reported promising short-term results can be sustained
through long-term follow-up. In a European multicenter
trial of 79 patients with clinically (not clearly defined)
N0 early oral cancer and a follow-up of at least 5 years, a
sensitivity of 87% and a negative predictive value of 94%
were found.45 The prospective observational multicenter
European Sentinel Node Trial with more than 400
patients, has completed accrual and is waiting for longterm follow-up.

Comparison of different imaging techniques

Because only a few studies compare the accuracy of
different imaging modalities cN0 patients with HNSCC,
also selected studies with unselected (cN0 and cN1)
patients with HNSCC will be discussed. van den Brekel
et al46 compared the performance of ultrasound, CT, and
MRI in 88 palpably N0 neck sides. Ultrasound-guided
FNAC was performed in only 43 neck sides. Routine histopathological examination of the neck dissection specimen was used as reference standard. Sensitivity,
specificity, and accuracy were for ultrasound 58%, 75%,
and 68%, for CT 49%, 78%, and 66%, for MRI 55%,
88%, and 75%, and for ultrasound-guided FNAC 73%,
100%, and 86%, respectively. Ultrasound-guided FNAC
did significantly better than the other diagnostic techniques.46 Stoeckli et al18 compared in 76 consecutive
patients with HNSCC the accuracy of CT, ultrasound,
ultrasound-guided FNAC, and 18F-FDG-PET-low-dose
CT to differentiate between N0 and N1 disease. Again,
ultrasound-guided FNAC had the best performance. Routine histopathological examination with immunohistochemistry of the neck dissection specimen served as the
reference standard. For CT, ultrasound, and ultrasoundguided FNAC, and PET-CT the sensitivity was 86.9%,
86.4%, 86.4%, and 86.4%, specificity was 53.8%, 57.1%,
85.7%, and 76.9%, positive predictive value was 89.8%,
89.5%, 85.7%, and 76.9%, and negative predictive value
was 46.7%, 50.0%, 60.0%, and 52,6%, respectively.18
Kovacs et al47 performed sentinel lymph node biopsy
in 39 patients with oral and oropharyngeal carcinoma
classified as N0 by 18F-FDG-PET and detected lymph
node metastasis in 8% of these patients. Civantos et al48
compared CT, 18F-FDG-PET, and sentinel lymph node
biopsy in 18 patients with OSCC. CT was negative for
lymph node metastasis in all patients. For 18F-FDG-PET
and SNB, the sensitivity was 27% and 91%, specificity
was 100% and 100%, positive predictive value was 100%
and 100%, and negative predictive was 47% and 88%,
respectively.
De Bondt et al49 performed a meta-analysis comparing
ultrasound, CT, MRI, ultrasound-guided FNAC, and
USPIO-MRI for the detection of lymph node metastases
in HNSCC. In this study, not all patients had a cN0. For
ultrasound, CT, MRI, ultrasound-guided FNAC, and
HEAD & NECKDOI 10.1002/HED

DECEMBER 2015

1833

DE

BREE ET AL.

USPIO-MRI, the mean sensitivity was 81% (95%

CI 5 6890), 87% (95% CI 5 7693), 81% (95%
CI 5 6591), 80% (95% CI 5 5792), and 74% (95%
CI 5 4491), the mean specificity was 76% (95%
CI 5 6287), 86% (95% CI 5 7493), 63% (95%
CI 5 4380), 98% (95% CI 5 9399), and 88% (95%
CI 5 6696), and the diagnostic odds ratio (a measure for
discriminatory power) was 14 (95% CI 5 6.629.7), 40
(95% CI 5 17.890.1), 7 (95% CI 5 3.117.8), 260 (95%
CI 5 51.71306), and 21 (95% CI 5 5.578.1), respectively. Ultrasound-guided FNAC showed the highest areas
under the curve.
To assess the diagnostic accuracy of 18F-FDG-PET in
detecting lymph node metastases in patients with
HNSCC, Kyzas et al28 performed a meta-analysis in
which a subgroup analysis was also done to compare
18F-FDG-PET with conventional radiological diagnostic
imaging methods (CT, MRI, CT/MRI, and ultrasoundguided FNAC). A total of 204 patients with cN0 HNSCC
were included in this analysis. No significant difference
was found. The data were too limited for comparison
based on the different types of conventional diagnostic
test separately.
Recently, a meta-analysis comparing CT, MRI, PET
(not otherwise specified), and ultrasound for the detection
of cervical lymph node metastasis in patients with
HNSCC with clinically (not defined) N0 necks was performed by Liao et al.50 There were no differences in sensitivity and specificity among these imaging modalities,
except that CT had a superior specificity as compared to
ultrasound. Because positive and negative predictive values of the test are dependent on the prevalence of the disease, these were calculated for different baseline
possibilities of lymph node metastasis. With preexamination nodal metastasis probabilities set at 10%,
20%, and 30%, the post-examination probabilities of positive nodal metastasis rates were 47%, 66%, and 77% for
CT; 27%, 46%, and 59% for MRI; 36%, 56%, and 69%
for PET; and 25%, 42%, and 56% for ultrasound, respectively. Negative nodal metastasis probabilities were 95%,
89%, and 82% for CT; 95%, 90%, and 84% for MRI;
96%, 91%, and 86% for PET; and 95%, 90%, and 84%
for ultrasound, respectively. In this study, ultrasoundguided FNAC was not included, for several methodological reasons. The most important studies are summarized
in Tables 1 [18, 28, 37, 39, 46, 49, 55] and 2 [25, 26, 28,
35, 41, 46, 50].

