Prognostic Significance of Invasion Depth in Oral Tongue Squamous Cell Carcinoma

Article (PDF Available)inORL 74(5):264-270 · November 2012with377 Reads
DOI: 10.1159/000343796 · Source: PubMed
Abstract
Purpose: Staging for tongue carcinoma does not consider its depth of invasion. We aim to determine the prognostic significance of invasion depth in tongue cancer. Materials and methods: Retrospective review of patients with tongue carcinoma who underwent curative surgery between 2002 and 2005; 67 patients were analyzed. Tumors were divided into 2 groups: group A = invasion depth <4 mm; group B = invasion depth ≥4 mm. Recurrence and survival rates were calculated for each group and compared. Results: The local recurrence rate in group B was significantly higher (10 vs. 29.7%, p = 0.048). Group A patients had a superior 5-year overall survival (68.8 vs. 41.6%, p = 0.012), disease-specific survival (67.1 vs. 41.1%, p = 0.026) and local recurrence-free survival (89.5 vs. 65.4%, p = 0.035). Five-year regional recurrence, locoregional recurrence and distant recurrence-free survival rates were not significantly different between the 2 groups (p = 0.390, p = 0.173 and p = 0.207). The impact of invasion depth on survival was maintained on multivariate analysis (p = 0.031). Conclusion: Invasion depth is an important prognostic indicator in tongue cancer.
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Original Paper
ORL
DOI: 10.1159/000343796
Prognostic Significance of Invasion Depth
in Oral Tongue Squamous Cell Carcinoma
Winson Jianhong Tan
a, b
Claramae Chia
a, b
Hiang Khoon Tan
a
Khee-Chee Soo
a
N. Gopalakrishna Iyer
a
a
Department of Surgical Oncology, National Cancer Centre Singapore, and
b
Department of General Surgery,
Singapore General Hospital, Singapore
Introduction
Head and neck cancer is the fifth most common cancer
worldwide and the most common neoplasm in Asia
[1] .
Squamous cell carcinoma (SCC) is the predominant ma-
lignancy in the oral cavity with the oral tongue being the
most common subsite. Current management guidelines
consider tumor thickness as a factor guiding the necessity
of adjuvant neck dissection in oral cavity cancers
[2] . Al-
though tumor thickness and depth of invasion are often
used synonymously, they are in reality different and
should be clearly differentiated
[39] . ‘Tumor thickness’
refers to the thickness of the entire tumor mass. Depth of
invasion refers to the extent of tumor growth into the tis-
sue beneath an epithelial surface. Comparing the two pa-
rameters, depth of invasion better reflects the tumor’s
proximity to blood vessels and lymphatics from an ana-
tomical viewpoint and may predict the risk of lymphatic
and hematogenous spread more accurately
[10] . This may
be particularly relevant in exophytic tumors where the use
of tumor thickness as a surrogate may overestimate the
true invasion depth. Unfortunately, previous studies have
failed to clearly differentiate between the two parameters
and current guidelines consider mainly tumor thickness
as a factor for the necessity of adjuvant neck dissection
[2] .
This paper specifically studies the prognostic signifi-
cance of invasion depth in SCC of the tongue.
Key Words
Tongue cancer Oral cancers Tumor thickness Depth of
invasion
Abstract
Purpose: Staging for tongue carcinoma does not consider its
depth of invasion. We aim to determine the prognostic sig-
nificance of invasion depth in tongue cancer. Materials and
Methods: Retrospective review of patients with tongue car-
cinoma who underwent curative surgery between 2002 and
2005; 67 patients were analyzed. Tumors were divided into 2
groups: group A = invasion depth ! 4 mm; group B = invasion
depth 6 4 mm. Recurrence and survival rates were calculat-
ed for each group and compared. Results: The local recur-
rence rate in group B was significantly higher (10 vs. 29.7%,
p = 0.048). Group A patients had a superior 5-year overall
survival (68.8 vs. 41.6%, p = 0.012), disease-specific survival
(67.1 vs. 41.1%, p = 0.026) and local recurrence-free survival
(89.5 vs. 65.4%, p = 0.035). Five-year regional recurrence, lo-
coregional recurrence and distant recurrence-free survival
rates were not significantly different between the 2 groups
(p = 0.390, p = 0.173 and p = 0.207). The impact of invasion
depth on survival was maintained on multivariate analysis
(p = 0.031). Conclusion: Invasion depth is an important prog-
nostic indicator in tongue cancer.
