Received: 3 January 2020 Revised: 17 March 2020 Accepted: 3 April 2020

DOI: 10.1002/hed.26177

ORIGINAL ARTICLE

Squamous cell carcinoma of the oral tongue:

Distinct epidemiological profile disease

Eyal Yosefof MD1,2 | Ohad Hilly MD1,2 | Sagit Stern MD1,2 |

Gideon Bachar MD1,2 | Thomas Shpitzer MD1,2 | Aviram Mizrachi MD1,2

1
Department of Otolaryngology—Head
and Neck Surgery, Rabin Medical Center,
Petah Tikva, Israel
2
Sackler Faculty of Medicine, Tel Aviv
University, Tel Aviv, Israel
Correspondence
Aviram Mizrachi, MD, Department of
Otorhinolaryngology—Head and Neck
Surgery, Rabin Medical Center, Beilinson
Campus, Petah Tikva 49100, Israel.
Email: aviramm2@clalit.org.il
Section Editor: Benjamin Judson
Abstract
Background: Oral squamous cell carcinoma (OSCC) occurs in different
subsites within the oral cavity. Our goal was to investigate the epidemiological
features of OSCC with relation to age and subsite.
Methods: Retrospective review of all patients treated for OSCC in a tertiary
care center between 2000 and 2018.
Results: A total of 360 patients were included. Five age groups were defined:
0 to 30, 31 to 45, 46 to 60, 61 to 75, and 76+. In the 0 to 30 and 31 to 45 groups,
94.6% of tumors originated in the oral tongue compared to 87%, 66%, and 61%
in the 46 to 60, 61 to 75, and 76+ groups, respectively (P < .001). A higher pro-
portion of oral tongue SCC (OTSCC) was found in nonsmokers (76% vs 62%,
P = .02). In nonsmokers aged 0 to 60, 97.9% had OTSCC compared to 67.5% in
the 61+ groups (P < .001).
Conclusions: OSCC in young nonsmokers originates primarily in the tongue.
The etiology of OTSCC in young patients may be different than other OSCC
subsites and not related to smoking.

KEYWORDS
epidemiological profile, oral cavity cancer, oral tongue cancer, risk factors, young patients

1 | INTRODUCTION
The oral cavity is one of the most common sites for head
and neck malignancies, with oral squamous cell carci-
noma (OSCC) representing the majority of the lesions.1
OSCC may occur in different subsites within the oral
cavity. These subsites might have a distinct host-related
profile, which may be genetic, environmental, or habitual.
The traditional risk factors for OSCC include smoking
and alcohol consumption, and these risk factors are con-
sidered to have a combined synergistic effect of up to
35 times on the risk for OSCC.2
This study was presented at the International Academy of Oral
Oncology Seventh World Congress, September 2019, Rome, Italy.
Over the last few decades, the incidence of OSCC has
been decreasing worldwide. This trend can be explained
by the raising awareness and decreased tobacco use dur-
ing the last decades.3
However, in young patients, the incidence of OSCC
and oral tongue SCC (OTSCC) specifically has been rais-
ing over the last decades.4-9
Furthermore, in young and nonsmoking patients, the
incidence of OSCC has yet to be explained by genetic, habit-
ual, or other specific factors, unlike the rising incidence of
oropharyngeal carcinoma in this group, which has been
strongly related to the human papillomavirus (HPV).10-12
The aim of our research was to investigate the epide-
miological features of OSCC, in relation to the different
tumor subsites, specifically regarding the oral tongue.