Recent and future developments

Imaging. CT and MRI can be used for the detection of
lymph node metastases when used for locoregional staging of HNSCC. However, as previously mentioned, both
modalities rely on size-related and morphological criteria
to differentiate between benign and malignant lymph
nodes. Their sensitivity is limited by the detection threshold to pick up small metastatic deposits and their specificity by the use of morphologic criteria in the absence of
cytological proof. However, recent developments in MRI
and the combination of different modalities, including
PET in particular, have the promise of improving the
diagnostic accuracy of these imaging modalities. These
1834

HEAD & NECKDOI 10.1002/HED

DECEMBER 2015

diagnostic techniques are not exclusively tested in

patients with cN0 necks.
Diffusion-weighted MRI uses strong magnetic field gradients to make the MRI signal sensitive to the molecular
motion of water and is able to characterize tissue and
generate imaging contrast based on differences in diffusion motion of water protons in the tissues. Diffusionweighted MRI measures differences in tissue microstructure based on the random displacement of water molecules. The differences in water mobility are quantified
using the apparent diffusion coefficient (ADC), which has
an inverse relationship with tissue cellularity. As such,
the technique is able to differentiate between tumoral tissue and normal or necrotic tissue.51 Abdel Razek et al52
performed a prospective study of 31 patients with
HNSCC with 87 cervical lymph nodes who underwent
diffusion-weighted MRI using the optimal threshold for
that study. They found a sensitivity of 98%, specificity of
88%, positive predictive value of 98.5%, and negative
predictive value of 83.7%. The smallest lymph node
detected measured 0.9 cm in diameter. Vandecaveye
et al51 prospectively determined that adding diffusionweighted MRI to conventional MRI increased the sensitivity of metastasis detection from 7% to 76% in normally
sized (49 mm) lymph nodes. In a later study, Dirix
et al53 found a sensitivity of 88.9% and a specificity of
97.4% per lymph node in 22 patients with locally
advanced HNSCC who underwent contrast-enhanced CT,
as well as MRI (with routine and diffusion-weighted
sequences) before neck dissection. Using morphologic criteria (minimal axial diameter >1 cm, internal attenuation
suggestive for necrosis, extracapsular extension, and/or
obliteration of fat or perivascular soft tissue planes) the
sensitivity of CT/MRI was 42.2% and the specificity was
93.5% in these patients. De Bondt et al54 evaluated 219
lymph nodes, predominantly smaller than 10 mm, in 16
consecutive patients with HNSCC. They found that, for
the diagnosis of lymph node metastasis, minimal axial
diameter larger than 10 mm and an optimal ADC threshold (1.0 3 1023 mm2/s) had a similar sensitivity (both
92.3%), but the specificity using the ADC threshold was
higher (60.0% vs 83.9%). The area under the curve
improved from 0.91 to 0.98 when ADC was added to
morphological criteria (size, border, and signal intensity).
A recent meta-analysis on the value of MRI for nodal
staging in patients with HNSCC showed that the subgroup
of MRI with diffusion-weighted imaging had a significantly higher pooled sensitivity (86%; 95% CI 5 7892)
than conventional MRI (71%; 95% CI 5 6879). The
specificity was similar: 95%; CI 5 9397 and 95%; 95%
CI 5 9297, respectively.55
The addition of diffusion weighted-MRI to conventional MRI for the detection of (subcentimeter) lymph
node metastasis is promising but is probably limited in
patients with HNSCC with a cN0. Dispersed small deposits in an otherwise healthy nodal architecture are less
likely to build up sufficient tumor boundaries to restrict
water diffusion.53 Further studies of this technique that
focus on the clinically N0 neck are needed.
Perfusion CT may be useful for differentiation between
malignant and benign lymph nodes, based on evaluation of

DIAGNOSTIC

the value of blood flow, blood volume, and permeability

surface.56 Perfusion MRI can also be used for differentiation of malignant from benign cervical lymph nodes.57
These techniques need to be further evaluated for their clinical value in detection of occult lymph node metastases.
PET-MRI combines the unique metabolic imaging
capabilities of PET with the excellent soft tissue contrast
of MRI. This new hybrid imaging modality is expected to
be of special use in body regions with difficult anatomy
and in organs in which the inherent soft tissue contrast of
MRI is superior to that of CT, such as the head and neck
region. Heusch et al21 have investigated the utility of
PET-MRI in the evaluation of nodal status using a
software-based fusion of sequentially acquired PET and
MRI (including diffusion-weighted images). Lymph nodes
were scored malignant on the basis of: short-axis diameter
of >1 cm; heterogeneous (in contrast with homogeneous)
pathological signal intensity; central necrosis; irregular (in
contrast with smooth) margins; contrast enhancement; high
signal on b-1000 diffusion-weighted images with signal
drop on corresponding ADC; and focal 18F-FDG-uptake.
They found that software-based fusion of 18F-FDG-PETMRI and 18F-FDG-PET-MRI plus diffusion-weighted
images did not increase the detection rates of nodal metastasis and accuracy in N classification in patients with
OSCC compared to ultrasound and 18F-FDG-PET-CT.