Copyright © 2012 S. Karger AG, Basel
Received: July 1, 2012
Accepted after revision: September 4, 2012
Published online: $ $ $
Dr. N. Gopalakrishna Iyer
National Cancer Centre Singapore
11 Hospital Drive
Singapore 169610 (Singapore)
E-Mail gopaliyer
@ yahoo.com
© 2012 S. Karger AG, Basel
03011569/12/0000–0000$38.00/0
Accessible online at:
www.karger.com/orl
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M e t h o d s
Patients with primary SCC of the tongue who were treated
with surgical resection from January 2002 to December 2005
were identified from an institutional database. During this pe-
riod, all patients with SCC of the tongue underwent at least a
selective neck dissection regardless of the T stage or depth of in-
vasion. Details on patient characteristics, tumor characteristics
and treatment, follow-up and eventual disease outcome were re-
corded by retrospective review of patient records up to Decem-
ber 2010. Tumor staging was based on pathological findings, ac-
cording to the American Joint Committee on Cancer Staging
System, 7th edition. In addition, the following variables were re-
corded: size of primary tumor, pathological invasion depth of
tumor, grade of differentiation, status of resection margins and
presence of lymphovascular and perineural invasion. Details on
the types of surgery and neck dissection performed and the ad-
ministration of adjuvant and/or neoadjuvant therapy were also
included.
Neck dissection was performed for all patients. In general, se-
lective neck dissection (supraomohyoid) was performed for pa-
tients with no clinical evidence of nodal disease while those with
clinical evidence of nodal disease underwent comprehensive neck
dissection. Decision for adjuvant radiotherapy or chemoradio-
therapy was made during weekly multidisciplinary meetings be-
tween head and neck surgeons, medical oncologists and radiation
oncologists.
D e f i n i t i o n s
Patients were divided into 2 groups: group A = tumor invasion
depth ! 4 mm; group B = tumor invasion depth 6 4 mm. There is
wide variation in the manner how invasion depth is measured in
the literature. This is illustrated in figure 1 adapted from Pente-
nero et al.
[10] . In our study, invasion depth was measured from
the line of the basement membrane to the deepest portion of the
tumor. In exophytic tumors, this corresponds to dimension C
while in ulcerative tumors, dimension F was taken as the depth of
invasion ( fig.1 ). Various studies have proposed different cut-off
values for tumor invasion depth ranging from 2 to 5 mm
[5, 8,
11–15]
. In our study, 4 mm was chosen as the cut-off value for the
2 groups as that was the value recommended in 4 other publica-
tions
[4, 8, 12, 13] .
Follow-up time was calculated from the date of surgical resec-
tion until the date of last hospital/clinic visit, admission or death,
and each event-free survival was calculated from the date of sur-
gical resection to the date of diagnosis of each event.
Statistical analysis was carried out using SPSS for Windows,
version 17.0.
Statistical Analysis
Overall survival (OS), disease-specific survival (DSS), local re-
currence (LR), regional recurrence (RR), locoregional recurrence
(LRR) and distant recurrence (DR)-free survival rates for each
group were calculated using the Kaplan-Meier method. The
2
test was used in the analysis of categorical data, and the Mann-
Whitney test was used for nonparametric continuous parameters.
Differences in survival rates were compared by the log-rank test.
Multivariate analysis was performed for invasion depth, tumor
stage, presence of nodal disease, grade of tumor, perineural and
lymphovascular invasion using Coxs proportional hazards mod-
el. A p value ^ 0.05 was considered statistically significant.
Ethical Considerations
The study was approved by the hospitals institutional review
board.
R e s u l t s
Patient Details
The study population consisted of 67 patients with pri-
mary SCC of the tongue treated by surgery. The median
follow-up duration was 50 months (range: 1105 months).
