The Laryngoscope

© 2020 The American Laryngological,

Rhinological and Otological Society, Inc.

Usefulness of Sentinel Lymph Node Biopsy for Oral Cancer:

A Systematic Review and Meta-Analysis

Do Hyun Kim, MD, PhD; Yeonji Kim, MD; Sung Won Kim, MD, PhD ; Se Hwan Hwang, MD, PhD

Objective: We assessed the diagnostic accuracy of sentinel lymph node biopsy (SLNB) for detecting neck nodal metastasis
in early oral squamous cell carcinoma (OSCC) as an alternative to elective neck dissection.
Study Design: A systematic search for relevant literature was conducted in the PubMed, SCOPUS, Embase, Web of Sci-
ence, and Cochrane databases.
Methods: Two reviewers individually searched the five databases up to November 2019. For studies that met inclusion
criteria, data on patient diagnoses were pooled, including true positives, true negatives, false positives, and false negatives.
Methodological quality was checked with the Quality Assessment of Diagnostic Accuracy Studies (version 2) tool.
Results: In total, 98 observational or retrospective studies were included. The diagnostic odds ratio of SLNB was 326.165
(95% confidence interval [CI]: 231.477–459.587; I2 = 0%). The area under the summary receiver operating characteristic curve
was 0.982. Sensitivity was 0.827 (95% CI: 0.804–0.848), and specificity was 0.981 (95% CI: 0.975–0.986). The correlation
between sensitivity and the false positive rate was −0.076, which indicates that heterogeneity did not exist. Subgroup analyses
were performed with the subgroups reference test type, publication year, and study type. No significant difference was found
within the reference test type subgroup. However, differences within the publication year and study type subgroups were sig-
nificant, where the retrospective study subgroup was significantly more sensitive and specific than the prospective study
subgroup.
Conclusion: Results of this meta-analysis imply that the high specificity of SLNB supports its role as a diagnostic tool for
patients with clinical tumor stage (CT)1-2 clinically negative (N0) OSCC. More studies should be done to further verify the
results of this study.
Key Words: Oral cancer, sentinel node biopsy, diagnostic accuracy, meta-analysis.
Level of Evidence: 2a
Laryngoscope, 00:1–7, 2020

INTRODUCTION treatment of choice in early OSCC. However, the use of

Oral squamous cell carcinoma (OSCC) is a common
malignancy in clinical practice today. Prior to distant
metastasis, OSCC typically spreads to regional cervical
lymph nodes. Metastasis to cervical lymph nodes decreases
the survival rate of patients by 50%. Thus, the pathologic
status of the cervical lymph nodes is a critical prognostic
factor for OSCC.1 The risk for occult metastasis in patients
with clinical stage clinically negative (N0) OSCC is 20% to
30%.2–4 Clinical examination and imaging are currently
used to detect lymph node metastasis, but these modalities
are not very reliable for distinguishing early nodal metasta-
sis.5 Therefore, elective neck dissection (END) is a
END has resulted in overtreatment for an estimated 70% of
patients and can also lead to considerable morbidity.6 In
addition, sentinel lymph node biopsy (SLNB) is more cost-
effective and less invasive than END.7–10
Sentinel lymph nodes, the first nodes to drain a cancer,
are at highest risk for metastasis.11 In some cancers, such as
melanoma and breast cancer, SLNB is widely used to iden-
tify whether lymph node metastasis is present. A negative
SLNB result indicates that elective lymph node dissection is
unnecessary12 and thus spares patients unnecessary surgery
and avoids surgical morbidity while accurately upstaging
malignancies.

