Squamous cell carcinoma of the oral tongue in patients 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

ORIGINAL ARTICLE

Objective: To assess the possible effect of young age on clinical behaviour and survival outcome of squamous cell carcinoma of the oral tongue. Design: Retrospective, case control study. Setting: A major tertiary referral centre. Participants: Eighty-five patients with oral tongue squamous cell carcinoma with at least 2 years of follow-up. Main outcome measurements: Clinical and histopathological staging, disease-free survival, disease-specific survival and overall survival. Results: Eleven patients (13%) were younger than 30 years. Compared to the older patients, they had a significantly worse N stage (P = 0.041), more perineural

invasion (P = 0.012), and higher rates, though not significant, of treatment failure (46%, including 60% with distant metastases, versus 35%, nearly all locoregional) and mortality (100% of treatment failures versus 73%). There were no significant between-group differences in 5-year disease-free, disease-specific, and overall survival. Conclusion: In this study, patients younger than 30 years of age presented with advanced tumour stages and with a different failure pattern compared to the older age group. This may be attributable to age-related biologic behaviour or delayed cancer diagnosis. Differences in disease free survival and overall survival could not be established.

Squamous cell carcinoma (SCC) of the oral tongue accounts for approximately 30% of oral cavity SCCs and is thus one of the most frequent head and neck cancers.1,2 Crude Incidence is on average between 10 and 20 cases per 100 000 in Europe and the USA.3 Differing patterns emerge when oral cancer incidence trends are analysed by age groups. Rising trends of oral cancer in the young and middle aged (under 50 years old), particularly cancer of the tongue, have been observed in European countries.2 In USA, despite the decreasing incidence of head and neck cancer, there is a significant increase in the incidence of squamous cell carcinoma (SCC) of the oral tongue, base of tongue and tonsils in young white patients aged 30–44 years.1 Differences in cancer pathogenesis and genetic alterations have been studied as possible causes for cancer in the young aged group.
Correspondence: T. Shpitzer, MD, Department of Otolaryngology Head and Neck Surgery, Rabin Medical Center, Beilinson Campus, Petah Tiqwa 49100, Israel. Tel.: 972-3-937 6456; fax: 972-3-937 6467; e-mail: thomas-s@zahav.net.il Ó 2010 Blackwell Publishing Ltd • Clinical Otolaryngology 35, 307–312

Prognostication and treatment decisions are currently based on TNM staging and presence of perineural and perivascular invasion on histopathological study. Age is not considered a prognostic factor. Most of the studies conducted to date on the potential prognostic significance of age in tongue cancer have yielded conflicting results.4–17 This might be explained by the almost exclusive use of 40–45 years as the cutoff for comparison, with a wide range of mean ages, from 30 to 38 years. Yet it is possible that the younger-than-40- to 45-year group is itself composed of heterogeneous subgroups and that lowering the cut-off would yield a more homogenous sample. Only two studies have evaluated oral tongue SCC in patients younger than 30 years,16,17 and both were done nearly 30 years ago, when the treatment approach was considerably different. The aim of the present study was to evaluate the clinical and histopathological parameters and survival outcomes of oral tongue SCC in patients younger than 30 years of age compared to older patients.
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Patients and methods
Ethical considerations

This is a retrospective chart review, and prior to the study, permission was obtained from the local institutional 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) and survival outcomes were documented, and the findings were compared between patients younger than 30 years and older patients.
Statistical analysis

Fig. 1. Age histogram.

