Comparative analysis of clinicopathological characteristics in young and elderly patients with oral squamous cell carcinoma: a retrospective study in Northeastern BrazilAbstract
The aim of this study was to perform a clinicopathological analysis of oral squamous cell carcinoma (OSCC) in young patients from the northeast of Brazil and compare with elderly individuals. This retrospective study reviewed 104 OSCC cases from 2000 to 2015, focusing on patients under 40 and over 60 at diagnosis. Forty-two patients under 40 years old (40.38%) and 62 patients over 60 years old (59.62%) were analyzed using descriptive statistics, chi-square, and Fisher’s exact tests for clinicopathological factors, and Kaplan-Meier and Cox models for survival and prognostics. Most of the patients were male, with younger patients having lower rates of smoking (45.24%) and alcohol use (28.57%) compared to older patients (82.30% and 40.32%, respectively). Younger patients had a higher prevalence of tongue cancer and smaller tumors but faced more compromised surgical margins, perineural invasion, local recurrence, regional metastasis, distant metastasis, and second primary tumors. Statistical findings highlighted age-related differences in clinicopathological features and indicated that despite similar overall survival rates, younger patients had a poorer prognosis related to local recurrences, regional recurrences, and second tumors. Perineural invasion emerged as an independent prognostic factor. The study suggests that younger OSCC patients require personalized management strategies to address their higher risk of adverse outcomes, with an emphasis on the prognostic significance of perineural invasion.
Squamous Cell Carcinoma of Head and Neck; Survival; Prognosis
Introduction
Oral squamous cell carcinoma (OSCC) is the most common malignant neoplasm of the oral cavity, accounting for more than 90% of all malignancies.1,2 In the general population, the most common anatomical site for oral OSCC is the lateral border of the tongue, followed by the floor of the mouth. It is more prevalent in male patients over 50 years of age who have used tobacco and alcohol for long periods.3-5 More than half of the patients are diagnosed at an advanced stage of the disease, leading to the need for multimodal treatment, including a surgical approach followed by radiotherapy, chemoradiotherapy and, more recently, targeted molecular therapy (immunotherapy) for advanced, recurrent, and metastatic disease.6-8
Recent evidence based on research conducted in several countries has shown a significant increase in the incidence of these tumors among young patients.9,10 During the last decade, several groups have investigated the clinicopathological and molecular aspects of oral cancer in young patients in order to better elucidate its pathogenesis in this important clinical scenario.11-13 It is believed that OSCC has a different pathophysiology in the younger population. Although smoking and alcohol consumption are the main risk factors for OSCC in the biological context of the elderly population, exposure to known risk habits does not seem to play an important role in the pathogenesis of OSCC in young patients.14,15
The prognosis of oral OSCC in young patients is still controversial.4 Some studies report a worse prognosis for young patients,16,17 while others report a similar,18,19 or even better survival rate in young patients.20,21 Therefore, the objective of this study was to contribute to the knowledge about OSCC in young patients through a clinicopathological assessment and a comparison of the survival rate between OSCC in young and elderly patients.
Methods
Sample selection and data collection
This retrospective study involved the analysis of clinicopathological data extracted from patient records at Dr. Luiz Antonio Hospital in Natal, Brazil. The sample selection criteria were patients diagnosed with OSCC and treated from 2000 to 2015, who were either below 40 or above 60 years of age at the time of diagnosis. Patients aged 41 to 59 years and those with tumors located in the oropharynx and lip were excluded from the study. In addition, a histopathological review was performed by an expert (MAL) to confirm the final diagnosis.
The clinical and pathological data obtained for further evaluation included: gender, age, smoking, alcohol consumption, duration of symptoms, tumor location, TNM staging, histopathological differentiation, surgical margins, presence of perineural invasion, treatment modalities, local recurrence, occurrence of second primary tumor, development of regional or distant metastasis, and survival rates in months. The histopathological grading and TNM classification were made considering the AJCC 8th edition.22
Survival data were classified as follows: a) Overall Survival: total follow-up time from start of treatment to the date of the last available information; b) Disease-Specific Survival (DSS): time from start of treatment to death by OSCC or to the last follow-up information available if the patient remained alive and c) Disease-Free Survival (DFS): time from start of treatment to diagnosis of the first recurrence (regional or distant metastasis) or to last follow-up information for patients who did not experience a recurrence.