SNB. The previously discussed technique of SNB has

been successful in the diagnostic evaluation of early oral
cancers. However, in some subsites of the oral cavity,
such as the floor of mouth (FOM), SNB has limitations.45
For instance, detection of the sentinel lymph node is
more difficult in patients with FOM cancers; the sentinel
lymph node(s) are harvested successfully in 88% of the
cases compared to 96% for tumors in other sites of the
oral cavity. Likewise, sensitivity of SNB is lower for
FOM tumors compared to other sites (80% vs 97%). This
is probably because of the close spatial relation between
the primary tumor and the first draining lymph nodes (ie,
sentinel lymph nodes). The injection site around the primary tumor produces a large hotspot on lymphoscintigraphy, possibly hiding sentinel lymph node(s) in close
proximity to the primary tumor, a phenomenon called
shine through. It is therefore of utmost importance to
improve SNB in patients with early OSCC at these subsites. Technical improvements are needed to bring SNB
for OSCC of all subsites to the same high level.
Although hybrid SPECT-CT has the potential to detect
more sentinel lymph nodes as compared to planar lymphoscintigraphy, it still has some difficulties in visualization of sentinel lymph nodes in close spatial relation to
the injection site.58 However, SPECT-CT can improve the
visualization of the relation of sentinel lymph nodes to
several vascular and neural structures, which makes the
removal of these nodes easier and safer. Recently, a PETtracer, 89-Zirconium nanocolloidal albumin, dedicated to
lymphatic mapping and sentinel lymph node detection
using high resolution PET-CT was developed. Compared
with g-based techniques, improved detection and more
precise localization of sentinel lymph nodes could be
achieved on PET-CT in recently performed clinical feasi-

MODALITIES FOR DETECTION OF LYMPH NODE METASTASIS

bility studies. PET-CT was able to identify sentinel lymph

nodes close to the injection site and lymphatic vessels
which were not visualized on SPECT-CT.59
The difficulty of intraoperative detection of sentinel lymph
nodes close to the primary is also affected by the high amount
of radioactivity present at the injection site of the primary
tumor. Gamma probe detection may be unreliable for differentiating between a sentinel lymph node and the injection site.
To improve the distinction between a primary tumor
and sentinel lymph node, a visual aid may be used. For this
purpose, vital blue dye (usually isosulfan blue) is frequently applied. Blue dye particles follow lymphatic vessels and accumulate in the draining lymph nodes, giving
them a blue stain. Real-time detection of this blue stain is
only possible if there is no overlying tissue. Moreover, blue
dye consists of small particles with a very poor retention in
the sentinel lymph node and the blue color is therefore
retained for a short period of time. This is probably because
of the fast lymphatic drainage in the head and neck area.
As a consequence, the use of blue dye may be of limited
value in certain areas of the head and neck.60
Technical innovations to improve intraoperative sentinel
lymph node localization include intraoperative real-time
imaging, freehand SPECT, and fluorescence imaging.
Intraoperative real-time imaging with the portable gamma
camera provides an overview of all radioactive spots and
can show sentinel lymph nodes near the injection site by
adjusting its position.61 Another advantage may be the certainty it can provide about the completeness and accuracy
of sentinel lymph node excision by showing the remaining
activity. Freehand SPECT is designed to determine the
position of the detector relative to the patient through generated 3D images. This provides the surgeon information
about the direction and depth of the sentinel lymph node in
relation to the probe. The possibility of generating images
in the operating room after removing the sentinel lymph
nodes, but before closing the wounds, may be useful to
confirm harvesting of all hotspots. Promising results in
patients with OSCC have been reported.62
Near infrared (NIR) fluorescence imaging may also be a
very attractive option to facilitate intraoperative detection.
NIR dyes have the advantage of reasonable tissue penetration of excited and emitted light with negligible autofluorescence, resulting in higher target-to-background contrast.
NIR fluorescence imaging provides high resolution images
that can be obtained in real time during the surgical procedure, even if the structure of interest is covered by some tissue (in contrast to blue dye). Another advantage of NIR
fluorescence imaging is that it is much better suited for
detection of sentinel lymph nodes close to the primary
tumor, because there is negligible influence of fluorescence
signal coming from the injection site. The feasibility of
NIR fluorescence-guided sentinel lymph node detection
has been demonstrated in HNSCC where fluorescence
imaging of indocyanin green was used as the fluorescent
tracer.63 Other tracers with improved optical properties
have been tested in HNSCC in preclinical settings.64 The
clinical utility of these techniques is still to be assessed.
Image-guided FNAC. Cytologic analysis may be improved
by quantitative molecular detection of lymph node aspirates. A quantitative reverse-transcriptase polymerase
HEAD & NECKDOI 10.1002/HED

DECEMBER 2015

1835

DE

BREE ET AL.

