Clinical Outcomes and Prognostic Factors in Multiple Primary Malignancies Involving Oral Cancer

Clinical Outcomes and Prognostic Factors in Multiple Primary Malignancies Involving Oral Cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical Outcomes and Prognostic Factors in Multiple Primary Malignancies Involving Oral Cancer Qiannan Liu, Shanshan Tang, Le Yang, Farong Ou, Kan Li, Huanzi Lu, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5780078/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Jul, 2025 Read the published version in BMC Oral Health → Version 1 posted 9 You are reading this latest preprint version Abstract Background : The incidence of multiple primary oral cancers (MPOCs) is rising, presenting significant diagnostic and treatment challenges and often resulting in poor prognosis. However, most research focuses on cases where all primary tumors originate within the oral cavity, with limited attention to scenarios where oral cancer arises as a second primary after initial tumors in other parts of the body. This study examines the clinical characteristics and prognosis in both scenarios. Methods : A retrospective review of 165 patients at the Affiliated Stomatological Hospital of Sun Yat-sen University identified 75 oral cancer first (OCF) cases and 90 non-oral cancer first (N-OCF) cases. We conducted a comparative analysis of clinical characteristics and prognosis between the two groups. Results : MPOCs were more common in males, with an average age of 59.4 years, primarily presenting as early-stage squamous cell carcinoma (SCC), with the tongue as the most frequent site for secondary primary cancer (SPC). In the OCF group, the most common site for the first primary cancers (FPC) was also the tongue, whereas in the N-OCF group, it was the nasopharynx. Survival rates were comparable between the two groups, with key prognostic factors including age(p=0.015), SPC T stage(p=0.003), cervical lymph node metastasis of SPC(p=0.021), and recurrence after SPC(p=0.020). Conclusions : Patients with a history of nasopharyngeal cancer require long-term oral follow-up. While the location of FPC and SPC does not impact prognosis, early diagnosis and treatment significantly improve outcomes by enabling timely intervention before tumors advance or metastasize. Effective management of OPMDs is crucial for improving outcomes in MPOCs patients. Multiple primary cancer Oral cancer Clinical features Prognosis Survival Figures Figure 1 Figure 2 Figure 3 Introduction Oral cancer, which is predominantly squamous cell carcinoma (SCC)[1], remains a major threat to global health. Malignant tumors occurring in the oral cavity are characterized not only by a high rate of local recurrence but also by a predisposition to developing multiple primary cancers (MPCs)[2]. With the increasing global incidence of oral cancer—particularly among individuals with risk factors such as tobacco use, alcohol consumption, and betel quid chewing—the incidence of multiple primary oral cancers (MPOCs) has also been rising[3], with reported rates ranging from 5% to 23.8%[4]. This trend poses significant diagnostic and therapeutic challenges. Compared to single primary oral cancer, which has a 10-year survival rate of 47.1%, MPOCs exhibit a more unfavorable long-term prognosis, with a 10-year survival rate of 42.2% [5]. This underscores the persistent challenges in the diagnosis and management of MPOCs[6]. However, to date, no comprehensive system has been established for the incidence, diagnosis, and treatment of MPOCs. Moreover, current studies mainly focus on patients whose first (also known as index tumor), second, and third primary cancers all occur within the oral cavity, with limited research on patients who develop oral cancer after tumors in other body parts (such as nasopharynx, lung, breast cancer, etc.). These patients may be more susceptible to developing oral cancer due to previous radiation therapy or chemotherapy, genetic mutations, or familial predisposition, and their clinical characteristics may also differ, resulting in different prognoses for the same treatment modality. Therefore, this study aims to analyze the clinical characteristics of patients with oral multiple primary cancers and compare their clinical characteristics and prognosis between two groups: those with all tumors originating in the oral cavity and those with oral cancer occurring after primary tumors in other parts of the body. Such analysis may offer valuable insights into the clinical treatment of these two types of oral multiple primary cancer patients. Materials And Methods Data Collection Demographic, lifestyle, and clinical data were collected from patient medical records, including age, gender, tobacco/alcohol use, oral mucosal diseases, and dental-related conditions. Follow-up data was gathered through regular outpatient visits and telephone interviews, focusing on recurrence or multiple primary cancers (MPCs), post-operative treatment, and overall survival. The time interval between the onset of the first and second primary cancers is used to define whether it is synchronous or metachronous. A time interval of less than 6 months is considered synchronous, while a time interval of more than 6 months is considered metachronous. In this study, patients were mainly divided into two groups based on the anatomical site of the first primary cancer (FPC). Patients whose first primary cancer originated in the oral cavity were classified as the oral cancer first (OCF) group. The non-oral cancer first (N-OCF) group included patients whose first primary cancer originated in a non-oral site (e.g., esophagus, lung) and later developed oral cancer as a second primary. Inclusion and Exclusion Criteria This study is primarily a retrospective analysis of patients who were diagnosed with malignant oral tumors and treated at Sun Yat-sen University Affiliated Stomatological Hospital from October 2012 to July 2023. According to the diagnostic criteria for multiple primary cancers proposed by Warren and Gates[7, 8], the inclusion criteria for this study are as follows: i) All malignant tumors must be definitively diagnosed through histopathological examination. ii) In cases where tumors occur within the same organ, they must be separated by a distance of more than 2 cm. iii) Tumors in the same anatomical region (e.g., right buccal mucosa) were considered multiple primary cancers if they developed more than five years apart. iv) MPCs must not be metastatic or recurrent from the first primary cancer. The exclusion criteria are as follows: i) Tumors diagnosed or suspected to be metastatic or recurrent. ii) Unclear medical records, or cases where the distance between the tumors is unknown, making it impossible to determine whether one is a recurrence. Oral potentially malignant disorders (OPMDs) include oral leukoplakia (without proliferative verrucous leukoplakia in this study), erythroplakia, oral lichen planus, and oral submucous fibrosis, with or without epithelial dysplasia. Dental-related issues, such as sharp tooth cusps, severely tilted teeth, and defective restorations, are also taken into consideration. The TNM staging of oral tumors is in accordance with the latest UICC TNM classification, which is based on a combination of clinical examination and CT or MRI results. The follow-up period commences from the diagnosis of the patient’s second primary cancer and ends in July 2024. Patients with missing critical information are deemed to be completely lost to follow-up. These patients are included in the analysis for reasons, location, and demographics, but are excluded from the survival analysis. Survival Analysis Protocol Patients with missing survival data (e.g., loss to follow-up) were excluded from the survival analysis but retained for clinical characteristic comparisons. No imputation methods were applied in this study. Statistical analysis All statistical analyses were performed using SPSS Statistics 26.0, and statistical significance was set at p < 0.05. Kaplan-Meier survival curves were used to illustrate survival outcomes between the two groups, and the log-rank test was applied for comparison. Additionally, the Cox proportional hazards regression model was used to assess the impact of multiple factors on survival. Results From October 2012 to July 2023, a total of 2,373 patients with oral malignancies were treated at our hospital. After an initial screening of the hospital database, 240 patients were identified as potential cases of MPOCs. After excluding cases of recurrence, metastasis, or those with ambiguous primary sites, 165 cases were confirmed. Among these patients, 75 were classified as the oral cancer first (OCF) group (68 metachronous MPOCs and 7 synchronous MPOCs), while 90 were classified as the non-oral cancer first (N-OCF) group (89 metachronous MPOCs and 1 synchronous MPOCs). Furthermore, among all patients, 18 developed a third, fourth, or even fifth primary cancer. Clinical characteristics The overall mean age of the MPOCs patients was 59.4 ± 10.2 years, with 95 males (57.6%). In the OCF group, the mean age was 62.0 ± 10.6 years, with 38 males (50.7%). In the N-OCF group, the mean age was 57.2 ± 9.2 years, with 57 males (63.3%). The OCF group was significantly older than the N-OCF group ( p = 0.0026), whereas no statistically significant difference was found in gender distribution. Fifty patients had OPMDs either before or after SPCs, including 29 (38.7%) patients in the OCF group and 21 (23.3%) in the N-OCF group. The p-value was 0.050, indicating a marginal statistical difference between the two groups. Of these, 30 had the disease before SPCs, with 24 progressing to SCC, while 13 developed it after SPCs, with 8 progressing to SCC. Additionally, 8 patients had OPMDs both before and after SPCs, 6 of whom progressed to SCC. In the OCF group, 31 patients (41.3%) exhibited habits of smoking, alcohol consumption, or betel nut chewing, whereas in the N-OCF group, 27 patients (30.0%) reported similar habits. Statistical analysis indicated no significant difference between the two groups. The overall median time interval between FPCs and SPCs was 106.9 months, with a median of 89.4 months in the OCF group and 121.2 months in the N-OCF group. A statistically significant difference in the time interval was observed between the two groups ( p = 0.0296). Among patients who experienced the occurrence of three primary cancers, the median interval between the first and second cancers was 65.3months, and between the second and third cancers, it was 16.3months. The histopathological results of both groups were predominantly SCC (160cases,97.0%). In the OCF group, 97.3% of the cases were SCC, while in the N-OCF group, 96.6% were SCC. In the OCF group, the remaining two cases were verrucous carcinoma, while in the N-OCF group, there was one case of central jaw carcinoma and two cases of osteosarcoma. Most SPCs in both groups were diagnosed at an early stage. The proportion of T1 + T2 was 72.0%(54cases) in the OCF group and 72.2% (65cases) in the N-OCF group, with no statistically significant difference between the two groups. For FPC treatment, in the OCF group (n=75), 47 patients (62.7%) underwent surgery, and 25 (33.3%) received additional radiation and/or chemotherapy, while 3 patients received primary radiotherapy or chemotherapy alone without surgical intervention. In the N-OCF group (n=90), 21 patients (23.3%) received radiation, 33 (36.7%) individuals received radiotherapy with surgery and/or chemotherapy, 22 (24.4%) patients underwent surgery alone without radiotherapy, and 13 (14.4%) patients received the combined modality of surgery plus chemotherapy (excluding radiotherapy). Treatment modality remained unknown for 1 (1.1%) patient in this group. Among the 54 patients who received radiotherapy, 45 (83.3%) had the radiation field involving the oral cavity. As for SPC treatment, both groups primarily received surgery. In the OCF group, 49 patients (65.3%) underwent surgery, with 18 (24.0%) also receiving radiation and/or chemotherapy. Treatment modality remained unknown for 8 (10.7%) patients in this group. In the N-OCF group, 69 patients (76.7%) underwent surgery, and 8 (8.9%) received additional radiation and/or chemotherapy; 6 (6.7%) patients received primary radiotherapy or chemotherapy alone (without surgical intervention), and treatment modality was unclear for 7 (7.7%) patients. A significant difference was observed between the two groups in the treatment of FPC, while no significant difference was found in the treatment of SPC. Table 1 Characteristics and treatment of patients with MPOCs Characteristics Total(n=165) OCF(n=75) N-OCF(n=90) P -value Age at diagnosis SPC (years) 0.0026* Mean (Range) 59.7 (36–85) 62.1 (41–85) 57.2 (36–80) Sex, n (%) 0.139 Male 95 (57.6%) 38 (50.6%) 57 (63.3%) Female 70 (42.4%) 37 (49.3%) 33 (36.7%) Smoking/alcohol/betel nut, n (%) 58 (35.1%) 31 (41.3%) 27 (30.0%) 0.176 