An analysis of the impact of risk factors on the occurrence, progression, and treatment outcomes of oral squamous cell carcinoma using data from the Oral Cancer Registry in Japan

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However, insufficient data was provided on whether these risk factors also influence the progression of the disease and its prognosis. The aim of this study is to investigate the role of risk factors, including smoking, alcohol, green/yellow vegetables, and chronic dental trauma, on the occurrence, progression, and treatment outcomes of oral squamous cell carcinoma (OSCC). Methods Data from 2,601 patients registered in the Japanese Oral Cancer Registry in 2018 who underwent a five-year follow-up survey were analyzed. The results of another health survey were used as a control to compare the effects of the risk factors on cancer development. Results The smoking rate among OSCC patients was significantly higher than that in the control group, except for elderly females. The prevalence of heavy alcohol consumption among OSCC patients was also significantly higher than that in the controls. OSCC patients consumed vegetables more frequently than the control group. Chronic dental trauma was potentially involved in the development of OSCC in 34.5% of patients. Significant correlations were found between the clinical stage of the tumor and both smoking volume and vegetable intake. The higher the smoking volume and the lower the vegetable intake, the more advanced the cancer. Furthermore, the incidence of double cancers was positively correlated with the volume of smoking. Smoking was the only factor that significantly affected the treatment outcomes. Conclusions These findings indicate that cigarette smoking can significantly influence the occurrence and progression of OSCC. Heavy alcohol consumption may also affect oral carcinogenesis. The effect of green and yellow vegetable intake on OSCC remains unclear. Smoking affects not only the development and progression of OSCC, but also its treatment outcomes. Oral cancer Risk factor Alcohol Smoking Vegetable Dental trauma Epidemiology Figures Figure 1 Background In Japan, oral cancer accounts for approximately 1% of all cancers, which is not particularly high compared to other countries. However, the incidence and mortality rates of this disease have been increasing annually. The Japanese Society of Oral and Maxillofacial Surgeons and the Japanese Society of Oral Oncology launched an Oral Cancer Registry in 2018 to establish a comprehensive dataset on the incidence, treatment strategies, and survival rates of oral cancer patients in Japan. By facilitating international comparison, this initiative aimed to promote research on oral cancer and support the advancement of clinical care for oral cancer patients in Japan. Initially, around 180 facilities took part in the program, registering approximately 2,800 cases. The number of participating facilities has now increased to about 600, with > 6,000 cases registered annually. One objective of the registry is to investigate the role of potential carcinogenic risk factors, including smoking, alcohol, green and yellow vegetables, and chronic dental trauma. Now that the five-year follow-up of the initial registry cases is complete, we analyzed the impact of the risk factors on the occurrence, progression, and treatment outcomes of oral squamous cell carcinoma (OSCC) using the registry data. Methods Data source The Oral Cancer Registry is a nationwide organ-specific cancer registry for oral cancers diagnosed and/or treated at facilities certified by the Japanese Society of Oral and Maxillofacial Surgeons and/or the Japanese Society of Oral Oncology. The registry was launched in 2018 and is organized and funded by the two societies. Certified facilities were allowed to register voluntarily when the program began in 2018, but from 2024 onward, registration became mandatory for all certified facilities. Detailed patient data are collected annually in a clinician-oriented manner for patients with primary oral malignant tumors and metastatic tumors treated at the participating hospitals. The survey collects data in two waves. The first survey collects data in February for patients treated from January 1 to December 31 of the previous year and includes the following data for each patient: basic information (gender, age, date of initial visit, presence of concurrent cancers), risk factors (smoking, alcohol consumption, intake of green and yellow vegetables, presence of absence of chronic dental trauma), tumor information (route of presentation, primary site, histological diagnosis, TNM classification [1]), and information about the treatment. In addition, data on smoking history (current and past), the number of cigarettes smoked per day, and duration of smoking are collected. The smoking index (number of cigarette packs × number of years) [2] is calculated to measure the smoking quantity. Regarding alcohol consumption, participants are asked about their drinking history, frequency of drinking, type of alcohol consumed, and daily alcohol intake. The daily alcohol intake (SAKE index; amount converted to ethanol in mL/day) [3] is calculated as a measure of alcohol consumption. The clinical follow-up data is manually entered after registration. The second survey is conducted five years after the registration and includes information on several outcomes (date of last visit, local recurrence, distant metastasis, oncological outcome, metachronous cancer, and survival). The study was approved by the ethics committees of the representative research institution, Shinshu University Medical Ethics Committee (approval number, #5662). We have read the Helsinki Declaration and have followed the guidelines in this investigation. Data extraction and analyses OSCC cases from the Oral Cancer Registry data for 2018 were extracted and analyzed in this study. The following data were extracted for each patient: gender, age, smoking habits, alcohol consumption, intake of green and yellow vegetables, chronic dental trauma, primary site of tumor, TNM stage, treatment strategy, presence of synchronous or metachronous multiple and/or double cancers, and overall survival (OS). Cases with missing values were not discarded; instead, they were treated as such. The primary objective of this study was to examine the risk factors associated with OSCC and investigate their relationship with the clinical characteristics of the cancer. As a secondary analysis, we estimated the impact of risk factors on OS. The results of the National Health and Nutrition Examination Survey (NHNES) [4] and those of a previous study [5] were used as controls to compare the risk prevalence rates. Statistical analysis Although a 5-year follow-up period was investigated, the Kaplan–Meier method was utilized for survival rate calculations due to incomplete follow-up in some cases. The Wilcoxon test was employed for analyses examining the correlation between a numerical and a categorical variable. Pearson’s Chi-square test was employed for correlations between two categorical variables. Spearman’s correlation coefficient was used to determine the correlation. The proportional hazard model was used to analyze the impact of each risk factor on OS. The model included explanatory factors such as patient age, gender, primary site, clinical stage, treatment modality (surgery, radiation, chemotherapy, immune checkpoint inhibitors, best supportive care, either alone or in combination), and risk factors. Statistical analyses were performed using JMP version 13 (SAS Institute Inc., North Carolina). A P-value of < 0.05 was considered significant. Results 2018 Oral Cancer Registry Results Summary In the first year of