1. Squamous cell carcinoma of the oral tongue in patients
ORIGINAL ARTICLE
younger than 30 years: clinicopathologic features and
outcome
Soudry, E.,*,† Preis, M.,*,† Hod, R.,* Hamzany, Y.,*,† Hadar, T.,*,† Bahar, G.,*,† Strenov, Y.‡
& Shpitzer, T.*,†
*Department of Otolaryngology-Head and Neck Surgery, Rabin Medical Center, Petah Tiqwa, Sackler School of
Medicine, Tel Aviv University, Tel Aviv, and àDepartment of Pathology, Rabin Medical Center, Petah Tiqwa,
Israel
Accepted for publication 2 June 2010
Clin. Otolaryngol. 2010, 35, 307–312
Objective: To assess the possible effect of young age on invasion (P = 0.012), and higher rates, though not signifi-
clinical behaviour and survival outcome of squamous cell cant, of treatment failure (46%, including 60% with
carcinoma of the oral tongue. distant metastases, versus 35%, nearly all locoregional)
Design: Retrospective, case control study. and mortality (100% of treatment failures versus 73%).
Setting: A major tertiary referral centre. There were no significant between-group differences in
Participants: Eighty-five patients with oral tongue 5-year disease-free, disease-specific, and overall survival.
squamous cell carcinoma with at least 2 years of follow-up. Conclusion: In this study, patients younger than
Main outcome measurements: Clinical and histopatho- 30 years of age presented with advanced tumour stages
logical staging, disease-free survival, disease-specific and with a different failure pattern compared to the older
survival and overall survival. age group. This may be attributable to age-related
Results: Eleven patients (13%) were younger than biologic behaviour or delayed cancer diagnosis. Differ-
30 years. Compared to the older patients, they had a ences in disease free survival and overall survival could
significantly worse N stage (P = 0.041), more perineural not be established.
Squamous cell carcinoma (SCC) of the oral tongue Prognostication and treatment decisions are currently
accounts for approximately 30% of oral cavity SCCs and based on TNM staging and presence of perineural and
is thus one of the most frequent head and neck cancers.1,2 perivascular invasion on histopathological study. Age is
Crude Incidence is on average between 10 and 20 cases not considered a prognostic factor.
per 100 000 in Europe and the USA.3 Differing patterns Most of the studies conducted to date on the poten-
emerge when oral cancer incidence trends are analysed by tial prognostic significance of age in tongue cancer have
age groups. Rising trends of oral cancer in the young and yielded conflicting results.4–17 This might be explained
middle aged (under 50 years old), particularly cancer of by the almost exclusive use of 40–45 years as the cut-
the tongue, have been observed in European countries.2 off for comparison, with a wide range of mean ages,
In USA, despite the decreasing incidence of head and from 30 to 38 years. Yet it is possible that the youn-
neck cancer, there is a significant increase in the inci- ger-than-40- to 45-year group is itself composed of het-
dence of squamous cell carcinoma (SCC) of the oral ton- erogeneous subgroups and that lowering the cut-off
gue, base of tongue and tonsils in young white patients would yield a more homogenous sample. Only two
aged 30–44 years.1 Differences in cancer pathogenesis and studies have evaluated oral tongue SCC in patients
genetic alterations have been studied as possible causes younger than 30 years,16,17 and both were done nearly
for cancer in the young aged group. 30 years ago, when the treatment approach was consid-
erably different.
The aim of the present study was to evaluate the clinical
Correspondence: T. Shpitzer, MD, Department of Otolaryngology Head
and histopathological parameters and survival outcomes of
and Neck Surgery, Rabin Medical Center, Beilinson Campus, Petah Tiq-
wa 49100, Israel. Tel.: 972-3-937 6456; fax: 972-3-937 6467; oral tongue SCC in patients younger than 30 years of age
e-mail: thomas-s@zahav.net.il compared to older patients.
Ó 2010 Blackwell Publishing Ltd • Clinical Otolaryngology 35, 307–312 307

2. 308 E. Soudry et al.