This study was approved by the Research Ethics Committee of the Liga Norte Riograndense Contra o Cancer, Dr. Luiz Antonio Hospital (Natal, Brazil) under the protocol 63958016.1.0000.5293.
Statistical analysis
Descriptive and quantitative data analysis was initially performed. Chi-square and Fisher’s exact tests were used to investigate associations between clinicopathological features and patient status (alive or dead). The Kaplan-Meier method was used to calculate survival curves, and the differences between the curves were investigated using the log-rank univariate test to identify potential prognostic factors. All variables that achieved significance in the univariate analysis and treatment modality were included in a multivariate model created using the Cox proportional hazard test to identify independent prognostic factors. SPSS (IBM®, New York, USA) Version 22.0 was used, and P ≤ 0.05 was considered statistically significant.
Results
In this study, 104 patients met the criteria, with a majority being men and with an average age of 42.6 years. We found that smoking and alcohol use were more common among older patients—smokers made up 49% of the older group compared to 18.2% of the younger group (p = 0.0034), and alcohol consumption was 24% in older patients and 11.5% in younger ones (p = 0.0143). Concerning tumor size, older patients often had larger tumors compared to their younger counterparts (p = 0.0177). Older patients also had significantly more cases staged as M0 compared to young individuals (42.3% vs. 21.1%, p = 0.0219).
Histological analysis indicated that the surgical margins were better for older patients, with fewer cases of positive surgical margins compared to young patients (11.5%% vs. 16.3%%, p = 0.0365) and more cases with no perineural invasion (34.6% vs. 8.6%, p = 0.0274). Moreover, absence of local, regional, and distant recurrence, and second primary tumor were more common in older patients and with statistically significant difference from younger patients (p = 0.0021, p = 0.0008, p = 0.0021, and p = 0.0157, respectively) (Table 1).
A univariate survival analysis using Kaplan-Meier was conducted to compare survival between OSCC patients under 40 and those over 60 years of age. The global 5-year survival rate was 39% for young patients and 40% for the elderly patients (p = 0.8289) (Figure A). The specific 5-year survival rate was 36% for young patients, compared to 39% for elderly patients (p = 0.8759) (Figure). The 5-year disease-free survival was 22% for young patients and 72% for elderly patients (p = 0.0003) (Figure C).
Survival analysis. A) The overall 5-year survival rate for young patients was 39%, compared to 40% for the elderly patients. B) The specific 5-year survival rate for young patients was 36%, compared to 39% for elderly patients. C) The 5-year disease-free survival was 22% for young patients and 72% for elderly patients.
Furthermore, the 5-year global survival rate was 40% for young patients with local recurrence (n = 28), while it was 74% for the elderly (n = 62) (p = 0.0121). In cases of regional recurrence, the survival rate was 27% for young patients (n = 25) and 61% for the elderly (n = 62) (p = 0.0136). Regarding second primary tumors, the survival rate for young patients was 65% (n = 17), and it reached 100% for the elderly (n = 62) (p = 0.0030). Additionally, the 5-year disease-specific survival analysis could not be conducted for local recurrence. For regional recurrence, the survival rate was 15% for young patients (n = 25) and 59% for elderly patients (n = 62) (p = 0.0054). The survival rate for second primary tumors was 73% for young patients (n = 17) and 100% for elderly patients (n = 62) (p = 0.0019). The 5-year disease-free survival rate observed in cases of local recurrence was 22% for young patients (n = 27) and 72% for elderly patients (n = 62) (p =0.0003). For regional recurrence, the rates were 18% for young patients (n = 25) and 50% for elderly patients (n = 62) (p = 0.0043). In the case of a second primary tumor, the survival rate was 71% for young individuals (n = 17) and 100% for elderly patients (n = 62) (p = 0.0012) (Table 2).
Cox regression was conducted to analyze the effects of various risk factors on the survival of patients with OSCC. In the model created, the presence of perineural invasion was identified as an independent prognostic factor of OSCC. Patients with perineural invasion had a 5.37-fold decreased survival (p = 0.0464) (Table 3).