the Oral Cancer Registry, 2,785 patients from 181 facilities were registered, of whom 2,601 had OSCC and were included in the analysis. The data is outlined in Table 1. A follow-up survey of treatment outcomes was conducted five years after the initial treatment for all cases. Excluding 17 cases with unsuccessful follow-up, the results were as follows: 1,824 cases of cancer-free survival, 151 cases of survival with cancer, 392 cases of death from the disease, and 217 cases of death from other causes. The five-year cumulative OS rate was 75.6% (carcinoma in situ [CIS], 91.6%; Stage I, 86.4%; Stage II, 81.7%; Stage III, 71.4%; Stage IVa, 59.8%; Stage IVb, 36.4%; and Stage IVc, 26.7%). Table 1 also shows the prevalence of the risk factors for OSCC. The prevalence rate for current/previous smokers was 49.4%. When examining the smoking index (cigarette pack-years), the percentage of individuals with a score of 50 or more, classified as high risk [3], was 10.6%. The prevalence rate of alcohol drinkers was 53.0%, while that of heavy drinkers (those consuming 60 mL or more of ethanol per day), which is considered high risk [3], was 27.5%. Regarding the intake of green and yellow vegetables, 45.3% of respondents consumed them daily, while 32.9% consumed them occasionally. A suspected relationship between cancer and local irritation was reported in 34.5% of cases. The influence of risk factors on the incidence of oral cancer We compared the smoking status of registered patients with the results of the 2018 NHNES to investigate the impact of smoking on the onset of OSCC [4]. Both surveys were conducted using questionnaires. Overall, the smoking rate was found to be 49.5% among OSCC patients, compared to 24.5% in the NHNES, indicating a statistically significant difference between the two groups (odds ratio [OR], 3.10; 95% confidence interval [CI], 2.81–3.41; p < 0.01). When analyzed by gender, the smoking rates were high among male OSCC patients in almost all age groups. Alternatively, among females, the smoking rates in OSCC patients were higher in the younger age group (< 50 years) and lower in the ≥ 50 age group (Table 2). The SAKE index was used to examine the effects of alcohol on carcinogenesis by comparing the results of the Oral Cancer Registry with those of the 2018 NHNES [4]. In the NHNES, 40 mL ethanol/day or more for males and 20 mL/day or more for females was analyzed as a risk factor [4]; this criterion was used for the comparisons in the current study. The rate of heavy alcohol consumption among OSCC patients was significantly higher than that in the control group for both sexes (38.5% vs. 11.8%; OR, 4.67; 95% CI, 4.17–5.22; p 40 years) and women of all age groups compared to those in the controls (Table 3). To investigate the effect of green and yellow vegetable intake on the occurrence of OSCC, we compared the frequency of intake between patients in the Oral Cancer Registry and the general population studied in a previous study (Japan Public Health Center-based Prospective Study) [5]. The study investigated the consumption of green and yellow vegetables separately and presented the results using the person-year method based on ten years of observation (Table 4). OSCC patients had a significantly higher frequency of intake of green and yellow vegetables than the control group (Chi-square test; p < 0.01). The influence of risk factors on the clinical features of OSCC Table 5 shows the associations between each risk factor and the clinical stage of OSCC. The greater the smoking index, the more advanced the cases (Spearman rank correlation test; r = 0.06, p < 0.01). A higher frequency of green and yellow vegetable intake was associated with a higher incidence of early-stage cancers (Spearman rank correlation test; r = 0.08, p < 0.01), as well as a greater number of early-stage cases suspected of chronic dental trauma (Wilcoxon test; p < 0.01). No significant association was found between alcohol consumption (SAKE index) and clinical stage (Spearman rank correlation test; p = 0.42). The association between each risk factor and the prevalence of multiple oral cancers was also analyzed (Table 6). The term “multiple cancers” referred to the patient’s condition at the time of their first visit, and the evaluation included both synchronous and past histories of multiple oral cancers. The results showed that the prevalence of multiple oral cancers was significantly lower among patients who smoked (≥ 50 pack-years [4.7%] vs. those who never smoked [7.3%]; Wilcoxon test; p < 0.01) and consumed alcohol heavily (≥ 60 mL [4.0%] vs. nondrinkers [8.3%]; Wilcoxon test; p < 0.01). No significant association was found between the prevalence of oral multiple cancers and the frequency of green and yellow vegetable intake (Wilcoxon test; p = 0.94) or chronic dental trauma (Chi-square test; p = 0.44). The association between each risk factor and the incidence of double cancer was analyzed (Table 7). Double cancer was estimated at the time of their first visit and during the follow-up. A significant association was found between smoking and the incidence of double cancers, with a higher incidence among those who smoked more (≥ 50 pack-years [29.3%] vs. those who never smoked [16.3%]; Wilcoxon test; p < 0.01). No significant association was found between the incidence of double cancer and other factors, such as alcohol consumption, intake of green and yellow vegetables, and chronic dental trauma (Wilcoxon test, p = 0.53; Wilcoxon test, p = 0.38; Chi-square test, p = 0.09; respectively). Figure 1 shows the association between each risk factor and the primary site of OSCC. Patients who smoked heavily had a higher prevalence of cancer in the floor of the mouth, tongue, soft palate, and hard palate (Steel-Dwass test; p < 0.05), while those who consumed high levels of alcohol had a significantly higher prevalence in the floor of the mouth, tongue, and buccal mucosal (Steel-Dwass test; p < 0.05). Additionally, patients with low green and yellow vegetable intake had a higher prevalence of cancer in the floor of the mouth. A significant association was observed between chronic dental trauma and the site of cancer. Local irritation was strongly suspected to be involved in carcinogenesis in the tongue, lower lip, and buccal mucosa (Chi-square test; p < 0.01). Impact of each risk factor on OS A proportional hazards model was used to analyze the impact of each risk factor on OS (Table 8). Patient age, clinical stage, and treatment modality significantly influenced OS (p < 0.01). Of the risk factors examined, only smoking was significantly associated with a negative effect on OS (p < 0.05). Discussion The results of this survey are based on data collected from facilities certified by the Japanese Society of Oral and Maxillofacial Surgeons and the Japanese Society of Oral Oncology. According to population-based cancer registration data in Japan, approximately 9,200 cases of oral cancer were diagnosed in 2018 [4]. In 2018, 2,785 cases were registered in the Oral Cancer Registry, accounting for approximately 30% of all oral cancers in Japan. Of these cases, 93.4% (2,601) were OSCC and the five-year cumulative OS rate for OSCC was 75.6%, which is higher than those in other studies (57.5% disease specific survival rate among 2,725 patients in Ireland [6]), 58.6% OS among 2,848 patients in Korea [7], and 66.3% 3-year OS among 101 patients in Western Australia [8]. Several contributing factors have been identified in the development of OSCC. The Oral Cancer Registry conducts registration surveys on smoking, alcohol consumption, green and yellow vegetable intake, and chronic dental trauma. The examination of the impact of smoking on OSCC incidence revealed a significant difference in