Dental-related issues, n (%) 57 (34.5%) 33 (44.0%) 24 (28.4%) 0.030* Oral premalignant disorders, n (%) 50 (30.3%) 29 (38.7%) 21 (23.3%) 0.05 Comorbidities, n (%) 68 (41.2%) 31 (41.3%) 37 (41.1%) 1 Family history, n (%) 16 (9.6%) 5 (6.7%) 11 (12.2%) 0.349 T stage of SPC, n (%) 1 T1+T2 119 (72.1%) 54 (72.0%) 65 (72.2%) T3+T4 46 (27.9%) 21 (28.0%) 25 (27.8%) Lymph node metastasis, n (%) 38 (23.0%) 18 (24.0%) 20 (22.2%) 0.933 Time interval (months), Median (Range) 106.9 (0.0–618.4) 83.4 (0–289.4) 121.2 (4.93–618.4) 1 Histopathology of SPC, n (%) 1 SCC 160 (97.0%) 73 (97.3%) 87 (96.7%) Other 5 (3.0%) 2 (2.7%) 3 (3.3%) Treatment for FPC, n (%) 0.000* Surgery 69 (41.8%) 47 (62.7%) 22 (24.4%) Radiotherapy 23 (13.9%) 2 (2.7%) 21 (23.3%) Surgery + Radiotherapy 16 (9.7%) 12 (16.0%) 4 (4.4%) Chemotherapy 2 (1.2%) 1 (1.3%) 1 (1.1%) Surgery + Chemotherapy 21 (12.7%) 8 (10.7%) 13 (14.4%) Surgery + Chemo + Radio 12 (7.3%) 5 (6.7%) 7 (7.8%) Chemo + Radio 21 (12.7%) 0 (0.0%) 21 (23.3%) Unknown 1 (0.6%) 0 (0.0%) 1 (1.1%) Treatment for SPC, n (%) 0.251 Surgery 118 (71.5%) 49 (65.3%) 69 (76.7%) Radiotherapy 0 (0.0%) 0 (0.0%) 0 (0.0%) Surgery + Radiotherapy 16 (9.7%) 9 (12.0%) 7 (7.8%) Chemotherapy 0 (0.0%) 0 (0.0%) 0 (0.0%) Surgery + Chemotherapy 6 (3.6%) 5 (6.7%) 1 (1.1%) Surgery + Chemo + Radio 8 (4.8%) 4 (5.3%) 4 (4.4%) Chemo + Radio 2 (1.2%) 0 (0.0%) 2 (2.2%) Unknown 15 (9.1%) 8 (10.7%) 7 (7.8%) Age at diagnosis SPC (years) 0.0026* Mean (Range) 59.7 (36–85) 62.1 (41–85) 57.2 (36–80) Sex, n (%) 0.139 Male 95 (57.6%) 38 (50.6%) 57 (63.3%) Female 70 (42.4%) 37 (49.3%) 33 (36.7%) Smoking/alcohol/betel nut, n (%) 58 (35.1%) 31 (41.3%) 27 (30.0%) 0.176 Abbreviations: SPC=Second primary cancer; FPC= First primary cancer; OCF= Oral cancer first; N-OCF= Non-Oral cancer first Statistical significance: *p < 0.05. Sites for FPC and SPC In the OCF group, the most common site for FPC was the tongue, accounting for 36 cases (48.0%), followed by the buccal mucosa (16 cases, 21.3%), gingiva (9 cases, 12.0%), and floor of the mouth (5 cases, 6.7%). For the SPCs, the tongue was also the most frequent site, with 26 cases (34.7%), followed by the buccal mucosa (22 cases, 29.3%), gingiva (9 cases, 12.0%), and hard palate (6 cases, 8.0%). Among these patients, 48 (64.0%) developed their SPCs on the same side as their FPCs in the oral cavity, while 27 (36%) patients developed their SPCs on the opposite side (Fig.1). The odds ratio (OR) for same-side occurrence was 3.16 [1.64, 6.11]. In the N - OCF group, the most common primary cancer was nasopharyngeal carcinoma (44 cases, 48.9%), followed by breast cancer (13 cases, 14.4%), laryngeal cancer (6 cases, 6.7%), and esophageal cancer (5 cases, 5.6%). Colorectal cancer accounted for 4 cases (4.4%), liver cancer for 3 cases (3.3%), lung cancer for 3 cases (3.3%), and cervical cancer for 3 cases (3.3%). Gastric cancer was present in 2 cases (2.2%), while bladder cancer, thyroid cancer, prostate cancer, ovarian cancer, renal cancer, uterine cancer, and lymphoma each had 1 case (1.1%). SPCs in this group were also most commonly located in the tongue (60 cases, 66.7%), followed by the buccal mucosa (9 cases, 10.0%), floor of the mouth (6 cases, 6.7%), gingiva (5 cases, 5.6%) (Fig.2). Survival Follow-up information was obtained from 143 patients, including 63 (44.1%) in the OCF group and 80 (55.9%) in the N-OCF group. A total of 31 deaths were recorded during the follow-up period, with 12 (38.7%) deaths occurring in the OCF group and 19 (61.3%) in the N-OCF group. In this study, the overall median survival time was 148.03 months (97.27,198.85 months), with 1-year, 3-year, and 5-year survival rates of 93.68%, 81.08%, and 74.03%, respectively. The OCF group had a median survival time of 148.03 months (57.05,239.00 months) and corresponding 1-year, 3-year, and 5-year survival rates of 94.50%, 85.30%, and 78.30%. In comparison, the N-OCF group had a median survival time of 103.84 months (94.28,114.38 months) and 1-year, 3-year, and 5-year survival rates of 92.99%, 76.96%, and 69.97%. Despite numerical differences in survival rates, the Kaplan-Meier survival curves revealed no statistically significant disparity between the OCF and N-OCF groups (log-rank test, χ² = 1.306, p = 0.253; Fig.3). A total of 15 variables were included in the Cox proportional hazards model，namely based on their clinical relevance and prior literature on MPOCs[9-12]: Age, Gender, Site of FPC, Site of SPC, Cervical lymph node metastasis of SPC, Differentiation grade of SPC, Synchronous multiple cancers, T stage of SPC, Treatment method for FPC, Treatment method for SPC, Three or more MPCs, Distant metastasis after SPC, Recurrence after SPC, Time interval between FPC and SPC, Comorbidities. In the univariate regression analysis, seven significant indicators were identified. However, after performing multivariate regression, only four variables remained significant with p < 0.05: age, T stage of SPC, cervical lymph node metastasis of SPC, and recurrence after SPC (Table 2). Table 2 Univariate and Multivariate cox regression analysis of risk factors of prognosis of MPOCs Variables Univariate Cox regression analyses Multivariate Cox regression analysis HR(95%CI) P -value HR (95%CI) P -value Age 1.036 (1.009, 1.063) 0.008* 1.618 (1.097, 2.388) 0.015* Gender 0.542 (0.315, 0.931) 0.026* 1.519 (0.749, 3.079) 0.247 Site of FPC 0.818 (0.493, 1.356) 0.436 Site of SPC 1.04 (0.969, 1.115) 0.275 Cervical lymph node metastasis of SPC 1.838 (1.082, 3.121) 0.024* 1.004 (1.001, 1.008) 0.021* Differentiation grade of SPC 0.994 (0.609, 1.62) 0.980 Synchronous multiple cancers 0.814 (0.325, 2.038) 0.661 T stage of SPC 1.573 (1.25, 1.979) 0.000* 2.883 (1.417, 5.864) 0.003* Treatment method for FPC 1.033 (0.922, 1.158) 0.577 Treatment method for SPC 0.987 (0.832, 1.17) 0.877 Three or more MPCs 0.814 (0.419, 1.582) 0.544 Distant metastasis after SPC 2.152 (1.067, 4.34) 0.032* 1.01 (0.969, 1.052) 0.645 Recurrence after SPC 1.003 (1.001, 1.006) 0.019* 0.405 (0.189, 0.869) 0.020* Time interval between FPC and SPC 1.756 (1.056, 2.92) 0.030* 1.36 (0.592, 3.123) 0.468 Comorbidities 1.008 (0.592, 1.716) 0.976 Note: HR: hazard ratio, CI: confidence interval Discussion Multiple Primary Cancers (MPCs) refer to the occurrence of two or more independent malignant tumors in the same or different organs[6]. The head and neck region is one of the most common sites for the occurrence of MPCs[13]. In previous literatures, the definition of MPOCs has often been limited to cases where all primary cancers occur within the oral cavity, overlooking patients who develop oral cancer after malignancies in other parts of the body. To address this, the present study classifies MPOCs patients into two groups based on the site of the first primary cancer: the OCF group (oral cavity first) and the N-OCF group (non-oral cavity first) in order to better understand the similarities and differences. Due to the relatively small number of patients with three primary malignancies, this study primarily focuses on the second primary cancer. By distinguishing OCF and N-OCF subgroups, this study aims to uncover distinct biological behaviors between the two groups and optimize personalized management for MPOCs patients. Previous studies have reported a higher prevalence of MPCs in the head and neck region among female[5, 9]. However, in this study, both the OCF group and the N-OCF group consisted of a higher number of male patients. This discrepancy may be due to the fact that in the OCF group, the majority of patients with unhealthy habits such as smoking and betel nut chewing, which are known to increase the risk of multiple primary cancers, were male. While in the N-OCF group, nasopharyngeal carcinoma— a type of cancer that predominantly affects males[14]—constituted the majority. In terms of age, the mean onset age of a SPC in MPOCs patients is 59.4± 10.2 years, which is younger than the ages reported in previous studies[5, 9, 15], suggesting a potential trend of MPOCs occurring at a younger age. Additionally, the onset age of a SPC in the N-OCF group is younger than in the OCF group, which may be related to the immune abnormalities caused by a FPC, the effects of chemotherapy and radiotherapy, or genetic susceptibility. The occurrence of MPOCs tends to show specific site-related characteristics[16]. While previous study has suggested a higher risk in keratinized epithelium[5], this study's findings differ. In the OCF group, the tongue was also the most common site for FPC, followed by the buccal mucosa and gingiva, with a notable tendency for the cancers to occur on the same side. This same-side preference support the “field cancerization” theory, suggesting that localized exposure to carcinogens (e.g., tobacco or alcohol) may induce widespread molecular alterations in adjacent tissues, predisposing them to malignant transformation [17]. Furthermore, as mentioned by Ko in his study[18], due to the complexity of surgery and the alteration of lymphatic drainage pathways, patients with contralateral SPCs may have better survival outcomes compared to those with ipsilateral SPCs. Among the 54 patients in the N-OCF group who received radiotherapy for their FPCs, 45 had the radiation field involving the oral cavity, with 43 of them receiving radiotherapy due to nasopharyngeal carcinoma (NPC). NPC is a disease with a high incidence in Guangdong Province[19], where radiotherapy is the primary treatment modality. Radiotherapy, while effective in targeting tumor cells, induces double-strand DNA breaks and chromosomal aberrations in adjacent normal tissues, which may accumulate over decades and culminate in secondary malignancies, particularly in the tongue and gingiva[20-22]. Moreover, the similarity in epithelial structure between the nasopharynx and the oral cavity, as well as their anatomical proximity, may enhance the effects of "field cancerization". In addition, shared risk factors, such as smoking, may simultaneously affect both sites[23], thus increasing the likelihood of developing oral cancer following NPC. As Vogt A[6] noted, MPCs are more likely to occur in different organs within the same system. These mechanisms are also relevant for patients with a FPC in the larynx or esophagus, as both are located in the upper digestive tract. The time interval between FPCs and SPCs may reflect the mechanisms of cancer development, the impact of FPCs treatment, and the patient's cancer risk. The median time interval in the N-OCF group (121.2 months) was significantly longer than that in the OCF group (89.4 months), with both intervals exceeding the 5-year mark. Importantly, radiation-induced SPCs typically manifest after prolonged latency periods of 15–20 years [24, 25], as demonstrated in this study by a patient who developed a giant cell osteosarcoma 609 months after NPC. This extended period is a time when both patients and doctors are likely to become less vigilant. Therefore, our findings underscore the importance of long-term, regular follow-ups, especially NPC patients receiving radiotherapy, not only of the nasopharynx but also of the oral cavity. Notably, among the 19 patients with three or more primary cancers, the time interval between the FPC and SPC was 65.3 months, but it significantly decreased to 16.3 months between the second and third cancers. Although the sample size is small, these findings suggest that patients with a history of MPOCs should be closely monitored. The etiology of MPOCs is not yet fully understood. However, it is well - established that behaviors such as smoking, alcohol consumption, and betel nut chewing are significantly associated with its development[4]. These factors can increase the risk of a SPC in a dose - dependent manner[26]. In our study, 35.1% of MPOCs patients had a history of these habits, thereby highlighting the susceptibility of the oral mucosa to carcinogens[27]. It is worth noting that 57.8% of patients who had quit these habits still developed MPCs, suggesting that the damage to the mucosa may be long - lasting. Furthermore, chronic irritations, such as poor oral hygiene or ill - fitting dentures, can also contribute to an increased risk of cancer[28]. Epidemiological studies have reported that 80% of oral cancers are preceded by OPMDs[29], and the incidence of OPMDs is higher among MPOCs patients[4]. In our study, OPMDs were detected in 38.7% of the OCF group and 23.3% of the N - OCF group, both before and after the development of SPCs. These findings underscore the persistence of OPMDs, as previous research has shown that they can even occur on free grafted flaps[30]. The high malignant transformation rate of OPMDs in this study also warrants attention, even though the data may overestimate the true situation, as many of the patients were referred to our department after unsuccessful treatment in oral mucosal clinics. Nevertheless, while surgical intervention reduces the risk of malignant transformation, it does not completely eliminate