Continuous variables are expressed as mean ± standard deviation (sd) and categorical variables as percentages. Differences in mean continuous variables between groups were analysed by Student t-test, and differences in categorical variables, by chi-square test or Fisher exact test. Disease-specific survival (DSS) rate and disease-free survival (DFS), defined by the interval between the date of diagnosis and the day of death or recurrence or the last follow-up, were calculated by the Kaplan-Meier method; log-rank test were used for univariate analysis to compare DSS and DFS between the groups. Multivariate analysis was performed using the Cox proportional hazards model, in which DSS or DFS was the dependent variable and, age, gender, pathological grade, T stage classification (T1 versus T2 + T3), N stage (N0 versus N1 + N2) and perineural invasion (yes versus no) were independent variables. A P-value of less than 0.05 was considered statistically significant. For statistical analyses, we used SPSS, version 15.0.1 software (SPSS, Chicago, IL, USA).
Results

Eighty-five patients met the study criteria. They included 39 male and 46 female patients of mean age 60.8 ± 20.5 years (Fig. 1 – age histogram). Eleven 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 younger group and 66.2 ± 15.7 years (range 32–94) in the older group. A history of smoking was positive in one patient (9%) in the younger group and 20 patients (27%) in the older group. Excessive alcohol intake was very rare in both groups of patients, which is in accordance with the overall low alcohol intake in our country.18 The clinical and histopathological characteristics of the patient groups are shown in Tables 1 and 2. Compared to the older group, the younger patients had a significantly worse clinical ⁄ radiological N stage (P = 0.041) in presentation and more evidence of perineural invasion (P = 0.012) on histopathological examination. There were no significant between-group differences in histological grade, tumour depth, or presence of lymph node extracapsular extension. Treatment consisted of resection of the tongue tumour in all cases. All but four patients also underwent elective or therapeutic neck dissection, all of whom had small tumours and were considered a very high operative risk. 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 resection margins were observed on final histopathological analysis in three of the young patients (27%) and 13 of the older group (18%). Postoperative radiation or chemoradiation was administered for advanced tumours
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Table 1. Clinical characteristics 30 years and older patients Age < 30 years, n = 11 Number Females Males T stage T1 T2 T3 T4 N stage N0 N1 N2 N3 AJCC stage I–II III–IV 5 6 5 4 2 0 5 2 4 0 3 8 % 45 55 46 36 18

of

patients

younger

than

Age > 30 years, n = 74 Number 41 33 38 30 5 1 54 13 7 0 51 23 % 55 45 51 41 7 1 72 18 10 P-value N.S.

N.S.

Treatment failure (Table 3) was documented in five patients in the younger group (46%), including three (60%) with distant metastases, one with local failure, and one with regional failure. Average time to failure was 14.5 months; all five patients ultimately died of their disease. In the older group, 27 patients (36%) failed treatment, of whom 25 had a locoregional recurrence and two had distant metastases. Average time to failure was 12.7 months; 20 patients (74%) ultimately died of their disease. A second primary tumour of the head and neck developed in five patients, all in the older group, which led to a total failure in 32 (43%) patients in the older group.
Disease specific and disease free survival

46 18 36

0.041

27 73

70 30

0.011

AJCC, American Joint Committee on Cancer; N.S., not significant.

and those with close or involved margins by standard protocols. The treatment field included the tongue and ipsilateral neck. For patients with N2, the contralateral necks were treated. Radiation dose ranged between 54 Gy and 60 Gy in most cases, and for positive margins, between 60 Gy and 66 Gy. Treatment was planned in most cases in three dimensional planes using 6 MV photons. Patients with very high risk features, such as positive margins massive extracapsular extension were treated with concomitant chemoradiation (either cisplatin or cisplatin and 5-FU).

The mean duration of follow-up for the 85 patients was 4.6 years (range 4 months to 13.5 years). The 5-year DFS rate was 55% in the younger group and 63% in the older group (Fig. 2). Corresponding rates for 5-year diseasespecific survival (DSS) were 55% and 73% (Fig. 3), and for 5-year overall survival, 55% and 61%. None of these between-group differences was statistically significant. The 5-year DSS and DFS according to age, gender, pathological grade, T stage classification (T1 versus T2 + T3), N stage (N0 versus N1 + N2) and perineural invasion (yes versus no) in 85 patients with tongue carcinoma were analysed as well. In DSS univariate analysis pathological grade, T stage classification (T1 versus T2 + T3), N stage (N0 versus N1 + N2) and perineural invasion (yes versus no) were significant (P = 0.015, P = 0.006, P = 0.002 and P = 0.006, respectively). DFS univariate analysis revealed that only (T1 versus T2 + T3) was significant (P = 0.001).