smoking rates between OSCC patients and healthy survey participants in the current study, identifying smoking as a significant risk factor for OSCC, consistent with previous reports [9–11]. The smoking rates were significantly higher among male OSCC patients across all age groups; however, different patterns were observed among females. Younger females had significantly higher smoking rates, while older OSCC patients exhibited lower smoking rates compared to their counterparts in the control group. A previous study suggested gender differences in the effects of smoking on carcinogenesis [12] and indicated that other carcinogenic factors may play a larger role in older female patients. In the present study, OSCC was more prevalent in the tongue, floor of the mouth, and hard and soft palate among smokers. These areas are frequently and directly exposed to cigarette smoke, which is believed to contribute to cancer development [13, 14]. Additionally, a significant association was observed between the smoking amount (number of pack-years of cigarette smoking) and the occurrence of double cancers. The higher the smoking amount, the higher the incidence of double cancers, which is consistent with the well-established finding that smoking is a risk factor for many types of cancer [15]. Furthermore, a significant correlation was observed between smoking amount and the stage of OSCC. Patients with higher smoking amounts had a higher incidence of advanced cancer. These results suggest that smoking promotes carcinogenesis and has a detrimental effect on cancer progression. A study evaluating the impact of risk factors on survival showed that smoking was the only factor with a significant effect on treatment outcomes. Thus, smoking influences not only carcinogenesis and progression but also the treatment outcomes. Heavy alcohol consumption is reported as a risk factor for OSCC [3, 9–11]. In the current study, the prevalence of heavy alcohol consumption among OSCC patients was significantly higher than that reported in the health surveys. This result was consistent across both sexes and all age groups, suggesting that heavy alcohol consumption increases the risk of developing OSCC. Despite the potential for confounding factors, such as smoking, an association between alcohol consumption and OSCC has been identified, even in nonsmokers [10]. When examining the relationship between alcohol consumption and the tumor sites, the results showed that heavy drinkers had a higher incidence of cancer in nonkeratinized mucous membranes, such as in the tongue, floor of the mouth, and cheek. Although the exact mechanism by which alcohol contributes to carcinogenesis is unclear, these results suggest that changes in mucosal epithelial permeability may play a role in this process. There are discrepancies regarding the relationship between beta-carotene in green and yellow vegetables and cancer [16–18]. In the present study, patients with OSCC consumed green and yellow vegetables more frequently than the healthy control group, suggesting that the consumption of these vegetables may negatively impact the development of OSCC. However, an examination of the association between the frequency of green and yellow vegetable consumption and the disease stage in OSCC patients revealed that those with advanced cancer consumed these vegetables less frequently. This indicates that green and yellow vegetables may have a beneficial effect on cancer progression. Nonetheless, no definitive conclusions regarding the effects of these vegetables on OSCC could be drawn in this study. A potential interaction between smoking and beta-carotene in green and yellow vegetables has been reported in lung cancer patients [19]. Several factors contribute to carcinogenesis and the progression of cancer. The results of this study are based on a cross-sectional analysis of one factor. Further studies are needed to comprehensively analyze the effects of other nutrients and carcinogenic factors. Chronic mucosal trauma (irritation) resulting from sharp dental edges, dentures, or faulty restoration has been frequently associated with the development of OSCC [20, 21]. A systematic review and meta-analysis showed a significant relationship between chronic oral mucosal irritation and OSCC, with an overall risk ratio of 2.56 (95% CI, 1.96–3.35) [22]. However, the effect of chronic dental stimulation on OSCC carcinogenesis could not be evaluated in this study due to the absence of a control group. In the current study, chronic dental trauma was potentially involved in the development of OSCC in 34.5% of patients, a rate comparable to those reported in previous meta-analysis [22]. Additionally, consistent with previous reports [20–22], many cases involved suspected local stimulation of the tongue, lower lip, and cheek. An analysis of the association between the presence of chronic dental trauma and the OSCC stage revealed that cases with suspected stimuli demonstrated a significantly higher incidence of early-stage cancer. Many of these cases exhibited symptoms such as local pain or difficulty in chewing due to chronic trauma. These symptoms were believed to have led to earlier medical consultations, and consequently, to earlier detection. Limitation This study has some limitations. This cross-sectional study did consider time when assessing the impact of the risk factors. Furthermore, the comparisons in this study may not be highly accurate because the control group was derived from other studies. The registration was not legally required, and research subjects were limited to cases that had been registered by facilities that participated in the Oral Cancer Registry. Therefore, not all cases of oral cancer may have been included in the registry. In the future, we plan to collect longitudinal data and conduct further studies with larger sample sizes. Conclusions The results of this study indicate that cigarette smoking can significantly influence the occurrence (excluding elderly females) and progression of OSCC, and the development of double cancer. Heavy alcohol consumption was found to potentially affect carcinogenesis in OSCC, especially in nonkeratinized mucosa. The effect of consuming green and yellow vegetables on OSCC remains unclear. Approximately one-third of cases showed a potential association between OSCC and chronic dental trauma. All these risk factors, except for cigarette smoking, did not affect the prognosis of OSCC in this study. However, additional studies are required to confirm these findings. Abbreviations OSCC oral squamous cell carcinoma OS overall survival NHNES The National Health and Nutrition Examination Survey OR odds ratio CI confidence interval Declarations Human ethics and consent to participate The study was approved by the ethics committees of the representative research institution, Shinshu University Medical Ethics Committee (approval number, #5662). We have read the Helsinki Declaration and have followed the guidelines in this investigation. Informed consent was obtained from all human participants. Participants were fully informed of the study's purpose, procedures, risks, and benefits, and were aware of their right to withdraw. Availability of data The data for study are available from the corresponding author on request. Competing interests None Clinical trial number Not applicable Funding This study was funded by the Japanese Society of Oral and Maxillofacial Surgeons and the Japanese Society of Oral Oncology. Authors' contributions Hiroshi Kurita: Writing–original draft, Investigation, Data curation. Seiji Nakamura: Writing–review & editing, Data curation, Project administration, Conceptualization. Kazuki Hasegawa: Writing–review & editing, Data curation, Project administration, Conceptualization. Souichi Yanamoto: Writing–review & editing, Data curation, Formal analysis. Hideki Nakayama: Writing–review & editing, Data curation, Formal analysis. Hiroyuki Harada: Writing–review & editing, Supervision, Funding acquisition. Michihiro Ueda: Writing–review & editing, Supervision, Funding acquisition. References Brierley JD, Gospodarowicz MK, Wittekind C. TNM Classification of Malignant Tumours, 8th Edition. Wiley-Blackwell, New Jersey, 2016. ISBN: 978-1-119-26357-9 Yokoyama A, Muramatsu T, Ohmori T, Makuuchi H, Higuchi S, Matsushita S, Yoshino K, Maruyama K, Nakano M, Ishii H. 