the possibility[31]. Therefore, preventive strategies should not only focus on the elimination of harmful habits but also include early screening, risk identification, and anti-inflammatory or chemopreventive interventions[32] to mitigate mucosal damage and prevent the occurrence of MPCs. The overall survival curves and median survival times in this study were higher than those reported in earlier literature. The authors speculate that this discrepancy may be attributed to advancements in cancer treatment in recent years, particularly with the advent of immune therapies such as PD-1/PD-L1 inhibitors[33] , which may improve long-term survival outcomes. Additionally, most patients in this study were diagnosed with SPCs at an early stage (T1 or T2) and received timely intervention, contributing to a favorable prognosis. Besides, the patients who were completely lost to follow-up may have also caused errors in the survival analysis. The survival curves between the two groups showed no notable differences. Nevertheless, the survival rate of the N-OCF group was slightly lower than that of the OCF group at 1, 3, and 5 years, with a noticeable decline in the N-OCF group’s survival rate after 100 months. The authors suggest that this may be due to the more diverse treatment modalities (e.g., chemotherapy and radiotherapy) used in the N-OCF group, which might lead to severe side effects that affect long-term health and survival. Furthermore, oral cancers are typically more localized, and, compared to cancers such as breast, lung, and colorectal cancers, they generally exhibit a lower rate of systemic metastasis[34-36]. Multivariate analysis identified four key prognostic factors: age, SPC T stage, cervical lymph node metastasis, and SPC recurrence (all p < 0.05). Although previous literature has reported that the site of FPC significantly affects long-term survival[37], in our study, through both univariate and multivariate analyses, that the FPC site does not have a significant effect on patient survival. Age, however, has been identified as a high-risk factor for the occurrence of MPCs[38], as in our study, age also emerged as an important factor influencing prognosis. Additionally, the T stage of SPC, cervical lymph node metastasis, and distant metastasis were found to be significant factors affecting survival. These results highlight the importance of regular postoperative follow-up, early detection, and timely treatment for patients with a history of cancer. Moreover, recurrence after SPC surgery significantly impacted survival, whereas the development of a third primary cancer did not. This may be due to two factors: the relatively small number of patients with third primary cancers in this study, and different mechanisms underlying recurrence and third primary cancers[39]. Recurrent tumors are often more aggressive and resistant to treatment, placing a greater burden on the patient, particularly when the immune system has not fully recovered. Gleber also pointed out that patients with multiple primary cancers are likely to have better long - term survival than those with recurrent cancers[40]. In contrast to Cai's study[41], which reported a higher mortality risk for patients with MPCs located in the floor of the mouth, our study found that the location of the SPCs did not affect survival. Similarly, whether the MPCs were synchronous or metachronous did not influence prognosis in our study, although previous literature often reports a poorer prognosis for patients with synchronous MPCs[5]. This discrepancy may be attributed to the smaller sample sizes of synchronous MPCs patients and those with floor of the mouth cancer in this study, which needs further research. The limitations of this study include: (1) Missing data, particularly regarding NPC patients who received radiotherapy in the OCF group (e.g., radiation dose, modality and EBV-related information), prevented further analysis of the impact of radiotherapy;(2) The inability to track non-oral malignancies after SPCs, affecting survival analysis; (3) Small sample sizes for patients with three or more primary cancers and synchronous cancers; (4) Missing follow-up data, leading to potential bias; (5) The lack of a solitary oral cancer comparison group in this single-center study. To the best of our knowledge, this is the first study focusing on the differences between OCF and N-OCF groups, which may contribute to a better understanding of the mechanisms underlying MPOCs, and potentially enable more personalized treatment strategies and prognosis predictions. Future multicenter studies with larger sample sizes and predictive biomarkers[42] are needed to refine treatment strategies and improve outcomes for MPOCs patients. Conclusion In both OCF and N-OCF cohorts, the tongue was the predominant site for the second primary malignancy. The OCF group also exhibited a preference for the tongue as the site of the FPC. Additionally, SPCs tended to occur on the same side as the FPCs. Nasopharyngeal carcinoma was the most common site for the FPC in the N-OCF group, with radiotherapy being the primary treatment modality. The diagnosis and management of OPMDs in MPOCs patients require attention. Survival does not significantly differ between OCF and N-OCF group. Key factors affecting MPOCs patient survival include age, T stage of SPC, cervical lymph node metastasis of SPC and recurrence after SPC. Declarations Conflict of interest statement The authors declare that they have no conflict of interest. Ethics Approval and Consent to Participate This study was conducted in strict accordance with the ethical principles of the Declaration of Helsinki and relevant national and international guidelines and was approved by the Medical Ethics Committee of the Affiliated Stomatological Hospital of Sun Yat-sen University. The approval number is ERC-[2017]-26. All participants in this clinical research provided informed consent before any study-related procedures were conducted. The informed consent form was reviewed and approved by the Ethics Committee, and all participants were fully informed about the study objectives, procedures, potential risks and benefits, and their rights to withdraw from the study at any time without any penalty. Consent for Publication All authors have given their consent for the publication of this manuscript. Availability of Data and Materials The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. Competing Interests The authors declare that they have no competing interests. Funding This study did not receive any funding from any organizations or institutions. Authors' Contributions Qiannan Liu*, Shanshan Tang*, Le Yang* These authors have contributed equally to this work and share the first authorship, they did data acquisition、statistical analysis and have drafted the work ,then substantively revised it. Guiqing Liao, Yujie Liang, Le Yang have made substantial contributions to the conception and design of the study, and reviewed the manuscript carefully. Farong Ou, Huanzi Lu, Kan Li, Zengyu Chen helped to do the data acquisition and analysis Acknowledgements We would like to acknowledge the contributions of all the participants in this study. We also thank the staff of Sun Yat-sen University Affiliated Stomatological Hospital for their support and assistance during the conduct of the study. Authors' Information Author 1: Qiannan Liu, First Author, Department of Stomatology, Hospital of Stomatology, Sun Yat-sen University, 56th Lingyuanxi Road, Guangzhou, Guangdong, 510055, China; Guangdong Province Key Laboratory of Stomatology, No. 74, 2nd Zhongshan Road, Guangzhou, 510080, Guangdong, China. Email: [email protected] . Author 2: Shanshan Tang, Co - first Author, Department of Stomatology, Hospital of Stomatology, Sun Yat-sen University, 56th Lingyuanxi Road, Guangzhou, Guangdong, 510055, China; Guangdong Province Key Laboratory of Stomatology, No. 74, 2nd Zhongshan Road, Guangzhou, 510080, Guangdong, China. Email: [email protected] Author 3: Le Yang, Co - first Author, Department of Stomatology, Hospital of Stomatology, Sun Yat-sen University, 56th Lingyuanxi Road, Guangzhou, Guangdong, 510055, China; Guangdong Province Key Laboratory of Stomatology, No. 74, 2nd Zhongshan Road, Guangzhou, 510080, Guangdong, China. Email: [email protected] Author 4: Farong Ou, Co - author, Department of Stomatology, Hospital of Stomatology, Sun Yat-sen University, 56th Lingyuanxi Road, Guangzhou, Guangdong, 510055, China; Guangdong Province Key Laboratory of Stomatology, No. 74, 2nd Zhongshan Road, Guangzhou, 510080, Guangdong, China. Email: [email protected] Author 5: Kan Li, Co - author, Department of Stomatology, Hospital of Stomatology, Sun Yat-sen University, 56th Lingyuanxi Road, Guangzhou, Guangdong, 510055, China; Guangdong Province Key Laboratory of Stomatology, No. 74, 2nd Zhongshan Road, Guangzhou, 510080, Guangdong, China. Email: [email protected] Author 6: Huanzi Lu, Co - author, Department of Stomatology, Hospital of Stomatology, Sun Yat-sen University, 56th Lingyuanxi Road, Guangzhou, Guangdong, 510055, China; Guangdong Province Key Laboratory of Stomatology, No. 74, 2nd Zhongshan Road, Guangzhou, 510080, Guangdong, China. Email: [email protected] Author 7: Zengyu Chen, Co - author, Department of Stomatology, Hospital of Stomatology, Sun Yat-sen University, 56th Lingyuanxi Road, Guangzhou, Guangdong, 510055, China; Guangdong Province Key Laboratory of Stomatology, No. 74, 2nd Zhongshan Road, Guangzhou, 510080, Guangdong, China. Email: [email protected] References Cheng J, Zhou X, Xu H, Dan H, Li J, Chen Q: Incidence and Survival of Oral Cavity and Oropharyngeal Cancer in the United States From 1975 to 2018 . Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons 2022, 80 (7):1294-1305. Bertolini F, Trudu L, Banchelli F, Schipilliti F, Napolitano M, Alberici MP, Depenni R, D'Angelo E, Mattioli F, Rubino L et al : Second primary tumors in head and neck cancer patients: The importance of a "tailored" surveillance . Oral diseases 2021, 27 (6):1412-1420. 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Liao YH, Chou WY, Chang CW, Lin MC, Wang CP, Lou PJ, Chen TC: Chemoprevention of oral cancer: A review and future perspectives . Head & neck 2023, 45 (4):1045-1059. Yang B, Liu T, Qu Y, Liu H, Zheng SG, Cheng B, Sun J: Progresses and Perspectives of Anti-PD-1/PD-L1 Antibody Therapy in Head and Neck Cancers . Frontiers in oncology 2018, 8 :563. Xie T, Qiu BM, Luo J, Diao YF, Hu LW, Liu XL, Shen Y: Distant metastasis patterns among lung cancer subtypes and impact of primary tumor resection on survival in metastatic lung cancer using SEER database . Scientific reports 2024, 14 (1):22445. Wang Y, Ye F, Liang Y, Yang Q: Breast cancer brain metastasis: insight into molecular mechanisms and therapeutic strategies . British journal of cancer 2021, 125 (8):1056-1067. Al Bitar S, El-Sabban M, Doughan S, Abou-Kheir W: Molecular mechanisms targeting drug-resistance and metastasis in colorectal cancer: Updates and beyond . World journal of gastroenterology 2023, 29 (9):1395-1426. Ventura L, Carbognani P, Gnetti L, Rossi M, Tiseo M, Silini EM, Sverzellati N, Silva M, Succi M, Braggio C et al : Multiple primary malignancies involving lung cancer: a single-center experience . Tumori 2021, 107 (3):196-203. Ho CM, Chen YH, Hsu WH, Wang WY, Yuan SF, Wu IC, Hsieh HM: Comparative effectiveness and stage-shift effect of endoscopic exam among newly diagnosed oral cancer patients with different stages in Taiwan . Head & neck 2022, 44 (10):2118-2128. Veronesi U, Marubini E, Del Vecchio M, Manzari A, Andreola S, Greco M, Luini A, Merson M, Saccozzi R, Rilke F et al : Local recurrences and distant metastases after conservative breast cancer treatments: partly independent events . Journal of the National Cancer Institute 1995, 87 (1):19-27. Gleber-Netto FO, Braakhuis BJ, Triantafyllou A, Takes RP, Kelner N, Rodrigo JP, Strojan P, Vander Poorten V, Rapidis AD, Rinaldo AJOo: Molecular events in relapsed oral squamous cell carcinoma: Recurrence vs secondary primary tumor . 2015, 51 (8):738-744. Cai X, Zhang J, Jing F, Zhou X, Zhang H, Li T: Clinical and prognostic features of multiple primary cancers with oral squamous cell carcinoma . Archives of oral biology 2023, 149 :105661. Simple M, Suresh A, Das D, Kuriakose MA: Cancer stem cells and field cancerization of oral squamous cell carcinoma . Oral oncology 2015, 51 (7):643-651. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 07 Jul, 2025 Read the published version in BMC Oral Health → Version 1 posted Editorial decision: Revision requested 29 Apr, 2025 Editor assigned by journal 29 Apr, 2025 Reviews received at journal 27 Apr, 2025 Reviews received at journal 25 Apr, 2025 Reviewers agreed at journal 16 Apr, 2025 Reviewers agreed at journal 14 Apr, 2025 Reviewers invited by journal 14 Apr, 2025 Submission checks completed at journal 11 Apr, 2025 First submitted to journal 10 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5780078","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":442809834,"identity":"07f9b69f-0390-43a8-a712-e91a8d8aa52b","order_by":0,"name":"Qiannan Liu","email":"","orcid":"","institution":"Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University","correspondingAuthor":false,"prefix":"","firstName":"Qiannan","middleName":"","lastName":"Liu","suffix":""},{"id":442809837,"identity":"9a46f474-382e-4128-8900-5eec601481f8","order_by":1,"name":"Shanshan Tang","email":"","orcid":"","institution":"Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University","correspondingAuthor":false,"prefix":"","firstName":"Shanshan","middleName":"","lastName":"Tang","suffix":""},{"id":442809838,"identity":"4683596b-e0ec-4052-a126-fb4683bb3541","order_by":2,"name":"Le Yang","email":"","orcid":"","institution":"Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University","correspondingAuthor":false,"prefix":"","firstName":"Le","middleName":"","lastName":"Yang","suffix":""},{"id":442809840,"identity":"0b52f32a-ce2f-4ab1-881f-2bef7a2b0205","order_by":3,"name":"Farong Ou","email":"","orcid":"","institution":"Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University","correspondingAuthor":false,"prefix":"","firstName":"Farong","middleName":"","lastName":"Ou","suffix":""},{"id":442809842,"identity":"6a479bd3-5cff-433a-8fd7-d56aea768e4b","order_by":4,"name":"Kan Li","email":"","orcid":"","institution":"Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University","correspondingAuthor":false,"prefix":"","firstName":"Kan","middleName":"","lastName":"Li","suffix":""},{"id":442809843,"identity":"4e9dfb91-13bc-423b-b56b-b6204f559e2a","order_by":5,"name":"Huanzi Lu","email":"","orcid":"","institution":"Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University","correspondingAuthor":false,"prefix":"","firstName":"Huanzi","middleName":"","lastName":"Lu","suffix":""},{"id":442809844,"identity":"5eddb093-0f55-417f-9aa7-e0f959ddcb71","order_by":6,"name":"Zengyu Chen","email":"","orcid":"","institution":"Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University","correspondingAuthor":false,"prefix":"","firstName":"Zengyu","middleName":"","lastName":"Chen","suffix":""},{"id":442809845,"identity":"06133cc7-90b5-4513-8948-5c9a3b5b5962","order_by":7,"name":"Guiqing Liao","email":"","orcid":"","institution":"Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University","correspondingAuthor":false,"prefix":"","firstName":"Guiqing","middleName":"","lastName":"Liao","suffix":""},{"id":442809846,"identity":"fa697c78-e4ec-478b-94ce-d1aac44abb35","order_by":8,"name":"Yujie Liang","email":"data:image/png;base64,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","orcid":"","institution":"Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University","correspondingAuthor":true,"prefix":"","firstName":"Yujie","middleName":"","lastName":"Liang","suffix":""}],"badges":[],"createdAt":"2025-01-07 09:53:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5780078/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5780078/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12903-025-06141-9","type":"published","date":"2025-07-07T15:57:14+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":80789185,"identity":"d3381fc0-b212-42f8-959e-b6d943b3931f","added_by":"auto","created_at":"2025-04-17 06:34:15","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":64630,"visible":true,"origin":"","legend":"\u003cp\u003eHeatmap of the association between the first and second primary cancer sites in the OCF group which shows the distribution of SPC sites (rows) relative to the FPC sites (columns), categorized by same side and opposite side occurrence. The intensity of the color represents the number of cases.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5780078/v1/8f281649f42ac107081bb400.png"},{"id":80789192,"identity":"9133ab13-a796-40cc-8b0e-91ed5953d662","added_by":"auto","created_at":"2025-04-17 06:34:15","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":298072,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e“\u003c/strong\u003eOral second primary cancer map” This “map” representation of the most common tumor sites for second primary cancers in patients with OCF and N-OCF. The left side (OCF) shows the four most frequent tumor sites: tongue (34.7%), buccal mucosa (29.3%), gingiva (12.0%), and hard palate (8.0%). The right side (N-OCF) shows the most common tumor sites: tongue (66.7%), buccal mucosa (10.0%), floor of the mouth (6.7%), gingiva (5.6%) . The numbers represent the sequential ranking of tumor site frequency in each group.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5780078/v1/7b0831258649d22786e4294e.png"},{"id":80790870,"identity":"57ca12da-7b37-4429-915f-0aa9c39e6faa","added_by":"auto","created_at":"2025-04-17 06:42:15","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":57514,"visible":true,"origin":"","legend":"\u003cp\u003eKM survival curves of patients in the MPOCs, OCF, and N-OCF groups Kaplan-Meier survival curves for patients with MPOCs, showing overall survival in the MPOCs group (left), the OCF group (middle), and the N-OCF group (right). The shaded areas represent the 95% confidence intervals. Survival rates decrease over time.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5780078/v1/dc3d09bac809be13a1e90f12.png"},{"id":86699455,"identity":"ae9b1f69-4a86-446d-a566-1254041b82d2","added_by":"auto","created_at":"2025-07-14 16:09:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2916503,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5780078/v1/f5eed2e2-5efc-4917-8438-3a4b69113003.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eClinical Outcomes and Prognostic Factors in Multiple Primary Malignancies Involving Oral Cancer \u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eOral cancer, which is predominantly squamous cell carcinoma (SCC)[1], remains a major threat to global health. Malignant tumors occurring in the oral cavity are characterized not only by a high rate of local recurrence but also by a predisposition to developing multiple primary cancers (MPCs)[2]. With the increasing global incidence of oral cancer\u0026mdash;particularly among individuals with risk factors such as tobacco use, alcohol consumption, and betel quid chewing\u0026mdash;the incidence of multiple primary oral cancers (MPOCs) has also been rising[3], with reported rates ranging from 5% to 23.8%[4]. This trend poses significant diagnostic and therapeutic challenges.\u003c/p\u003e\n\u003cp\u003eCompared to single primary oral cancer, which has a 10-year survival rate of 47.1%, MPOCs exhibit a more unfavorable long-term prognosis, with a 10-year survival rate of 42.2% [5]. This underscores the persistent challenges in the diagnosis and management of MPOCs[6]. However, to date, no comprehensive system has been established for the incidence, diagnosis, and treatment of MPOCs. Moreover, current studies mainly focus on patients whose first (also known as index tumor), second, and third primary cancers all occur within the oral cavity, with limited research on patients who develop oral cancer after tumors in other body parts (such as nasopharynx, lung, breast cancer, etc.). These patients may be more susceptible to developing oral cancer due to previous radiation therapy or chemotherapy, genetic mutations, or familial predisposition, and their clinical characteristics may also differ, resulting in different prognoses for the same treatment modality.\u003c/p\u003e\n\u003cp\u003eTherefore, this study aims to analyze the clinical characteristics of patients with oral multiple primary cancers and compare their clinical characteristics and prognosis between two groups: those with all tumors originating in the oral cavity and those with oral cancer occurring after primary tumors in other parts of the body. Such analysis may offer valuable insights into the clinical treatment of these two types of oral multiple primary cancer patients.\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cp\u003eData Collection\u003c/p\u003e\n\u003cp\u003eDemographic, lifestyle, and clinical data were collected from patient medical records, including age, gender, tobacco/alcohol use, oral mucosal diseases, and dental-related conditions. Follow-up data was gathered through regular outpatient visits and telephone interviews, focusing on recurrence or multiple primary cancers (MPCs), post-operative treatment, and overall survival. The time interval between the onset of the first and second primary cancers is used to define whether it is synchronous or metachronous. A time interval of less than 6 months is considered synchronous, while a time interval of more than 6 months is considered metachronous. In this study, patients were mainly divided into two groups based on the anatomical site of the first primary cancer (FPC). Patients whose first primary cancer originated in the oral cavity were classified as the oral cancer first (OCF) group. The non-oral cancer first (N-OCF) group included patients whose first primary cancer originated in a non-oral site (e.g., esophagus, lung) and later developed oral cancer as a second primary.\u003c/p\u003e\n\u003cp\u003eInclusion and Exclusion Criteria\u003c/p\u003e\n\u003cp\u003eThis study is primarily a retrospective analysis of patients who were diagnosed with malignant oral tumors and treated at Sun Yat-sen University Affiliated Stomatological Hospital from October 2012 to July 2023. According to the diagnostic criteria for multiple primary cancers proposed by Warren and Gates[7, 8], the inclusion criteria for this study are as follows:\u003c/p\u003e\n\u003cp\u003ei) All malignant tumors must be definitively diagnosed through histopathological examination.\u003c/p\u003e\n\u003cp\u003eii) In cases where tumors occur within the same organ, they must be separated by a distance of more than 2 cm.\u003c/p\u003e\n\u003cp\u003eiii) Tumors in the same anatomical region (e.g., right buccal mucosa) were considered multiple primary cancers if they developed more than five years apart.\u003c/p\u003e\n\u003cp\u003eiv) MPCs must not be metastatic or recurrent from the first primary cancer.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe exclusion criteria are as follows:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ei) Tumors diagnosed or suspected to be metastatic or recurrent.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eii) Unclear medical records, or cases where the distance between the tumors is unknown, making it impossible to determine whether one is a recurrence.\u003c/p\u003e\n\u003cp\u003eOral potentially malignant disorders (OPMDs) include oral leukoplakia (without proliferative verrucous leukoplakia in this study), erythroplakia, oral lichen planus, and oral submucous fibrosis, with or without epithelial dysplasia. Dental-related issues, such as sharp tooth cusps, severely tilted teeth, and defective restorations, are also taken into consideration. The TNM staging of oral tumors is in accordance with the latest UICC TNM classification, which is based on a combination of clinical examination and CT or MRI results. The follow-up period commences from the diagnosis of the patient\u0026rsquo;s second primary cancer and ends in July 2024. Patients with missing critical information are deemed to be completely lost to follow-up. These patients are included in the analysis for reasons, location, and demographics, but are excluded from the survival analysis.\u003c/p\u003e\n\u003cp\u003eSurvival Analysis Protocol\u003cbr\u003e\u0026nbsp;Patients with missing survival data (e.g., loss to follow-up) were excluded from the survival analysis but retained for clinical characteristic comparisons. No imputation methods were applied in this study.\u003c/p\u003e\n\u003cp\u003eStatistical analysis\u003c/p\u003e\n\u003cp\u003eAll statistical analyses were performed using SPSS Statistics 26.0, and statistical significance was set at \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05. Kaplan-Meier survival curves were used to illustrate survival outcomes between the two groups, and the log-rank test was applied for comparison. Additionally, the Cox proportional hazards regression model was used to assess the impact of multiple factors on survival.\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eFrom October 2012 to July 2023, a total of 2,373 patients with oral malignancies were treated at our hospital. After an initial screening of the hospital database, 240 patients were identified as potential cases of MPOCs. After excluding cases of recurrence, metastasis, or those with ambiguous primary sites, 165 cases were confirmed. Among these patients, 75 were classified as the oral cancer first (OCF) group (68 metachronous MPOCs and 7 synchronous MPOCs), while 90 were classified as the non-oral cancer first (N-OCF) group (89 metachronous MPOCs and 1 synchronous MPOCs). Furthermore, among all patients, 18 developed a third, fourth, or even fifth primary cancer.