Patients and methods
Ethical considerations
This is a retrospective chart review, and prior to the
study, permission was obtained from the local institu-
tional review board to review the patients’ medical charts,
histopathological reports and follow up data.
Patients
The study was conducted in a tertiary university-affiliated
medical centre. The medical files of all patients who were
treated for tongue cancer in our department from 1992
to 2007 and followed for a minimum of 2 years, were
reviewed. Only patients with histologically-proven pure
oral tongue squamous cell carcinoma were included.
Demographic background, habits, clinicopathological
parameters (clinical stage, and histopathologic features),
treatment (surgical procedure, postoperative treatment)
Fig. 1. Age histogram.
and survival outcomes were documented, and the find-
ings were compared between patients younger than
30 years and older patients. (13%) were younger than 30 years and 74 were older,
including 10 who were aged 30–45 years. Average age at
presentation was 24.1 ± 4.9 years (range 15–29) in the
Statistical analysis
younger group and 66.2 ± 15.7 years (range 32–94) in
Continuous variables are expressed as mean ± standard the older group.
deviation (sd) and categorical variables as percentages. A history of smoking was positive in one patient (9%)
Differences in mean continuous variables between groups in the younger group and 20 patients (27%) in the older
were analysed by Student t-test, and differences in cate- group. Excessive alcohol intake was very rare in both
gorical variables, by chi-square test or Fisher exact test. groups of patients, which is in accordance with the over-
Disease-specific survival (DSS) rate and disease-free sur- all low alcohol intake in our country.18
vival (DFS), defined by the interval between the date of The clinical and histopathological characteristics of the
diagnosis and the day of death or recurrence or the last patient groups are shown in Tables 1 and 2. Compared
follow-up, were calculated by the Kaplan-Meier method; to the older group, the younger patients had a signifi-
log-rank test were used for univariate analysis to compare cantly worse clinical ⁄ radiological N stage (P = 0.041) in
DSS and DFS between the groups. presentation and more evidence of perineural invasion
Multivariate analysis was performed using the Cox pro- (P = 0.012) on histopathological examination. There were
portional hazards model, in which DSS or DFS was the no significant between-group differences in histological
dependent variable and, age, gender, pathological grade, grade, tumour depth, or presence of lymph node extra-
T stage classification (T1 versus T2 + T3), N stage (N0 capsular extension.
versus N1 + N2) and perineural invasion (yes versus no) Treatment consisted of resection of the tongue tumour
were independent variables. A P-value of less than 0.05 in all cases. All but four patients also underwent elective
was considered statistically significant. For statistical anal- or therapeutic neck dissection, all of whom had small
yses, we used SPSS, version 15.0.1 software (SPSS, Chi- tumours and were considered a very high operative risk.
cago, IL, USA). Radial forearm free flap reconstruction of the tongue
defect was performed in 21 (25%) patients of whom 4
were younger than 30 years. Close (<5 mm) or involved
Results
resection margins were observed on final histopathologi-
Eighty-five patients met the study criteria. They included cal analysis in three of the young patients (27%) and 13
39 male and 46 female patients of mean age of the older group (18%). Postoperative radiation or
60.8 ± 20.5 years (Fig. 1 – age histogram). Eleven patients chemoradiation was administered for advanced tumours
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3. Oral tongue SCC in under-30 age group 309
Table 1. Clinical characteristics of patients younger than Treatment failure (Table 3) was documented in five
30 years and older patients patients in the younger group (46%), including three
Age < 30 - Age > 30 years, (60%) with distant metastases, one with local failure, and
years, n = 11 n = 74 one with regional failure. Average time to failure was
14.5 months; all five patients ultimately died of their dis-
Number % Number % P-value ease. In the older group, 27 patients (36%) failed treat-
Females 5 45 41 55 N.S. ment, of whom 25 had a locoregional recurrence and two
Males 6 55 33 45 had distant metastases. Average time to failure was
T stage 12.7 months; 20 patients (74%) ultimately died of their
T1 5 46 38 51 N.S. disease. A second primary tumour of the head and neck
T2 4 36 30 41 developed in five patients, all in the older group, which
T3 2 18 5 7 led to a total failure in 32 (43%) patients in the older
T4 0 1 1 group.
