Predictive Value of Tumor Thickness
for Cervical Lymph-Node
Involvement in Squamous Cell
Carcinoma of the Oral Cavity
A Meta-analysis of Reported Studies
Shao Hui Huang, MSc1,2, David Hwang, MB2, Gina Lockwood, MMath3, David P. Goldstein, MD4,5,
and Brian O’Sullivan, MD2,4
BACKGROUND: Tumor thickness (TT) appears to be a strong predictor for cervical lymph-node involve-
ment in squamous cell carcinoma of the oral cavity (OSCC), but a precise clinically optimal TT cutoff point
has not been established. To address this question, the authors conducted a meta-analysis. METHODS: All
relevant articles were identified from MEDLINE and EMBASE as well as from cross-referenced publications
cited in relevant articles. Lymph-node involvement was confirmed and identified as positive lymph-node
declaration (PLND) by either pathologic positivity on immediate neck dissection or by neck recurrence
identified after follow-up ?2 years. Odds ratios (OR) were calculated to quantify the predictive value of TT.
Negative predictive values (and the percentage of patients falsely predicted to not have PLND [FN-PLND])
were compared to determine the optimal TT cutoff point. RESULTS: Sixteen studies were selected from 72
potential studies, yielding a pooled total of 1136 patients. Data were examined for the following TT cutoff
points: 3 mm (4 studies, 387 patients), 4 mm (9 studies, 778 patients), 5 mm (6 studies, 367 patients), and
6 mm (4 studies, 488 patients). The OR (95% CI) was 7.3 (5.3-10.1) for the overall group. The proportion of
FN-PLND was 5.3% (95% CI, 2.0-11.2), 4.5% (2.6-7.2), 16.6% (11.5-22.8), and 13.0% (9.7-16.9) for TT<3, <4, <5,
and <6 mm, respectively. There was a statistically significant difference between the 4-mm and 5-mm TT
cutoff points (P ¼ .007). CONCLUSIONS: TT was a strong predictor for cervical lymph-node involvement.
The optimal TT cutoff point was 4 mm. Cancer 2009;115:1489–97. V
C 2009 American Cancer Society.
KEY WORDS: tumor thickness, cervical lymph-node metastases, squamous cell carcinoma, oral cavity
The presence of cervical lymph-node metastasis is consistently a strong determinant of survival in
patients with squamous cell carcinoma of the oral cavity (OSCC).1-5The incidence of occult lymph-node
Received: August 18, 2008; Revised: October 1, 2008; Accepted: October 3, 2008
Published online: February 5, 2009, V
C 2009 American Cancer Society
DOI: 10.1002/cncr.24161, www.interscience.wiley.com
Corresponding author: Brian O’Sullivan, MD, Room 5-624, Department of Radiation Oncology, Princess Margaret Hospital, 610 University Avenue,
Toronto, ON, Canada. M5G 2M9; Fax: (416) 946-6566; email@example.com
1Radiation Medicine Program, Princess Margaret Hospital, Toronto, Ontario, Canada;
Toronto, Ontario, Canada;3Department of Biostatistics, Princess Margaret Hospital, Toronto, Ontario, Canada;4Department of Otolaryngology-Head
& Neck Surgery, University of Toronto, Toronto, Ontario, Canada;
2Department of Radiation Oncology, University of Toronto,
5Department Surgical Oncology, Princess Margaret Hospital, Toronto, Ontario,
April 1, 2009
metastasis in early-stage tumors (primary site T-categori-
zation T1 or T2) has been reported to be between 27%-
40%.6-8In general, management of the neck, especially
using elective neck dissection (END) is advocated when
the risk of cervical lymph-node involvement is greater
than 15%-20%.9,10END may be both diagnostic and
therapeutic. It provides pathological information on the
status of neck nodes, thus helping to determine the need
for adjuvant therapies. As well, it removes any clinically