Discussion
It is well-known that OSCC has low survival rates globally, which is concerning given that half of newly diagnosed patients will succumb to the disease within 5 years, even after receiving multimodal treatments.23 In recent years, there has been a notable rise in OSCC incidence among young adult patients. This trend has spurred research in scientific literature to investigate its etiology, pathogenesis, and prognosis in comparison to OSCC in elderly patients.24 It is worth mentioning that studies on this subject employ varied criteria to define the age range of young patients. Some studies consider individuals under the age of 45 as “young” patients,25,26 while others set the threshold at under the age of 40.27,28 Therefore, the age limits for categorizing patients as young adults are not consistent across the literature.2 In this study, patients up to the age of 40 were classified as young adults.
The prevalence of the disease was higher in male patients, while some sporadic studies indicate a predominance of women.2 In the current study, the male-to-female ratio was 1.9:1 among patients with OSCC, similar with the majority of studies described in the literature.5,29,30 In our study, we observed that lifestyle habits associated with OSCC, especially smoking and alcohol consumption, were more prevalent in older patients, challenging the common perception that these habits affect both age groups uniformly. In particular, 45.24% of young patients smoked and 28.57% drank, with significantly higher rates observed in the elderly. This discrepancy suggests that the duration and intensity of exposure to these risk factors are fundamental to the development of OSCC, as supported by Llewellyn et al,31 who observed that an average of at least 21 years of smoking is necessary for it to be a risk factor among young patients.
In the present study, the results also showed that the relationship between lifestyle factors and OSCC can vary according to age, with genetic factors potentially playing a role in young adults.2,11 The higher incidence of alcohol and tobacco consumption among older patients highlights the complexity of the pathogenesis of OSCC and underlines the need for age-specific research into the interactions of genetic and environmental factors in the development of OSCC. This approach is fundamental for understanding the different risk profiles and improving prevention and treatment strategies in different age groups, especially in young patients.32,33
Interestingly, younger patients often delay seeking care, typically waiting 4 to 6 months, compared to 1 to 3 months for older patients, due to various factors.33 These may include a lack of urgency or perception of the severity of their symptoms, challenges with healthcare access such as insurance issues or resource availability, insufficient awareness of the importance of early medical consultation, and lifestyle or financial constraints.35 Psychological or cultural attitudes towards health may also contribute to this delay.32 This information is discussed in detail, as the delay in seeking care among younger patients can significantly impact prognosis. An extended delay may result in disease progression before treatment is initiated, potentially resulting in more advanced stage at diagnosis and poorer outcomes.34-36
It is important to mention that our study showed a clinical presentation and prognosis of OSCC that contrasts with some previous findings.34,35 Despite reports that younger patients typically present with smaller tumors, our results suggested a more aggressive biological behavior in this group. In particular, younger patients had a significantly higher rate of positive surgical margins and a higher incidence of perineural invasion. These results may reflect challenges in achieving clear surgical margins, potentially due to a more conservative surgical approach or inherently more aggressive tumor characteristics in younger patients.34-36Unlike what has been described in the literature, the rates of regional lymph node invasion and distant metastasis were not significantly different between the groups in our study. This is in contrast to the data in the literature, which show that young patients have a greater tendency towards lymph node involvement and distant metastasis due to their more aggressive biological behavior compared to elderly patients.30,34-36