Additional supporting information may be found in the online version of this article.
From the Department of Otolaryngology-Head and Neck Surgery (D.H.K., Y.K., S.W.K.), Seoul St. Mary’s Hospital, College of Medicine, The Catholic
University of Korea, Seoul, South Korea; Department of Otolaryngology-Head and Neck Surgery (S.H.H.), Bucheon St. Mary’s Hospital, College of Medicine,
The Catholic University of Korea, Seoul, South Korea.
Editor’s Note: This Manuscript was accepted for publication on April 14, 2020.
Supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education
(grant 2018R1D1A1B07045421); the Bio & Medical Technology Development Program of the NRF funded by the Ministry of Science & ICT, (grants
2018M3A9E8020856, 2019M3A9H2032424, 2019M3E5D5064110); and the Institute of Clinical Medicine Research of Bucheon St. Mary’s Hospital, Research
Fund (2017, 2018). This research was also supported by a grant from the ENT Fund of the Catholic University of Korea (program years 2017–2018). The
sponsors had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have no other
funding, financial relationships, or conflicts of interest to disclose.
The English in this document has been checked by at least two professional editors, both native speakers of English. For a certificate, please see:
http://www.textcheck.com/certificate/EwLy2y
Send correspondence to Se Hwan Hwang, MD, PhD, Department of Otolaryngology–Head and Neck Surgery, Bucheon St. Mary’s Hospital, College of
Medicine, The Catholic University of Korea, 327 Sosa-ro, Bucheon-si, Gyeonggi-do, 14647, Republic of Republic of Korea. E-mail: yellobird@catholic.ac.kr

DOI: 10.1002/lary.28728

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1
 However, to date there is no consensus on the role of to assess diagnostic accuracy with 95% confidence intervals
SLNB in managing N0 OSCC.5,13–15 Previous meta- (CIs). DOR ranges from zero to infinity, and a higher DOR indi-
analyses are limited in the conclusions they were able to cates greater diagnostic accuracy. If the DOR value is 1, this test
draw. Therefore, we conducted a bivariate meta-analysis cannot diagnose the presence or absence of disease because TP,
FP, FN, and TN are all the same. The logarithmic DOR (logDOR)
using diagnostic odds ratios (DORs) and pooled sensitivities
was also calculated given its simplicity and approximately nor-
and/or specificities to evaluate the diagnostic accuracy of mal distribution.103 SROC analyses are recommended for meta-
SLNB for detecting neck nodal metastasis in OSCC as an analyses of studies presenting pairs of sensitivity and specificity.
alternative to END. In addition, we used subgroup analyses As the discriminatory power of a test improves, the graph of its
with a refined time category to depict time-dependent SROC curve approaches the top left-hand corner of the ROC
changes in diagnostic accuracy in recent years. space, trending toward the point where sensitivity and specificity
are both equal to 1 (100%).104 AUC values range from 0 to 1, and
higher values suggest more excellent test performance. Diagnos-
tic accuracy was estimated by the SROC AUC, with
MATERIALS AND METHODS
excellent = 0.90–1.0, good = 0.80–0.90, fair = 0.70–0.80,
Literature Search Strategy poor = 0.60–0.70, and failure = 0.50–0.60.105 We compiled data
Two authors searched five databases (PubMed, SCOPUS,
Embase, the Web of Science, and the Cochrane Central Register
of Controlled Trials) up to November 2019. The search terms
included “oral cavity cancer,” “oral cancer,” “head and neck
cancer,” “sentinel node biopsy,” and “occult metastasis.” Article
language was restricted to English. The two authors indepen-
dently manually reviewed titles and abstracts of all articles,
screened for irrelevant studies, and used inclusion criteria. Ref-
erence lists of articles were examined to identify additional stud-
ies for inclusion.

Selection Criteria
Articles were included in this meta-analysis if they
described patients who underwent surgery on early OSCC, such
as tumor (T)1 and T2; reported on prospective or retrospective
studies; compared SLNB to END in histologic assessments; and
presented data on sensitivity and specificity. Articles were
excluded from the analysis if they were case studies, were
reviews, reported on other cancers such as oropharynx cancer or
extended cancer such as T3 or T4, or reported data that did not
correspond to the diagnostic value of sentinel biopsy. Figure 1
summarizes the search strategy and study inclusion screening.

Data Extraction and Risk of Bias Assessment

Two authors individually collected data from included arti-
cles in forms commensurate with each other. Diagnostic accu-
racy, represented by DOR, summary receiver operating
characteristic (SROC) curve, and area under the curve (AUC),
was calculated.1,5,11–102 DOR was calculated as (true positive
[TP]/false positive [FP])/(false negative [FN]/true negative [TN])

Fig. 1. Diagram of the selection of studies for meta-analysis. Fig. 2. Forest plot of the diagnostic odds ratio.