Clinicopathological characteristics for the cohort are
summarized in table1 . Details on patient treatment are
summarized in table2 . Four patients received neoadju-
vant therapy (3 chemoradiotherapy and 1 radiotherapy)
prior to surgery.
The median depth of invasion for the cohort was 7 mm
(range: 135 mm). Thirty patients (45%) had invasion
depth ! 4 mm (group A) while 37 patients (55%) had inva-
sion depth 6 4 mm (group B). Characteristics for group
A and B are compared in table3 .
Survival Analysis
The median overall survival in the study population
was 49 months. The 5-year OS and DSS for the entire co-
hort were 66.6 and 71%, respectively.
LR, RR, LRR and DR rates in groups A and B were
compared in table4 . The LR rate for group B patients was
approximately 3 times that of group A (p = 0.048). The
5-year OS for patients in groups A and B were 68.8 and
41.6%, respectively (p = 0.012), while the 5-year DSS in
groups A and B were 67.1 and 41.1%, respectively (p =
0.026; fig.2 , 3 ). Patients with pathological invasion depth
6 4 mm (group B) were 1.8 times more likely to die from
disease compared to patients with invasion depth ! 4
A
B
D
E
F
C
Fig. 1. Diagram showing different definitions for the measure-
ment of depth of invasion (adapted from Pentenero et al. [10]).
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Table 1. C linicopathological characteristics of the entire cohort
Baseline characteristic Total
Sex
Male 43 (64)
Female 24 (36)
Age, years
Median 63
Range 24–94
Clinical T stage
cT1 29 (43)
cT2 28 (42)
cT3 7 (10)
cT4 3 (5)
Clinical N stage
cN0 41 (61)
cN+ 26 (39)
cN1 13 (19)
cN2/cN3 13 (19)
Overall TNM stage
I 23 (35)
II 15 (30)
III 15 (22)
IV 14 (22)
Tumor differentiation
Well 20 (30)
Moderate 37 (55)
Poor 7 (10)
Unknown 3 (5)
Margins
Negative 54 (81)
Positive 5 (7)
Unknown 8 (12)
Results are numbers with percentages in parentheses unless
stated otherwise.
Table 2. T reatment characteristics of the cohort (n = 67)
Baseline characteristic
Primary treatment
Surgery only 41 (61)
Surgery followed by radiotherapy 19 (28)
Surgery followed by chemotherapy and radiotherapy 7 (10)
Details of surgery
Type of surgery performed
Partial glossectomy 9 (13)
Hemiglossectomy 51 (76)
Subtotal glossectomy 1 (2)
Total glossectomy 6 (9)
Type of neck dissection
Comprehensive 36
Selective (supraomohyoid) 31
Results are numbers with percentages in parentheses.
Table 3. C omparison of characteristics between groups A and B
Baseline characteristic T otal, n p value
group A
(n = 30)
group B
(n = 37)
Sex 0.897
Male 19 (63) 24 (65)
Female 11 (37) 13 (35)
Median age, years 62.5 64 0.468
Clinical T stage 0.351
cT1 17 (57) 12 (32)
cT2 10 (33) 18 (49)
cT3 2 (7) 5 (14)
cT4 1 (3) 2 (5)
Clinical N stage 0.931
cN0 19 (63) 22 (60)
cN1 6 (20) 7 (19)
cN2/ cN3 5 (17) 8 (21)
Overall TNM stage 0.082
I 15 (50) 8 (22)
II 3 (10) 12 (32)
III 7 (23) 8 (22)
IV 5 (17) 9 (24)
Tumor differentiation 0.211
Well 12 (40) 8 (22)
Moderate 12 (40) 25 (68)
Poor 4 (13) 3 (8)
Unknown 2 (7) 1 (3)
Margins 0.228
Negative 23 (77) 31 (84)
Positive 4 (13) 1 (3)
Unknown 3 (10) 5 (13)
Adjuvant therapy
Nil
Radiotherapy
Chemoradiotherapy
0.948
19 (63) 22 (59)
8 (27) 11 (30)
3 (10) 4 (11)
Figures in parentheses indicate percentages.