\u003c/p\u003e\n\u003cp\u003eClinical characteristics\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The overall mean age of the MPOCs patients was 59.4 \u0026plusmn; 10.2 years, with 95 males (57.6%). In the OCF group, the mean age was 62.0 \u0026plusmn; 10.6 years, with 38 males (50.7%). In the N-OCF group, the mean age was 57.2 \u0026plusmn; 9.2 years, with 57 males (63.3%). The OCF group was significantly older than the N-OCF group (\u003cem\u003ep\u003c/em\u003e = 0.0026), whereas no statistically significant difference was found in gender distribution.\u003c/p\u003e\n\u003cp\u003eFifty patients had OPMDs either before or after SPCs, including 29 (38.7%) patients in the OCF group and 21 (23.3%) in the N-OCF group. The p-value was 0.050, indicating a marginal statistical difference between the two groups. Of these, 30 had the disease before SPCs, with 24 progressing to SCC, while 13 developed it after SPCs, with 8 progressing to SCC. Additionally, 8 patients had OPMDs both before and after SPCs, 6 of whom progressed to SCC.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the OCF group, 31 patients (41.3%) exhibited habits of smoking, alcohol consumption, or betel nut chewing, whereas in the N-OCF group, 27 patients (30.0%) reported similar habits. Statistical analysis indicated no significant difference between the two groups.\u003c/p\u003e\n\u003cp\u003eThe overall median time interval between FPCs and SPCs was 106.9 months, with a median of 89.4 months in the OCF group and 121.2 months in the N-OCF group. A statistically significant difference in the time interval was observed between the two groups (\u003cem\u003ep\u003c/em\u003e = 0.0296). Among patients who experienced the occurrence of three primary cancers, the median interval between the first and second cancers was 65.3months, and between the second and third cancers, it was 16.3months.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe histopathological results of both groups were predominantly SCC (160cases,97.0%). In the OCF group, 97.3% of the cases were SCC, while in the N-OCF group, 96.6% were SCC. In the OCF group, the remaining two cases were verrucous carcinoma, while in the N-OCF group, there was one case of central jaw carcinoma and two cases of osteosarcoma.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMost SPCs in both groups were diagnosed at an early stage. The proportion of T1 + T2 was 72.0%(54cases) in the OCF group and 72.2% (65cases) in the N-OCF group, with no statistically significant difference between the two groups.\u003c/p\u003e\n\u003cp\u003eFor FPC treatment, in the OCF group (n=75), 47 patients (62.7%) underwent surgery, and 25 (33.3%) received additional radiation and/or chemotherapy,\u0026nbsp;while 3 patients received primary radiotherapy or chemotherapy alone without surgical intervention. In the N-OCF group (n=90), 21 patients (23.3%) received radiation, 33 (36.7%) individuals received radiotherapy with surgery and/or chemotherapy, 22 (24.4%) patients underwent surgery alone without radiotherapy, and 13 (14.4%) patients received the combined modality of surgery plus chemotherapy (excluding radiotherapy). Treatment modality remained unknown for 1 (1.1%) patient in this group. Among the 54 patients who received radiotherapy, 45 (83.3%) had the radiation field involving the oral cavity.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;As for SPC treatment, both groups primarily received surgery. In the OCF group, 49 patients (65.3%) underwent surgery, with 18 (24.0%) also receiving radiation and/or chemotherapy. Treatment modality remained unknown for 8 (10.7%) patients in this group. In the N-OCF group, 69 patients (76.7%) underwent surgery, and 8 (8.9%) received additional radiation and/or chemotherapy; 6 (6.7%) patients received primary radiotherapy or chemotherapy alone (without surgical intervention), and treatment modality was unclear for 7 (7.7%) patients. A significant difference was observed between the two groups in the treatment of FPC, while no significant difference was found in the treatment of SPC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1\u0026nbsp;\u003c/strong\u003eCharacteristics and treatment of patients with MPOCs\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"625\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003eTotal(n=165)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003eOCF(n=75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003eN-OCF(n=90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003eAge at diagnosis SPC (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e0.0026*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003e\u0026emsp;\u0026emsp;Mean (Range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e59.7 (36\u0026ndash;85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e62.1 (41\u0026ndash;85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e57.2 (36\u0026ndash;80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003eSex, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e0.139\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003e\u0026emsp;\u0026emsp;Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e95 (57.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e38 (50.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e57 (63.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003e\u0026emsp;\u0026emsp;Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e70 (42.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e37 (49.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e33 (36.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003eSmoking/alcohol/betel nut, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e58 (35.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e31 (41.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e27 (30.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e0.176\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003eDental-related issues, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e57 (34.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e33 (44.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e24 (28.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e0.030*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003eOral premalignant disorders, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e50 (30.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e29 (38.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e21 (23.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003eComorbidities, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e68 (41.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e31 (41.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e37 (41.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003eFamily history, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e16 (9.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e5 (6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e11 (12.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e0.349\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003eT stage of SPC, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003e\u0026emsp;\u0026emsp;T1+T2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e119 (72.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e54 (72.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e65 (72.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003e\u0026emsp;\u0026emsp;T3+T4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e46 (27.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e21 (28.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e25 (27.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003eLymph node metastasis, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e38 (23.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e18 (24.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e20 (22.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e0.933\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003eTime interval (months), Median (Range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e106.9 (0.0\u0026ndash;618.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e83.4 (0\u0026ndash;289.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e121.2 (4.93\u0026ndash;618.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003eHistopathology of SPC, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003e\u0026emsp;\u0026emsp;SCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e160 (97.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e73 (97.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e87 (96.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003e\u0026emsp;\u0026emsp;Other\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e5 (3.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e2 (2.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e3 (3.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003eTreatment for FPC, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e0.000*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003e\u0026emsp;\u0026emsp;Surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e69 (41.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e47 (62.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e22 (24.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003e\u0026emsp;\u0026emsp;Radiotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e23 (13.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e2 (2.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e21 (23.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003e\u0026emsp;\u0026emsp;Surgery + Radiotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e16 (9.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e12 (16.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e4 (4.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003e\u0026emsp;\u0026emsp;Chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e2 (1.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e1 (1.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e1 (1.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003e\u0026emsp;\u0026emsp;Surgery + Chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e21 (12.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e8 (10.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e13 (14.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003e\u0026emsp;\u0026emsp;Surgery + Chemo + Radio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e12 (7.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e5 (6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e7 (7.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003e\u0026emsp;\u0026emsp;Chemo + Radio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e21 (12.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e0 (0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e21 (23.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003e\u0026emsp;\u0026emsp;Unknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e1 (0.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e0 (0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e1 (1.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003eTreatment for SPC, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e0.251\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003e\u0026emsp;\u0026emsp;Surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e118 (71.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e49 (65.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e69 (76.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003e\u0026emsp;\u0026emsp;Radiotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e0 (0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e0 (0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e0 (0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003e\u0026emsp;\u0026emsp;Surgery + Radiotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e16 (9.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e9 (12.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e7 (7.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003e\u0026emsp;\u0026emsp;Chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e0 (0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e0 (0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e0 (0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003e\u0026emsp;\u0026emsp;Surgery + Chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e6 (3.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e5 (6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e1 (1.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003e\u0026emsp;\u0026emsp;Surgery + Chemo + Radio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e8 (4.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e4 (5.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e4 (4.