chain reaction (qRT-PCR) assay based on TaqMan

technology using the squamous cell-specific antigen E48
(Ly-6D) as a molecular marker was able to diagnose 59%
of aspirates that were not evaluable at cytology. Using
histopathology (including step-serial sectioning) and clinical follow-up as reference standard E48 qRT-PCR was
able to increase sensitivity from 56% to 67%. However,
specificity decreased from 100% to 92%.65 More recently,
a multiplexed qRT-PCR assay directed against pemphigus
vulgaris antigen and epithelial cell adhesion molecule was
developed. Used in intraoperative diagnosis of sentinel
nodes, it showed a sensitivity up to 92% and a specificity
up to 96% using the consensus of 2 academic pathologists
applying frozen sections and immunohistochemistry as
the reference standard. The authors expect that this technique may also be used for fine-needle aspirates.66 Other,
even more promising markers, which have recently been
developed, have yet to be tested.
Although the conventional selection is based on standard drainage patterns and lymph node size and morphology, lymphatic mapping identifying the sentinel lymph
node may improve selection of the lymph nodes with the
highest risk of harboring metastases to be aspirated. A
few studies reported on ultrasound-guided FNAC of sentinel lymph nodes in early oral cancer. Colnot et al67
reported in 2001 the initial experiences of Vrije Universiteit, University Medical Center, in 12 patients with oral
and oropharyngeal cancer and a cN0. After visualization
of the sentinel lymph node, the position was marked on
the overlying skin with the use of a point-of-source 57Cobalt marker and confirmed with a gamma probe. After
preparation of the cytologic smears, residues of the aspirates from sentinel lymph nodes were counted in a liquid
scintillation counter to confirm correct aspiration. Cytologic examination of the aspirated sentinel lymph nodes
revealed lymph node metastases in 6 patients who underwent neck dissection. Among the remaining patients who
underwent only transoral excision, 1 false-negative result
was observed. They concluded that this combined
approach is expected to improve the detection of occult
lymph node metastases.67 In a further study, Nieuwenhuis
et al8 reported in 2002 that in 39 patients with early oral
and oropharyngeal SCC undergoing conventional and sentinel lymph node-guided ultrasound-guided FNAC, 11
additional lymph nodes were aspirated because of the sentinel lymph node procedure. Because these lymph nodes
were all tumor-negative or contained insufficient material
at cytologic examination, no additional value of sentinel
lymph node aspiration could be demonstrated. During
follow-up, 10 of these 39 patients (26%) developed a
lymph node metastasis in the nontreated neck (after negative ultrasound-guided FNAC). All but 2 patients developed metastasis in levels of the neck, which corresponded
to those of sentinel lymph nodes identified at the initial
staging, suggesting a sampling error of the aspirate.8
However, aspiration of radioactivity does not prove that
the real sentinel lymph node has been aspirated, because
also second echelon nodes eventually become radioactive.
SPECT-CT, which may be especially helpful in identification and localization of sentinel lymph nodes close to
the injection site and differentiation between sentinel
lymph nodes and second echelon nodes, was not used.
1836

HEAD & NECKDOI 10.1002/HED

DECEMBER 2015

Moreover, late images were only performed in 9 of 39

patients, potentially missing sentinel lymph nodes.68 Hoft
et al69 reported on 16 patients diagnosed with oral, oropharyngeal, or SCC of the skin who had been staged as
N0 and underwent lymphoscintigraphy to localize sentinel
lymph nodes and ultrasound-guided FNAC on sentinel
lymph nodes before elective neck dissection. In 14 of 16
patients, a sentinel lymph node could be visualized. Seventeen ipsilateral and 4 contralateral nodes were identified
as sentinel lymph nodes. No gamma probe was used. In 9
of these 21 sentinel lymph nodes, it was difficult to differentiate the sentinel node from other lymph nodes in
close proximity in the ultrasound examination. In 6 of
these 14 patients, lymph node metastases were found in
the neck dissection specimen. All patients had at least
macrometastases. In only 1 of these 6 patients, metastasis
was detected by ultrasound-guided FNAC of the sentinel
lymph node. In this patient, this lymph node contained a
micrometastasis.69 In this study, it is debatable if without
the use of a gamma probe and confirmation of radioactivity in the aspirate the real sentinel lymph nodes are punctured. Improvement of ultrasound-guided FNAC by
aspiration of the real sentinel lymph node can probably
increase the sensitivity of the detection of occult lymph
node metastasis, but cannot address the problem of lymph
nodes too small for aspiration, insufficient aspirated material, and sampling error. However, any occult lymph node
metastasis detected by ultrasound-guided FNAC will
reduce the number of SNBs needed to give patients with
early OSCC the best prognosis without unnecessary
extensive diagnostic procedures. Freehand SPECT, if integrated with video or anatomic images, provided helpful
information facilitating the sentinel lymph node biopsy
procedure.62 If SPECT images can be integrated with
ultrasound, ultrasound-guided FNAC of the real sentinel
lymph nodes can be improved aiming to reduce the number of SNBs needed for the currently most sensitive
detection method of occult lymph node metastases. The
first prototypes have been tested very recently.