With regards to treatment, both age groups received similar therapeutic modalities, with a notable preference for combined treatments. The primary therapeutic strategy for OSCC is surgical resection, often complemented by radiotherapy and chemotherapy, especially in more advanced cases diagnosed at a late stage.35,36 Montero et al.36 carried out a systematic review examining the characteristics of OSCC in young patients and observed that surgical treatment, often combined with radiotherapy, was the predominant initial approach. Also according to Montero et al.,36 the addition of chemotherapy could be beneficial for the management of more advanced tumors, particularly when surgical margins are compromised by neoplastic infiltration. Interestingly, treatment patterns for young patients were found to align closely with those used for older patients, supporting our study’s findings that similar treatment protocols are applied to different age groups. This alignment emphasizes the need for ongoing treatment evaluation and potential adjustments to optimize outcomes in younger patients, who may present distinct disease dynamics due to different biological behavior.37
The presence of compromised surgical margins is associated to local recurrence and lower survival rates. Additionally, the survival of patients with OSCC can be significantly impacted by the presence of lymph node metastases.2,5,35 In the current study, young patients had a higher incidence of compromised margins, which may have contributed to metastases and recurrences. However, the presence of lymph node metastasis was not associated with a change in patient survival, even when stratified by age. There is no consensus in the literature regarding age as a prognostic factor in patients with OSCC.2,5,9 Some research groups have reported better survival outcomes for young patients, while others have found a worse prognosis for this demographic group.26,27,36
In addition, young patients had higher rates of local and regional recurrence, distant metastases, and second primary tumors compared to their older counterparts. These observations are consistent with other studies showing similar patterns.21,25,26 Consequently, the 5-year disease-free survival rates for young patients were significantly lower (22% compared to 72% in older patients), indicating a worse prognosis for this group. This is in line with other studies that indicate similar disparities in survival results in different age groups.29,31
When discussing survival in relation to specific complications, it is recognized in the literature that health problems and comorbidities, which are more prevalent in the elderly, significantly affect prognosis.10,15,29 Despite this, our statistical analysis revealed that younger patients typically had better overall survival rates, probably due to fewer comorbidities. However, the marked aggressiveness of their tumors substantially decreased this survival advantage. This observation is in line with broader findings in this field, but our study particularly highlights the high aggressiveness of the disease in younger patients, which drastically impairs survival rates, similar to previous studies in the scientific literature.37,38
Finally, perineural invasion emerged as a critical independent prognostic indicator. Patients with perineural invasion had a 5.37 times decreased survival than patients without this feature, underlining its significant prognostic value. This finding suggests that perineural invasion into prognostic assessments in order to better understand and manage OSCC in different age groups. Targeted therapeutic approaches based on these differentiated risk profiles should be emphasized, since perineural invasion is associated with a higher recurrence rate and compromised surgical margins. 8,21,29
Although this study provided valuable insights into the clinicopathological and demographic features of OSCC in a Brazilian population, several limitations must be acknowledged. The retrospective design and reliance on patient medical records may have introduced information bias, particularly regarding risk factors such as smoking and alcohol consumption. Additionally, the exclusion of patients aged 41 to 59 years and those with tumors located in the oropharynx and lip may limit the generalizability of the findings. Despite these limitations, the study contributes with important data on OSCC in a region that has been relatively underexplored. These findings can aid practitioners in developing targeted preventive measures and improving diagnostic strategies for the disease.
Conclusion
This study underscores the prognostic disparities between younger and older OSCC patients, revealing that individuals under 40 exhibit a higher risk for local and regional recurrences and second primary tumors. Such findings demonstrate the need for the development of target therapeutic strategies that consider the unique clinical profile of this younger cohort. The identification of perineural invasion as a significant prognostic factor further highlights the need for detailed histopathological assessment in guiding OSCC management. Consequently, this research advocates for personalized treatment approaches to improve outcomes of younger OSCC patients.
References