undetectable metastases. While the rate of occult lymph-
node metastases in early stage OSCC warrants considera-
tion of END, a significant number of patients undergoing
END will have no evidence of regional lymph-node me-
tastases and may be subjected to the potential morbidity
of a neck dissection. Efforts to identify reliable parameters
that predict the risk of cervical lymph-node involvement
In the 1970s, Breslow established a strong link
between tumor thickness (TT) and both tumor-free sur-
vival and metastasis in patients with cutaneous mela-
noma.11,12Mohit-Tabatabai et al and Spiro et al first
applied Breslow’s hypothesis regarding the link between
lymph-node involvement and TT to OSCC.13,14Since
then, many studies have been carried out to test this rela-
tionship. Most studies have suggested that TT is a strong
predictor for lymph-node involvement in OSCC, includ-
ing observations from our institution.15-18However, con-
troversy exists about the optimal TT cutoff point for a
clinically relevant risk to the neck of harboring micro-
The objective of this study was to perform a meta-
analysis to assess the relationship between TT and the risk
of cervical lymph-node involvement and, furthermore, to
determine the optimal TT cutoff point for prompting
MATERIALS AND METHODS
We conducted an electronic search for relevant studies
examining the relationship between TT and cervical
lymph-node involvement in OSCC. Literature searches
were performed through MEDLINE (1966 to January,
2007) as well as an inclusive search of EMBASE. Because
both ‘‘tumor thickness’’ and ‘‘depth of invasion’’ are com-
monly used as synonyms in many of the studies,19both
terms were used for the literature search. Search strategies
were developed and independently conducted by the first
author and an experienced medical librarian. The search
query used for the MEDLINE database was ((‘‘mouth
neoplasms/[MeSH Terms]’’ or ‘‘oral cavity’’ or ‘‘tongue’’
or ‘‘floor of mouth’’ or ‘‘buccal mucosa’’) and (‘‘tumo(u)r
thickness’’ or ‘‘thickness of tumo(u)r’’ or ‘‘depth of inva-
sion’’ or ‘‘invasion depth’’)). For the term ‘tumor’, both
American and British English spelling conventions were
used in literature search. The electronic search was sup-
plemented with papers obtained by crosschecking the
bibliographies of relevant articles. Only original articles
published in English on human subjects were selected for
further review. Studies published later than the search
Two reviewers analyzed each selected article independ-
ently according to inclusion/exclusion criteria established
by the senior author of this study before review. The
inclusion criteria were: OSCC treated with primary sur-
gery; all T and N categories at inception; TT measured on
the surgical specimen; TT or depth of invasion described
and a minimum follow-up period of 2 years for untreated
necks. Studies were excluded if they included nonoral cav-
ity cancers or histologies other than regular SCC within
the cohort (verrucous carcinoma and variants of squa-
mous cell carcinoma including papillary or adenosqua-
mous histologies were not included); patients treated
primarily by nonsurgical therapies; adjuvant or neoadju-
vant treatment other than surgery for the untreated neck;
TT measured by methods other than on pathologic exam-
modalities; inability to separate regional lymph-node fail-
ure from locoregional failure; or studies reporting only
statistical summaries without absolute numbers. The 2
reviewers selected articles and retrieved data independ-
ently according to the above inclusion/exclusion criteria.