CONCLUSIONS
Novel diagnostic imaging techniques improve the
detection of occult lymph node metastases, potentially
obviating the need for elective neck treatment. However,
to this date, none of these imaging techniques alone has
proven to be accurate enough to detect occult regional
metastasis and replace elective treatment of the neck with
a wait and see or watchful waiting follow-up policy.
Only a wait and scan strategy using ultrasound-guided
FNAC may be considered to avoid elective neck treatment in selected patients. This strategy could be considered only in centers with investigators experienced in the
technique and after counseling the patients. In this counseling, the risks of relatively more aggressive therapy initially (ie, elective neck dissection) should be weighed
against the risk of later detection of metastases during
follow-up requiring even more aggressive therapy (ie,
more comprehensive types of neck dissection and higher
chances of chemoradiotherapy). SNB is able to detect
occult lymph node metastasis with a high sensitivity and
high negative predictive value and to reliably select

DIAGNOSTIC

MODALITIES FOR DETECTION OF LYMPH NODE METASTASIS

TABLE 1. Selection of important studies on detection of lymph node metastases (cN0 and cN1).
Study

Type

cN0 patients, %

Diagnostic technique

Sensitivity, %

Specificity, %

Single center

51%

de Bondt et al49

Meta-analysis

N/A

Kyzas et al28

Meta-analysis

N/A
NA

Stoeckli et al18

Single center

N/A

Lee et al37

Single center

N/A

Wu et al55

Meta-analysis

N/A

Ultrasound
CT
MRI
Ultrasound-guided FNAC
Ultrasound
CT
MRI
Ultrasound-guided FNAC
USPIO-MRI
PET*
PET*
CT/MRI/ultrasound-guided FNAC
Ultrasound
CT
Ultrasound-guided FNAC
PET-low-dose CT
Ultrasound
CT
MRI
PET-contrast-enhanced CT
MRI
Diffusion weighted-MRI
MRI
Ultrasound
MRI
CT
MRI
PET*
Dual time point PET

75
83
82
90
81
87
81
80
74
79
80
75
86
87
86
86
65
63
66
69
76
86
67
45
67
64
67
66
60

75
70
81
100
76
86
63
98
88
86
86
79
90
90
86
77
94
94
95
89
86
95
78
82
79
75
77
81
71

van den Brekel et al

46

N/A
N/A
N/A
Carlson et al39

Single center

N/A

Abbreviations: cN0, clinically negative; cN1, clinically positive neck; ultrasound-guided FNAC, ultrasound-guided fine-needle aspiration cytology; N/A, not available; USPIO, ultra-small superparamagnetic iron oxide; PET, positron emission tomography.
* Not specified.

Head-to-head comparison.

patients for treatment of the neck, but its application

remains reserved to OSCC and selected oropharyngeal
SCC. Further improvements in diagnostic imaging will
likely reduce elective treatments and subsequent morbid-

ity in patients with HNSCC with a cN0. However, the

limitations of all imaging techniques will be the detection
threshold below which small tumor deposits will remain
undetected. Therefore, complementary to improvements

TABLE 2. Selection of important studies on detection of occult lymph node metastases (cN0).
Study

Type

Diagnostic technique

Sensitivity, %

Specificity, %

van den Brekel et al46

Single center

Righi et al25

Multicenter

Takes et al26

Multicenter

Kyzas et al28

Meta-analysis

Ozer et al35
Liao et al50

Single center
Meta-analysis

Govers et al41

Meta-analysis

Ultrasound
CT
MRI
Ultrasound-guided FNAC
Ultrasound
CT
Ultrasound
CT
PET
PET*
CT/MRI/ultrasound-guided FNAC*
PET
Ultrasound
CT
MRI
PET
SNB

58
49
55
73
50
60
48
54
50
52
45
57
66
52
65
66
93

75
78
88
100
100
100
100
92
87
93
87
82
78
93
81
87
100

cN0

On palpation

On palpation
On palpation
Not defined
Not defined
On palpation, CT and/or MRI
Not defined

Not defined

Abbreviations: cN0, clinically node-negative; ultrasound-guided FNAC, ultrasound-guided fine-needle aspiration cytology; PET: positron emission tomography; SNB, sentinel node biopsy.
* Head-to-head comparison.

HEAD & NECKDOI 10.1002/HED

DECEMBER 2015

1837

DE

BREE ET AL.

in imaging techniques, developments in more invasive

diagnostic procedures, such as the SNB and noninvasive
tests, such as the development of biomarkers associated
with metastatic behavior, are important in the attempts to
improve the accuracy of diagnostic algorithms for the
staging of the neck.

