Research

JAMA Otolaryngology–Head & Neck Surgery | Original Investigation

Assessment of the Rate of Skip Metastasis to Neck Level IV

in Patients With Clinically Node-Negative Neck
Oral Cavity Squamous Cell Carcinoma
A Systematic Review and Meta-analysis
Anton Warshavsky, MD; Roni Rosen, BS; Narin Nard-Carmel, MD; Sara Abu-Ghanem, MD;
Yael Oestreicher-Kedem, MD; Avraham Abergel, MD; Dan M. Fliss, MD; Gilad Horowitz, MD

Invited Commentary
IMPORTANCE The rate of skip metastasis to neck level IV in patients with clinically page 548
node-negative neck (cN0) oral cavity squamous cell carcinoma (OCSCC) remains
controversial.

OBJECTIVE To provide a high level of evidence using a meta-analysis on the rate of skip
metastasis to level IV in this subset of patients.

DATA SOURCES The Embase, PubMed, and Google Scholar databases were searched for
articles published during the period of January 1, 1970, through December 31, 2017, using the
following key terms: neck dissection, N0 neck, squamous cell carcinoma, skip metastasis,
radical neck dissection, lymph node management, neck metastasis, oral cavity cancer, and
tongue cancer. Some terms were also used in combination, and the reference section of each
article was searched for additional potentially relevant publications. Data were analyzed from
January 8 through 11, 2018.

STUDY SELECTION Inclusion criteria were all cohorts, including from any randomized clinical
trial, case-control study, case study, and case report; studies of patients with the
histopathologic diagnosis of OCSCC; and studies that differentiated data between skip
metastasis and sequential metastasis to neck level IV. Of the 115 articles retrieved from the
literature, 11 retrospective studies and 2 prospective randomized clinical trials (n = 1359
patients) were included.

DATA EXTRACTION AND SYNTHESIS Meta-analysis of Observational Studies in Epidemiology

guidelines were followed. Fixed-effects model and 95% CIs were estimated, and data of
included studies were pooled using a fixed-effects model.

MAIN OUTCOMES AND MEASURES Overall proportion of neck involvement and the rate of
level IV skip metastasis. Subgroup analysis for primary site and tumor staging.

RESULTS The rate of level IV involvement in patients with cN0 ranged between 0% and
11.40% with a fixed-effects model of 2.53% (95% CI, 1.64%-3.55%). The rate of skip
metastasis ranged from 0% to 5.50% with a fixed-effects model of 0.50% (95% CI,
0.09%-1.11%). The rate of level IV skip metastasis did not increase significantly in cases that
involved neck levels I through III. Tumor staging and primary site tumor did not significantly
affect the rate of skip metastasis.
Author Affiliations: Department of
Otolaryngology–Head and Neck
CONCLUSIONS AND RELEVANCE This meta-analysis showed very low rates of skip metastasis Surgery and Maxillofacial Surgery,
to neck level IV in patients diagnosed with cN0 OCSCC. Encountering an allegedly positive Tel Aviv Sourasky Medical Center,
Sackler Faculty of Medicine, Tel Aviv
lymph node during neck dissection does not portend high rates of level IV involvement.
University, Tel Aviv, Israel.
Supraomohyoid neck dissection is therefore adequate for this subset of patients.
Corresponding Author: Gilad
Horowitz, MD, Department of
Otolaryngology–Head and Neck
Surgery, Tel Aviv Sourasky Medical
JAMA Otolaryngol Head Neck Surg. 2019;145(6):542-548. doi:10.1001/jamaoto.2019.0784 Center, 6 Weizmann St, Tel Aviv,
Published online May 9, 2019. Israel (giladhorowitz@gmail.com).