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003e\u0026emsp;\u0026emsp;Chemo + Radio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e2 (1.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e0 (0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e2 (2.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003e\u0026emsp;\u0026emsp;Unknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e15 (9.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e8 (10.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e7 (7.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003eAge at diagnosis SPC (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e0.0026*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003e\u0026emsp;\u0026emsp;Mean (Range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e59.7 (36\u0026ndash;85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e62.1 (41\u0026ndash;85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e57.2 (36\u0026ndash;80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003eSex, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e0.139\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003e\u0026emsp;\u0026emsp;Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e95 (57.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e38 (50.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e57 (63.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003e\u0026emsp;\u0026emsp;Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e70 (42.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e37 (49.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e33 (36.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 242px;\"\u003e\n \u003cp\u003eSmoking/alcohol/betel nut, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e58 (35.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e31 (41.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e27 (30.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 96px;\"\u003e\n \u003cp\u003e0.176\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: SPC=Second primary cancer; FPC= First primary cancer; OCF= Oral cancer first; N-OCF= Non-Oral cancer first\u003c/p\u003e\n\u003cp\u003eStatistical significance: *p \u0026lt; 0.05.\u003c/p\u003e\n\u003cp\u003eSites for FPC and SPC\u003c/p\u003e\n\u003cp\u003eIn the OCF group, the most common site for FPC was the tongue, accounting for 36 cases (48.0%), followed by the buccal mucosa (16 cases, 21.3%), gingiva (9 cases, 12.0%), and floor of the mouth (5 cases, 6.7%). For the SPCs, the tongue was also the most frequent site, with 26 cases (34.7%), followed by the buccal mucosa (22 cases, 29.3%), gingiva (9 cases, 12.0%), and hard palate (6 cases, 8.0%). Among these patients, 48 (64.0%) developed their SPCs on the same side as their FPCs in the oral cavity, while 27 (36%) patients developed their SPCs on the opposite side (Fig.1). The odds ratio (OR) for same-side occurrence was 3.16 [1.64, 6.11]. In the N - OCF group, the most common primary cancer was nasopharyngeal carcinoma (44 cases, 48.9%), followed by breast cancer (13 cases, 14.4%), laryngeal cancer (6 cases, 6.7%), and esophageal cancer (5 cases, 5.6%). Colorectal cancer accounted for 4 cases (4.4%), liver cancer for 3 cases (3.3%), lung cancer for 3 cases (3.3%), and cervical cancer for 3 cases (3.3%). Gastric cancer was present in 2 cases (2.2%), while bladder cancer, thyroid cancer, prostate cancer, ovarian cancer, renal cancer, uterine cancer, and lymphoma each had 1 case (1.1%). SPCs in this group were also most commonly located in the tongue (60 cases, 66.7%), followed by the buccal mucosa (9 cases, 10.0%), floor of the mouth (6 cases, 6.7%), gingiva (5 cases, 5.6%) (Fig.2).\u003c/p\u003e\n\u003cp\u003eSurvival\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFollow-up information was obtained from 143 patients, including 63 (44.1%) in the OCF group and 80 (55.9%) in the N-OCF group. A total of 31 deaths were recorded during the follow-up period, with 12 (38.7%) deaths occurring in the OCF group and 19 (61.3%) in the N-OCF group. In this study, the overall median survival time was 148.03 months (97.27,198.85 months), with 1-year, 3-year, and 5-year survival rates of 93.68%, 81.08%, and 74.03%, respectively. The OCF group had a median survival time of 148.03 months (57.05,239.00 months) and corresponding 1-year, 3-year, and 5-year survival rates of 94.50%, 85.30%, and 78.30%. In comparison, the N-OCF group had a median survival time of 103.84 months (94.28,114.38 months) and 1-year, 3-year, and 5-year survival rates of 92.99%, 76.96%, and 69.97%. Despite numerical differences in survival rates, the Kaplan-Meier survival curves revealed no statistically significant disparity between the OCF and N-OCF groups (log-rank test, \u0026chi;\u0026sup2; = 1.306, \u003cem\u003ep\u003c/em\u003e= 0.253; Fig.3).\u003c/p\u003e\n\u003cp\u003eA total of 15 variables were included in the Cox proportional hazards model，namely based on their clinical relevance and prior literature on MPOCs[9-12]: Age, Gender, Site of FPC, Site of SPC, Cervical lymph node metastasis of SPC, Differentiation grade of SPC, Synchronous multiple cancers, T stage of SPC, Treatment method for FPC, Treatment method for SPC, Three or more MPCs, Distant metastasis after SPC, Recurrence after SPC, Time interval between FPC and SPC, Comorbidities. In the univariate regression analysis, seven significant indicators were identified. However, after performing multivariate regression, only four variables remained significant with p \u0026lt; 0.05: age, T stage of SPC, cervical lymph node metastasis of SPC, and recurrence after SPC (Table 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e\u0026nbsp; Univariate and Multivariate cox regression analysis of risk factors of prognosis of MPOCs\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"541\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31.9075%;\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 12.6443%;\"\u003e\n \u003cp\u003eUnivariate Cox\u003c/p\u003e\n \u003cp\u003eregression analyses\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 31.5364%;\"\u003e\n \u003cp\u003eMultivariate Cox\u003c/p\u003e\n \u003cp\u003eregression analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31.9075%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.0755%;\"\u003e\n \u003cp\u003eHR(95%CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.203%;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.2204%;\"\u003e\n \u003cp\u003eHR (95%CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.316%;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 31.9075%;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 22.0755%;\"\u003e\n \u003cp\u003e1.036 (1.009, 1.063)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.203%;\"\u003e\n \u003cp\u003e0.008*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.2204%;\"\u003e\n \u003cp\u003e1.618 (1.097, 2.388)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.316%;\"\u003e\n \u003cp\u003e0.015*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 31.9075%;\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 22.0755%;\"\u003e\n \u003cp\u003e0.542 (0.315, 0.931)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.203%;\"\u003e\n \u003cp\u003e0.026*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.2204%;\"\u003e\n \u003cp\u003e1.519 (0.749, 3.079)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.316%;\"\u003e\n \u003cp\u003e0.247\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 31.9075%;\"\u003e\n \u003cp\u003eSite of FPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 22.0755%;\"\u003e\n \u003cp\u003e0.818 (0.493, 1.356)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.203%;\"\u003e\n \u003cp\u003e0.436\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.2204%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.316%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 31.9075%;\"\u003e\n \u003cp\u003eSite of SPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 22.0755%;\"\u003e\n \u003cp\u003e1.04 (0.969, 1.115)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.203%;\"\u003e\n \u003cp\u003e0.275\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.2204%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.316%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 31.9075%;\"\u003e\n \u003cp\u003eCervical lymph node metastasis of SPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 22.0755%;\"\u003e\n \u003cp\u003e1.838 (1.082, 3.121)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.203%;\"\u003e\n \u003cp\u003e0.024*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.2204%;\"\u003e\n \u003cp\u003e1.004 (1.001, 1.008)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.316%;\"\u003e\n \u003cp\u003e0.021*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 31.9075%;\"\u003e\n \u003cp\u003eDifferentiation grade of SPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 22.0755%;\"\u003e\n \u003cp\u003e0.994 (0.609, 1.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.203%;\"\u003e\n \u003cp\u003e0.980\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.2204%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.316%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 31.9075%;\"\u003e\n \u003cp\u003eSynchronous multiple cancers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 22.0755%;\"\u003e\n \u003cp\u003e0.814 (0.325, 2.038)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.203%;\"\u003e\n \u003cp\u003e0.661\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.2204%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.316%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 31.9075%;\"\u003e\n \u003cp\u003eT stage of SPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 22.0755%;\"\u003e\n \u003cp\u003e1.573 (1.25, 1.979)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.203%;\"\u003e\n \u003cp\u003e0.000*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.2204%;\"\u003e\n \u003cp\u003e2.883 (1.417, 5.864)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.316%;\"\u003e\n \u003cp\u003e0.003*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 31.9075%;\"\u003e\n \u003cp\u003eTreatment method for FPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 22.0755%;\"\u003e\n \u003cp\u003e1.033 (0.922, 1.158)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.203%;\"\u003e\n \u003cp\u003e0.577\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.2204%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.316%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 31.9075%;\"\u003e\n \u003cp\u003eTreatment method for SPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 22.0755%;\"\u003e\n \u003cp\u003e0.987 (0.832, 1.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.203%;\"\u003e\n \u003cp\u003e0.877\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.2204%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.316%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 31.9075%;\"\u003e\n \u003cp\u003eThree or more MPCs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 22.0755%;\"\u003e\n \u003cp\u003e0.814 (0.419, 1.582)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.203%;\"\u003e\n \u003cp\u003e0.544\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.2204%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.316%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 31.9075%;\"\u003e\n \u003cp\u003eDistant metastasis after SPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 22.0755%;\"\u003e\n \u003cp\u003e2.152 (1.067, 4.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.203%;\"\u003e\n \u003cp\u003e0.032*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.2204%;\"\u003e\n \u003cp\u003e1.01 (0.969, 1.052)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.316%;\"\u003e\n \u003cp\u003e0.645\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 31.9075%;\"\u003e\n \u003cp\u003eRecurrence after SPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 22.0755%;\"\u003e\n \u003cp\u003e1.003 (1.001, 1.006)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.203%;\"\u003e\n \u003cp\u003e0.019*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.2204%;\"\u003e\n \u003cp\u003e0.405 (0.189, 0.869)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.316%;\"\u003e\n \u003cp\u003e0.020*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 31.9075%;\"\u003e\n \u003cp\u003eTime interval between FPC and SPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 22.0755%;\"\u003e\n \u003cp\u003e1.756 (1.056, 2.