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Gupta AA, Kheur S, Varadarajan S, Parveen S, Dewan H, Alhazmi YA, Raj TA, Testarelli L, Patil S. Chronic mechanical irritation and oral squamous cell carcinoma: a systematic review and meta-analysis. Bosn J Basic Med Sci 2021; 21: 647-658. doi: 10.17305/bjbms.2021.5577. Tables Tables 1 to 8 are available in the Supplementary Files section. Additional Declarations No competing interests reported. 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University","correspondingAuthor":false,"prefix":"","firstName":"Hideki","middleName":"","lastName":"Nakayama","suffix":""},{"id":520575369,"identity":"94ccfc90-66fb-4da0-b345-0efa6201062b","order_by":5,"name":"Michihiro Ueda","email":"","orcid":"","institution":"Hokkaido Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Michihiro","middleName":"","lastName":"Ueda","suffix":""},{"id":520575370,"identity":"93402825-d3fd-42ce-a07c-672ed73a9b9c","order_by":6,"name":"Hiroyuki Harada","email":"","orcid":"","institution":"Institute of Science Tokyo","correspondingAuthor":false,"prefix":"","firstName":"Hiroyuki","middleName":"","lastName":"Harada","suffix":""}],"badges":[],"createdAt":"2025-09-01 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01:09:11","extension":"xml","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":76171,"visible":true,"origin":"","legend":"","description":"","filename":"386ff64cde704109b6f9f28a86bf92af1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7508092/v1/c13888a1b0b8de5f090ab24a.xml"},{"id":92681312,"identity":"9f9eee69-e6f5-427d-aee5-625d22ff55a0","added_by":"auto","created_at":"2025-10-03 01:09:11","extension":"html","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":87514,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7508092/v1/a8aac2a842a8304699ced59f.html"},{"id":92681304,"identity":"2c8f3131-b196-47e7-859e-5dc4ddafc47e","added_by":"auto","created_at":"2025-10-03 01:09:11","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":260607,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAssociation between each risk factor and the primary site of oral squamous cell carcinoma.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA. Amount of cigarette smoking vs. the primary site. B. Amount of alcohol drinking vs. the primary site. C. Frequency of green/yellow vegetable intake vs. the primary site. D. Chronic dental trauma vs. the primary site.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7508092/v1/040b99e5b9e9775f6b0e0300.png"},{"id":92681315,"identity":"afc6a8d1-3fc2-4ebb-bee2-fb5edc76d814","added_by":"auto","created_at":"2025-10-03 01:09:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":831581,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7508092/v1/6bdb28a7-7b27-489e-8f7f-8e8a7b43ea13.pdf"},{"id":92681306,"identity":"881d0cb9-2b2d-47ba-bb0b-7bc0d22467ae","added_by":"auto","created_at":"2025-10-03 01:09:11","extension":"xlsx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":31974,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7508092/v1/75daaadf055803a7968be4d9.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eAn analysis of the impact of risk factors on the occurrence, progression, and treatment outcomes of oral squamous cell carcinoma using data from the Oral Cancer Registry in Japan\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eIn Japan, oral cancer accounts for approximately 1% of all cancers, which is not particularly high compared to other countries. However, the incidence and mortality rates of this disease have been increasing annually. The Japanese Society of Oral and Maxillofacial Surgeons and the Japanese Society of Oral Oncology launched an Oral Cancer Registry in 2018 to establish a comprehensive dataset on the incidence, treatment strategies, and survival rates of oral cancer patients in Japan. By facilitating international comparison, this initiative aimed to promote research on oral cancer and support the advancement of clinical care for oral cancer patients in Japan.\u003c/p\u003e\u003cp\u003eInitially, around 180 facilities took part in the program, registering approximately 2,800 cases. The number of participating facilities has now increased to about 600, with \u0026gt;\u0026thinsp;6,000 cases registered annually. One objective of the registry is to investigate the role of potential carcinogenic risk factors, including smoking, alcohol, green and yellow vegetables, and chronic dental trauma. Now that the five-year follow-up of the initial registry cases is complete, we analyzed the impact of the risk factors on the occurrence, progression, and treatment outcomes of oral squamous cell carcinoma (OSCC) using the registry data.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eData source\u003c/h2\u003e\u003cp\u003eThe Oral Cancer Registry is a nationwide organ-specific cancer registry for oral cancers diagnosed and/or treated at facilities certified by the Japanese Society of Oral and Maxillofacial Surgeons and/or the Japanese Society of Oral Oncology. The registry was launched in 2018 and is organized and funded by the two societies. Certified facilities were allowed to register voluntarily when the program began in 2018, but from 2024 onward, registration became mandatory for all certified facilities.\u003c/p\u003e\u003cp\u003eDetailed patient data are collected annually in a clinician-oriented manner for patients with primary oral malignant tumors and metastatic tumors treated at the participating hospitals. The survey collects data in two waves. The first survey collects data in February for patients treated from January 1 to December 31 of the previous year and includes the following data for each patient: basic information (gender, age, date of initial visit, presence of concurrent cancers), risk factors (smoking, alcohol consumption, intake of green and yellow vegetables, presence of absence of chronic dental trauma), tumor information (route of presentation, primary site, histological diagnosis, TNM classification [1]), and information about the treatment. In addition, data on smoking history (current and past), the number of cigarettes smoked per day, and duration of smoking are collected. The smoking index (number of cigarette packs \u0026times; number of years) [2] is calculated to measure the smoking quantity.\u003c/p\u003e\u003cp\u003eRegarding alcohol consumption, participants are asked about their drinking history, frequency of drinking, type of alcohol consumed, and daily alcohol intake. The daily alcohol intake (SAKE index; amount converted to ethanol in mL/day) [3] is calculated as a measure of alcohol consumption. The clinical follow-up data is manually entered after registration. The second survey is conducted five years after the registration and includes information on several outcomes (date of last visit, local recurrence, distant metastasis, oncological outcome, metachronous cancer, and survival).\u003c/p\u003e\u003cp\u003e The study was approved by the ethics committees of the representative research institution, Shinshu University Medical Ethics Committee (approval number, #5662). We have read the Helsinki Declaration and have followed the guidelines in this investigation.