Any discrepancies on the eligibility of the specific article
or the retrieved data were reconciled by re-reviewing the
article. The reasons for exclusion were also recorded and
compared. Each reviewer independently appraised the
methodological quality of all studies and abstracted the
April 1, 2009
data from the included studies. Both the terms ‘‘tumor
thickness’’ and ‘‘depth of invasion’’ have been used in var-
ious studies. For this meta-analysis, we adopted the most
prevalent convention of using the term ‘‘tumor thickness’’
This has generally been defined according to the defini-
tion proposed by Moore et al20to be ‘‘the deepest inva-
sion of tumor in the tissue from the mucosal surface’’
(Fig. 1). In the case of any studies that did not define this
explicitly, we accepted those that used the term ‘tumor
Cervical lymph-node involvement was confirmed based on
1) pathological lymph-node metastasis (PNM) in regional
lymph nodes for cases that underwent a neck dissection as
part of their initial treatment, ie, pathological positive
lymph node(s); or 2) the development of delayed lymph-
node metastasis (DNM) for cases that did not undergo a
neck dissection as part of their initial treatment but devel-
oped a recurrence in the neck after a minimum 2 years of
follow-up. The designation ‘‘Positive Lymph node Decla-
ration’’ (PLND) was used as the aggregate observation
derived from the detection of either pathologic positivity
on immediate neck dissection or alternatively delayed
lymph-node recurrence at follow-up. The absolute number
from each eligible study was recorded. Odds Ratios (OR)
for PLND with 95% Confidence Intervals (CI) were calcu-
lated for individual studies using the Peto estimates
method21to detect heterogeneity of each study. OR forthe
pooled data were calculated using the DerSimonian and
Laird method21to determine the predictive value of TT.
The pooled OR represents the effect of comparing small
TT to large TT where the underlying continuous TT pa-
rameter has been dichotomized with some variability
because the TT cutoff points between studies varied from
assessed using negative predictive values (NPV). The per-
centage of cases with PLND below the TT cutoff point (ie,
percentage falsely predicted negative [FN-PLND, ¼ 1-
NPV]) and 95% confidence interval (CI) were calculated
and compared between TT cutoff points using Logistic
Regression with Generalized Estimating Equations to
account for study clusters. Positive predictive values were
not compared because of variability in inclusion criteria
across studies. Specifically, the outer limit of tumor thick-
ness varied between studies but was not sufficiently
After we combined electronic searching results from the 2
electronic searching databases as well as cross-referencing
were selected for further review. Sixteen studies (15 retro-
spective and 1 prospective) that satisfied all the inclusion/
exclusion criteria were chosen for this meta-analy-
sis.15,16,22-36Among them, 9 studies included clinical
T1-2 before surgery, 10 contained clinical N0, and 7
addressed clinical stage I&II (T1-2N0). Twelve studies
clearly defined TT following the recommendation of
Moore et al to measure ‘‘from a theoretical reconstructed
normal mucosal line to the deepest portion of tumor’’.20
of the tumor excluding keratin, parakeratin, and inflam-
matory exudates. The remaining 2 did not specify how
the TT was measured. Eight studies used an ocular micro-
meter to measure TT with an accuracy of 0.1 mm while
TT was measured on formalin-fixed, paraffin-embedded,
FIGURE 1. Schematic diaphragm of tumor thickness measurement is measured from the surface of adjacent normal mucosa to
the deepest point of tumor invasion. Ca indicates carcinoma.
Tumor Thickness and Oral Cavity Cancer/Huang et al
April 1, 2009
tissue samples obtained from primary surgery. The details
of theeligiblestudiesarelisted (Table1).
The selected studies yielded a pooled total of 1136
patients for this meta-analysis. The disease subsites were
as follows: 47% (537 of 1136) oral tongue, 17% (192 of
1136) buccal mucosa, 12% (137 of 1136) floor of mouth,
and 23% (263 of 1136) lower lip. The pooled data were
further examined by varying the TT cutoff points. This
provided 4 studies for TT cutoff point at 3 mm, 9 at 4
mm, 6 at 5 mm, and 4 at 6 mm yielding a pooled subtotal
of 387, 778, 367, and 488 data observations, respectively.
Although 1136 patients were involved in the study, a total
of 2020 data observations were used in the analysis
were used twice for 2 different TT cutoff points and 1
study26wasused 4-timesfor4different TTcutoff points.