REFERENCES
1. Sparano A, Weinstein G, Chalian A, Yodul M, Weber R. Multivariate predictors of occult neck metastasis in early oral tongue cancer. Otolaryngol
Head Neck Surg 2004;131:472476.
2. Goerkem M, Braun J, Stoeckli SJ. Evaluation of clinical and histomorphological parameters as potential predictors of occult metastases in sentinel
lymph nodes of early squamous cell carcinoma of the oral cavity. Ann Surg
Oncol 2010;17:527535.
3. van Hooff SR, Leusink FK, Roepman P, et al. Validation of a gene expression signature for assessment of lymph node metastasis in oral squamous
cell carcinoma. J Clin Oncol 2012;30:41044110.
4. Nguyen DX, Bos PD, Massague J. Metastasis: from dissemination to
organ-specific colonization. Nat Rev Cancer 2009;9:274284.
5. van Wouwe M, de Bree R, Kuik DJ, et al. Shoulder morbidity after nonsurgical treatment of the neck. Radiother Oncol 2009;90:196201.
6. Teymoortash A, Hoch S, Eivazi B, Werner JA. Postoperative morbidity
after different types of selective neck dissection. Laryngoscope 2010;120:
924929.
7. Borgemeester MC, van den Brekel MW, van Tinteren H, et al. Ultrasoundguided aspiration cytology for the assessment of the clinically N0 neck:
factors influencing its accuracy. Head Neck 2008;30:15051513.
8. Nieuwenhuis EJ, Castelijns JA, Pijpers R, et al. Wait-and-see policy for the
N0 neck in early-stage oral and oropharyngeal squamous cell carcinoma
using ultrasonography-guided cytology: is there a role for identification of
the sentinel node? Head Neck 2002;24:282289.
9. Flach GB, Tenhagen M, de Bree R, et al. Outcome of patients with early
stage oral cancer managed by an observation strategy towards the N0 neck
using ultrasound guided fine needle aspiration cytology: no survival difference as compared to elective neck dissection. Oral Oncol 2013;49:157
164.
10. de Bree R, Hoekstra OS. The potential of FDG-PET in the detection of
occult lymph node metastasis: importance of patient selection and reference standard. Eur Arch Otorhinolaryngol 2013;270:21732174.
11. Rinaldo A, Devaney KO, Ferlito A. Immunohistochemical studies in the
identification of lymph node micrometastases in patients with squamous
cell carcinoma of the head and neck. ORL J Otorhinolaryngol Relat Spec
2004;66:3841.
12. de Bree R. How to analyze the diagnostic value of sentinel node biopsy in
head and neck cancer. Eur Arch Otorhinolaryngol 2013;270:789791.
13. de Bree R, Roos JC, Verel I, van Dongen GA, Snow GB. Radioimmunodiagnosis of lymph node metastases in head and neck cancer. Oral Dis
2003;9:241248.
14. Borjesson PK, Jauw YW, Boellaard R, et al. Performance of immunopositron emission tomography with zirconium-89-labeled chimeric monoclonal antibody U36 in the detection of lymph node metastases in head and
neck cancer patients. Clin Cancer Res 2006;12:21332140.
15. van den Brekel MW, Stel HV, Castelijns JA, et al. Cervical lymph node
metastasis: assessment of radiologic criteria. Radiology 1990;177:379384.
16. Som PM. Detection of metastasis in cervical lymph nodes: CT and MR criteria and differential diagnosis. AJR Am J Roentgenol 1992;158:961969.
17. Curtin HD, Ishwaran H, Mancuso AA, Dalley RW, Caudry DJ, McNeil BJ.
Comparison of CT and MR imaging in staging of neck metastases. Radiology 1998;207:123130.
18. Stoeckli SJ, Haerle SK, Strobel K, Haile SR, Hany TF, Schuknecht B. Initial staging of the neck in head and neck squamous cell carcinoma: a comparison of CT, PET/CT, and ultrasound-guided fine-needle aspiration
cytology. Head Neck 2012;34:469476.
19. Wu L, Cao Y, Liao C, Huang J, Gao F. Diagnostic performance of USPIOenhanced MRI for lymph-node metastases in different body regions: a
meta-analysis. Eur J Radiol 2011;80:582589.
20. Sigal R, Vogl T, Casselman J, et al. Lymph node metastases from head and
neck squamous cell carcinoma: MR imaging with ultrasmall superparamagnetic iron oxide particles (Sinerem MR) results of a phase-III multicenter
clinical trial. Eur Radiol 2002;12:11041113.
21. Heusch P, Sproll C, Buchbender C, et al. Diagnostic accuracy of ultrasound, 18F-FDG-PET/CT, and fused 18F-FDG-PET-MR images with DWI
for the detection of cervical lymph node metastases of HNSCC. Clin Oral
Investig 2014;18:969678.
22. Castelijns JA, van den Brekel MW. Imaging of lymphadenopathy in the
neck. Eur Radiol 2002;12:727738.
23. van den Brekel MW, Castelijns JA, Snow GB. The size of lymph nodes in
the neck on sonograms as a radiologic criterion for metastasis: how reliable
is it? AJNR Am J Neuroradiol 1998;19:695700.