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eData extraction and analyses\u003c/h3\u003e\n\u003cp\u003eOSCC cases from the Oral Cancer Registry data for 2018 were extracted and analyzed in this study. The following data were extracted for each patient: gender, age, smoking habits, alcohol consumption, intake of green and yellow vegetables, chronic dental trauma, primary site of tumor, TNM stage, treatment strategy, presence of synchronous or metachronous multiple and/or double cancers, and overall survival (OS). Cases with missing values were not discarded; instead, they were treated as such.\u003c/p\u003e\u003cp\u003eThe primary objective of this study was to examine the risk factors associated with OSCC and investigate their relationship with the clinical characteristics of the cancer. As a secondary analysis, we estimated the impact of risk factors on OS. The results of the National Health and Nutrition Examination Survey (NHNES) [4] and those of a previous study [5] were used as controls to compare the risk prevalence rates.\u003c/p\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eAlthough a 5-year follow-up period was investigated, the Kaplan\u0026ndash;Meier method was utilized for survival rate calculations due to incomplete follow-up in some cases. The Wilcoxon test was employed for analyses examining the correlation between a numerical and a categorical variable. Pearson\u0026rsquo;s Chi-square test was employed for correlations between two categorical variables. Spearman\u0026rsquo;s correlation coefficient was used to determine the correlation. The proportional hazard model was used to analyze the impact of each risk factor on OS. The model included explanatory factors such as patient age, gender, primary site, clinical stage, treatment modality (surgery, radiation, chemotherapy, immune checkpoint inhibitors, best supportive care, either alone or in combination), and risk factors. Statistical analyses were performed using JMP version 13 (SAS Institute Inc., North Carolina). A P-value of \u0026lt;\u0026thinsp;0.05 was considered significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cem\u003e2018 Oral Cancer Registry Results Summary\u003c/em\u003e\u003c/p\u003e\u003cp\u003e In the first year of the Oral Cancer Registry, 2,785 patients from 181 facilities were registered, of whom 2,601 had OSCC and were included in the analysis. The data is outlined in Table\u0026nbsp;1. A follow-up survey of treatment outcomes was conducted five years after the initial treatment for all cases. Excluding 17 cases with unsuccessful follow-up, the results were as follows: 1,824 cases of cancer-free survival, 151 cases of survival with cancer, 392 cases of death from the disease, and 217 cases of death from other causes. The five-year cumulative OS rate was 75.6% (carcinoma in situ [CIS], 91.6%; Stage I, 86.4%; Stage II, 81.7%; Stage III, 71.4%; Stage IVa, 59.8%; Stage IVb, 36.4%; and Stage IVc, 26.7%).\u003c/p\u003e\u003cp\u003eTable\u0026nbsp;1 also shows the prevalence of the risk factors for OSCC. The prevalence rate for current/previous smokers was 49.4%. When examining the smoking index (cigarette pack-years), the percentage of individuals with a score of 50 or more, classified as high risk [3], was 10.6%. The prevalence rate of alcohol drinkers was 53.0%, while that of heavy drinkers (those consuming 60 mL or more of ethanol per day), which is considered high risk [3], was 27.5%. Regarding the intake of green and yellow vegetables, 45.3% of respondents consumed them daily, while 32.9% consumed them occasionally. A suspected relationship between cancer and local irritation was reported in 34.5% of cases.\u003c/p\u003e\n\u003ch3\u003eThe influence of risk factors on the incidence of oral cancer\u003c/h3\u003e\n\u003cp\u003eWe compared the smoking status of registered patients with the results of the 2018 NHNES to investigate the impact of smoking on the onset of OSCC [4]. Both surveys were conducted using questionnaires. Overall, the smoking rate was found to be 49.5% among OSCC patients, compared to 24.5% in the NHNES, indicating a statistically significant difference between the two groups (odds ratio [OR], 3.10; 95% confidence interval [CI], 2.81\u0026ndash;3.41; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). When analyzed by gender, the smoking rates were high among male OSCC patients in almost all age groups. Alternatively, among females, the smoking rates in OSCC patients were higher in the younger age group (\u0026lt;\u0026thinsp;50 years) and lower in the \u0026ge;\u0026thinsp;50 age group (Table\u0026nbsp;2).\u003c/p\u003e\u003cp\u003eThe SAKE index was used to examine the effects of alcohol on carcinogenesis by comparing the results of the Oral Cancer Registry with those of the 2018 NHNES [4]. In the NHNES, 40 mL ethanol/day or more for males and 20 mL/day or more for females was analyzed as a risk factor [4]; this criterion was used for the comparisons in the current study. The rate of heavy alcohol consumption among OSCC patients was significantly higher than that in the control group for both sexes (38.5% vs. 11.8%; OR, 4.67; 95% CI, 4.17\u0026ndash;5.22; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). When analyzed by age group, the rate of heavy alcohol consumption in OSCC patients was higher among older men (\u0026gt;\u0026thinsp;40 years) and women of all age groups compared to those in the controls (Table\u0026nbsp;3).\u003c/p\u003e\u003cp\u003eTo investigate the effect of green and yellow vegetable intake on the occurrence of OSCC, we compared the frequency of intake between patients in the Oral Cancer Registry and the general population studied in a previous study (Japan Public Health Center-based Prospective Study) [5]. The study investigated the consumption of green and yellow vegetables separately and presented the results using the person-year method based on ten years of observation (Table\u0026nbsp;4). OSCC patients had a significantly higher frequency of intake of green and yellow vegetables than the control group (Chi-square test; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eThe influence of risk factors on the clinical features of OSCC\u003c/h2\u003e\u003cp\u003eTable\u0026nbsp;5 shows the associations between each risk factor and the clinical stage of OSCC. The greater the smoking index, the more advanced the cases (Spearman rank correlation test; r\u0026thinsp;=\u0026thinsp;0.06, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). A higher frequency of green and yellow vegetable intake was associated with a higher incidence of early-stage cancers (Spearman rank correlation test; r\u0026thinsp;=\u0026thinsp;0.08, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), as well as a greater number of early-stage cases suspected of chronic dental trauma (Wilcoxon test; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). No significant association was found between alcohol consumption (SAKE index) and clinical stage (Spearman rank correlation test; p\u0026thinsp;=\u0026thinsp;0.42).\u003c/p\u003e\u003cp\u003eThe association between each risk factor and the prevalence of multiple oral cancers was also analyzed (Table\u0026nbsp;6). The term \u0026ldquo;multiple cancers\u0026rdquo; referred to the patient\u0026rsquo;s condition at the time of their first visit, and the evaluation included both synchronous and past histories of multiple oral cancers. The results showed that the prevalence of multiple oral cancers was significantly lower among patients who smoked (\u0026ge;\u0026thinsp;50 pack-years [4.7%] vs. those who never smoked [7.3%]; Wilcoxon test; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and consumed alcohol heavily (\u0026ge;\u0026thinsp;60 mL [4.0%] vs. nondrinkers [8.3%]; Wilcoxon test; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). No significant association was found between the prevalence of oral multiple cancers and the frequency of green and yellow vegetable intake (Wilcoxon test; p\u0026thinsp;=\u0026thinsp;0.94) or chronic dental trauma (Chi-square test; p\u0026thinsp;=\u0026thinsp;0.44).