N stage
N0 5 46 54 72 0.041
N1 2 18 13 18 Disease specific and disease free survival
N2 4 36 7 10
N3 0 0 The mean duration of follow-up for the 85 patients was
AJCC stage 4.6 years (range 4 months to 13.5 years). The 5-year DFS
I–II 3 27 51 70 0.011 rate was 55% in the younger group and 63% in the older
III–IV 8 73 23 30 group (Fig. 2). Corresponding rates for 5-year disease-
specific survival (DSS) were 55% and 73% (Fig. 3), and
AJCC, American Joint Committee on Cancer; N.S., not signifi-
for 5-year overall survival, 55% and 61%. None of these
cant.
between-group differences was statistically significant.
and those with close or involved margins by standard The 5-year DSS and DFS according to age, gender,
protocols. The treatment field included the tongue and pathological grade, T stage classification (T1 versus
ipsilateral neck. For patients with N2, the contralateral T2 + T3), N stage (N0 versus N1 + N2) and perineural
necks were treated. Radiation dose ranged between 54 Gy invasion (yes versus no) in 85 patients with tongue carci-
and 60 Gy in most cases, and for positive margins, noma were analysed as well. In DSS univariate analysis
between 60 Gy and 66 Gy. Treatment was planned in pathological grade, T stage classification (T1 versus
most cases in three dimensional planes using 6 MV pho- T2 + T3), N stage (N0 versus N1 + N2) and perineural
tons. Patients with very high risk features, such as posi- invasion (yes versus no) were significant (P = 0.015,
tive margins massive extracapsular extension were treated P = 0.006, P = 0.002 and P = 0.006, respectively). DFS
with concomitant chemoradiation (either cisplatin or cis- univariate analysis revealed that only (T1 versus T2 + T3)
platin and 5-FU). was significant (P = 0.001).
Table 2. Histopathological characteristics of patients younger than 30 years and older patients
Age < 30 years, Age > 30 years,
n = 11 n = 74
Number % Number % P-value
Pathological stage I–II 3 27 51 69 0.011
Pathological stage III–IV 8 73 23 31
Histology
Well differentiated 2 18 30 44 N.S.
Moderately differentiated 8 73 27 40
Poorly differentiated 1 9 11 16
Mean tumour thickness ± sd (mm) 9.4 ± 5.4 7.8 ± 5.2 N.S.
Perineural invasion 5 50 9 13 0.012
Number of metastatic lymph nodes (average ± sd) 2.4 ± 2.7 0.9 ± 2.3 0.004
Extracapsular extension 2 20 6 9 N.S.
N.S., not significant.
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4. 310 E. Soudry et al.
Table 3. Analysis of failures in patients younger than 30 years
and older patients
Age < 30 years, Age > 30 years,
n = 11 n = 74
Number % Number %
Failure 5 46 27 36
Local 1 20 8 30
Regional 1 20 13 48
Loco-regional 0 4 15
Distant 3 60 2 4
Second primary 0 5
Total failures 5 46 32 43
Fig. 3. Disease-specific survival for patients younger than
30 years and older patients.
patients younger than 30 years and female patients, com-
prised a much larger fraction (13% and 54%, respec-
tively) of the study group than expected according to the
literature. It is possible that our study group as a whole
differed from previously reported groups in that most of
the patients lacked the traditional risk factors of smoking
and alcohol intake. Thus, the tongue carcinoma in our
sample may have had a different epidemiology. This
question requires further investigation.
Fig. 2. Disease-free survival curves for patients younger than Strengths of the study
30 years and older patients.