Head & Neck. 2020;1–5. wileyonlinelibrary.com/journal/hed © 2020 Wiley Periodicals, Inc. 1

2 YOSEFOF ET AL.

2 | P A T I E N T S A N D ME T H O D S TABLE 1 Clinical and pathological characteristics of 360

patients with oral squamous cell carcinoma
2.1 | Patients Variable No. of patients (%)
Sex
We performed a retrospective review of all patients who
were treated for OSCC at a university affiliated tertiary Female 183 (50.8)
care center between 2000 and 2018. Data were collected Male 177 (49.2)
from patients' medical charts and included demographics Age (y)
(age, gender, smoking, and alcohol consumption), clinical ≤30 22 (6.1)
and pathological features including tumor's site of origin, 31-45 34 (9.4)
staging, treatment modalities, and outcomes. Patients with
46-60 55 (15.3)
insufficient data were excluded from the study.
61-75 112 (31.1)
≥76 137 (38.1)
2.2 | Statistical analysis Smoking
Yes 91 (25.3)
All analyses were performed using IBM SPSS Statistics for No 161 (44.7)
Windows, version 25.0 (IBM Corp., Armonk, New York).
Unknown 108 (30)
The statistical significance of differences in categorical var-
Origin site
iables was calculated using the Pearson chi-square test.
The statistical significance of dose-response interactions Tongue 259 (71.9)
between age groups and tumor sites was evaluated using Buccal mucosa 39 (10.8)
the Mantel-Haenszel test for trend. Continuous variables Alveolar ridge 25 (6.9)
were presented as mean (±SD), and compared using the Floor of mouth 15 (4.2)
student's t test for independent samples. Retromolar trigone 12 (3.3)
The study was approved by the institutional review
Hard palate 10 (2.8)
board with a waiver of informed consent.
Initial stage
I 98 (27.2)
3 | R E SUL T S II 66 (18.3)
III 56 (15.5)
A total of 360 patients with oral cavity SCC were IV 92 (25.5)
included in the study, 183 females and 177 males
Undetermined 48 (13.3)
(Table 1). The mean age of patients was 66.6 (±18.3)
years, ranging from 15 to 98. Patients were divided into
five age subgroups: 0 to 30, 31 to 45, 46 to 60, 61 to
75, and 76 years or older. The number of patients in each difference in the age of smokers and nonsmokers (63.5 vs
group was 22, 34, 55, 112, and 137, respectively. 67.2, respectively; P = .12). A higher percentage of OTSCC
A similar proportion of OTSCC out of all subsites was was demonstrated for the nonsmokers group as for them
found for male (74%) and female (69%) patients. 76.4% of OSCC originated in the oral tongue, compared to
We then looked at the subsite distribution for each age 62.6% in the smokers group (P = .02).
group. For the 0 to 30 subgroup, all cases originated in the When comparing different subsites for the non-
oral tongue. For the 31 to 45 subgroup, 91.2% of cases orig- smokers group, for the 0 to 30 and 31 to 45 subgroups,
inated in the oral tongue (31/34). The percentage of oral we found that all cases originated in the oral tongue, and
tongue origin out of the total cases for each subgroup grad- for the 46 to 60 all cases but 1 (19 out of 20) originated in
ually decreased to 87.3%, 66.1%, and 61.3% in the 46 to the oral tongue. For the 61 to 75 and 76+ subgroups this
60, 61 to 75, and 76+ years age groups, respectively ratio decreased to 65% and 69%, respectively (Figure 2).
(Figure 1). The difference between all groups was statisti- The difference remained highly significant when all
cally significant (Mantel-Haenszel test for trend, P < .001). groups were compared (Mantel-Haenszel test for trend,
We divided the patients to smokers (current or past P < .001). When comparing the 0 to 60 subgroup to the
smokers, n = 161) and nonsmokers (never smoked, n = 91). 61+ patient subgroup, a highly significant higher per-
For the rest of the patients no information was available centage of OTSCC was found for the first subgroup (98%
regarding smoking history. There was no significant vs 67.5%, P < .001) (Figure 3).
YOSEFOF ET AL. 3

F I G U R E 1 Site distribution for

each age subgroup distribution among
360 patients with oral squamous cell
carcinoma [Color figure can be viewed
at wileyonlinelibrary.com]

F I G U R E 2 Site distribution for

each age subgroup distribution among
161 nonsmokers [Color figure can be
viewed at wileyonlinelibrary.com]