Table 2. Histopathological characteristics of patients younger than 30 years and older patients Age < 30 years, n = 11 Number Pathological stage I–II Pathological stage III–IV Histology Well differentiated Moderately differentiated Poorly differentiated Mean tumour thickness ± sd (mm) Perineural invasion Number of metastatic lymph nodes (average ± sd) Extracapsular extension N.S., not significant.
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Age > 30 years, n = 74 % 27 73 18 73 9 50 20 Number 51 23 30 27 11 7.8 ± 5.2 9 0.9 ± 2.3 6 % 69 31 44 40 16 13 9 P-value 0.011

3 8 2 8 1 9.4 ± 5.4 5 2.4 ± 2.7 2

N.S.

N.S. 0.012 0.004 N.S.

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Table 3. Analysis of failures in patients younger than 30 years and older patients Age < 30 years, n = 11 Number Failure Local Regional Loco-regional Distant Second primary Total failures 5 1 1 0 3 0 5 % 46 20 20 60 46 Age > 30 years, n = 74 Number 27 8 13 4 2 5 32 % 36 30 48 15 4 43

Fig. 3. Disease-specific survival 30 years and older patients.

for

patients

younger

than

patients younger than 30 years and female patients, comprised a much larger fraction (13% and 54%, respectively) 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 30 years and older patients. Strengths of the study

Multivariate Cox proporttional hazard model revealed that only T stage was statistically significant predictor of a reduced DFS (hazard ratio 4.45; 95% CI 1.89–10.50, P = 0.001) and T stage and lymph node involvement were statistically significant predictor of a reduced DSS (hazard ratio 3.24; 95% CI 1.31–8.02, P = 0.011 and hazard ratio 2.81; 95% CI 1.23–6.42, P = 0.014, respectively). In both univariate and multivariate analysis, age was not associated with DSS or DFS.
Discussion

In the literature, the reported median age at diagnosis of cancer of the oral tongue is of 61 years and that approximately 9% of patients are diagnosed before age of 45 years, and 2%, before age 35 years, and that the overall 5-year relative survival is 60%.1 In the present study,

Studies of the possible prognostic significance of age on the clinical course of oral tongue SCC reported conflicting results.4–17 The present study focused on the clinical and pathological findings and outcome of 11 patients less than 30 years old (average 24 years) with oral tongue SCC. All underwent primary surgical resection of the tongue tumour and neck dissection, either electively or therapeutically. Postoperative radiation or chemoradiation was administered for advanced tumours by standard protocols. This study is distinct from earlier reports because 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 evidence-based conclusions can not be made. Nonetheless, it should be remembered that SCC of the oral tongue is relatively rare in the young adult population and thus reaching a large homogenous group of patients is difficult, especially in the younger than 30-year-old group. Studies featuring large groups of young patients
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were based on literature reviews. Moreover, any evidence that can shed light on this unique group of patients is of value.
Comparison with other studies

In a literature review of published cases of patients younger than 40 years with tongue carcinoma (n = 122), Pitman et al.4 found a similar outcome to patients older than 40 years, in agreement with several studies.5–7 Others, however, noted better disease-free and overall survival in young adults than in older ones,8–10 whereas Friedlander et al.11 described worse disease-free survival in patients younger than 40 years, with no difference from older patients in overall survival.9 Sarkaria and Harari,12 in another literature review of 152 patients younger than 40 years with tongue cancer, the failure rate was 57% and the death rate, 47%. The authors concluded that younger adults have a worse prognosis than older ones. These findings were in line with a 2007 study wherein diseasefree and overall survival were lower in the under-40-year age group (n = 46) than the older group,13 and an earlier study using a 45-year cut-off.14 A previous study from our department showed that, in general, patients younger than 45 years have the same outcome as older patients. However, within the younger group, we noted two distinct disease patterns: an extremely aggressive course with a high mortality rate within 2 years, and a more indolent course with a lower mortality rate.15 Only two studies evaluated oral tongue cancer in patients less than 30 years old (average age 23). Byers16 investigated the clinical course of 11 patients treated and following during 1956–1973. Seven (64%) had stage 3–4 disease at presentation. The patients were treated by various modalities, with an overall survival of 45%. The second study was conducted by Newman et al.17 in 1983 and included 13 patients, 46% with stage 3–4 disease at presentation, who underwent various initial treatments. Eight patients died of disease (62%). The authors concluded that the under-30 age group had a similar prognosis by stage to older patients. The younger patients in our cohort had a higher N stage than the older patients and therefore a more advanced tumour stage (73% stage 3–4), in agreement with the high proportion of advanced tumours in the younger groups of Byers16 and Newman et al.17 This finding has two potential explanations: a delay in diagnosis owing to a lower index of clinical suspicion of tongue SCC in younger patients or a more aggressive age-related biologic behaviour of the tumour. The latter assumption is supported by the significantly higher rate of perineural invasion on histopathological examination in our younger
Ó 2010 Blackwell Publishing Ltd • Clinical Otolaryngology 35, 307–312