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 Skip Metastasis in Patients With Clinically Node-Negative Neck Oral Cavity Squamous Cell Carcinoma
T
he treatment of oral cavity squamous cell carcinoma
(OCSCC) has changed considerably over the past few
decades.1 The pendulum has swung from extensive and
radical neck surgeries to modified and selective types of neck
dissections (NDs).2-5 The term supraomohyoid neck dissection
(SOHND) refers to the removal of lymph nodes contained in lev-
els I through III of the neck and is currently referred to as a se-
lective ND in levels I through III.6 This type of ND has been fre-
quently used in the management of clinically node-negative
neck (cN0) in OCSCC and provides similar control rates as more
extensive forms of NDs.7-9 However, several studies have con-
cluded that SOHND is inadequate in patients with OCSCC, ow-
ing to occult metastasis to neck level IV, and that this level should
be routinely dissected.10,11 The designation of the neck level of
skip metastasis, the involvement of neck level IV without the
involvement of previous levels, in patients with OCSCC re-
mains a matter of controversy.12 Advocates for including level
IV in routine NDs claim that it minimizes neck recurrence and
improves prognosis, while opponents remain doubtful of its sur-
vival benefit and further argue that it harbors added morbidity
and longer surgical time.13
The aim of this study is to conduct a meta-analysis of all
relevant published literature to scrutinize the rate of skip me-
tastasis to level IV in patients diagnosed with OCSCC without
preoperative evidence of neck involvement.
Methods
Information Sources and Search Strategy
We performed a methodical and comprehensive search for all
relevant articles in the English literature published between
January 1970 and December 2017 by using the electronic da-
tabases Embase, PubMed, and Google Scholar to search the key
terms neck dissection, N0 neck, squamous cell carcinoma, skip
metastasis, radical neck dissection, lymph node management,
neck metastasis, oral cavity cancer, and tongue cancer. Some
terms were also used in combination. The reference section
of each article was searched for additional potentially rel-
evant publications.
Study Eligibility Criteria
All studies that included patients who underwent an ND of at
least levels I through IV and were judged clinically to be pre-
operatively free of lymph node metastasis were eligible for in-
clusion in this meta-analysis. The inclusion criteria for the study
design were (1) any prospective or retrospective cohort, includ-
ing from any randomized clinical trial, case-control study, case
study, and case report; (2) a study population with the histo-
pathologic diagnosis of OCSCC; and (3) studies that differen-
tiated between true skip metastasis (metastasis solely at neck
level IV) and sequential metastasis to neck level IV. Studies that
involved mixed populations of cN0 and clinically node-
positive (cN+) necks were included only if they enabled
sequestration of data that pertained solely to the cN0 necks.
Exclusion criteria were (1) studies on patients who had under-
gone preoperative radiotherapy and chemotherapy, (2) stud-
ies on recurrent tumors, and (3) studies that did not enable
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Original Investigation Research
Key Points
Question What is the rate of skip metastasis to neck level IV in
patients with clinically node-negative neck (cN0) oral cavity
squamous cell carcinoma (OCSCC)?
Findings In this meta-analysis of 13 studies, the rate of skip
metastasis to neck level IV in patients with cN0 OCSCC was found
to be extremely low. The overall rate of level IV involvement was
between 0% and 11.4%.
Meaning Supraomohyoid neck dissection appears to be an
adequate treatment for patients with cN0 OCSCC.
differentiation between data extracted from patients with cN+
and those with cN0 necks.
Data Extraction
Information regarding study design, patient characteristics, pri-
mary tumor treatment, sample size, and average follow-up time
was retrieved from the selected articles. Data were initially ex-
tracted and evaluated by the 2 principal investigators (A.W. and
R.R.) and thereafter rechecked and confirmed by 3 other in-
vestigators (N.C., D.M.F., and G.H.). The distributions of the
T category, extent of ND, subsite of the primary tumor, and
nodal metastasis were recorded (Table 1). A skip metastasis was
defined as a positive level IV node on final pathology without
the involvement of higher levels (ie, levels I-III). A level IV nodal
metastasis coexisting with nodes at other neck levels was as-
sessed separately. Because most of the available studies were
retrospective and observational, we followed the guidelines
for meta-analysis of observational studies.14
Statistical Analysis
Fixed-effects and random-effects meta-analyses of single pro-
portions were used in conjunction with the inverse variance
method to calculate the overall proportion. The Freeman-
Tukey double arcsine transformation was implemented to cal-
culate overall proportions. The Clopper-Pearson method (ex-
act binomial) was used to calculate the CI for the individual
study results. Result heterogeneity among the studies was
quantified using the inconsistency index I2, and a value higher
than 75% was considered to be substantial heterogeneity.
Statistical analysis was conducted using R statistical soft-
ware (version 3.3.3, R Foundation).
Results
Study Selection
The search strategy identified 115 articles published from
January 1, 1970, to December 31, 2017. These articles were se-
lected and transferred into EndNote (Thomson Reuters), and
replicates were removed. The various phases of assessing the
abstracts and reasons for exclusion from the meta-analysis are
depicted in Figure 1. A total of 11 retrospective and 2 prospec-
tive randomized clinical studies that met our inclusion crite-
ria, with a total of 1359 patients, were subsequently included
in the meta-analysis (Table 1).5,9,10,12,13,15-22
543
 Research Original Investigation Skip Metastasis in Patients With Clinically Node-Negative Neck Oral Cavity Squamous Cell Carcinoma