\u003c/p\u003e\u003cp\u003eThe association between each risk factor and the incidence of double cancer was analyzed (Table\u0026nbsp;7). Double cancer was estimated at the time of their first visit and during the follow-up. A significant association was found between smoking and the incidence of double cancers, with a higher incidence among those who smoked more (\u0026ge;\u0026thinsp;50 pack-years [29.3%] vs. those who never smoked [16.3%]; Wilcoxon test; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). No significant association was found between the incidence of double cancer and other factors, such as alcohol consumption, intake of green and yellow vegetables, and chronic dental trauma (Wilcoxon test, p\u0026thinsp;=\u0026thinsp;0.53; Wilcoxon test, p\u0026thinsp;=\u0026thinsp;0.38; Chi-square test, p\u0026thinsp;=\u0026thinsp;0.09; respectively).\u003c/p\u003e\u003cp\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the association between each risk factor and the primary site of OSCC. Patients who smoked heavily had a higher prevalence of cancer in the floor of the mouth, tongue, soft palate, and hard palate (Steel-Dwass test; p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), while those who consumed high levels of alcohol had a significantly higher prevalence in the floor of the mouth, tongue, and buccal mucosal (Steel-Dwass test; p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Additionally, patients with low green and yellow vegetable intake had a higher prevalence of cancer in the floor of the mouth. A significant association was observed between chronic dental trauma and the site of cancer. Local irritation was strongly suspected to be involved in carcinogenesis in the tongue, lower lip, and buccal mucosa (Chi-square test; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eImpact of each risk factor on OS\u003c/h3\u003e\n\u003cp\u003eA proportional hazards model was used to analyze the impact of each risk factor on OS (Table\u0026nbsp;8). Patient age, clinical stage, and treatment modality significantly influenced OS (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Of the risk factors examined, only smoking was significantly associated with a negative effect on OS (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe results of this survey are based on data collected from facilities certified by the Japanese Society of Oral and Maxillofacial Surgeons and the Japanese Society of Oral Oncology. According to population-based cancer registration data in Japan, approximately 9,200 cases of oral cancer were diagnosed in 2018 [4]. In 2018, 2,785 cases were registered in the Oral Cancer Registry, accounting for approximately 30% of all oral cancers in Japan. Of these cases, 93.4% (2,601) were OSCC and the five-year cumulative OS rate for OSCC was 75.6%, which is higher than those in other studies (57.5% disease specific survival rate among 2,725 patients in Ireland [6]), 58.6% OS among 2,848 patients in Korea [7], and 66.3% 3-year OS among 101 patients in Western Australia [8].\u003c/p\u003e\u003cp\u003eSeveral contributing factors have been identified in the development of OSCC. The Oral Cancer Registry conducts registration surveys on smoking, alcohol consumption, green and yellow vegetable intake, and chronic dental trauma. The examination of the impact of smoking on OSCC incidence revealed a significant difference in smoking rates between OSCC patients and healthy survey participants in the current study, identifying smoking as a significant risk factor for OSCC, consistent with previous reports [9\u0026ndash;11]. The smoking rates were significantly higher among male OSCC patients across all age groups; however, different patterns were observed among females. Younger females had significantly higher smoking rates, while older OSCC patients exhibited lower smoking rates compared to their counterparts in the control group. A previous study suggested gender differences in the effects of smoking on carcinogenesis [12] and indicated that other carcinogenic factors may play a larger role in older female patients.\u003c/p\u003e\u003cp\u003eIn the present study, OSCC was more prevalent in the tongue, floor of the mouth, and hard and soft palate among smokers. These areas are frequently and directly exposed to cigarette smoke, which is believed to contribute to cancer development [13, 14]. Additionally, a significant association was observed between the smoking amount (number of pack-years of cigarette smoking) and the occurrence of double cancers. The higher the smoking amount, the higher the incidence of double cancers, which is consistent with the well-established finding that smoking is a risk factor for many types of cancer [15]. Furthermore, a significant correlation was observed between smoking amount and the stage of OSCC. Patients with higher smoking amounts had a higher incidence of advanced cancer. These results suggest that smoking promotes carcinogenesis and has a detrimental effect on cancer progression. A study evaluating the impact of risk factors on survival showed that smoking was the only factor with a significant effect on treatment outcomes. Thus, smoking influences not only carcinogenesis and progression but also the treatment outcomes.\u003c/p\u003e\u003cp\u003eHeavy alcohol consumption is reported as a risk factor for OSCC [3, 9\u0026ndash;11]. In the current study, the prevalence of heavy alcohol consumption among OSCC patients was significantly higher than that reported in the health surveys. This result was consistent across both sexes and all age groups, suggesting that heavy alcohol consumption increases the risk of developing OSCC. Despite the potential for confounding factors, such as smoking, an association between alcohol consumption and OSCC has been identified, even in nonsmokers [10]. When examining the relationship between alcohol consumption and the tumor sites, the results showed that heavy drinkers had a higher incidence of cancer in nonkeratinized mucous membranes, such as in the tongue, floor of the mouth, and cheek. Although the exact mechanism by which alcohol contributes to carcinogenesis is unclear, these results suggest that changes in mucosal epithelial permeability may play a role in this process.\u003c/p\u003e\u003cp\u003eThere are discrepancies regarding the relationship between beta-carotene in green and yellow vegetables and cancer [16\u0026ndash;18]. In the present study, patients with OSCC consumed green and yellow vegetables more frequently than the healthy control group, suggesting that the consumption of these vegetables may negatively impact the development of OSCC. However, an examination of the association between the frequency of green and yellow vegetable consumption and the disease stage in OSCC patients revealed that those with advanced cancer consumed these vegetables less frequently. This indicates that green and yellow vegetables may have a beneficial effect on cancer progression. Nonetheless, no definitive conclusions regarding the effects of these vegetables on OSCC could be drawn in this study. A potential interaction between smoking and beta-carotene in green and yellow vegetables has been reported in lung cancer patients [19]. Several factors contribute to carcinogenesis and the progression of cancer. The results of this study are based on a cross-sectional analysis of one factor. Further studies are needed to comprehensively analyze the effects of other nutrients and carcinogenic factors.