F I G U R E 3 Site distribution for

patients aged 0 to 60 and 61+ among
161 nonsmokers [Color figure can be
viewed at wileyonlinelibrary.com]

4 | DISCUSSION patients raises questions regarding disease etiology in this

Our study's goal was to investigate the epidemiological
features of OSCC, and OTSCC in particular. We found
that in young and nonsmoking patients, OSCC originates
almost exclusively in the oral tongue.
Traditionally, OSCC is mainly related to two known
risk factors—tobacco and alcohol consumption. How-
ever, the occurrence of OSCC in young, nonsmoking
subpopulation.
When looking at tobacco and alcohol abuse in the
general population in Israel and the United States
(according to recent WHO statistics) we found that while
the prevalence of tobacco use is similar in both countries
(19.8% in the United States compared to 18.5% in Israel),
alcohol consumption is much more prevalent in the
United States (7.7% in the United States compared to
4 YOSEFOF ET AL.
3.3% in Israel). Thus, our study focused mainly on
smoking as a risk factor for OSCC.
Li et al13 compared the epidemiological features of
different subsites between 1688 OSCC cases treated surgi-
cally between 1990 and 2009. They found that OTSCC
was much more common among white patients younger
than 40, compared to other oral cavity subsites.
A study by Shiboski et al8 has shown an increase in
the incidence of oral tongue cancer and oropharyngeal
cancer in young patients aged 20 to 44. Patel et al14
showed that the incidence of OTSCC is increasing among
patients aged 18 to 44, especially among women. Myers
et al9 performed a review of OTSCC incidence in M. D.
Anderson cancer center between 1973 and 1995 and
showed an increase in the proportion of patients younger
than 40 years old, from 4% of all cases in 1971 to 18% in
1993. Another study by Ng et al15 also showed an increase
in OSCC incidence in the young population worldwide,
specifically in female patients in some regions.
Cariati et al16 compared 33 patients with oral and oro-
pharyngeal SCC who were 45 years old or younger with
100 patients older than 45. While the oral tongue was the
most common subsite, in the young group, the propor-
tion of oral tongue cancer among young patients was less
than that shown in our cohort (54.5%, 18/33). They found
that in the young patients group, smoking and alcohol
consumption was less common compared to the older
age group as 51.5% of patients in the young group never
smoked or consumed alcohol, compared to only 13% in
the older age group.
Hilly et al17 studied the differences in OTSCC
between patients younger than 30 (n = 16) and patients
older than 60 years (n = 62). The younger patients group
were more likely to present initially with regional metas-
tasis (75% vs 19%), and although no difference in overall
survival or disease free survival was shown between the
groups, recurrences among young patients were more
likely to be distant and resulted in death in all cases com-
pared to 50% 3 years survival for recurrent cases in the
older patients group.
As we know, in the last decade, the rising incidence of
oropharyngeal cancer in the young population has been
strongly linked to HPV infection.10 However, no link was
shown between OSCC and HPV infection. A study by
Tachibana et al18 examined whether HPV infection can
explain the rising incidence of OTSCC in young patients.
Although the study found a higher expression of p16
among patients younger than 40 compared to older
patients, the p16 expression did not correlate with a higher
detection of HPV DNA in the younger patients group.
Pickering et al19 isolated DNA from oral tongue
tumors of 16 nonsmoking patients younger than 45 years
and 28 smoking patients older than 45 years. They
performed genomic sequencing on both groups, and found
no genomic difference between the groups. Although a
trend toward a higher mutation rate of TP53 was observed