Table 1. Study Characteristics

Sample Age Male/
Year of Size, Range, Female, ND T Metastasis
Source Design Accrual No. y No. Level Subsite(s) Stage to Level IV Follow-up
Khafif et al,15 Retrospective 1983-1998 17a 24-79 NA I-IV Tongue 1-3 1 Average, 4.1
2001 y
Byers et al,10 1997 Retrospective 1970-1990 163a NA NA I-IV Tongue 1-4 9 >1 y
Balasubramanian Retrospective 2003-2008 52 27-80 43/9 I-IV Tongue 1-4 2 Average,
et al,16 2012 2y
13
Crean et al, 2003 Retrospective 1996-1999 49 Average, 24/25 I-IV Tongue, alveolus, buccal 1-4 5 1-3 y
63 mucosa, FOM, lip, RMT,
hard palate
Feng et al,17 2014 Retrospective 1995-2010 190a 19-87 NA I-IV Tongue, alveolus, buccal 1-4 6 3-18 y
mucosa, FOM, lip, RMT,
hard palate
Mishra et al,18 Retrospective 2006-2008 13a NA NA I-IV Tongue, alveolus, buccal 1-3 0 Minimum,
2010 mucosa, FOM, lip, RMT 1-3 y
Vishak and Retrospective 2006-2007 57 25-65 43/14 I-IV Tongue 1 2 NA
Rohan,19 2014
Cariati et al,20 Retrospective 2004-2010 88a 19-81 NA I-IV Tongue 1-4 10 ≥5 y
2018
Dias et al,12 2006 Retrospective 1987-1997 71a
NA NA I-IV Tongue, FOM 1-4 3 ≥3 y
Shah et al,5 1990 Retrospective 1965-1986 192a 17-95 NA I-IV Tongue, alveolus, buccal 1-4 6 NA
mucosa, FOM, RMT
Guo et al,21 2014 Retrospective 1999-2010 160a NA 84/76 I-V Tongue, alveolus, RMT, 1-4 2 Median,
buccal mucosa, hard 76 mo
palate
Brazilian Head and Prospective 1990-1993 76a NA 58/18 I-IV Tongue, alveolus, FOM, 2-4 5 NA
Neck Cancer Study RMT
Group,9 1998
Agarwal et al,22 Prospective 2011-2015 231 22-82 190/41 I-IV Tongue, alveolus, buccal 1-4 0 Mean,
2018 mucosa, FOM, lip 21 mo

Abbreviations: FOM, floor of mouth; NA, not available; ND, neck dissection; RMT, retromolar trigone.
a
Sample size extracted for analysis and is not the entire cohort of the study.

tremely low, ranging from 0% to 5.50% with a fixed-effects

Figure 1. Article Selection
200 Records identified through 49 Additional records identified
database search through reference lists of articles
134 Articles excluded based
on lack of relevance
115 Potentially relevant articles
identified
40 Articles excluded
37 Inappropriate based
on title and abstract
3 Reviews
75 Full-text articles assessed for
eligibility
62 Full-text articles excluded
(not meeting inclusion
criteria, lacking essential
data, or same population)
model of 0.50% (95% CI, 0.09%-1.11%) (Figure 2B).5,9,10,12,13,15-22
Various combinations of metastatic patterns with involve-
ment of level IV were analyzed separately in subgroup analy-
ses (Table 2).9,12,13,15-19,21,22 The rate of level IV metastasis did
not increase significantly in cases that involved higher levels
(ie, levels I-III) of the neck. In fact, the highest fixed-effect
model was 0.04% (95% CI, 0%-0.63%) for involvement of lev-
els I, II, and IV. All other fixed-effects models equaled 0% (95%
CI, 0%-0.75%). A subgroup analysis according to T stage
showed that level IV involvement was 0% (n = 401; 95% CI,
0%-0.63%) for stages I and II and 0% (n = 129; 95% CI, 0%-
1.16%) for stages III and IV.
Categorization by oral cavity subsites revealed signifi-
cant findings only on oral tongue primary lesions. The
analysis included 8 studies with 590 patients. The rate
of involvement of neck level IV was 0% to 11.40% with a
fixed-effects model of 3.60% (95% CI, 2.09%-5.42%)
(Figure 3).5,10,12,15,16,19,20,22