-
1 Rodrigues PC, Miguel MC, Bagordakis E, Fonseca FP, Aquino SN, Santos-Silva AR, et al. Clinicopathological prognostic factors of oral tongue squamous cell carcinoma: a retrospective study of 202 cases. Int J Oral Maxillofac Implants. 2014 Jul;43(7):795-801. https://doi.org/10.1016/j.ijom.2014.01.014
» https://doi.org/10.1016/j.ijom.2014.01.014 -
2 Morais EF, Mafra RP, Gonzaga AK, Souza DL, Pinto LP, Silveira ÉJ. Prognostic factors of oral squamous cell carcinoma in young patients: a systematic review. J Oral Maxillofac Surg. 2017 Jul;75(7):1555-66. https://doi.org/10.1016/j.joms.2016.12.017
» https://doi.org/10.1016/j.joms.2016.12.017 -
3 Curado MP, Johnson NW, Kerr AR, Silva DRM, Lanfranchi H, Pereira DL, et al. Oral and oropharynx cancer in South America: incidence, mortality trends and gaps in public databases as presented to the Global Oral Cancer Forum. Transl Res Oral Oncol. 2016;1:1-7. https://doi.org/10.1177/2057178X16653761
» https://doi.org/10.1177/2057178X16653761 -
4 Santos-Silva AR, Andrade MAC, Jorge J, Almeida OP, Vargas PA, Lopes MA. Tongue squamous cell carcinoma in young nonsmoking and nondrinking patients: 3 clinical cases of orthodontic interest. Am J Orthod Dentofacial Orthop. 2014 Jan;145(1):103-7. https://doi.org/10.1016/j.ajodo.2012.09.026
» https://doi.org/10.1016/j.ajodo.2012.09.026 -
5 Louredo BV, Vargas PA, Pérez-de-Oliveira ME, Lopes MA, Kowalski LP, Curado MP. Epidemiology and survival outcomes of lip, oral cavity, and oropharyngeal squamous cell carcinoma in a southeast Brazilian population. Med Oral Patol Oral Cir Bucal. 2022 May;27(3):e274-84. https://doi.org/10.4317/medoral.25147
» https://doi.org/10.4317/medoral.25147 -
6 Chow LQ. Head and Neck Cancer. N Engl J Med. 2020 Jan;382(1):60-72. https://doi.org/10.1056/NEJMra1715715
» https://doi.org/10.1056/NEJMra1715715 -
7 Pedroso CM, Migliorati CA, Epstein JB, Ribeiro AC, Brandão TB, Lopes MA, et al. Over 300 radiation caries papers: reflections from the rearview mirror. Front Oral Health. 2022 Jul;3:961594. https://doi.org/10.3389/froh.2022.961594
» https://doi.org/10.3389/froh.2022.961594 -
8 Martínez-Flores R, Gómez-Soto B, Lozano-Burgos C, Niklander SE, Lopes MA, González-Arriagada WA. Perineural invasion predicts poor survival and cervical lymph node metastasis in oral squamous cell carcinoma. Med Oral Patol Oral Cir Bucal. 2023 Sep;28(5):e496-503. https://doi.org/10.4317/medoral.25916
» https://doi.org/10.4317/medoral.25916 -
9 Ng JH, Iyer NG, Tan MH, Edgren G. Changing epidemiology of oral squamous cell carcinoma of the tongue: a global study. Head Neck. 2017 Feb;39(2):297-304. https://doi.org/10.1002/hed.24589
» https://doi.org/10.1002/hed.24589 -
10 Satgunaseelan L, Allanson BM, Asher R, Reddy R, Low HT, Veness M, et al. The incidence of squamous cell carcinoma of the oral tongue is rising in young non-smoking women: an international multi-institutional analysis. Oral Oncol. 2020 Nov;110:104875. https://doi.org/10.1016/j.oraloncology.2020.104875
» https://doi.org/10.1016/j.oraloncology.2020.104875 -
11 Fonseca FP, Coletta RD, Azevedo MB, Ribeiro ACP, Soubhia AMP, Miyahara GI, et al. Stromal myofibroblasts in squamous cell carcinoma of the tongue in young patients - a multicenter collaborative study. Oral Surg Oral Med Oral Pathol Oral Radiol. 2014 Oct;118(4):483-9. https://doi.org/10.1016/j.oooo.2014.07.012
» https://doi.org/10.1016/j.oooo.2014.07.012 -
12 Costa SFS, Brennan PA, Gomez RS, Fregnani ER, Santos-Silva AR, Martins MD, et al. Molecular basis of oral squamous cell carcinoma in young patients: is it any different from older patients? J Oral Pathol Med. 2018 Jul;47(6):541-6. https://doi.org/10.1111/jop.12642
» https://doi.org/10.1111/jop.12642 -
13 Galvis MM, Santos-Silva AR, Jardim JF, Fonseca FP, Lopes MA, Almeida OP, et al. Different patterns of expression of cell cycle control and local invasion-related proteins in oral squamous cell carcinoma affecting young patients. J Oral Pathol Med. 2018 Jan;47(1):32-9. https://doi.org/10.1111/jop.12601
» https://doi.org/10.1111/jop.12601 -
14 Ferreira E Costa R, Leão ML, Sant'Ana MS, Mesquita RA, Gomez RS, Santos-Silva AR, et al. Oral squamous cell carcinoma frequency in young patients from referral centers around the world. Head Neck Pathol. 2022 Sep;16(3):755-62. https://doi.org/10.1007/s12105-022-01441-w
» https://doi.org/10.1007/s12105-022-01441-w -
15 Mneimneh WS, Xu B, Ghossein C, Alzumaili B, Sethi S, Ganly I, et al. Clinicopathologic characteristics of young patients with oral squamous cell carcinoma. Head Neck Pathol. 2021 Dec;15(4):1099-108. https://doi.org/10.1007/s12105-021-01320-w
» https://doi.org/10.1007/s12105-021-01320-w - 16 Sun Q, Fang Q, Guo S. A comparison of oral squamous cell carcinoma between young and old patients in a single medical center in China. Int J Clin Exp Med. 2015 Aug;8(8):12418-23.