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Fig. 3. SROC curve for SLNB in occult metastasis. The thick curved
line is the SROC curve; the thin circular line is the 95% confidence
interval; and the small circle is the summary estimate. SLNB = sen-
tinel lymph node biopsy; SROC = summary receiver operating
characteristic.
on the number of patients; study design (prospective or retro-
spective); publication year; reference test type (END or neck
recurrence during the follow-up period); and diagnostic TP, TN,
FP, and FN (to compute AUC and DOR). The quality of each
study was evaluated with the Quality Assessment of Diagnostic
Accuracy Studies (version 2) tool.
is performed to calculate the slope and y-intercept. These coeffi-
cients are then entered into the sROC equation to generate the
sROC curve.
Heterogeneity was calculated with the I2 test: The I2 test
describes the rate of variation across studies because of heterogene-
ity rather than probabilistic chance; the measure ranges from
0 (no heterogeneity) to 100 (maximum heterogeneity). When signifi-
cant heterogeneity among outcomes was found (defined as I2 > 50),
the random-effects model, according to DerSimonian-Laird, was
used. Those outcomes that did not present a significant level of het-
erogeneity (I2 < 50) were analyzed with the fixed-effects model. The
fixed-effects model uses the inverse variance approach, and it is
assumed that all studies come from a common population. We used
a funnel plot and Egger’s test simultaneously to detect potential
publication bias. We stratified results by reference test type (END
or neck recurrence during the follow-up period), study design (pro-
spective or retrospective), and publication year (early: before 2011,
intermediate: 2011–2015, or late: 2016 or later) to determine possi-
ble effects of different study characteristics on the diagnostic effi-
cacy of SLNB. We developed forest plots of sensitivity, specificity,
and the SROC curve.
RESULTS
A total of 98 studies including 5,917 patients were
analyzed in this meta-analysis. The results of bias assess-
ment and study characteristics are shown in Table S1.
Egger’s test (P > .05) on these measurements suggested
that a bias source was not evident in this sample of stud-
ies (Fig. S1).

Statistical Analyses and Outcome Measures

We used “mada” and “meta” packages in R version 3.6.1 for
statistical analyses (R Foundation for Statistical Computing,
Vienna, Austria). The sensitivity (TP/(TP + FN)) and the specific-
ity (TN/(TN + FP)) are proportion-type data, and DOR of the
2 × 2 format is binary data. The logit-transformation of data is
used to adjust the data distribution. Upon completion of the cal-
culation of the summary statistics, they are reverted to their
original values for interpretation. The sROC curve is initially
constructed by plotting the sensitivity (true positivity) and false
positivity (1 - specificity) of each study. After mathematical
manipulation of the true and false positivities, linear regression
Study Characteristics
The publication years of the 98 studies ranged from
2001 to 2019. Of the studies, 35 were published in 2001
to 2010; 36 were published in 2011 to 2015; and all others
were published in 2016 or later. The majority of studies
(n = 76) were prospective in nature. A smaller number
(n = 27) were retrospective. SLNB metastasis was deter-
mined based on histopathology in all studies. The pooled
SLNB identification rate was 98%. Table S1 shows the
TP, FP, FN, and TN results for the individual studies.

TABLE I.
Subgroup Analyses According to Study Type, Publication Year, and Reference Test Type.
Subgroup Study (n) DOR [95% CIs] Sensitivity [95% CIs] Specificity [95% CIs] AUC

Reference test and study type

Follow-up and prospective subgroup 41 239.333 [142.568; 401.777] 0.794[0.757; 0.827] 0.98 [0.969; 0.987] 0.975
Follow-up and retrospective subgroup 21 555.134 [277.707; 1109.709] 0.841[0.795; 0.878] 0.99[0.981; 0.995] 0.984
Neck dissection and prospective subgroup 35 292.460 [156.693; 545.860] 0.861 [0.815; 0.897] 0.973 [0.957; 0.983] 0.98
Neck dissection and retrospective subgroup 1 NA 0.877[0.805; 0.925] 0.998 [0.975;1] 0.989
Publication year
~2010 35 231.891 [125.189; 429.538] 0.854 [0.808; 0.890] 0.969 [0.951; 0.980] 0.973
2011 ~ 2015 37 286.238 [166.309; 492.653] 0.808 [0.762; 0.847] 0.984 [0.976; 0.99] 0.983
2016~ 26 559.996 [296.770; 1056.694] 0.827 [0.790; 0.859] 0.989 [0.980; 0.993] 0.983

AUC = area under the curve; CI = confidence interval; NA = nonapplicable; DOR = diagnostic odds ratios.