The odds ratio (OR) with 95% confidence interval (CI)
for PLND based on TT for the individual studies are
shown in Figure 2. The OR varied considerably from 3.2
(95% CI, 0.8-12.1) to 57.1 (13.1-248.2). For the overall
group, T1-2, N0 and the stage I and II (T1-2N0) sub-
group, the OR (95% CI) of PLND were 7.3 (95% CI, 5.3-
10.1), 6.2 (4.1 – 9.3), 8.8 (5.3 – 14.7) and 7.1 (4.3-11.8),
Table 1. Eligible Studies Chosen for This Meta-analysis*
NamePLND Category Disease SiteStage Total No. TT cutoff point
de Visscher 199833
T1-3 all N
T1-2 all N
T1-3 all N
T1-2 all N
all T all N
T1-4 all N
4 mm, 6 mm
3 mm, 4 mm, 5 mm, 6 mm
3 mm, 6 mm
3 mm, 5 mm
4 mm, 6 mm
PLND indicates positive lymph node declaration; PNM, pathological nodal metastasis; DNM, delayed nodal metastasis; FOM, floor of mouth; TT, tumor
*TT cutoff point indicated in this table was derived from source data but not necessarily the only cutoff point used in the original study. Some of eligible stud-
ies divided source data into ‘<¼’’ vs. ‘>’ categories, while others ‘<’ vs. ‘>¼’. Since the possibility of TT measured exactly ‘¼’ 3.0 or 4.0 or 5.0 or 6.0 mm is
rare, we have grouped studies ‘‘<¼’’ and ‘‘<’’ certain TT cutoff point together as ‘‘<¼’’; and grouped ‘>’ and ‘>¼’ together as ‘>’. In this meta-analysis, 4
studies were used twice for 2 different TT cutoff points and 1 study was used 4 times for 4 different TT cutoff points.
FIGURE 2. Forest plot for all studies in the meta-analysis is
depicted. The width of a rectangle indicating the odds ratio
(OR) on the Forest plot is proportional to the size of the
study. ORs ranged from 3.2 (95% confidence interval [CI],
0.8-12.1) to 57.1 (95% CI, 13.1-248.2) among individual studies.
April 1, 2009
Optimal Tumor-Thickness Cutoff Point
The NPV and FN-PLND for the different TT (? 3 mm,
? 4 mm, ?5 mm, and ?6 mm) were calculated (Table
3). There was a significant increasing trend in the FN-
PLND as the TT cutoff point increased (P ¼ .03). The
incidence of FN-PLND for a TT cutoff point of 4 mm and
5 mm was 4.5% (95%CI: 2.6-7.2) and 16.6% (11.5-
22.8), respectively, which was statistically significant (P ¼
This meta-analysis has several unavoidable limitations,
including its almost entire reliance on retrospective stud-
ies. Diagnostic meta-analysis with retrospective data is rel-
atively new, and its use has only been introduced since
1990.37-41The statistical methods are not as well defined
as those used for prospective randomized trials.42To
ensure data quality, we set up several quality assurance
measures in the literature search, selection of eligible stud-
ies and retrieving data from eligible studies. In addition,
the absence of TT data derived from individual patients
in the original studies limited the statistical power for this
meta-analysis. Furthermore, vagueness of TT definition
in the original studies created uncertainty of source data.
In this meta-analysis, we included 2 studies that stated
that TT was measured from the surface of tumor exclud-
ing keratin, parakeratin, and inflammatory exudates.26,28
One of these studies stated that for exophytic, papillary
lesions, TT was measured from the tip of a papilla to an
imaginary line connecting the bases of 2 adjacent pegs.28
As well, the inability to confirm whether regional lymph-
nodefailure wasthe firstsite offailure in theoriginalstud-
ies creates a further potential confounding of source data.
Finally, TT was measured on pathological samples from
surgery, which limits the putative pretreatment value of
this parameter. However, studies on validating the corre-
lation of TT detected on preoperative ultrasonography
and /orMRI arebeinginvestigated.23,30,43-45
A significant percentage of patients with OSCC
present with T1 or T2 disease. Occult metastasis to the
neck may occur in up to 40% of these patients with no
clinically or radiographically evident regional disease.