13 Studies included in meta-analysis

Meta-analysis Results
The rate of involvement of level IV among the patients with
cN0 was 0% to 11.40% with a fixed-effects model of 2.53% (95%
CI, 1.64%-3.55%) (Figure 2A).5,9,10,12,13,15-22 According to re-
sults of the meta-analysis, the rate of skip metastasis was ex-
Discussion
Although it is well established that patients with OCSCC are
at high risk for lymph node metastasis, the extent of nodal
involvement for each neck level remains controversial.12 One
of the main confounders is the heterogeneity of the study
groups, which results in the lack of data stratification by
T stages, subsites, and involvement of other neck levels.
Another bias in many publications stems from combining the

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 Skip Metastasis in Patients With Clinically Node-Negative Neck Oral Cavity Squamous Cell Carcinoma Original Investigation Research

Figure 2. Rate of Level IV Involvement and True Skip Metastasis in Preoperative Patients
With Clinically Node-Negative Necks

A Rate of level IV involvement

Favors No Favors
Source Events Total Proportion, % Involvement Involvement Weight, %
Khafif et al,15 2001 1 17 5.88 (0.15-28.69) 1.3
Byers et al,10 1997 9 163 5.52 (2.56-10.22) 12.0
Balasubramanian et al,16 2012 2 52 3.85 (0.47-13.21) 3.8
Crean et al,13 2003 5 49 10.20 (3.40-22.23) 3.6
Feng et al,17 2014 6 190 3.16 (1.17-6.75) 14.0
Mishra et al,18 2010 0 13 0.00 (0.00-24.71) 1.0
Vishak and Rohan,19 2014 2 57 3.51 (0.43-12.11) 4.2
Cariati et al,20 2018 10 88 11.36 (5.59-19.91)
6.5
Dias et al,12 2006 3 71 4.23 (0.88-11.86)
5.2
Shah et al,5 1990 6 192 3.12 (1.16-6.68)
14.1
Guo et al,21 2014 2 160 1.25 (0.15-4.44)
11.8
Brazilian Head and Neck
5 76 6.58 (2.17-14.69) 5.6
Cancer Study Group,9 1998
Agarwal et al,22 2018 0 231 0.00 (0.00-1.58) 17.0
Fixed-effect model 1359 2.53 (1.64-3.55) 100

–0.05 0 0.05 0.10 0.15 0.20 0.25

Level IV Involvement

B Rate of level IV true skip metastasis

Favors No Favors
Source Events Total Proportion, % Involvement Involvement Weight, %
Khafif et al,15 2001 0 17 0.00 (0.00-19.51) 1.3
Byers et al,10 1997 9 163 5.52 (2.56-10.22) 12.0
Balasubramanian et al,16 2012 1 52 1.92 (0.05-10.26) 3.8
Crean et al,13 2003 2 49 4.08 (0.50-13.98) 3.6
Feng et al,17 2014 0 190 0.00 (0.00-1.92) 14.0
Mishra et al,18 2010 0 13 0.00 (0.00-24.71) 1.0
Vishak and Rohan,19 2014 1 57 1.75 (0.04-9.39) 4.2
Cariati et al,20 2018 1 88 1.14 (0.03-6.17) 6.5
Dias et al,12 2006 1 71 1.41 (0.04-7.60)
5.2
Shah et al,5 1990 3 192 1.56 (0.32-4.50)
14.1
Guo et al,21 2014 0 160 0.00 (0.00-2.28)
11.8
Brazilian Head and Neck
2 76 2.63 (0.32-9.18) 5.6
Cancer Study Group,9 1998
Agarwal et al,22 2018 0 231 0.00 (0.00-1.58) 17.0
Fixed-effect model 1359 0.50 (0.09-1.11) 100