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Diagnostic Accuracy
Overall, sensitivity was 0.827 (95% CI: 0.804–0.848;
I2 = 36.3%), and specificity was 0.981 (95% CI: 0.975–0.986;
I2 = 31.4% %) (Fig. S2). The DOR of SLNB was 326.165
(95% CI: 231.477–459.587; I2 = 0%), and logDOR was 5.787
(95% CI: 5.444–6.130) (Fig. 2). The SROC AUC was 0.982.
There was no significant heterogeneity in sensitivity and
specificity (I2 < 50%). The SROC AUC fell between 0.90 and
1.0, which implies excellent diagnostic accuracy (Fig. 3).105
However, although there was no statistical heteroge-
neity in diagnostic accuracy, the heterogeneity and diver-
sity of the enrolled studies needed to be confirmed
whether there was not significant biases or not. Subgroup
analyses were performed to analyze the impacts of differ-
ent study characteristics on the diagnostic efficacy
of SLNB.
Subgroups included reference test type, study type, and
publication year. Neck dissection and retrospective subgroup
enrolled only one study, which would be difficult to compare
this subgroup with the other three subgroups. However,
among three subgroups, the two follow-up subgroups—
including prospective and retrospective subgroup—had a
tendency to be less sensitive (0.794 and 0.841 vs. 0.861) but
more specific (0.98 and 0.99 vs. 0.973) than the neck dis-
section and prospective subgroup. Furthermore, there were
differences within the publication date subgroup. The early
publication and END subgroups tended to be more sensitive
than the intermediate and late publication subgroups or the
clinical follow-up subgroup (0.854 [early] vs. 0.808 [interme-
diate]/0.827 [late] and 0.827 vs. 0.811, respectively). In turn,
the late publication and clinical follow-up subgroups tended
to be more specific than the early publication and END sub-
groups (0.984 [intermediate]/0.989 [late] vs. 0.969 [early]
and 0.984 vs. 0.975, respectively) (Table I).
DISCUSSION
There have been numerous investigations into the
diagnostic accuracy of SLNB, including attendant methods
and schedules for identifying sentinel lymph node cancer.
Three previous meta-analyses investigated and affirmed
the efficacy of SLNB in distinguishing occult lymph node
metastasis in patients with early oral OSCC.6,106,107
However, there are several problems with these pre-
vious analyses. All three presented combined sensitivity
and negative predictive value across the enrolled stud-
ies.6,106,107 Although predictive values may be intuitive
summary metrics, they depend on prevalence estimates.
Because prevalence is often wide-ranging, it is not mean-
ingful to directly combine these values across studies. For
example, Govers et al. estimated the prevalence of metas-
tasis at 14% to 60%.107 By contrast, for a given diagnostic
test sensitivity and specificity are not influenced by prev-
alence. Therefore, we calculated sensitivity and specificity
for each study for greater commensurability and compari-
son across study populations with different prevalence
rates.108,109
In addition, because DOR is closely linked to sensi-
tivity and specificity, we were able to assess the odds
ratios in line with standard meta-analysis practice. DOR
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4
analysis is useful for assessing the correlations between
the sensitivities and specificities of the included studies
while allowing for an assessment of heterogeneity
between studies with stratification based on relevant
parameters of the included articles. Thus, DOR analysis
is a robust methodology for meta-analyses of diagnostic
studies.6 We used a bivariate approach to meta-analysis
using DORs and pooled sensitivities and specificities.
Since Liu et al.’s study6 in particular, many studies have
evaluated SLNB. In this meta-analysis, we used detailed
time categories to examine publication date subgroups to
reflect time-dependent changes in diagnostic accuracy
because diagnostic accuracy has changed in recent years.
Our meta-analysis used data from studies that used
diverse protocols of sentinel node detection, such as
lymphangiography, gamma probe, single-photon emission
computed tomography (CT)/CT, and several others. Previ-
ous reviews also included studies that used diverse proto-
cols to evaluate the efficacy of SLNB for diagnosing occult
metastasis with early oral cancer but mainly shared the
common basic principle with sentinel node identification.
The results of this meta-analysis indicate that SLNB
may be a routine and important step in treating patients
who present with early OSCC. Our analyses showed over-
all high sensitivity (0.827) and specificity (0.981) using
this method. The DOR of SLNB was 326.165 and the
SROC AUC was 0.982, revealing no significant heteroge-