Table 4. C omparison of LR, RR, LRR and DR between groups A
and B
Type of
recurrence
R ate of recurrence, % p value
gr oup A group B
LR 10.0 29.7
0.048*
RR 13.3 5.4 0.258
LRR 23.3 35.1 0.294
DR 6.7 13.5 0.362
The asterisk denotes a statistically significant result.
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mm. Five-year LR-free survival rates were 89.5 and 65.4%
in groups A and B, respectively (p = 0.035; fig.4 ). Patients
with pathological invasion depth 6 4 mm (group B) were
3.3 times more likely to suffer from LR compared to
group A. The 5-year RR-, LRR- and DR-free survival rates
were not significantly different between the 2 groups
(p = 0.390, p = 0.173 and p = 0.207). Multivariate analysis
for OS and LR-free survival showed invasion depth to be
statistically significant for OS (p = 0.031) but it did not
reach statistical significance for LR-free survival (p =
0.053; tables 5 , 6 ).
Discussion
Our results indicate that tumors with pathological in-
vasion depth 6 4 mm were 3.3 times more likely to suffer
from local recurrence compared with tumors of inva-
sion depth ! 4 mm (5-year LR-free survival: 89.5 vs.
65.4%, p = 0.035). In contrast, RR and LRR rates were not
significantly different between the 2 groups. Invasion
depth 6 4 mm was also shown in our cohort to be asso-
ciated with reduced OS and DSS ( fig.2, 3 ). The associa-
tion remained significant on multivariate analysis (p =
0.031). In contrast, neither T stage nor N stage were sig-
nificant predictors of survival or recurrence in our
study. This could be explained as our study population
consisted of merely 67 patients of which the majority had
early-stage disease with only 15% with T3/T4 and 19%
with N2/N3 disease. Thus, the study may be insuffi-
ciently powered to detect any impact of T stage or N
stage on survival, as seen by the statistics which show
that higher T or N stage results in poorer outcome but
1.0
0.8
0.6
0.4
0.2
0
010
20
30
40 50
60
Proportion surviving
Time (months)
p = 0.012*
Group A – 5-year OS 68.8%
Group B – 5-year OS 41.6%
Fig. 2. Kaplan-Meier plot showing 5-year OS stratified by groups
A and B (pathological invasion depth). The asterisk denotes sta-
tistically significant results compared using the log-rank test.
Color version available online
1.0
0.8
0.6
0.4
0.2
0
0
Proportion surviving
10
20 30 40 50
60
p = 0.026*
Group A – 5-year DSS 67.1%
Group B – 5-year DSS 41.1%
Time (months)
Fig. 3. Kaplan-Meier plot showing 5-year DSS stratified by groups
A and B (pathological invasion depth). The asterisk denotes sta-
tistically significant results compared using the log-rank test.
Color version available online
1.0
Proportion surviving
0.9
0.8
0.7
0.6
0.5
0
10
20
30
40
50
60
Time (months)
p = 0.035*
Group B – 5-year LR-free survival 65.4%
Group A – 5-year LR-free survival 89.5%
Fig. 4. Kaplan-Meier plot showing 5-year LR-free survival strati-
fied by groups A and B (pathological invasion depth). The asterisk
denotes statistically significant results compared using the log-
rank test.
Color version available online
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Invasion Depth in Tongue Cancer
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not reaching statistical significance. Despite the limita-
tions in sample size, invasion depth was such a signifi-
cant prognostic indicator that differences in survival
and recurrence were clearly evident between the 2
groups. While we acknowledge that our study was inad-
equately powered to demonstrate the superiority of in-
vasion depth compared to the conventional T staging
(tumor size) in terms of prognostication, we have raised
sufficient cause for further research to be performed to
answer this important clinical question. The prognostic
significance of invasion depth needs to be validated in
large populations and compared head to head with the
tumor size to decide if it should replace or supplement
tumor size in the T staging of tongue cancer before in-
corporation into future staging.