1838

HEAD & NECKDOI 10.1002/HED

DECEMBER 2015

24. van den Brekel MW, Castelijns JA, Stel HV, et al. Occult metastatic neck
disease: detection with US and US-guided fine-needle aspiration cytology.
Radiology 1991;180:457461.
25. Righi PD, Kopecky KK, Caldemeyer KA, Ball VA, Weisberger EC,
Radpour S. Comparison of ultrasound-fine needle aspiration and computed
tomography in patients undergoing elective neck dissection. Head Neck
1997;19:604610.
26. Takes RP, Righi P, Meeuwis CA, et al. The value of ultrasound with
ultrasound-guided fine-needle aspiration biopsy compared to computed
tomography in the detection of regional metastases in the clinically negative neck. Int J Radiat Oncol Biol Phys 1998;40:10271032.
27. Haerle SK, Strobel K, Ahmad N, Soltermann A, Schmid DT, Stoeckli SJ.
Contrast-enhanced 18F-FDG-PET/CT for the assessment of necrotic lymph
node metastases. Head Neck 2011;33:324329.
28. Kyzas PA, Evangelou E, DenaxaKyza D, Ioannidas JP. 18F-fluorodeoxyglucose positron emission tomography to evaluate cervical node metastases
in patients with head and neck squamous cell carcinoma: a meta-analysis. J
Natl Cancer Inst 2008;100:712720.
29. Roh JL, Yeo NK, Kim JS, et al. Utility of 2-18F fluoro-2-deoxy-D-glucose positron emission tomography and positron emission tomography/
computed tomography imaging in the preoperative staging of head and
neck squamous cell carcinoma. Oral Oncol 2007;43:887893.
30. Krabbe CA, Dijkstra PU, Pruim J, et al. FDG PET in oral and oropharyngeal cancer. Value for confirmation of N0 neck and detection of occult
metastases. Oral Oncol 2008;44:3136.
31. Brouwer J, de Bree R, Comans EF, Castelijns JA, Hoekstra OS, Leemans
CR. Positron emission tomography using 18Ffluorodeoxyglucose (FDGPET) in the clinically negative neck: is it likely to be superior? Eur Arch
Otorhinolaryngol 2004;261:479483.
32. Wensing BM, Vogel WV, Marres HA, et al. FDG-PET in the clinically
negative neck in oral squamous cell carcinoma. Laryngoscope 2006;116:
809813.
33. Jeong HS, Baek CH, Son YI, et al. Use of integrated 18F-FDG PET/CT to
improve the accuracy of initial cervical nodal evaluation in patients with
head and neck squamous cell carcinoma. Head Neck 2007;29:203210.
34. Ng SH, Yen TC, Chang JT, et al. Prospective study of 18Ffluorodeoxyglucose positron emission tomography and computed tomography and
magnetic resonance imaging in oral cavity squamous cell carcinoma with
palpably negative neck. J Clin Oncol 2006;24:43714376.
35. Ozer E, Naibo
glu B, Meacham R, Ryoo C, Agrawal A, Schuller DE. The
value of PET/CT to assess clinically negative necks. Eur Arch Otorhinolaryngol 2012;269:24112414.
36. Cetin B, Atasever T, Akdemir UO, et al. The role of positron emission
tomography with 18F-fluorodeoxyglucose in nodal staging of clinical and
radiological N0 head and neck cancers. Eur Arch Otorhinolaryngol 2013;
270:23072313.
37. Lee SH, Huh SH, Jin SM, Rho YS, Yoon DY, Park CH. Diagnostic value
of only 18F-fluorodeocyglucose positron emission tomography/computed
tomography-positive lymph nodes in head and neck squamous cell carcinoma. Otolaryngol Head Neck Surg 2012;147:692698.
38. Gilbert MR, Branstetter BF IV, Kim S. Utility of positron-emission tomography/computed tomography imaging in the management of the neck in
recurrent laryngeal cancer. Laryngoscope 2012;122:821825.
39. Carlson ER, Schaefferkoetter J, Townsend D, McCoy JM, Campbell PD Jr,
Long M. The use of multiple time point dynamic positron emission tomography/computed tomography in patients with oral/head and neck cancer
does not predictably identify metastatic cervical lymph nodes. J Oral Maxillofac Surg 2013;71:162177.
40. Alkureishi LW, Burak Z, Alvarez JA, et al. Joint practice guidelines for
radionuclide lymphoscintigraphy for sentinel node localization in oral/oropharyngeal squamous cell carcinoma. Ann Surg Oncol 2009;16:31903210.
41. Govers TM, Hannink G, Merkx MA, Takes RP, Rovers MM. Sentinel node
biopsy for squamous cell carcinoma of the oral cavity and oropharynx: a
diagnostic meta-analysis. Oral Oncol 2013;49:726732.
42. Murer K, Huber GF, Haile SR, Stoeckli SJ. Comparison of morbidity
between sentinel node biopsy and elective neck dissection for treatment of
the N0 neck in patients with oral squamous cell carcinoma. Head Neck
2011;33:12601264.
43. Govers TM, Takes RP, Baris Karakullukcu M, et al. Management of the
N0 neck in early stage oral squamous cell cancer: a modeling study of the
cost-effectiveness. Oral Oncol 2013;49:771777.
44. Broglie MA, Haile SR, Stoeckli SJ. Long-term experience in sentinel node
biopsy for early oral and oropharyngeal squamous cell carcinoma. Ann
Surg Oncol 2011;18:27322738.
45. Alkureishi LW, Ross GL, Shoaib T, et al. Sentinel node biopsy in head and
neck squamous cell cancer: 5-year follow-up of a European multicenter
trial. Ann Surg Oncol 2010;17:24592464.
46. van den Brekel MW, Castelijns JA, Stel HV, Golding RP, Meyer CJ, Snow
GB. Modern imaging techniques and ultrasound-guided aspiration cytology
for the assessment of neck node metastases: a prospective comparative
study. Eur Arch Otorhinolaryngol 1993;250:1117.
47. Kovacs AF, Landes CA, Hamscho N, Risse JH, Berner U, Menzel C. Sentinel node biopsy as staging tool in a multimodality treatment approach to
cancer of the oral cavity and the oropharynx. Otolaryngol Head Neck Surg
2005;132:570576.