neity. These high scores demonstrate excellent diagnostic
accuracy. Our results showed high specificity (0.981, 95%
CI: 0.975–0.986) and slightly lower sensitivity (0.827,
95% CI: 0.804–0.848), similar to those of another recent
meta-analysis6 but different from two earlier meta-ana-
lyses.106,107 This discrepancy in results may be due to the
large number of studies related to SLNB in recent years
influencing our results. In our subgroup analyses, the
early publication subgroup demonstrated greater sensi-
tivity than the intermediate and late publication sub-
groups. Lui et al. also found a similar decreasing trend in
sensitivity, which they attributed to the use of END
(I-III) in most earlier publications, which would have
resulted in exaggerated sensitivity.6
In our reference test type subgroup analyses, the
END subgroup showed better sensitivity than the clinical
follow-up subgroup. In turn, the clinical follow-up sub-
group had higher specificity compared to the END sub-
group. This pattern resembles the results for the
publication date subgroups. Although histologic examina-
tion, including immunostaining, following END is a cru-
cial contributor to occult lymph node (LN) metastasis,110
follow-up clinically can be more efficient in determining
the occult LN metastasis/micro-metastasis because there
are also considerable degrees of nonspecific or false posi-
tive results in histologic examinations.111 As the publica-
tion years became more recent, the ratio of clinical follow-up
to END as the reference test increased from 0.85 (early publi-
cation) to 2.1 (intermediate publication) to 3.1 (most recent
publication). This pattern also explains the increase in speci-
ficity as publication year increased. In addition, SLNB
became a more important diagnostic practice throughout the
publication date range, and SLNB was possibly still in a vali-
dation stage in the earliest publication years.6 Although now
Kim et al.: Sentinel Lymph Node Biopsy for Oral Cancer
widely accepted, SLNB is still in its infancy, and many of the
finer technical points of preoperative treatment,
intraoperative localization, specimen processing, and so forth,
are being further developed each year.91
Studies on diagnostic accuracy are crucial for evaluat-
ing diagnostic tests. The excellent diagnostic accuracy of
SLNB for detecting occult metastasis was demonstrated in
this meta-analysis through the high SROC AUC (0.982),
where the curve was located in the high upper left-hand cor-
ner of the plot.105 This is significant, because recent studies
suggest that SLNB can lead to more comprehensive patho-
logic studies of tumor markers and HPV status. In addition,
preoperative lymphoscintigraphy with intraoperative
gamma probe SLN localization can help detect atypical
lymph drainage patterns. This technique shows promise for
detecting SLN cancer that could possibly be missed in
END.59 Considering SROC and the SROC AUC, SNL should
be considered for its accuracy diagnosing occult metastasis.
In diagnostic medicine, both retrospective and pro-
spective studies are used to evaluate the merit of diagnos-
tic tests. Patients’ clinical data are easier to obtain in a
prospective study than in a retrospective study because
standardized tests and procedures can be performed uni-
formly on all enrolled patients.112 Despite the challenges
obtaining data, retrospective studies are useful, in partic-
ular when data can be thoroughly documented in a study
population and when there are clear clinical indications
to conduct SLNB diagnostic tests in early OSCC. Sample
size is of great importance in evaluating the accuracy of
diagnostic tools in medicine.113 These factors may explain
our differences between subgroups, which presented the
tendency to be more sensitive and specific in the retro-
spective study subgroups compared to the prospective
study subgroups.
CONCLUSION
Overall, SLNB is an accurate diagnostic tool that
can be used in clinical practice to identify LN occult
metastasis in early oral cancer.
AUTHOR CONTRIBUTIONS
Do Hyun Kim: study conception and design, acquisi-
tion of data, analysis and interpretation of data, drafting
the article and revisions, final approval of article; Yeonji
Kim: study conception and design, analysis and interpre-
tation of data, drafting the article and revisions, final
approval of article; Sung Won Kim: study conception and
design, analysis and interpretation of data, drafting the
article and revisions, final approval of article; Se Hwan
Hwang: study conception and design, acquisition of data,
analysis and interpretation of data, drafting the article
and revisions, final approval of article.
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