Neck dissections are performed electively for T1 tumors
and frequently for T2 tumors because of concerns about
occult regional lymph-node metastases. Management of
the clinically negative neck in these patients continues to
be controversial. Thereare2 commonlyusedstrategiesfor
tion or observation with treatment reserved for recur-
rence. Less commonly, the N0 neck is electively managed
with radiation. Proponents of elective neck management
Table 2. Odds Ratio and 95% Confidence Interval of
Cervical Lymph-Node Involvement Based on Tumor
Thickness for the Overall Group and Various Subgroups
Group No. of StudyOR 95% CI
OR indicates odds ratio; CI, confidence interval.
OR was obtained by including all studies using cutoff points provided in
each study (see Fig. 2 for cutoff points).
Table 3. Negative Predictive Values (NPV) and Percentage of Falsely Predicted Negative (1-NPV) for Tumor Thickness
Cutoff Points of 3 mm, 4 mm, 5 mm, and 6 mm*
No. of Observations
at Lower Range of
TT Cutoff Point
NPV indicates negative predictive value; PLND, positive lymph node declaration.
*FN-PLND, percentage of patients with PLND who fall below the TT cutpoint; FN-PLND L 95% and FN-PLND U 95%, lower and upper limit of 95% confidence
interval for FN-PLND respectively. FN-PLND represents the percentage of patients with lymph node metastasis at the given TT cutoff. There was a significant
trend for FN-PLND as the TT cutoff point increased (test for trend, P ¼.03).
yWhen the TT cutoff point migrates from 4 mm to 5 mm, the rate of PLND increased from 4.5% to 16.6% (P ¼.007).
Tumor Thickness and Oral Cavity Cancer/Huang et al
April 1, 2009
believe that the incidence of occult lymph-node metasta-
rant management. Neck dissections should allow for
correct staging for prognosis and determination of the
need for adjuvant therapies.As well, removalof metastatic
lymph nodes would potentially reduce the risk of recur-
rence. Proponents of an observation strategy believe that
stases nor develop regional lymph-node metastases, and
therefore would be unnecessarily subjected to the poten-
To reduce the number of therapeutic neck interven-
tions, significant effort has been made in searching for
clinical, pathologic and genetic predictors of cervical
lymph-node involvement. While commonly used, the T
category of the current TNM staging system is not a sensi-
tive indicator for the occurrence of lymph-node involve-
ment in OSCC.20,46-49TT, as the ‘‘third dimension’’ of a
tumor,hasbeenshownto bea strongindependent predic-
tor for cervical lymph-node metastasis in many studies
and has also been confirmed in this meta-analysis. The
association of TT with lymph-node metastasis is believed
to reflect the aggressiveness of tumor growth20and/or is
an objective indicator for the proximity of the tumor to
lymphovascular structures.50Another theory for the posi-
tive relationship between TT and the presence of lymph-
cult to form in the small-caliber lymphatics of superficial
areas than in the wider lymphatics of deeper tissue.51
Several authors have suggested combining TT with the
pathological TNM staging system to obtain a modified
Discrepancy exists over the optimal cutoff point for
TT to predict clinical risk of cervical lymph-node involve-
ment. Previous studies have suggested a cutoff point of
between 3 mm to 6 mm. In this study, the FN-PLND rate
was chosen for comparison to determine the optimal TT
cutoff point and should be as low as possible. It is our
impression that a high NPV (low FN-PLND) is the most
clinically relevant factor for decision making to correctly
tive neckmanagement.We found a statistically significant
difference in the percentage of FN-PLND between a TT
cutoff point of 4 mm and 5 mm. The cutoff point at the
5-mm subgroup had a FN-PLND rate of 16.6% compared
with 4.5% for the 4-mm subgroup, which represents both
a statistically and clinically significant risk of cervical
lymph-node metastases. Thus, we conclude that the opti-
mal cutoff point is 4 mm for consideration of neck man-
agement. This coincides with the majority of previous
studies.1,16,23-27,31,33,34,48,54Patients with TT ?4 mm
canbe sparedfrom subsequentEND.