\u003c/p\u003e\u003cp\u003eChronic mucosal trauma (irritation) resulting from sharp dental edges, dentures, or faulty restoration has been frequently associated with the development of OSCC [20, 21]. A systematic review and meta-analysis showed a significant relationship between chronic oral mucosal irritation and OSCC, with an overall risk ratio of 2.56 (95% CI, 1.96\u0026ndash;3.35) [22]. However, the effect of chronic dental stimulation on OSCC carcinogenesis could not be evaluated in this study due to the absence of a control group. In the current study, chronic dental trauma was potentially involved in the development of OSCC in 34.5% of patients, a rate comparable to those reported in previous meta-analysis [22]. Additionally, consistent with previous reports [20\u0026ndash;22], many cases involved suspected local stimulation of the tongue, lower lip, and cheek. An analysis of the association between the presence of chronic dental trauma and the OSCC stage revealed that cases with suspected stimuli demonstrated a significantly higher incidence of early-stage cancer. Many of these cases exhibited symptoms such as local pain or difficulty in chewing due to chronic trauma. These symptoms were believed to have led to earlier medical consultations, and consequently, to earlier detection.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eLimitation\u003c/h2\u003e\u003cp\u003eThis study has some limitations. This cross-sectional study did consider time when assessing the impact of the risk factors. Furthermore, the comparisons in this study may not be highly accurate because the control group was derived from other studies. The registration was not legally required, and research subjects were limited to cases that had been registered by facilities that participated in the Oral Cancer Registry. Therefore, not all cases of oral cancer may have been included in the registry. In the future, we plan to collect longitudinal data and conduct further studies with larger sample sizes.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe results of this study indicate that cigarette smoking can significantly influence the occurrence (excluding elderly females) and progression of OSCC, and the development of double cancer. Heavy alcohol consumption was found to potentially affect carcinogenesis in OSCC, especially in nonkeratinized mucosa. The effect of consuming green and yellow vegetables on OSCC remains unclear. Approximately one-third of cases showed a potential association between OSCC and chronic dental trauma. All these risk factors, except for cigarette smoking, did not affect the prognosis of OSCC in this study. However, additional studies are required to confirm these findings.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eOSCC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eoral squamous cell carcinoma\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eOS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eoverall survival\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNHNES\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eThe National Health and Nutrition Examination Survey\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eOR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eodds ratio\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003econfidence interval\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eHuman ethics and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the ethics committees of the representative research institution, Shinshu University Medical Ethics Committee (approval number, #5662). We have read the Helsinki Declaration and have followed the guidelines in this investigation. Informed consent was obtained from all human participants. Participants were fully informed of the study\u0026apos;s purpose, procedures, risks, and benefits, and were aware of their right to withdraw.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data for study are available from the corresponding author on request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by the Japanese Society of Oral and Maxillofacial Surgeons and the Japanese Society of Oral Oncology.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHiroshi Kurita: Writing\u0026ndash;original draft, Investigation, Data curation. Seiji Nakamura: Writing\u0026ndash;review \u0026amp; editing, Data curation, Project administration, Conceptualization. Kazuki Hasegawa: Writing\u0026ndash;review \u0026amp; editing, Data curation, Project administration, Conceptualization. Souichi Yanamoto: Writing\u0026ndash;review \u0026amp; editing, Data curation, Formal analysis. Hideki Nakayama: Writing\u0026ndash;review \u0026amp; editing, Data curation, Formal analysis. Hiroyuki Harada: Writing\u0026ndash;review \u0026amp; editing, Supervision, Funding acquisition. Michihiro Ueda: Writing\u0026ndash;review \u0026amp; editing, Supervision, Funding acquisition.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBrierley JD, Gospodarowicz MK, Wittekind C. TNM Classification of Malignant Tumours, 8th Edition. Wiley-Blackwell, New Jersey, 2016. ISBN: 978-1-119-26357-9\u003c/li\u003e\n\u003cli\u003eYokoyama A, Muramatsu T, Ohmori T, Makuuchi H, Higuchi S, Matsushita S, Yoshino K, Maruyama K, Nakano M, Ishii H. Multiple primary esophageal and concurrent upper aerodigestive tract cancer and the aldehyde dehydrogenase-2 genotype of Japanese alcoholics. Cancer 1996; 77: 1986-1990. doi: 10.1002/(sici)1097-0142(19960515)77:10\u0026lt;1986::aid-cncr4\u0026gt;3.0.co;2-f.\u003c/li\u003e\n\u003cli\u003eNomura T, Shibata T, Noma H, Yamane G, Yokoyama A, Muramatsu T, Ohmori T. A study of smoking and drinking habits as carcionogens in the development of oral cancer. Head Neck Cancers 1998; 24; 83-89. [Japanese literature with English abstract]\u003c/li\u003e\n\u003cli\u003eCancer Statistics. Oral cavity and pharynx. https://ganjoho.jp/reg_stat/statistics/stat/cancer/3_oral.html, (accessed 20 June 2025)\u003c/li\u003e\n\u003cli\u003eKobayashi M, Tsubono Y, Sasazuki S, Sasaki S, Tsugane S; JPHC Study Group. Vegetables, fruit and risk of gastric cancer in Japan: a 10-year follow-up of the JPHC study cohort I. Int J Cancer 2002; 102: 39-44. doi: 10.1002/ijc.10659.\u003c/li\u003e\n\u003cli\u003eSexton GP, Hintze JM, Walsh P, Moriarty F, Lennon P, Fitzgerald CWR, O\u0026apos;Neill JP. Epidemiology and management of oral cavity squamous cell carcinoma in Ireland. Am J Otolaryngol 2024; 45: 104235. doi: 10.1016/j.amjoto.2024.104235. \u003c/li\u003e\n\u003cli\u003eSun JR, Kim SM, Seo MH, Kim MJ, Lee JH, Myoung H. Oral cancer incidence based on annual cancer statistics in Korea. J Korean Assoc Oral Maxillofac Surg 2012; 38: 20-28.\u003c/li\u003e\n\u003cli\u003eHendriks T, Cardemil F, Sader C. Oral cavity cancer treatment outcomes in Western Australia. Australian J Otolaryngol 2019; 2: 20. DOI:10.21037/ajo.2019.06.01\u003c/li\u003e\n\u003cli\u003eMaier H, Dietz A, Gewelke U, Heller WD, Weidauer H. Tobacco and alcohol and the risk of head and neck cancer. Clin Investig 1992; 70: 320-327. doi: 10.1007/BF00184668. \u003c/li\u003e\n\u003cli\u003eHashibe M, Brennan P, Benhamou S, Castellsague X, Chen C, Curado MP, Dal Maso L, Daudt AW, Fabianova E, Fernandez L, W\u0026uuml;nsch-Filho V, Franceschi S, Hayes RB, Herrero R, Koifman S, La Vecchia C, Lazarus P, Levi F, Mates D, Matos E, Menezes A, Muscat J, Eluf-Neto J, Olshan AF, Rudnai P, Schwartz SM, Smith E, Sturgis EM, Szeszenia-Dabrowska N, Talamini R, Wei Q, Winn DM, Zaridze D, Zatonski W, Zhang ZF, Berthiller J, Boffetta P. Alcohol drinking in never users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. J Natl Cancer Inst 2007; 99: 777-789. doi: 10.1093/jnci/djk179.