In contrast to 2 other studies which demonstrate an
association between invasion depth and RR, this was not
demonstrated in our study
[11, 16] . In these 2 centers, pro-
phylactic neck dissection was employed selectively in pa-
tients in with early-stage tongue cancer. In contrast, it
was our institutions practice during the duration of study
to offer prophylactic neck dissection to all cases of early-
stage tongue cancer. We postulate that this policy could
have negated the impact of invasion depth on nodal re-
currence and thus, RR and LRR rates. This is supported
by a recently published study which suggested that pro-
phylactic neck dissection may improve regional control
in tongue cancer
[17] .
The findings of an association between invasion depth
and OS and DSS is mirrored by several other studies on
Table 5. U nivariate and multivariate analysis of OS
Variable 5-year
survival
%
O S
univariate anal-
ysis: p value
multivariate analysis:
RR; 95% CI; p value
T stage
T1 66 0.456
T2 41
T3 57
T4 33
T status
T1 + T2 53 0.426 NS
T3 + T4 50
N stage
N0 58 0.669
N1 45
N2 51
N status
N0 58 0.514 NS
N+ 48
Overall clinical stage
I 69 0.203
II 32
III 51
IV 54
Morphology
Exophytic 50 0.448
Endophytic 55
Thickness
<4 mm 69 0.012 2.7; 1.1–6.7; 0.031
≥4 mm 42
For univariate analysis, p values are based on the log-rank
test. For multivariate analysis, p values and relative risk (RR) are
based on the Cox proportional hazards model; NS denotes factors
not significant in multivariate analysis.
Table 6. U nivariate and multivariate analysis of LR-free survival
Variable 5-year
survival
%
LR-free survival
univariate anal-
ysis: p value
mult ivariate analysis:
RR; 95% CI; p value
T stage
T1 89 0.739
T2 69
T3 83
T4 100
T status
T1 + T2 74 0.479 NS
T3 + T4 89
N stage
N0 73 0.381
N1 83
N2 89
N status
N0 73 0.334 NS
N+ 84
Overall clinical stage
I 69 0.203
II 32
III 51
IV 54
Morphology
Exophytic 67 0.112
Endophytic 80
Thickness
<4 mm 90 0.035 2.0; 0.9–4.7; 0.053
≥4 mm 65
For univariate analysis, p values are based on the log-rank
test. For multivariate analysis, p value and relative risk (RR) are
based on the Cox proportional hazards model; NS denotes factors
not significant in multivariate analysis.
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the prognostic significance of pathological invasion
depth
[8, 15, 16] . However, despite its importance, patho-
logical invasion depth hardly features in the staging for
SCC of the tongue. Management guidelines also use tu-
mor thickness rather than invasion depth to determine
the need for elective neck dissection despite its anatomi-
cal relevance mentioned earlier in our paper
[2] . It would
be worthwhile to perform studies which compare the
prognostic significance of tumor thickness versus inva-
sion depth to determine which variable ought to be con-
sidered during decision making for neck dissection or
adjuvant therapy.
As recurrent oral tongue cancer is known for its ex-
tremely low salvage rates
[18] , an adequate extent of initial
treatment is important. Studies demonstrate an increased
risk of nodal disease with an increased depth of invasion
and recommend prophylactic neck dissection in these pa-
tients
[5, 8, 11–13] . In contrast to other studies, our entire
cohort of patients underwent either a prophylactic or
therapeutic neck dissection. It appears that the effect of
invasion depth on survival and LR persisted in spite of
neck dissection. This raises the question of the adequacy
of prophylactic neck dissection in isolation in the treat-
ment of tumors with invasion depth 6 4 mm. It remains
unknown if invasion depth should guide the necessity for
adjuvant therapy. In a recent study, Shim et al.
[15] pro-
posed postoperative radiotherapy in tongue tumors with
invasion depth 1 0.5 cm. Their data revealed no local fail-
ure among patients with risk factors who had received
adjuvant radiotherapy, although the numbers are too
small to achieve statistical significance. Subgroup analy-
sis of tumors with invasion depth 6 4 mm in our study
also revealed higher OS rates among patients who had
received adjuvant therapy (60 vs. 27.3%, p = 0.046). As
this study was not designed specifically to demonstrate
the benefit of adjuvant therapy in patients with increased
depth of invasion, we await the results of high-quality tri-
als to answer this important clinical question.