Although most studies have confirmed a link
between TT and cervical lymph-node involvement, the
strength of the association appears to be variable among
individual studies. This finding probably explains the
large variation in OR for individual studies shown in this
meta-analysis and maybe attributableto severalfactors.
First, the studies exhibited heterogeneity in terms of
treatment offered and length of follow-up. Upon review-
ing the literature for the meta-analysis, we noted that
some studies included patients receiving adjuvant thera-
pies such as postoperative radiation. While adjuvant
therapies and insufficient length of follow-up would not
influence the frequency of lymph-node involvement
noted in patients undergoing elective neck dissection,
both would potentially influence the reported outcome of
late development of lymph-node metastases in patients in
whom elective neck dissection was not performed. To
avoid this confounding effect, such studies were excluded
Second, differences in results could be attributable
to the imprecise definition of TT used between studies.
Several ways of defining TT have been used in the previ-
ous studies and summarized by Pentenero et al50as fol-
lows: a) from surface/base of the ulcer to deepest point of
invasion; b) from adjacent intact mucosa to deepest point
of invasion; c) from basal membrane to deepest point of
invasion. Moore et al20found that survival correlated bet-
ter with TT when measured from a theoretical construc-
tion of a basement membrane through the tumor than
from the surface of the tumor.20Kane et al has also com-
from adjacent normal mucosa and concluded that the
latter (referred to as microscopic depth) had a stronger
with most studies including less than 100 cases. Determi-
nation of the optimal cutoff point is extremely data de-
pendent and there may be a variable distribution of cases
among small studies even when the selection criteria are
consistent.55It has been suggested that the optimal cutoff
April 1, 2009
point is better determined based on the findings from
multiple investigations with a larger cohort.55As well,
there is significant variation in the selection of subsites of
the oral cavity included in the studies. The relationship of
lymph-node involvement as a function of TT may vary
between subsites because of either potential differences in
biologic behavior or the ease with which depth can be
determined pathologically between subsites. Limitation
on sample size has prevented us from performing a sub-
Lastly, while studies may vary according to T and N
categories, most are confined to T1 and/or T2 cases.
However, considering the impact of various imaging
modalities and technical advances over time, we believed
limiting the inclusion criteria to early stage clinical N0
cases might introduce bias on the studies reported from
different institutions or over different time periods; there-
fore, we included all clinical T and N categories in this
This meta-analysis was performed with a publica-
tion cutoff date of January 2007. We have also performed
an updated electronic literature search for MEDLINE
entries up to January 2008. Six additional studies were
found. Upon review of the full text of these articles, 2
were considered potentially eligible.46,56However, both
were small studies (27 cases for 1 study using a 3-mm TT
cutoff point,46and 53 for the other56using a 5-mm TT
cutoff point) and would have had negligible impact on
the current results. In addition to these reports, a recent
description of sentinel lymph-node biopsy suggests that
the 4-mm TT cutoff point is potentially most appropriate
for the risk stratification for cervical lymph-node
An association between TT and cervical lymph-node
involvement is confirmed in this study. The optimal cut-
off point for TT is 4 mm. For oral cavity tumors thicker
than 4 mm, prophylactic neck management is generally
recommended. Standardization of the measuring method
of TT is required for using TT as valid predictor in plan-
ning neck treatment. A less invasive method of assessment
is needed if this parameter is to be incorporated into clini-
Conflict of Interest Disclosures
Funding was provided by the Bartley-Smith/Wharton Founda-
tion at the Princess Margaret Hospital.
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