-
17 Patel SC, Carpenter WR, Tyree S, Couch ME, Weissler M, Hackman T, et al. Increasing incidence of oral tongue squamous cell carcinoma in young white women, age 18 to 44 years. J Clin Oncol. 2011 Apr;29(11):1488-94. https://doi.org/10.1200/JCO.2010.31.7883
» https://doi.org/10.1200/JCO.2010.31.7883 -
18 Pytynia KB, Grant JR, Etzel CJ, Roberts D, Wei Q, Sturgis EM. Matched analysis of survival in patients with squamous cell carcinoma of the head and neck diagnosed before and after 40 years of age. Arch Otolaryngol Head Neck Surg. 2004 Jul;130(7):869-73. https://doi.org/10.1001/archotol.130.7.869
» https://doi.org/10.1001/archotol.130.7.869 -
19 Friedlander PL, Schantz SP, Shaha AR, Yu G, Shah JP. Squamous cell carcinoma of the tongue in young patients: a matched-pair analysis. Head Neck. 1998 Aug;20(5):363-8. https://doi.org/10.1002/(SICI)1097-0347(199808)20:5<363::AID-HED1>3.0.CO;2-W
» https://doi.org/10.1002/(SICI)1097-0347(199808)20:5<363::AID-HED1>3.0.CO;2-W -
20 Toner M, O'Regan EM. Head and neck squamous cell carcinoma in the young: a spectrum or a distinct group? Part 2. Head Neck Pathol. 2009 Sep;3(3):249-51. https://doi.org/10.1007/s12105-009-0137-y
» https://doi.org/10.1007/s12105-009-0137-y -
21 Nadaf A, Bavle RM, Soumya M, D'mello S, Kuriakose MA, Govindan S. Analysis of the invasive edge in primary and secondary oral squamous cell carcinoma: an independent prognostic marker: A retrospective study. J Oral Maxillofac Pathol. 2016;20(2):239-45. https://doi.org/10.4103/0973-029X.185931
» https://doi.org/10.4103/0973-029X.185931 - 22 Amin MB, Greene FL, Edge SB, Compton CC, Gershenwald JE, Brookland RK et al., editors. AJCC cancer staging manual. 8th ed. New York: Springer; 2017.
-
23 Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68(6):394-424. https://doi.org/10.3322/caac.21492
» https://doi.org/10.3322/caac.21492 -
24 Miranda-Galvis M, Soares CC, Carnielli CM, Buttura JR, Sá RS, Kaminagakura E, et al. New insights into the impact of human papillomavirus on oral cancer in young patients: proteomic approach reveals a novel role for S100A8. Cells. 2023 May;12(9):1323. https://doi.org/10.3390/cells12091323
» https://doi.org/10.3390/cells12091323 -
25 Park JO, Sun DI, Cho KJ, Joo YH, Yoo HJ, Kim MS. Clinical outcome of squamous cell carcinoma of the tongue in young patients: a stage-matched comparative analysis. Clin Exp Otorhinolaryngol. 2010 Sep;3(3):161-5. https://doi.org/10.3342/ceo.2010.3.3.161
» https://doi.org/10.3342/ceo.2010.3.3.161 -
26 Ho HC, Lee MS, Hsiao SH, Hwang JH, Hung SK, Chou P, et al. Squamous cell carcinoma of the oral cavity in young patients: a matched-pair analysis. Eur Arch Otorhinolaryngol. 2008 Jul;265(S1 Suppl 1):S57-61. https://doi.org/10.1007/s00405-007-0496-5
» https://doi.org/10.1007/s00405-007-0496-5 -
27 Soudry E, Preis M, Hod R, Hamzany Y, Hadar T, Bahar G, et al. Squamous cell carcinoma of the oral tongue in patients younger than 30 years: clinicopathologic features and outcome. Clin Otolaryngol. 2010 Aug;35(4):307-12. https://doi.org/10.1111/j.1749-4486.2010.02164.x
» https://doi.org/10.1111/j.1749-4486.2010.02164.x -