–0.05 0 0.05 0.10 0.15 0.20 0.25

Level IV Involvement

results of the primary neck surgery with those of revision sur-
geries for neck recurrences. These drawbacks became appar-
ent during the process of data extraction, and they were ad-
dressed by excluding all patients with revision NDs and by
omitting all groups lacking this information.
After performing a meta-analysis of all extracted data, we
found that the actual rate of skip metastasis to level IV was only
0.5%. We also performed several subgroup analyses, the first
of which was designed to account for the various primary tu-
mor sites. Unfortunately, data in almost all of the analyzed
articles failed to report the relations between the primary tu-
mor site and the neck levels involved by metastatic tumor. Only
primary lesions of the tongue could be accurately assessed.
That analysis again confirmed a relatively low rate of skip me-
tastasis, with a fixed-effects model of 3.60% (range, 0%-
11.40%; 95% CI, 2.09%-5.42%). Another subgroup analysis
was made on the various T stages. Once again, the majority of
articles reviewed did not provide the rates of lymph node
involvement according to the pathological T staging. Many ar-
ticles did not differentiate between the various T stages or com-
bined them into low (I-II) and high (III-IV) stages. Even so, the
rate of the various T stages had relatively low influence on the
rate of skip metastasis. Specifically, the rate of skip metasta-
sis was 0% for advanced stage disease as well as for early stage
disease, which was surprising considering that higher T stages
are associated with infamously high rates of lymph node in-
volvement. However, this figure probably represents a selec-
tion bias. Because only a small number of articles provided the
correlation between T stages and skip metastasis, these ar-
ticles shift the statistical analysis to manifest negligible level
IV metastasis. On the same note, a recently published study
on the Surveillance, Epidemiology, and End Results Program
database23 did find a linear correlation between the initial
T stage and neck involvement, including level IV, but did not
differentiate patients deemed preoperative as clinically cN0.
This article also provided data on the relation between the

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 Research Original Investigation Skip Metastasis in Patients With Clinically Node-Negative Neck Oral Cavity Squamous Cell Carcinoma

Table 2. Subgroup Analysis Showing Metastatic Patterns With Involvement of Level IV in Preoperative Patients
With Clinically Node-Negative Necks
Combination of Involved Fixed-Effect
Neck Levels Source No. of Patients Model (95% CI), %
I, II, III, IV Khafif et al,15 2001
Balasubramanian et al,16 2012
Mishra et al,18 2010 384 0 (0-0.75)
Dias et al,12 2006
Agarwal et al,22 2018
I, II, IV Crean et al,13 2003
Feng et al,17 2014
Mishra et al,18 2010 643 0.04 (0-0.63)
Guo et al,21 2014
Agarwal et al,22 2018
I, III, IV Crean et al,13 2003
Mishra et al,18 2010 293 0 (0-0.23)
Agarwal et al,22 2018
I, IV Mishra et al,18 2010
Brazilian Head and Neck Cancer Study Group,9 1998 320 0 (0-0.27)
Agarwal et al,22 2018
II, III, IV Feng et al,17 2014
Mishra,18 et al 2010
491 0 (0-0.37)
Vishak and Rohan,19 2014
Agarwal et al,22 2018
II, IV Feng et al,17 2014
Mishra et al,18 2010 434 0 (0-0.35)
Agarwal et al,22 2018
III, IV Crean et al,13 2003
Feng et al,17 2014
Mishra et al,18 2010 643 0 (0-0.23)
Guo et al,21 2014
Agarwal et al,22 2018

Figure 3. Oral Tongue Primary: Rate of Level IV Involvement in Preoperative Patients

With Clinically Node-Negative Necks

Favors No Favors
Source Events Total Proportion, % Involvement Involvement Weight, %
Khafif et al,15 2001 1 17 5.88 (0.15-28.69) 2.9
Byers et al,10 1997 9 163 5.52 (2.56-10.22) 27.5
Balasubramanian et al,16 2012 2 52 3.85 (0.47-13.21) 8.8
Vishak and Rohan,19 2014 2 57 3.51 (0.43-12.11) 9.7
Cariati et al,20 2018 10 88 11.36 (5.59-19.91) 14.9
Dias et al,12 2006 1 71 1.41 (0.04-7.60) 12.0
Shah et al,5 1990 2 58 3.45 (0.42-11.91) 9.8
Agarwal et al,22 2018 0 84 0.00 (0.00-4.30) 14.2
Fixed-effect model 590 3.60 (2.09-5.42) 100
–0.05 0 0.05 0.10 0.15 0.20 0.25
Level IV Involvement