among the young patients and a trend toward higher
FAT1 and PIK3CA was shown in the older patients group,
these differences were not statistically significant.
Several studies examined the effect of oral hygiene
and mouthwash use on the incidence of head and neck
SCC and OSCC in particular. A case-control study per-
formed in India by Dholam et al20 compared 85 patients
aged 18 to 45 with oral and oropharyngeal cancer with
85 patients who never had cancer. The study found a cor-
relation between OSCC and poor oral hygiene, dental
trauma and smoking habits—including smoking and
chewing tobacco and betel nut use. Unlike our study
group, the most common subsite was the buccal mucosa
(39% of all cases), followed by the oral tongue (31%). This
difference in subsites distribution can be mainly related
to a much higher prevalence of betel nut and tobacco-
chewing habits in India compared to Israel.
Our study shows that for young patients aged 0 to
45, almost all cases of OSCC originated in the oral
tongue. The percentage of oral tongue cases out of the
total OSCC subsites gradually decreased in the older age
groups. When we looked at nonsmoking patients only,
we saw an even more significant trend of oral tongue ori-
gin among the young patients' subgroups, compared to a
more diverse distribution between different oral subsites
in older patients.
These findings suggest that OTSCC in young,
nonsmoking patients may have a different etiology than
the traditional risk factors of OSCC in older patients.
Speculations and theories on alternative etiologies for
OSCC have been previously made. Exposure to different
irritating chemicals such as mouthwash was recently
linked to increased risk of developing head and neck can-
cer in general and specifically OSCC.
Boffetta et al21 performed a pooled analysis of nine
studies, including a total of 8891 cases and 10 090 con-
trols. They found that the OR for OSCC for patients who
used mouthwash at any time was 1.11. However, between
nonsmoker and nondrinkers no effect of mouthwash use
was shown. It is assumed that the alcohol found in many
mouthwash brands may be responsible for its possible
carcinogenic effect. A study by Eliot et al22 compared
513 head and neck cancer patients with 567 controls and
examined the effect of periodontal disease and mouth-
wash use on the incidence of OSCC and found that the
association between mouthwash with alcohol and OSCC
was stronger than that of alcohol-free mouthwash (odds
ratio (OR) 1.24 compared to 1.07). Periodontal disease
was also found to be associated with an elevated risk for
OSCC with an OR of 1.07.
YOSEFOF ET AL.
Nevertheless, these etiologies need to be further
investigated both clinically and mechanistically.
5 | C ON C L U S I ON S
The present study clearly illustrates that in our tertiary
center OSCC in young nonsmoking patients originates
almost exclusively in the oral tongue. These findings
imply that oral tongue cancer in the young nonsmoking
population may have a certain genetic, infectious, envi-
ronmental or habitual etiology that has yet been identi-
fied. Further research is needed in order to try and isolate
such factors and possibly promote prevention and early
detection of OTSCC in the young population.
ORCID
Eyal Yosefof https://orcid.org/0000-0001-8211-9774
R EF E RE N C E S
1. Lambert R, Sauvaget C, de Camargo CM, Sankaranarayanan R.
Epidemiology of cancer from the oral cavity and oropharynx.
Eur J Gastroenterol Hepatol. 2011;23:633-641.
2. Blot WJ, McLoughlin JK, Winn DM, et al. Smoking and drink-
ing in relation to oral and pharyngeal cancer. Cancer Res. 1988;
48:3282-3287.
3. Shiboski CH, Shiboski SC, Silverman S Jr. Trends in oral can-
cer rates in the United States, 1973-1996. Community Dent Oral
Epidemiol. 2000;28:249-256.
4. De Morais EF, Mafra RP, Gonzaga AKG, de Souza DLB,