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.203%;\"\u003e\n \u003cp\u003e0.030*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.2204%;\"\u003e\n \u003cp\u003e1.36 (0.592, 3.123)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.316%;\"\u003e\n \u003cp\u003e0.468\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 31.9075%;\"\u003e\n \u003cp\u003eComorbidities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 22.0755%;\"\u003e\n \u003cp\u003e1.008 (0.592, 1.716)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.203%;\"\u003e\n \u003cp\u003e0.976\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.2204%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11.316%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eNote: HR: hazard ratio, CI: confidence interval\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eMultiple Primary Cancers (MPCs) refer to the occurrence of two or more independent malignant tumors in the same or different organs[6]. The head and neck region is one of the most common sites for the occurrence of MPCs[13]. In previous literatures, the definition of MPOCs has often been limited to cases where all primary cancers occur within the oral cavity, overlooking patients who develop oral cancer after malignancies in other parts of the body. To address this, the present study classifies MPOCs patients into two groups based on the site of the first primary cancer: the OCF group (oral cavity first) and the N-OCF group (non-oral cavity first) in order to better understand the similarities and differences. Due to the relatively small number of patients with three primary malignancies, this study primarily focuses on the second primary cancer. By distinguishing OCF and N-OCF subgroups, this study aims to uncover distinct biological behaviors between the two groups and optimize personalized management for MPOCs patients.\u003c/p\u003e\n\u003cp\u003ePrevious studies have reported a higher prevalence of MPCs in the head and neck region among female[5, 9]. However, in this study, both the OCF group and the N-OCF group consisted of a higher number of male patients. This discrepancy may be due to the fact that in the OCF group, the majority of patients with unhealthy habits such as smoking and betel nut chewing, which are known to increase the risk of multiple primary cancers, were male. While in the N-OCF group, nasopharyngeal carcinoma\u0026mdash; a type of cancer that predominantly affects males[14]\u0026mdash;constituted the majority. In terms of age, the mean onset age of a SPC in MPOCs patients is 59.4\u0026plusmn;\u0026nbsp;10.2 years, which is younger than the ages reported in previous studies[5, 9, 15], suggesting a potential trend of MPOCs occurring at a younger age. Additionally, the onset age of a SPC in the N-OCF group is younger than in the OCF group, which may be related to the immune abnormalities caused by a FPC, the effects of chemotherapy and radiotherapy, or genetic susceptibility.\u003c/p\u003e\n\u003cp\u003eThe occurrence of MPOCs tends to show specific site-related characteristics[16]. While previous study has suggested a higher risk in keratinized epithelium[5], this study\u0026apos;s findings differ. In the OCF group, the tongue was also the most common site for FPC, followed by the buccal mucosa and gingiva, with a notable tendency for the cancers to occur on the same side. This same-side preference support the \u0026ldquo;field cancerization\u0026rdquo; theory, suggesting that localized exposure to carcinogens (e.g., tobacco or alcohol) may induce widespread molecular alterations in adjacent tissues, predisposing them to malignant transformation [17]. Furthermore, as mentioned by Ko in his study[18], due to the complexity of surgery and the alteration of lymphatic drainage pathways, patients with contralateral SPCs may have better survival outcomes compared to those with ipsilateral SPCs.\u003c/p\u003e\n\u003cp\u003eAmong the 54 patients in the N-OCF group who received radiotherapy for their FPCs, 45 had the radiation field involving the oral cavity, with 43 of them receiving radiotherapy due to nasopharyngeal carcinoma (NPC). NPC is a disease with a high incidence in Guangdong Province[19], where radiotherapy is the primary treatment modality. Radiotherapy, while effective in targeting tumor cells, induces double-strand DNA breaks and chromosomal aberrations in adjacent normal tissues, which may accumulate over decades and culminate in secondary malignancies, particularly in the tongue and gingiva[20-22]. Moreover, the similarity in epithelial structure between the nasopharynx and the oral cavity, as well as their anatomical proximity, may enhance the effects of \u0026quot;field cancerization\u0026quot;. In addition, shared risk factors, such as smoking, may simultaneously affect both sites[23], thus increasing the likelihood of developing oral cancer following NPC. As Vogt A[6] noted, MPCs are more likely to occur in different organs within the same system. These mechanisms are also relevant for patients with a FPC in the larynx or esophagus, as both are located in the upper digestive tract.\u003c/p\u003e\n\u003cp\u003eThe time interval between FPCs and SPCs may reflect the mechanisms of cancer development, the impact of FPCs treatment, and the patient\u0026apos;s cancer risk. The median time interval in the N-OCF group (121.2 months) was significantly longer than that in the OCF group (89.4 months), with both intervals exceeding the 5-year mark. Importantly, radiation-induced SPCs typically manifest after prolonged latency periods of 15\u0026ndash;20 years [24, 25], as demonstrated in this study by a patient who developed a giant cell osteosarcoma 609 months after NPC. This extended period is a time when both patients and doctors are likely to become less vigilant. Therefore, our findings underscore the importance of long-term, regular follow-ups, especially NPC patients receiving radiotherapy, not only of the nasopharynx but also of the oral cavity.\u0026nbsp;Notably, among the 19 patients with three or more primary cancers, the time interval between the FPC and SPC was 65.3 months, but it significantly decreased to 16.3 months between the second and third cancers. Although the sample size is small, these findings suggest that patients with a history of MPOCs should be closely monitored.\u003c/p\u003e\n\u003cp\u003eThe etiology of MPOCs is not yet fully understood. However, it is well - established that behaviors such as smoking, alcohol consumption, and betel nut chewing are significantly associated with its development[4]. These factors can increase the risk of a SPC in a dose - dependent manner[26]. In our study, 35.1% of MPOCs patients had a history of these habits, thereby highlighting the susceptibility of the oral mucosa to carcinogens[27]. It is worth noting that 57.8% of patients who had quit these habits still developed MPCs, suggesting that the damage to the mucosa may be long - lasting. Furthermore, chronic irritations, such as poor oral hygiene or ill - fitting dentures, can also contribute to an increased risk of cancer[28].\u003c/p\u003e\n\u003cp\u003eEpidemiological studies have reported that 80% of oral cancers are preceded by OPMDs[29], and the incidence of OPMDs is higher among MPOCs patients[4]. In our study, OPMDs were detected in 38.7% of the OCF group and 23.3% of the N - OCF group, both before and after the development of SPCs. These findings underscore the persistence of OPMDs, as previous research has shown that they can even occur on free grafted flaps[30]. The high malignant transformation rate of OPMDs in this study also warrants attention, even though the data may overestimate the true situation, as many of the patients were referred to our department after unsuccessful treatment in oral mucosal clinics. Nevertheless, while surgical intervention reduces the risk of malignant transformation, it does not completely eliminate the possibility[31]. Therefore, preventive strategies should not only focus on the elimination of harmful habits but also include early screening, risk identification, and anti-inflammatory or chemopreventive interventions[32] to mitigate mucosal damage and prevent the occurrence of MPCs.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The overall survival curves and median survival times in this study were higher than those reported in earlier literature. The authors speculate that this discrepancy may be attributed to advancements in cancer treatment in recent years, particularly with the advent of immune therapies such as PD-1/PD-L1 inhibitors[33] , which may \u0026nbsp;improve long-term survival outcomes. Additionally, most patients in this study were diagnosed with SPCs at an early stage (T1 or T2) and received timely intervention, contributing to a favorable prognosis. Besides, the patients who were completely lost to follow-up may have also caused errors in the survival analysis. The survival curves between the two groups showed no notable differences. Nevertheless, the survival rate of the N-OCF group was slightly lower than that of the OCF group at 1, 3, and 5 years, with a noticeable decline in the N-OCF group\u0026rsquo;s survival rate after 100 months. The authors suggest that this may be due to the more diverse treatment modalities (e.g., chemotherapy and radiotherapy) used in the N-OCF group, which might lead to severe side effects that affect long-term health and survival. Furthermore, oral cancers are typically more localized, and, compared to cancers such as breast, lung, and colorectal cancers, they generally exhibit a lower rate of systemic metastasis[34-36].\u003c/p\u003e\n\u003cp\u003eMultivariate analysis identified four key prognostic factors: age, SPC T stage, cervical lymph node metastasis, and SPC recurrence (all p \u0026lt; 0.05). Although previous literature has reported that the site of FPC significantly affects long-term survival[37], in our study, through both univariate and multivariate analyses, that the FPC site does not have a significant effect on patient survival. Age, however, has been identified as a high-risk factor for the occurrence of MPCs[38], as in our study, age also emerged as an important factor influencing prognosis. Additionally, the T stage of SPC, cervical lymph node metastasis, and distant metastasis were found to be significant factors affecting survival. These results highlight the importance of regular postoperative follow-up, early detection, and timely treatment for patients with a history of cancer. Moreover, recurrence after SPC surgery significantly impacted survival, whereas the development of a third primary cancer did not. This may be due to two factors: the relatively small number of patients with third primary cancers in this study, and different mechanisms underlying recurrence and third primary cancers[39]. Recurrent tumors are often more aggressive and resistant to treatment, placing a greater burden on the patient, particularly when the immune system has not fully recovered. Gleber also pointed out that patients with multiple primary cancers are likely to have better long - term survival than those with recurrent cancers[40]. In contrast to Cai\u0026apos;s study[41], which reported a higher mortality risk for patients with MPCs located in the floor of the mouth, our study found that the location of the SPCs did not affect survival. Similarly, whether the MPCs were synchronous or metachronous did not influence prognosis in our study, although previous literature often reports a poorer prognosis for patients with synchronous MPCs[5]. This discrepancy may be attributed to the smaller sample sizes of synchronous MPCs patients and those with floor of the mouth cancer in this study, which needs further research.\u003c/p\u003e\n\u003cp\u003eThe limitations of this study include: (1) Missing data, particularly regarding NPC patients who received radiotherapy in the OCF group (e.g., radiation dose, modality and EBV-related information), prevented further analysis of the impact of radiotherapy;(2) The inability to track non-oral malignancies after SPCs, affecting survival analysis; (3) Small sample sizes for patients with three or more primary cancers and synchronous cancers; (4) Missing follow-up data, leading to potential bias; (5) The lack of a solitary oral cancer comparison group in this single-center study.\u003c/p\u003e\n\u003cp\u003eTo the best of our knowledge, this is the first study focusing on the differences between OCF and N-OCF groups, which may contribute to a better understanding of the mechanisms underlying MPOCs, and potentially enable more personalized treatment strategies and prognosis predictions. Future multicenter studies with larger sample sizes and predictive biomarkers[42] are needed to refine treatment strategies and improve outcomes for MPOCs patients.\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn both OCF and N-OCF cohorts, the tongue was the predominant site for the second primary malignancy. The OCF group also exhibited a preference for the tongue as the site of the FPC. Additionally, SPCs tended to occur on the same side as the FPCs. Nasopharyngeal carcinoma was the most common site for the FPC in the N-OCF group, with radiotherapy being the primary treatment modality. The diagnosis and management of OPMDs in MPOCs patients require attention. Survival does not significantly differ between OCF and N-OCF group. Key factors affecting MPOCs patient survival include age, T stage of SPC, cervical lymph node metastasis of SPC and recurrence after SPC.