There are several limitations in this study based on a
retrospective nature. The varying definitions for invasion
depth used by different institutions may also render the
comparison of studies studying invasion depth meaning-
less. It would thus be ideal if the head and neck commu-
nity could come to a consensus regarding the way inva-
sion depth should be defined and measured. Nonetheless,
this study reiterates the prognostic significance of tumor
invasion depth in oral tongue cancer. The data has also
raised questions regarding the adequacy of surgical ther-
apy (resection and neck dissection) in isolation in the
management of tongue tumors with invasion depth 6 4
mm.
Conclusion
Depth of invasion is an important prognostic indica-
tor in tongue cancer. The role of adjuvant therapy in
tongue tumors with invasion depth 6 4 mm needs to be
further studied.
Disclosure Statement
There are no conflicts of interest.
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  • Full-text · Article · Feb 2014
  • [Show abstract] [Hide abstract] ABSTRACT: To summarize recent acquisitions in three-dimensional tongue and floor of mouth anatomy that can help in better evaluation of the pathways of cancer progression within these oral subsites, thus giving some hints for refining of the current TNM staging system. The Visual Human Project is an initiative aimed at establishing a three-dimensional dataset of anatomy of two cadavers made available free to the scientific community. Visual Human data have been analyzed by specific software thus improving our three-dimensional understanding of the tongue myostructure. It is already known that there is limited prognostic utility in using the two-dimensional surface diameter alone as criterion for T1-T3 definition. Recently, also the T4a categorization for the infiltration of 'deep' or extrinsic tongue muscles has been criticized. This is largely because the descriptor 'deep' does not take into account the fact that considerable portions of these muscles lie in a very superficial plane. Different prognosticators have been proposed for inclusion into the TNM staging system of oral cancer but 'depth of tumor infiltration' seems to be the most robust, universally recognized, and reproducible in the preoperative, intraoperative, and postoperative settings. Oral tongue and floor of mouth cancer needs to be classified according to a revised TNM staging system in which 'depth of infiltration' should be taken into account. An 'ideal cut off' for distinguishing 'low' (T1-T2) from 'high-risk' (T3-T4) categories has been proposed based on the literature review, but needs retrospective as well as large prospective trials before its validation.
    Full-text · Article · Feb 2014
  • [Show abstract] [Hide abstract] ABSTRACT: This study aims to establish an orthotopic transplantation model of rabbit tongue carcinoma and study its biological characteristics. Tongue carcinoma was induced in purebred New Zealand white rabbits by exposure to 7,12-dimethylbenz[α]anthracene and mechanical stimulation. Fresh tumor tissues obtained from the induced tongue carcinoma model were then serially transplanted orthotopically into tongues of healthy rabbits. The tumor formation rate, invasion to surrounding tissues, regional lymph node metastases, and distant-organ metastases were investigated. Morphological observation by optical and electron microscopy, immunohistochemical examination, and chromosome analysis were performed. An orthotopic transplantation model of rabbit tongue carcinoma, designated as RSCC-2, was established. The tongue cancer was poorly differentiated squamous cell carcinoma. The tumor cell was hypotetraploid with a chromosome mode of 70. Immunohisto chemical examination showed positive staining for keratin. The tongue carcinoma survived in rabbits for 73 rounds of transplantation, using 465 rabbits in total. The average latent period was 12.5 days, and the average rabbit survival period was 37.5 days. The tumor formation rate was 10% to 20% in the first 20 rounds and increased gradually thereafter. After the 45th transplantation, the tumor formation rate and success rate of preservation in liquid nitrogen reached 100%. Regional lymph node metastases (35%) and lung metastases (20%) occurred after 50 rounds. In the advanced stage, tumors invaded the entire tongue. Animals suffered from weight loss and died of cachexia. RSCC-2 is the first animal model for orthotopical transplantation of primary tongue carcinoma. It successfully simulates the clinical pathological process of primary tongue cancer in human, provides invaluable insights into the pathogenesis and metastasis mechanisms, and can be useful for evaluating new therapeutics for the treatment of tongue cancer.
    Article · May 2014
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