Studies of the possible prognostic significance of age on
the clinical course of oral tongue SCC reported conflict-
Multivariate Cox proporttional hazard model revealed ing results.4–17 The present study focused on the clinical
that only T stage was statistically significant predictor of and pathological findings and outcome of 11 patients less
a reduced DFS (hazard ratio 4.45; 95% CI 1.89–10.50, than 30 years old (average 24 years) with oral tongue
P = 0.001) and T stage and lymph node involvement SCC. All underwent primary surgical resection of the ton-
were statistically significant predictor of a reduced DSS gue tumour and neck dissection, either electively or ther-
(hazard ratio 3.24; 95% CI 1.31–8.02, P = 0.011 and haz- apeutically. Postoperative radiation or chemoradiation
ard ratio 2.81; 95% CI 1.23–6.42, P = 0.014, respectively). was administered for advanced tumours by standard pro-
In both univariate and multivariate analysis, age was tocols. This study is distinct from earlier reports because
not associated with DSS or DFS. of the younger age of the patients (<30 years versus 40–
45 years) and the uniform treatment administered.
We are aware that due to the limited sample size, solid
Discussion
evidence-based conclusions can not be made. Nonethe-
In the literature, the reported median age at diagnosis of less, it should be remembered that SCC of the oral ton-
cancer of the oral tongue is of 61 years and that approxi- gue is relatively rare in the young adult population and
mately 9% of patients are diagnosed before age of thus reaching a large homogenous group of patients is
45 years, and 2%, before age 35 years, and that the over- difficult, especially in the younger than 30-year-old
all 5-year relative survival is 60%.1 In the present study, group. Studies featuring large groups of young patients
Ó 2010 Blackwell Publishing Ltd • Clinical Otolaryngology 35, 307–312

5. Oral tongue SCC in under-30 age group 311
were based on literature reviews. Moreover, any evidence group. Perineural invasion has been shown to be associ-
that can shed light on this unique group of patients is of ated with a high risk of regional metastases, local recur-
value. rence, and decreased survival.19,20 At the same time,
second head and neck primary tumours developed only
in the older patients in our study. Together, these results
Comparison with other studies
suggest that tumour biology may be age-related.
In a literature review of published cases of patients youn- Analysis of other clinical or histopathological parame-
ger than 40 years with tongue carcinoma (n = 122), Pit- ters yielded no significant differences between the age
man et al.4 found a similar outcome to patients older groups perhaps because of the small sample size.
than 40 years, in agreement with several studies.5–7 Oth- On univariate and multivariate analysis, age was not
ers, however, noted better disease-free and overall survival associated with DFS and DSS. Only T stage was associ-
in young adults than in older ones,8–10 whereas Fried- ated with DFS; T stage and N stage were associated on
lander et al.11 described worse disease-free survival in multivariate analysis with DSS. The differences in disease-
patients younger than 40 years, with no difference from specific and overall survival were not statistically signifi-
older patients in overall survival.9 Sarkaria and Harari,12 cant between the two patient groups. In addition, there
in another literature review of 152 patients younger than was no between-group difference in the rate of treatment
40 years with tongue cancer, the failure rate was 57% and failure in our study. However, each group exhibited a dis-
the death rate, 47%. The authors concluded that younger tinct pattern of failure. Most of the younger patients had
adults have a worse prognosis than older ones. These a distant recurrence (60%), and all died of the disease,
findings were in line with a 2007 study wherein disease- whereas most of the older patients failed locoregionally
free and overall survival were lower in the under-40-year (93%), and only 74% ultimately died of their disease. The
age group (n = 46) than the older group,13 and an earlier percentage of distant failure in the younger group is con-
study using a 45-year cut-off.14 A previous study from siderably higher than the 3–8% rate of distant failure in
our department showed that, in general, patients younger SCC reported in previous studies.4–14 This finding, too,
than 45 years have the same outcome as older patients. raises the question of a different cancer pathogenesis and
However, within the younger group, we noted two dis- tumour biology in young patients.