primary site tumor and neck metastasis. As for both para-
meters (T stage and primary site), neck level IV involvement
did not exceed 11.2%, even for patients with a cN+ neck on
presentation.
The idea of skip metastasis was initially described by
Byers et al10 and refers to the condition in which OCSCC
bypasses levels I, II, or both and goes directly to levels III or
IV. Those authors reported a 15.8% rate of skip metastasis
and therefore recommended routine dissection at neck level
IV. Careful analysis of their data, however, revealed that only
5.5% of patients with clinical cN0 disease had skip metasta-
sis to level IV in the initial ND specimen. Moreover, they
described another 9 patients (9.9%) with recurrences at neck
level IV, which had not been included in an earlier ND.
Accounting for neck recurrence as a missed pathological
lymph node in the primary surgery is problematic. The neck

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 Skip Metastasis in Patients With Clinically Node-Negative Neck Oral Cavity Squamous Cell Carcinoma Original Investigation Research

has now lost its anatomical lymphatic drainage and, in many
cases, radiated. Because no data on recurrence in other dis-
sected levels were provided, it is impossible to accurately
calculate the rate of regional recurrence. Notwithstanding,
even when accounting for all of the cases mentioned in this
study, the incidence of skip metastasis or subsequent recur-
rence in level IV was only 4.8% (13 of 270). As such, conclud-
ing that neck level IV should be routinely dissected is open
to question, even with a low tolerance threshold for adding
neck levels to diminish recurrences.
Crean et al13 demonstrated that 5 of 49 (10%) patients
had involvement of neck level IV despite having been preop-
eratively diagnosed with a cN0 neck. Only one of those
patients (2%) had a true skip metastasis to level IV. After
revisiting the database, our main criticism is the obvious
inclination of the study population toward advanced dis-
ease, with 39% of the patients at stage T4 and only 6% at
stage T1. However, the results of the study raise the question
of the necessity of performing a level IV ND in advanced
stage disease. The results of the present study failed to find
advanced stage disease as an indication for extending
the ND.
Another article, by Cariati et al,20 was recently published
and demonstrated double-figure recurrences in the neck. No-
tably, the true rate of level IV involvement, as clearly stated
by the authors, was 7.4%. There was only 1 case (1.2%) of skip
metastasis to level IV. Although they did report the relation-
ship between various risk factors and neck involvement, they
did not provide a subgroup analysis of skip metastasis with re-
gard to the initial T stage. We therefore disagree with those au-
thors’ opinion that all NDs must include level IV. Our rebuttal
is based on the results of the present meta-analysis, which is
almost 20-fold larger and reveals an overall involvement rate
of 2.53% and skip metastasis rate of 0.50%, which does not
justify routinely dissecting neck level IV. Additionally, pa-
tients diagnosed with a cN0 neck prior to surgery still had
relatively low rates of skip metastasis, including patients with
advanced stage tumors.
Another reported surgical option was to extend the neck
dissection to level IV nodes whenever suspicious nodes at
levels II and III were encountered during SOHND. 15, 2 4
The results in the current meta-analysis do not support this
protocol. After performing statistical analyses for combina-
tions of various neck level involvement, the rate of level IV
involvement remained extremely low (Table 2). However,
this data was based on smaller cohorts compared with
the entire meta-analysis. This is because many articles
did not provide the entire data set on the involvement of
the various neck levels. We therefore concur that the sub-
group analysis on the metastatic patterns of lymph node
involvement in the neck (Table 2) should be addressed
with caution.
Limitations
There are obvious limitations to this study. The retrospective
nature of most studies included in this meta-analysis is one.
The fact that many studies did not match the tumor staging
and tumor subsite to the extent of neck disease per patient also
hampered statistics and subgroup analysis. However, we found
very low rates of skip metastasis.
Conclusions
The results of this meta-analysis demonstrate very low rates
of skip metastasis to neck level IV in patients diagnosed with
cN0 OCSCC. Various tumor stages and subsites had similarly
low rates of skip metastasis. These findings oppose routine dis-
section of neck level IV in these patients. Encountering a lymph
node suspected as being positive during ND does not portend
high rates of level IV involvement, and SOHND is adequate for
this subset of patients.