group. Perineural invasion has been shown to be associated with a high risk of regional metastases, local recurrence, 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 suggest that tumour biology may be age-related. Analysis of other clinical or histopathological parameters yielded no significant differences between the age groups perhaps because of the small sample size. On univariate and multivariate analysis, age was not associated with DFS and DSS. Only T stage was associated with DFS; T stage and N stage were associated on multivariate analysis with DSS. The differences in diseasespecific and overall survival were not statistically significant between the two patient groups. In addition, there was no between-group difference in the rate of treatment failure in our study. However, each group exhibited a distinct pattern of failure. Most of the younger patients had a distant recurrence (60%), and all died of the disease, whereas most of the older patients failed locoregionally (93%), and only 74% ultimately died of their disease. The percentage of distant failure in the younger group is considerably higher than the 3–8% rate of distant failure in SCC reported in previous studies.4–14 This finding, too, raises the question of a different cancer pathogenesis and tumour biology in young patients. Several previous authors postulated that human papilloma virus, herpes simplex virus, and Epstein Barr virus may play a pathogenetic role in head and neck carcinoma in young patients, but no supportive evidence relative to older patients was found.21,22 The association between HNSCC and HPV has been studied intensively in the past two decades and was found to be strongest for oropharyngeal SCC, specifically for cancers of the palatine and lingual tonsils. In a landmark paper, HPV-16 seropositivity was most strongly associated with increased risk of oropharyngeal cancer and was more weakly associated with risk of developing oral cavity cancer.23 A recent meta-analysis of 17 studies that aimed to define the association of HPV with the different head and neck subsites, found that HPV is most strongly associated with tonsillar cancer, is intermediate for oropharyngeal cancer in general, and is weakest for oral cancer.24 Overall, it seems HPV is not associated with the recent surge in the incidence of biologically aggressive oral cavity cancer in young populations.25 Genetic alterations and distinct molecular patterns have also been studied in this context. It has been shown that patients younger than 30 years exhibited a significantly increased chromosome fragility compared to older patients following mutagen exposure.22 In addition a higher frequency of microsatellite instability has been

312 E. Soudry et al.

found in younger patients.22 Conversely, no significant differences were found in the expression of p53, p21, Rb and MDM2 proteins between patients younger than 35 years and older than 75 years.22 Thus the possible influence of viruses and genetics in young patients remains to be fully elucidated.
Synopsis of key findings

In conclusion, this study, although limited by sample size, indicates that patients younger than 30 years with SCC of the oral tongue more often present with more advanced disease than older patients, and may have a distinct pattern of failure. These differences may be due to agerelated differences in the biologic behaviour of the tumour or delayed cancer diagnosis owing to clinician bias because of the patients’ younger age. Although oral tongue SCC occurs rarely in younger adults, suspicious lesions should not be disregarded, and histopathologically proven tumours should be treated aggressively with intensive follow-up. Further studies are needed to elucidate the biological factors underlying the development of tongue cancer in young adults.
Conflict of interest

None to declare.
References
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