28 Fang QG, Shi S, Liu FY, Sun CF. Tongue squamous cell carcinoma as a possible distinct entity in patients under 40 years old. Oncol Lett. 2014 Jun;7(6):2099-102. https://doi.org/10.3892/ol.2014.2054
» https://doi.org/10.3892/ol.2014.2054 -
29 Frare JC, Sawazaki-Calone I, Ayroza-Rangel AL, Bueno AG, de Morais CF, Nagai HM, et al. Histopathological grading systems analysis of oral squamous cell carcinomas of young patients. Med Oral Patol Oral Cir Bucal. 2016 May;21(3):e285-98. https://doi.org/10.4317/medoral.20953
» https://doi.org/10.4317/medoral.20953 -
30 Udeabor SE, Rana M, Wegener G, Gellrich NC, Eckardt AM. Squamous cell carcinoma of the oral cavity and the oropharynx in patients less than 40 years of age: a 20-year analysis. Head Neck Oncol. 2012 May;4(1):28. https://doi.org/10.1186/1758-3284-4-28
» https://doi.org/10.1186/1758-3284-4-28 -
31 Llewellyn CD, Linklater K, Bell J, Johnson NW, Warnakulasuriya S. An analysis of risk factors for oral cancer in young people: a case-control study. Oral Oncol. 2004 Mar;40(3):304-13. https://doi.org/10.1016/j.oraloncology.2003.08.015
» https://doi.org/10.1016/j.oraloncology.2003.08.015 -
32 Kaminagakura E, Vartanian JG, da Silva SD, dos Santos CR, Kowalski LP. Case-control study on prognostic factors in oral squamous cell carcinoma in young patients. Head Neck. 2010 Nov;32(11):1460-6. https://doi.org/10.1002/hed.21347
» https://doi.org/10.1002/hed.21347 -
33 Ribeiro AC, Silva AR, Simonato LE, Salzedas LM, Sundefeld ML, Soubhia AM. Clinical and histopathological analysis of oral squamous cell carcinoma in young people: a descriptive study in Brazilians. Br J Oral Maxillofac Surg. 2009 Mar;47(2):95-8. https://doi.org/10.1016/j.bjoms.2008.05.004
» https://doi.org/10.1016/j.bjoms.2008.05.004 -
34 Iamaroon A, Pattanaporn K, Pongsiriwet S, Wanachantararak S, Prapayasatok S, Jittidecharaks S, et al. Analysis of 587 cases of oral squamous cell carcinoma in northern Thailand with a focus on young people. Int J Oral Maxillofac Surg. 2004 Jan;33(1):84-8. https://doi.org/10.1054/ijom.2003.0503
» https://doi.org/10.1054/ijom.2003.0503 -
35 Pfeiffer J, Wiech T, Maier W, Ridder GJ, Laszig R, Birkenhäger R. Head and neck cancer in young adults and nonsmokers: study of cancer susceptibility by genome-wide high-density SNP microarray mapping. Acta Otolaryngol. 2011 Oct;131(10):1091-8. https://doi.org/10.3109/00016489.2011.590151
» https://doi.org/10.3109/00016489.2011.590151 -
36 Montero PH, Patel SG. Cancer of the oral cavity. Surg Oncol Clin N Am. 2015 Jul;24(3):491-508. https://doi.org/10.1016/j.soc.2015.03.006
» https://doi.org/10.1016/j.soc.2015.03.006 -
37 Benevenuto TG, Nonaka CF, Pinto LP, de Souza LB. Immunohistochemical comparative analysis of cell proliferation and angiogenic index in squamous cell carcinomas of the tongue between young and older patients. Appl Immunohistochem Mol Morphol. 2012 May;20(3):291-7. https://doi.org/10.1097/PAI.0b013e31823277f6
» https://doi.org/10.1097/PAI.0b013e31823277f6 -
38 Monsjou HS, Lopez-Yurda MI, Hauptmann M, Brekel MW, Balm AJ, Wreesmann VB. Oral and oropharyngeal squamous cell carcinoma in young patients: the Netherlands Cancer Institute experience. Head Neck. 2013 Jan;35(1):94-102. https://doi.org/10.1002/hed.22935
» https://doi.org/10.1002/hed.22935