Pinto LP, da Silveira ÉJD. Prognostic factors of oral squamous
cell carcinoma in young patients: a systematic review. J Oral
Maxillofac Surg. 2017;75:1555-1566.
5. Gamez ME, Kraus R, Hinni ML, et al. Treatment outcomes of
squamous cell carcinoma of the oral cavity in young adults.
Oral Oncol. 2018;87:43-48.
6. Schantz SP, Yu GP. Head and neck cancer incidence trends in
young Americans, 1973-1997, with a special analysis for tongue
cancer. Arch Otolaryngol Head Neck Surg. 2002;128:268-274.
7. Müller S, Pan Y, Li R, Chi AC. Changing trends in oral squa-
mous cell carcinoma with particular reference to young
patients: 1971–2006. The Emory University experience. Head
Neck Pathol. 2008;2:60-66.
8. Shiboski CH, Schmidt BL, Jordan RC. Tongue and tonsil carci-
noma: increasing trends in the U.S. population ages
20-44 years. Cancer. 2005;103:1843-1849.
9. Myers JN, Elkins T, Roberts D, Byers RM. Squamous cell carci-
noma of the tongue in young adults: increasing incidence and
factors that predict treatment outcomes. Otolaryngol Head Neck
Surg. 2000 Jan;122(1):44-51.
10. Mehanna H, Jones TM, Gregoire V, Ang KK. Oropharyngeal
carcinoma related to human papillomavirus. BMJ. 2010;25:340.
5
11. Gillison ML, Shah KV. Human papillomavirus-associated head
and neck squamous cell carcinoma: mounting evidence for an
etiologic role for human papillomavirus in a subset of head and
neck cancers. Curr Opin Oncol. 2001;13(3):183-188.
12. Chaturvedi AK, Engels EA, Anderson WF, Gillison ML. Inci-
dence trends for human papillomavirus-related and unrelated
oral squamous cell carcinomas in the United States. J Clin
Oncol. 2008;26:612-619.
13. Li R, Koch WM, Fakhry C, Gourin CG. Distinct epidemiologic
characteristics of oral tongue cancer patients. Otolaryngol Head
Neck Surg. 2013;148(5):792-796.
14. Patel SC, Carpenter WR, Tyree S, et al. Increasing incidence of
oral tongue squamous cell carcinoma in young white women,
age 18 to 44 years. J Clin Oncol. 2011;29(11):1488-1494.
15. Ng JH, Iyer NG, Tan MH, Edgren G. Changing epidemiology
of oral squamous cell carcinoma of the tongue: a global study.
Head Neck. 2017;39(2):297-304.
16. Cariati P, Cabello-Serrano A, Perez-de Perceval-Tara M,
Monsalve-Iglesias F, Martínez-Lara I. Oral and oropharyngeal
squamous cell carcinoma in young adults: a retrospective study
in Granada University Hospital. Med Oral Patol Oral Cir Bucal.
2017;22(6):e679-e685.
17. Hilly O, Shkedy Y, Hod R, et al. Carcinoma of the oral tongue
in patients younger than 30 years: comparison with patients
older than 60 years. Oral Oncol. 2013 Oct;49(10):987-990.
18. Tachibana T, Orita Y, Gion Y, et al. Young adult patients with squa-
mous cell carcinoma of the tongue strongly express p16 without
human papillomavirus infection. Acta Otolaryngol. 2019;139(1):
80-84.
19. Pickering CR, Zhang J, Neskey DM, et al. Squamous cell carci-
noma of the oral tongue in young non-smokers is genomically
similar to tumors in older smokers. Clin Cancer Res. 2014 Jul
15;20(14):3842-3848.
20. Dholam KP, Chouksey GC. Squamous cell carcinoma of the oral
cavity and oropharynx in patients aged 18-45 years: a case-control
study to evaluate the risk factors with emphasis on stress, diet, oral
hygiene, and family history. Indian J Cancer. 2016;53(2):244-251.
21. Boffetta P, Hayes RB, Sartori S, et al. Mouthwash use and
cancer of the head and neck: a pooled analysis from the Inter-
national Head and Neck Cancer Epidemiology Consortium.
Eur J Cancer Prev. 2016;25(4):344-348.
22. Eliot MN, Michaud DS, Langevin SM, McClean MD,
Kelsey KT. Periodontal disease and mouthwash use are risk
factors for head and neck squamous cell carcinoma. Cancer
Causes Control. 2013;24(7):1315-1322.
How to cite this article: Yosefof E, Hilly O,
Stern S, Bachar G, Shpitzer T, Mizrachi A.
Squamous cell carcinoma of the oral tongue:
Distinct epidemiological profile disease. Head &
Neck. 2020;1–5. https://doi.org/10.1002/hed.26177