DIAGNOSTIC
48. Civantos FJ, Gomez C, Duque C, et al. Sentinel node biopsy in oral cavity
cancer: correlation with PET scan and immunohistochemistry. Head Neck
2003;25:19.
49. de Bondt RB, Nelemans PJ, Hofman PA, et al. Detection of lymph node
metastases in head and neck cancer: a meta-analysis comparing US, USgFNAC, CT and MR imaging. Eur J Radiol 2007;64:266272.
50. Liao LJ, Lo WC, Hsu WL, Wang CT, Lai MS. Detection of cervical lymph
node metastasis in head and neck cancer patients with clinically N0 neck
a meta-analysis comparing different imaging modalities. BMC Cancer
2012;12:236.
51. Vandecaveye V, De Keyzer F, Vander Poorten V, et al. Head and neck
squamous cell carcinoma: value of diffusion-weighted MR imaging for
nodal staging. Radiology 2009;251:134146.
52. Abdel Razek AA, Soliman NY, Elkhamary S, Alsharaway MK, Tawfik A.
Role of diffusion-weighted MR imaging in cervical lymphadenopathy. Eur
Radiol 2006;16:14681477.
53. Dirix P, Vandecaveye V, De Keyzer F, et al. Diffusion-weighted MRI for
nodal staging of head and neck squamous cell carcinoma: impact on radiotherapy planning. Int J Radiat Oncol Biol Phys 2010;76:761766.
54. de Bondt RB, Hoeberigs MC, Nelemans PJ, et al. Diagnostic accuracy and
additional value of diffusion-weighted imaging for discrimination of malignant cervical lymph nodes in head and neck squamous cell carcinoma. Neuroradiology 2009;51:183192.
55. Wu LM, Xu JR, Liu MJ, et al. Value of magnetic resonance imaging for
nodal staging in patients with head and neck squamous cell carcinoma: a
meta-analysis. Acad Radiol 2012;19:331340.
56. Trojanowska A, Trojanowski P, Bisdas S, et al. Squamous cell cancer of
hypopharynx and larynx evaluation of metastatic nodal disease based on
computed tomography perfusion studies. Eur J Radiol 2012;81:10341039.
57. Abdel Razek AA, Gaballa G. Role of perfusion magnetic resonance imaging in cervical lymphadenopathy. J Comput Assist Tomogr 2011;35:2125.
58. Haerle SK, Hany TF, Strobel K, Sidler D, Stoeckli SJ. Is there an additional
value of SPECT/CT over planar lymphoscintigraphy for sentinel node mapping in oral/oropharyngeal squamous cell carcinoma? Ann Surg Oncol
2009;16:31183124.
59. Heuveling DA, van Schie A, Vugts DJ, et al. Pilot study on the feasibility
of PET/CT lymphoscintigraphy with 89Zr-nanocolloidal albumin for sentinel node identification in oral cancer patients. J Nucl Med 2013;54:585
589.

MODALITIES FOR DETECTION OF LYMPH NODE METASTASIS

60. Ross G, Shoaib T, Soutar DS, et al. The use of sentinel node biopsy to
upstage the clinically N0 neck in head and neck cancer. Arch Otolaryngol
Head Neck Surg 2002;128:12871291.
61. Vermeeren L, Valdes Olmos RA, Klop WM, Balm AJ, van den Brekel
MW. A portable gamma-camera for intraoperative detection of sentinel
nodes in the head and neck region. J Nucl Med 2010;51:700703.
62. Heuveling DA, Karagozoglu KH, van Schie A, van Weert S, van Lingen A,
de Bree R. Sentinel node biopsy using 3D lymphatic mapping by freehand
SPECT in early stage oral cancer: a new technique. Clin Otolaryngol 2012;
371:8990.
63. van den Berg NS, Brouwer OR, Klop WM, et al. Concomitant radio- and
fluorescence-guided sentinel lymph node biopsy in squamous cell carcinoma of the oral cavity using ICG-(99m)Tc-nanocolloid. Eur J Nucl Med
Mol Imaging 2012;39:11281136.
64. Heuveling DA, Visser GW, de Groot M, et al. Nanocolloidal albuminIRDye 800CW: a near-infrared fluorescent tracer with optimal retention in
the sentinel lymph node. Eur J Nucl Med Mol Imaging 2012;39:1161
1168.
65. Nieuwenhuis EJ, Leemans CR, Kummer JA, Denkers F, Snow GB,
Brakenhoff RH. Assessment and clinical significance of micrometastases
in lymph nodes of head and neck cancer patients detected by E48 (Ly-6D)
quantitative reverse transcription-polymerase chain reaction. Lab Invest
2003;83:12331240.
66. Ferris RL, Stefanika P, Xi L, Gooding W, Seethala RR, Godfrey TE. Rapid
molecular detection of metastatic head and neck squamous cell carcinoma
as an intraoperative adjunct to sentinel lymph node biopsy. Laryngoscope
2012;122:10201030.
67. Colnot DR, Nieuwenhuis EJ, van den Brekel MW, et al. Head and neck
squamous cell carcinoma: US-guided fine-needle aspiration of sentinel
lymph nodes for improved staginginitial experience. Radiology 2001;218:
289293.
68. Heuveling DA, Flach GB, van Schie A, et al. Visualization of the sentinel
node in early-stage oral cancer: limited value of late static lymphoscintigraphy. Nucl Med Commun 2012;33:10651069.
69. H
oft S, Muhle C, Brenner W, Sprenger E, Maune S. Fine-needle aspiration
cytology of the sentinel lymph node in head and neck cancer. J Nucl Med
2002;43:15851590.

HEAD & NECKDOI 10.1002/HED

DECEMBER 2015

1839