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of interest statement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval and Consent to Participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in strict accordance with the ethical principles of the Declaration of Helsinki and relevant national and international guidelines and was approved by the Medical Ethics Committee of the Affiliated Stomatological Hospital of Sun Yat-sen University. The approval number is ERC-[2017]-26. All participants in this clinical research provided informed consent before any study-related procedures were conducted. The informed consent form was reviewed and approved by the Ethics Committee, and all participants were fully informed about the study objectives, procedures, potential risks and benefits, and their rights to withdraw from the study at any time without any penalty.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors have given their consent for the publication of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data and Materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study did not receive any funding from any organizations or institutions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eQiannan Liu*, Shanshan Tang*, Le Yang* These authors have contributed equally to this work and share the first authorship, they did data acquisition、statistical analysis and have drafted the work ,then substantively revised it. Guiqing Liao, Yujie Liang, Le Yang have made substantial contributions to the conception and design of the study, and reviewed the manuscript carefully. Farong Ou, Huanzi Lu, Kan Li, Zengyu Chen helped to do the data acquisition and analysis\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to acknowledge the contributions of all the participants in this study. We also thank the staff of Sun Yat-sen University Affiliated Stomatological Hospital for their support and assistance during the conduct of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; Information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor 1:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eQiannan Liu, First Author, Department of Stomatology, Hospital of Stomatology, Sun Yat-sen University, 56th Lingyuanxi Road, Guangzhou, Guangdong, 510055, China; Guangdong Province Key Laboratory of Stomatology, No. 74, 2nd Zhongshan Road, Guangzhou, 510080, Guangdong, China. Email: [email protected].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor 2:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eShanshan Tang, Co - first Author, Department of Stomatology, Hospital of Stomatology, Sun Yat-sen University, 56th Lingyuanxi Road, Guangzhou, Guangdong, 510055, China; Guangdong Province Key Laboratory of Stomatology, No. 74, 2nd Zhongshan Road, Guangzhou, 510080, Guangdong, China. Email: [email protected]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor 3:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLe Yang, Co - first Author, Department of Stomatology, Hospital of Stomatology, Sun Yat-sen University, 56th Lingyuanxi Road, Guangzhou, Guangdong, 510055, China; Guangdong Province Key Laboratory of Stomatology, No. 74, 2nd Zhongshan Road, Guangzhou, 510080, Guangdong, China. Email: [email protected]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor 4:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFarong Ou, Co - author, Department of Stomatology, Hospital of Stomatology, Sun Yat-sen University, 56th Lingyuanxi Road, Guangzhou, Guangdong, 510055, China; Guangdong Province Key Laboratory of Stomatology, No. 74, 2nd Zhongshan Road, Guangzhou, 510080, Guangdong, China. Email: [email protected]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor 5:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKan Li, Co - author, Department of Stomatology, Hospital of Stomatology, Sun Yat-sen University, 56th Lingyuanxi Road, Guangzhou, Guangdong, 510055, China; Guangdong Province Key Laboratory of Stomatology, No. 74, 2nd Zhongshan Road, Guangzhou, 510080, Guangdong, China. Email: [email protected]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor 6:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHuanzi Lu, Co - author, Department of Stomatology, Hospital of Stomatology, Sun Yat-sen University, 56th Lingyuanxi Road, Guangzhou, Guangdong, 510055, China; Guangdong Province Key Laboratory of Stomatology, No. 74, 2nd Zhongshan Road, Guangzhou, 510080, Guangdong, China. Email: [email protected]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor 7:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZengyu Chen, Co - author, Department of Stomatology, Hospital of Stomatology, Sun Yat-sen University, 56th Lingyuanxi Road, Guangzhou, Guangdong, 510055, China; Guangdong Province Key Laboratory of Stomatology, No. 74, 2nd Zhongshan Road, Guangzhou, 510080, Guangdong, China. Email: [email protected]\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCheng J, Zhou X, Xu H, Dan H, Li J, Chen Q: \u003cstrong\u003eIncidence and Survival of Oral Cavity and Oropharyngeal Cancer in the United States From 1975 to 2018\u003c/strong\u003e. \u003cem\u003eJournal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons \u003c/em\u003e2022, \u003cstrong\u003e80\u003c/strong\u003e(7):1294-1305.\u003c/li\u003e\n\u003cli\u003eBertolini F, Trudu L, Banchelli F, Schipilliti F, Napolitano M, Alberici MP, Depenni R, D\u0026apos;Angelo E, Mattioli F, Rubino L\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eSecond primary tumors in head and neck cancer patients: The importance of a \u0026quot;tailored\u0026quot; surveillance\u003c/strong\u003e. \u003cem\u003eOral diseases \u003c/em\u003e2021, \u003cstrong\u003e27\u003c/strong\u003e(6):1412-1420.\u003c/li\u003e\n\u003cli\u003eGupta AK, Kanaan M, Siddiqi K, Sinha DN, Mehrotra R: \u003cstrong\u003eOral Cancer Risk Assessment for Different Types of Smokeless Tobacco Products Sold Worldwide: A Review of Reviews and Meta-analyses\u003c/strong\u003e. \u003cem\u003eCancer prevention research (Philadelphia, Pa) \u003c/em\u003e2022, \u003cstrong\u003e15\u003c/strong\u003e(11):733-746.\u003c/li\u003e\n\u003cli\u003eLin X, Wu X, Gomaa A, Chen J, Wu L, Xie X, Hu Y, Jiang C: \u003cstrong\u003eAnalysis of risk factors for multiple primary oral squamous cell carcinoma: a cohort study\u003c/strong\u003e. \u003cem\u003eClinical oral investigations \u003c/em\u003e2020, \u003cstrong\u003e24\u003c/strong\u003e(9):3147-3155.\u003c/li\u003e\n\u003cli\u003eMochizuki Y, Harada H, Ikuta M, Shimamoto H, Tomioka H, Tanaka K, Hirai H, Omura K: \u003cstrong\u003eClinical characteristics of multiple primary carcinomas of the oral cavity\u003c/strong\u003e. \u003cem\u003eOral oncology \u003c/em\u003e2015, \u003cstrong\u003e51\u003c/strong\u003e(2):182-189.\u003c/li\u003e\n\u003cli\u003eVogt A, Schmid S, Heinimann K, Frick H, Herrmann C, Cerny T, Omlin A: \u003cstrong\u003eMultiple primary tumours: challenges and approaches, a review\u003c/strong\u003e. \u003cem\u003eESMO open \u003c/em\u003e2017, \u003cstrong\u003e2\u003c/strong\u003e(2):e000172.\u003c/li\u003e\n\u003cli\u003eWarren S GO:\u003cstrong\u003e Mutiple primary malignant tumors: a survey of the liter ature and a statistical study\u003c/strong\u003e. \u003cem\u003eAmerican J Cancer \u003c/em\u003e1932, \u003cstrong\u003e16\u003c/strong\u003e:1358-1141.\u003c/li\u003e\n\u003cli\u003eHong WK LS, Itri LM, Karp DD, Lee JS, Byers RM, Schantz SP, Kramer AM, Lotan R, Peters LJ, et al: \u003cstrong\u003ePrevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck\u003c/strong\u003e. \u003cem\u003eN Engl J Med \u003c/em\u003e1990 Sep 20, \u003cstrong\u003e323\u003c/strong\u003e:795-801.\u003c/li\u003e\n\u003cli\u003eChoi SW, Thomson P: \u003cstrong\u003eMultiple oral cancer development-Clinico-pathological features in the Hong Kong population\u003c/strong\u003e. \u003cem\u003eJ Oral Pathol Med \u003c/em\u003e2020, \u003cstrong\u003e49\u003c/strong\u003e(2):145-149.\u003c/li\u003e\n\u003cli\u003eMochizuki Y, Harada H, Ikuta M, Shimamoto H, Tomioka H, Tanaka K, Hirai H, Omura K: \u003cstrong\u003eClinical characteristics of multiple primary carcinomas of the oral cavity\u003c/strong\u003e. \u003cem\u003eOral oncology \u003c/em\u003e2015, \u003cstrong\u003e51\u003c/strong\u003e(2):182-189.\u003c/li\u003e\n\u003cli\u003eQaisi M, Vorrasi J, Lubek J, Ord R: \u003cstrong\u003eMultiple primary squamous cell carcinomas of the oral cavity\u003c/strong\u003e. \u003cem\u003eJournal of Oral and Maxillofacial Surgery \u003c/em\u003e2014, \u003cstrong\u003e72\u003c/strong\u003e(8):1511-1516.\u003c/li\u003e\n\u003cli\u003eDe Vries N, Van der Waal I, Snow G: \u003cstrong\u003eMultiple primary tumours in oral cancer\u003c/strong\u003e. \u003cem\u003eInternational journal of oral and maxillofacial surgery \u003c/em\u003e1986, \u003cstrong\u003e15\u003c/strong\u003e(1):85-87.\u003c/li\u003e\n\u003cli\u003eChen Q, Huang B, Anderson AM, Durbin EB, Arnold SM, Kolesar JM: \u003cstrong\u003eAssociation of first primary cancer with risk of subsequent primary cancer among survivors of adult-onset cancers in Kentucky and Appalachian Kentucky\u003c/strong\u003e. \u003cem\u003eFrontiers in oncology \u003c/em\u003e2023, \u003cstrong\u003e13\u003c/strong\u003e:1193487.\u003c/li\u003e\n\u003cli\u003eChang ET, Ye W, Zeng YX, Adami HO: \u003cstrong\u003eThe Evolving Epidemiology of Nasopharyngeal Carcinoma\u003c/strong\u003e. \u003cem\u003eCancer epidemiology, biomarkers \u0026amp; 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This study examines the clinical characteristics and prognosis in both scenarios.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: A retrospective review of 165 patients at\u0026nbsp;the Affiliated Stomatological Hospital of Sun Yat-sen University\u0026nbsp;identified 75 oral cancer first (OCF) cases and 90 non-oral cancer first (N-OCF) cases. We conducted a comparative analysis of clinical characteristics and prognosis between the two groups.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: MPOCs were more common in males, with an average age of 59.4 years, primarily presenting as early-stage squamous cell carcinoma (SCC), with the tongue as the most frequent site for secondary primary cancer (SPC). In the OCF group, the most common site for the first primary cancers\u0026nbsp;(FPC) was also the tongue, whereas in the N-OCF group, it was the nasopharynx. Survival rates were comparable between the two groups, with key prognostic factors including age(p=0.015), SPC T stage(p=0.003), cervical lymph node metastasis of SPC(p=0.021), and recurrence after SPC(p=0.020).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: Patients with a history of nasopharyngeal cancer require long-term oral follow-up. While the location of FPC and SPC does not impact prognosis, early diagnosis and treatment significantly improve outcomes by enabling timely intervention before tumors advance or metastasize. Effective management of OPMDs is crucial for improving outcomes in MPOCs patients.\u003c/p\u003e","manuscriptTitle":"Clinical Outcomes and Prognostic Factors in Multiple Primary Malignancies Involving Oral Cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-17 06:34:10","doi":"10.21203/rs.3.rs-5780078/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-29T09:19:41+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-29T09:17:17+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-27T22:23:20+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-25T12:53:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"18493267769037947239219065715438638310","date":"2025-04-16T11:37:05+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"100800239549965153506510608995080630536","date":"2025-04-14T15:31:54+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-14T10:16:54+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-11T07:20:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Oral Health","date":"2025-04-10T04:27:50+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":"7a99de9a-90e0-48ff-80c7-679e74254772","owner":[],"postedDate":"April 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-07-14T16:04:44+00:00","versionOfRecord":{"articleIdentity":"rs-5780078","link":"https://doi.org/10.1186/s12903-025-06141-9","journal":{"identity":"bmc-oral-health","isVorOnly":false,"title":"BMC Oral Health"},"publishedOn":"2025-07-07 15:57:14","publishedOnDateReadable":"July 7th, 2025"},"versionCreatedAt":"2025-04-17 06:34:10","video":"","vorDoi":"10.1186/s12903-025-06141-9","vorDoiUrl":"https://doi.org/10.1186/s12903-025-06141-9","workflowStages":[]},"version":"v1","identity":"rs-5780078","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5780078","identity":"rs-5780078","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}