Epidemiology and survival outcomes of lip, oral cavity, and oropharyngeal squamous cell carcinoma in a southeast Brazilian population

Background Lip, oral cavity, and oropharyngeal squamous cell carcinoma (SCC) represent a major health problem in the global scenario. In South America, the highest incidence rates are seen in Brazil. Therefore, the epidemiological and clinical profile and survival outcomes of lip, oral cavity, and oropharyngeal SCC was studied in São Paulo State, Brazil. Material and Methods The clinicopathological data of 12,099 patients with lip, oral cavity, and oropharyngeal SCC were obtained from hospital cancer registries of the Fundação Oncocentro de São Paulo, Brazil (2010–2015). Survival rates and other analyses were performed using SPSS software. Results A clear male predominance was observed, particularly for patients with oropharyngeal SCC (88.3%). The average age of patients was higher for lip cases (65 ± 13.5 years) compared to other sites. The schooling level was low for most patients, especially in lip cases (87.9%). Most of the patients with oral cavity (71.8%) and oropharyngeal (86.3%) SCC had advanced-stage (III–IV) disease. However, the majority of lip cases (83.3%) were at an early stage (I–II). Surgical excision was the main treatment for lip (72%) and oral cavity SCC (23.5%), and chemoradiotherapy was the main treatment for oropharyngeal SCC (40.2%). The 5-year overall survival (OS) for patients with lip, oral cavity, and oropharyngeal SCC were 66.3, 30.9, and 22.6%, respectively. Multivariate analysis revealed that the determinants of OS were different for lip, oral cavity, and oropharyngeal SCC, except for those at the clinical stage, which was an independent predictor for all sites. Conclusions OS-independent determinants varied according to the affected site. Oral cavity and oropharyngeal SCC presented worse survival rates than those for lip SCC. Key words:Squamous cell carcinoma of head and neck, lip neoplasms, mouth neoplasms, oropharyngeal neoplasms, survival analysis.


Introduction
Oral cancer, including lip cancer, is one of the most common cancers around the world, falling within the top ten cancers in several countries, with an estimated 377,713 new cases in 2020. When analysed together with the oropharynx, these two locations comprise approximately 476,125 new cases, accounting for 2.5% of all cancer cases and 225,900 deaths (177,757 deaths for oral cancer and 48,143 deaths for oropharyngeal cancer) (1,2). In 2020, the estimated age-standardised rates of oral cancer were 6.0 and 2.3 per 100,000 in men and women, respectively, whereas for oropharyngeal cancer, they were 1.8 and 0.4 per 100,000 in men and women, respectively (2). Most patients diagnosed with oral cavity and oropharyngeal cancers report a previous history of smoking and alcohol consumption, which are well recognised risk factors (3). Additionally, human papillomavirus (HPV) infection has been associated with the development of a distinct subset of head and neck squamous cell carcinomas (SCC), particularly in the oropharynx (4), and ultraviolet radiation from sunlight exposure for lip SCC (2). The incidence of oral and oropharyngeal cancer in Central and South America is not homogenous, and the highest rates are seen in Brazil, particularly for males, and are up to three-times higher than in other Central and South American countries (5). The Fundação Oncocentro de São Paulo (FOSP) is a Brazilian public database that collects data from all hospitals that perform cancer treatment in São Paulo State, and it is updated every three months. The epidemiological and clinical profile and survival outcomes of the lip, oral cavity, and oropharyngeal SCC were assessed in the São Paulo State, Brazil, from a FOSP database (2010)(2011)(2012)(2013)(2014)(2015).

Material and Methods
-Sample This is a retrospective cross-sectional study using secondary data. Data I-II and III-IV), time between diagnosis and treatment, cancer treatment, and patients' status (alive or died). -Statistical analysis The qualitative and quantitative data were presented descriptively, and missing values were excluded from the analysis, with only valid percentages being considered. An association analysis between demographic and clinicopathological variables with tumour site was performed using the Chi-square test. All lip, oral cavity, and oropharyngeal SCC cases that reported the patients' follow-up and status were included for survival analysis. The Kaplan-Meier method was used to estimate survival rates, and the difference between survival curves was investigated by using the Log-Rank univariate test. The univariate Cox proportional hazard regression model was employed to identify potential prognostic factors. A multivariate Cox regression model was created using all variables that achieved a p-value ≤ 0.20. Data analyses were performed with SPSS software version 22.0 (IBM Corporation, Armonk, NY, USA), and a p-value ≤ 0.05 was considered statistically significant.