ARTICLE INFORMATION Conflict of Interest Disclosures: None reported. 109-113. doi:10.1002/1097-0142(19900701)66:

Accepted for Publication: March 19, 2019.
Published Online: May 9, 2019.
doi:10.1001/jamaoto.2019.0784
Author Contributions: Dr Horowitz had full access
to all of the data in the study and takes
responsibility for the integrity of the data and the
accuracy of the data analysis. Dr Warshavsky and
Ms Rosen contributed equally to the study.
Study concept and design: Warshavsky, Rosen,
Abu-Ghanem, Abergel, Fliss, Horowitz.
Acquisition, analysis, or interpretation of data:
Warshavsky, Rosen, Nard-Carmel,
Oestreicher-Kedem, Horowitz.
Drafting of the manuscript: Warshavsky, Rosen,
Nard-Carmel, Abergel, Horowitz.
Critical revision of the manuscript for important
intellectual content: Rosen, Abu-Ghanem,
Oestreicher-Kedem, Fliss, Horowitz.
Statistical analysis: Warshavsky, Rosen,
Nard-Carmel, Horowitz.
Administrative, technical, or material support:
Rosen, Nard-Carmel, Oestreicher-Kedem.
Study supervision: Carmel, Fliss, Horowitz.
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 Research Original Investigation Skip Metastasis in Patients With Clinically Node-Negative Neck Oral Cavity Squamous Cell Carcinoma

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Invited Commentary

Inclusion of Neck Level IV in Treatment of Patients

With Clinically Node-Negative Oral Cavity Cancer
Arun Sharma, MD, MS

The extent of neck dissection (ND) for treatment of head and
neck cancer has been an area of active research and changes
in clinical practice for the last several decades. Radical NDs have
largely been replaced by
modified and selective NDs.1
Related article page 542 The classic neck levels at risk
for oral cavity cancers are lev-
els I through III; elective dissection of these levels with a su-
praomohyoid neck dissection (SOHND) is recommended for
many patients with clinical node-negative (cN0) oral cavity can-
cers given the risk of occult nodal disease.1,2 However, many
authors, including Byers and colleagues,3 have suggested that
SOHND is inadequate and that level IV should be included
owing to the risk of skip metastasis from oral cavity cancer.
To ascertain whether inclusion of level IV is beneficial in
patients with cN0 oral cavity cancer undergoing elective ND,
Warshavsky and colleagues 4 performed a meta-analysis
published in this issue of JAMA Otolaryngology–Head & Neck
Surgery to determine the proportion of level IV involvement
and level IV skip metastasis (ie, level IV involvement without
involvement of levels I-III). The meta-analysis included 13 stud-
ies and 1359 patients. Using fixed-effects models, the risk of
level IV involvement was 2.53% and the risk of level IV skip
metastasis was 0.50%. In a subgroup analysis, the pathologi-
cal finding of positive nodes in levels I through III was not
associated with an increased risk of level IV involvement.
In performing their meta-analysis, Warshavsky and
colleagues4 used appropriate methodology and reporting in
compliance with accepted guidelines of Meta-analyses of
Observational Studies in Epidemiology.5 Despite their rigor-
ous methods, a key limitation is that not all of the studies in-
cluded in the meta-analysis provided enough data for the sub-
group analyses. For each combination of pathologically
involved nodal levels, only up to 5 studies (range, 3-5 studies
depending on the exact combination of nodal levels) could be
included in each of the subgroup analyses. Subsites that were
included varied between studies, because some studies only
included oral tongue cancers while others included a variety
of oral cavity subsites. The subgroup analysis of oral tongue
cancers included 8 studies with 590 patients and showed that
the risk of level IV involvement was higher than oral cavity
cancer overall (3.60% vs 2.53%), although still less than 5%.
Although the concept of skip metastasis in oral cancer has
been discussed for decades and most head and neck sur-
geons have anecdotes of level IV involvement from their own
patients, the meta-analysis by Warshavsky and colleagues4
shows that the risk of level IV involvement is less than 5%. For
that reason, the authors conclude that elective treatment of
level IV is not required in patients with cN0 oral cavity can-
cer. However, in my clinical practice, there are 2 situations in
which I would consider adding level IV to the standard SOHND.
The first situation would be when there is gross macroscopic

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