tinct disease patterns: an extremely aggressive course with Several previous authors postulated that human papil-
a high mortality rate within 2 years, and a more indolent loma virus, herpes simplex virus, and Epstein Barr virus
course with a lower mortality rate.15 may play a pathogenetic role in head and neck carcinoma
Only two studies evaluated oral tongue cancer in in young patients, but no supportive evidence relative to
patients less than 30 years old (average age 23). Byers16 older patients was found.21,22 The association between
investigated the clinical course of 11 patients treated and HNSCC and HPV has been studied intensively in the past
following during 1956–1973. Seven (64%) had stage 3–4 two decades and was found to be strongest for oropha-
disease at presentation. The patients were treated by vari- ryngeal SCC, specifically for cancers of the palatine and
ous modalities, with an overall survival of 45%. The sec- lingual tonsils. In a landmark paper, HPV-16 seropositiv-
ond study was conducted by Newman et al.17 in 1983 ity was most strongly associated with increased risk of
and included 13 patients, 46% with stage 3–4 disease at oropharyngeal cancer and was more weakly associated
presentation, who underwent various initial treatments. with risk of developing oral cavity cancer.23 A recent
Eight patients died of disease (62%). The authors con- meta-analysis of 17 studies that aimed to define the asso-
cluded that the under-30 age group had a similar progno- ciation of HPV with the different head and neck subsites,
sis by stage to older patients. found that HPV is most strongly associated with tonsillar
The younger patients in our cohort had a higher N cancer, is intermediate for oropharyngeal cancer in gen-
stage than the older patients and therefore a more eral, and is weakest for oral cancer.24 Overall, it seems
advanced tumour stage (73% stage 3–4), in agreement HPV is not associated with the recent surge in the inci-
with the high proportion of advanced tumours in the dence of biologically aggressive oral cavity cancer in
younger groups of Byers16 and Newman et al.17 This find- young populations.25
ing has two potential explanations: a delay in diagnosis Genetic alterations and distinct molecular patterns have
owing to a lower index of clinical suspicion of tongue also been studied in this context. It has been shown that
SCC in younger patients or a more aggressive age-related patients younger than 30 years exhibited a significantly
biologic behaviour of the tumour. The latter assumption increased chromosome fragility compared to older
is supported by the significantly higher rate of perineural patients following mutagen exposure.22 In addition a
invasion on histopathological examination in our younger higher frequency of microsatellite instability has been
Ó 2010 Blackwell Publishing Ltd • Clinical Otolaryngology 35, 307–312

6. 312 E. Soudry et al.
found in younger patients.22 Conversely, no significant 8 Lee C.C., Ho H.C., Chen H.L. et al. (2007) Squamous cell carci-
differences were found in the expression of p53, p21, Rb noma of the oral tongue in young patients: a matched pair anal-
and MDM2 proteins between patients younger than ysis. Acta Otolaryngol. 127, 1214–1217
9 Davidson B.J., Root W.A. & Trock B.J. (2001) Age and survival
35 years and older than 75 years.22 Thus the possible
from squamous cell carcinoma of the oral tongue. Head Neck
influence of viruses and genetics in young patients 23, 273–279
remains to be fully elucidated. 10 McGregor G.I., Davis N. & Robins R.E. (1983) Squamous cell
carcinoma of the tongue and lower oral cavity in patients under
40 years of age. Am. J. Surg. 146, 88–92
Synopsis of key findings 11 Friedlander P.L., Schantz S.P., Shaha A.R. et al. (1998) Squa-
In conclusion, this study, although limited by sample size, mous cell carcinoma of the tongue in young patients: a matched
pair analysis. Head Neck 20, 363–368
indicates that patients younger than 30 years with SCC of
12 Sarkaria J.N. & Harari P.M. (1994) Oral tongue cancer in young
the oral tongue more often present with more advanced adults less than 40 years of age: rationale for aggressive therapy.