\u003c/li\u003e\n\u003cli\u003eYuan Y, Huang JW, Cao JL, Wu JH, Wang LL, Gan H, Xu JH, Ye F. Tobacco and alcohol use are the risk factors responsible for the greatest burden of head and neck cancers: a study from the Global Burden of Disease Study 2019. Ann Med 2025; 57: 2500693. doi: 10.1080/07853890.2025.2500693.\u003c/li\u003e\n\u003cli\u003eShin JW, Minh NT, Jee SH. Sex-specific associations of total bilirubin, ALBI, and PALBI with lung cancer risk: interactions with smoking and alcohol. Healthcare (Basel) 2025; 13: 1321. doi: 10.3390/healthcare13111321.\u003c/li\u003e\n\u003cli\u003eSasco AJ, Secretan MB, Straif K. Tobacco smoking and cancer: a brief review of recent epidemiological evidence. Lung Cancer 2004; 45 Suppl 2: S3-S9. \u003c/li\u003e\n\u003cli\u003eHecht SS, Hatsukami DK. Smokeless tobacco and cigarette smoking: chemical mechanisms and cancer prevention. Nat Rev 2022; 22: 143-155.\u003c/li\u003e\n\u003cli\u003eInoue M, Hanaoka T, Sasazuki S, Sobue T, Tsugane S; JPHC Study Group. Impact of tobacco smoking on subsequent cancer risk among middle-aged Japanese men and women: data from a large-scale population-based cohort study in Japan--the JPHC study. Prev Med 2004; 38: 516-522. doi: 10.1016/j.ypmed.2003.11.026. PMID: 15066353.\u003c/li\u003e\n\u003cli\u003eQin Y, Chen L, Zhao Z, Li Y, Tian X, Feng M, Tang J, Ji K. Dietary nutrient intake and cancer presence: evidence from a cross-sectional study. Front Nutr 2025; 12: 1551822. doi: 10.3389/fnut.2025.1551822. \u003c/li\u003e\n\u003cli\u003eZheng S, Yan J, Wang J, Wang X, Kang YE, Koo BS, Shan Y, Liu L. Unveiling the effects of cruciferous vegetable intake on different cancers: a systematic review and dose-response meta-analysis. Nutr Rev 2025; 83: 842-858. doi: 10.1093/nutrit/nuae131. \u003c/li\u003e\n\u003cli\u003eWei J, Xiao Y, Feng Q, Liu H, Zou K, Li L. The association between fruit and vegetable intake and gastrointestinal cancers risk from Mendelian randomization analysis. Sci Rep 2024; 14: 28860. doi: 10.1038/s41598-024-79650-2.\u003c/li\u003e\n\u003cli\u003eSun Y, Wu J, Yoon HS, Buchowski MS, Cai H, Deppen SA, Steinwandel MD, Zheng W, Shu XO, Blot WJ, Cai Q. Associations of dietary intakes of carotenoids and vitamin a with lung cancer risk in a low-income population in the southeastern United States. Cancers (Basel) 2022; 14: 5159. doi: 10.3390/cancers14205159.\u003c/li\u003e\n\u003cli\u003eSinghvi HR, Malik A, Chaturvedi P. The role of chronic mucosal trauma in oral cancer: a review of literature. Indian J Med Paediatr Oncol 2017; 38: 44-50. doi: 10.4103/0971-5851.203510..\u003c/li\u003e\n\u003cli\u003eChiesa-Estomba CM, Mayo-Yanez M, Vaira LA, Maniaci A, Feng AL, Landa-Garmendia M, Cardin-Pereda A, Lechien JR. Oral cavity cancer secondary to dental trauma: a scoping review. Biomedicines 2024; 12: 2024. doi: 10.3390/biomedicines12092024. \u003c/li\u003e\n\u003cli\u003eGupta AA, Kheur S, Varadarajan S, Parveen S, Dewan H, Alhazmi YA, Raj TA, Testarelli L, Patil S. Chronic mechanical irritation and oral squamous cell carcinoma: a systematic review and meta-analysis. Bosn J Basic Med Sci 2021; 21: 647-658. doi: 10.17305/bjbms.2021.5577. \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 8 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-oral-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ohea","sideBox":"Learn more about [BMC Oral Health](http://bmcoralhealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ohea/default.aspx","title":"BMC Oral Health","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Oral cancer, Risk factor, Alcohol, Smoking, Vegetable, Dental trauma, Epidemiology","lastPublishedDoi":"10.21203/rs.3.rs-7508092/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7508092/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eIt is well known that smoking, alcohol consumption, eating green and yellow vegetables, and local irritation are risk factors for oral cancer. However, insufficient data was provided on whether these risk factors also influence the progression of the disease and its prognosis. The aim of this study is to investigate the role of risk factors, including smoking, alcohol, green/yellow vegetables, and chronic dental trauma, on the occurrence, progression, and treatment outcomes of oral squamous cell carcinoma (OSCC).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eData from 2,601 patients registered in the Japanese Oral Cancer Registry in 2018 who underwent a five-year follow-up survey were analyzed. The results of another health survey were used as a control to compare the effects of the risk factors on cancer development.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eThe smoking rate among OSCC patients was significantly higher than that in the control group, except for elderly females. The prevalence of heavy alcohol consumption among OSCC patients was also significantly higher than that in the controls. OSCC patients consumed vegetables more frequently than the control group. Chronic dental trauma was potentially involved in the development of OSCC in 34.5% of patients. Significant correlations were found between the clinical stage of the tumor and both smoking volume and vegetable intake. The higher the smoking volume and the lower the vegetable intake, the more advanced the cancer. Furthermore, the incidence of double cancers was positively correlated with the volume of smoking. Smoking was the only factor that significantly affected the treatment outcomes.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eThese findings indicate that cigarette smoking can significantly influence the occurrence and progression of OSCC. Heavy alcohol consumption may also affect oral carcinogenesis. The effect of green and yellow vegetable intake on OSCC remains unclear. Smoking affects not only the development and progression of OSCC, but also its treatment outcomes.\u003c/p\u003e","manuscriptTitle":"An analysis of the impact of risk factors on the occurrence, progression, and treatment outcomes of oral squamous cell carcinoma using data from the Oral Cancer Registry in Japan","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-03 01:09:06","doi":"10.21203/rs.3.rs-7508092/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-03-25T16:07:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"58233656929591456653807792114545218905","date":"2026-03-25T14:33:13+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-05T15:03:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"16833217412342860975397441850671334967","date":"2025-09-25T12:38:34+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-21T09:21:51+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-09-16T08:46:50+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-12T01:54:20+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-12T01:54:08+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Oral Health","date":"2025-09-01T11:47:44+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-oral-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ohea","sideBox":"Learn more about [BMC Oral Health](http://bmcoralhealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ohea/default.aspx","title":"BMC Oral Health","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"91d6ce80-6bb6-4a95-af45-53e5eef2b3ba","owner":[],"postedDate":"October 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-10-03T01:09:06+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-03 01:09:06","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7508092","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7508092","identity":"rs-7508092","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}