disease than older patients, and may have a distinct pat- Head Neck 16, 107–111
tern of failure. These differences may be due to age- 13 Garavello W., Spreafico R. & Gaini R.M. (2007) Oral tongue
related differences in the biologic behaviour of the cancer in young patients: a matched analysis. Oral Oncol. 43,
tumour or delayed cancer diagnosis owing to clinician 894–897
bias because of the patients’ younger age. Although oral 14 Jones J.B., Lampe H.B. & Cheung H.W. (1989) Carcinoma of
the tongue in young patients. J. Otolaryngol. 18, 105–108
tongue SCC occurs rarely in younger adults, suspicious
15 Popovtzer A., Shpitzer T., Bahar G. et al. (2004) Squamous cell
lesions should not be disregarded, and histopathologically
carcinoma of the oral tongue in young patients. Laryngoscope
proven tumours should be treated aggressively with inten- 114, 915–917
sive follow-up. Further studies are needed to elucidate the 16 Byers R.M. (1975) Squamous cell carcinoma of the oral tongue
biological factors underlying the development of tongue in patients less than thirty years of age. Am. J. Surg. 130, 475–
cancer in young adults. 478
17 Newman A.N., Rice D.H., Ossof R.H. et al. (1983) Carcinoma
of the tongue in Persons younger than 30 years of age. Arch. Ot-
Conflict of interest olaryngol. 109, 302–304
18 Neumark Y.D., Rahav G., Teichman M. et al. (2001) Alcohol
None to declare. drinking patterns among Jewish and Arab men and women in
Israel. J. Stud. Alcohol 62, 443–447
19 Brandwein-Gensler M., Teixeira M.S., Lewis C.M. et al. (2005)
References
Oral squamous cell carcinoma: histologic risk assessment, but
1 Horner M.J., Ries L.A.G., Krapcho M. et al. (2006) SEER Cancer not margin status, is strongly predictive of local disease-free and
Statistics Review, 1975–2006, National Cancer Institute. Bethesda, overall survival. Am. J. Surg. Pathol. 29, 167–178
MD, http://seer.cancer.gov/csr/1975_2006/, based on November 20 Maddox W.A. & Urist M.M. (1990) Histopathological prognos-
2008. SEER data submission, posted to the SEER web site, 2009 tic factors of certain primary oral cavity cancers. Oncology (Will-
2 Oral cancer – UK incidence statistics. http: ⁄ ⁄ info.cancerresearchuk. iston Park) 4, 39–42
org ⁄ cancerstats ⁄ types ⁄ oral ⁄ incidence ⁄ 21 Brown B., Barnes L., Mazariegos J. et al. (1989) Prognostic fac-
3 Curado M.P. & Hashibe M. (2009) Recent changes in the epide- tors in mobile tongue and floor of mouth carcinoma. Cancer
miology of head and neck cancer. Curr. Opin. Oncol. 21, 194– 64, 1195–1202
200 22 Goldstein D.P. & Irish J.C. (2005) Squamous cell carcinoma in
4 Pitman K.T., Johnson J.T., Wagner B.S. et al. (2000) Cancer of the young. Curr. Opin. Otolaryngol. Head Neck Surg. 13, 207–
the tongue in patients less than forty. Head Neck 22, 297–302 211
5 Manuel S., Raghavan K.N. & Sebastian P. (2003) Survival in 23 Mork J., Lie A.K., Glattre E. et al. (2001) Human papillomavirus
patients under 45 years with squamous cell carcinoma of the infection as a risk factor for squamous cell carcinoma of the
oral tongue. Int. J. Oral Maxillofac. Surg. 32, 167–173 head and neck. N. Engl. J. Med. 344, 1125–1131
6 Siegelmann-Danieli N., Hanlon A., Ridge J.A. et al. (1998) Oral 24 Hobbs C.G., Sterne J.A., Bailey M. et al. (2006) Human papillo-
tongue cancer in patients less than 45 years old: institutional mavirus and head and neck cancer: a systematic review and
experience and comparison with older patients. J. Clin. Oncol. meta-analysis. Clin. Otolaryngol. 31, 259–266
16, 745–753 25 Salem A. (2010) Dismissing links between HPV and aggressive
7 Veness M.J., Morgan G.J., Sathiyaseelan Y. et al. (2003) Anterior tongue cancer in young patients. Ann. Oncol. 21, 13–17
tongue cancer: age is not a predictor of outcome and should
not alter treatment. ANZ J. Surg. 73, 899–904
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