Results
The data collected from 76 hospital cancer registries (HCRs) of the São Paulo State found a total of 368,116 cancer cases in the period between 2010 and 2015. Of these, 12,099 patients were diagnosed with lip, oral cavity, and oropharyngeal SCC (Fig. 1). Fig. 2 shows the distribution of all cases according to the 17 HRDs in São Paulo State. The demographic and clinicopathological features of the 12,099 cases of lip, oral cavity, and oropharyngeal SCC are summarised in Table 1. -Lip SCC About 73.3% (732 cases) of 998 patients with lip SCC were male, with a male-to-female ratio of 2.8:1. Regarding schooling level, most individuals (87.9%; 717 cases) had less than or equal to 8 years of formal education. The patients' ages ranged from 22 to 104 years old, with a mean age at diagnosis of 65.0 ± 13.5 years, mainly affecting patients over 60 years (61.8%; 616 cases). The most common site-affected subsite was the lower lip (79.4%; 793 cases), followed by lip, not otherwise specified (NOS; 9.5%; 95 cases) and upper lip (7.5%; 75 cases; Supplement 1). Most patients presented early-stage tumours (stages I-II) at diagnosis (83.3%; 810 cases). For most patients, the treatment was performed 60 days after diagnosis (69.5%; 423 cases), with surgery being the main treatment modality (72.0%; 718 cases), followed by radiotherapy (RT) alone (7.1%; 71 cases), and a combination of surgery and RT (7%; 69 cases). Approximately 5.1% (51 cases) of cases did not receive any active treatment, and the main reason was not specified (2.8%; 29 cases).

Discussion
Lip, oral cavity, and oropharyngeal cancers represent a major health problem in the global scenario, and together, comprise the eighth most common malignancy worldwide. Brazil has the highest incidence of oral and oropharyngeal cancer in Central and South America,   al. (3) reported a trend towards stabilization and even a slight decline in the incidence of OSCC and a significantly increased of OPSCC cases, mainly HPV-positive OPSCC, in middleand high-income countries in the past decades, including Brazil. The high rate of OPSCC found in our study may reflect this increase observed in these tumours in the recent decades. However, the FOSP database did not report the HPV status in the recorded OPSCC cases, which makes the association between HPV infection and the high number of cases of OPSCC difficult. Recent studies from Brazil shows that the prevalence of HPV-positive OPSCC ranges from 6.1% to 59.1% (4,13).
Lip SCC and OSCC mainly occurred in older people.
The average age at the time of diagnosis was approximately 65 ± 13.5 years and 60.3 ± 12.1 years in the present study, respectively, which corroborates previous studies performed in Italy (10), Mexico (14), and the United States (US) (15) for lip SCC and Brazil (8), Japan (16), and Australia (17) for OSCC. In contrast, the mean age at diagnosis was lowest for OPSCC (58.6 ± 10 years), with the prevalence peaking in the sixth decade of life. Similar findings were reported by other studies (6,18), in which the average age was lower compared to lip SCC and OSCC, mainly in the cases of HPV-positive OPSCC, where the mean age was usually less than 60 years (19,20). Oral cancer is related to socioeconomic status and deprivation, with the highest incidence rates occurring in the most disadvantaged population groups. Moro et al.  (19) and Australia (12), reported higher educational levels in these patients. The definition of the limits of the oral cavity varies between studies. Some authors include lips (9,14,22), whereas others do not (8,21). Due to this controversy, the lip and oral cavity were classified as different sites in this study. Lip SCC accounted for approximately onethird of OSCC cases (15). When lip SCC was exclusively analysed, previous studies reported that the lower lip was the most commonly affected site (10,15,23), similar to our findings. In the oral cavity, according to previous reports (7,9,14,22) and our results, the tongue (excluding the base of the tongue) was the most commonly affected subsite. However, in India and surrounding countries, the most frequent subsite of OSCC was the buccal mucosa, as a repercussion of the habit of chewing tobacco (24). Elwood et al. (18) and Dahlstrom et al. (19) reported that the most common subsite for OPSCC were tonsils, which is in contrast with the present study, where the base of the tongue was the most common subsite.
In general, the lip region is more accessible, facilitating early cancer detection and diagnosis (9). Previous studies performed in the US (15) and Serbia (23) reported that most lip SCC cases were in the early stage (stages I-II) at diagnosis, with few patients presenting regional and distant metastasis. In contrast, Fukumoto et al. (16), Oliveira et al. (21), and Listl et al. (25) described that the diagnosis of OSCC was usually delayed, allowing for local extension and regional metastasis; consequently, most cases were advanced-stage disease (stages III-IV).
Schroeder et al. (20) and Kowalski et al. (8) observed that more than 70% of OPSCC patients were at stages III-IV. In agreement, these observations were consistent with our findings for the three sites.
Due to the early stages at the time of diagnosis, surgical resection with wide local excision is the main choice of treatment for lip SCC (15,23). Likewise, in our sample, 72% of lip SCC cases were treated with surgery alone. Although most cases were in the advanced stage, surgery alone was the most frequently employed treatment for OSCC cases in our sample, which corroborates previous reports (8,16,26). Nevertheless, in the studies performed by Asio et al. (22) and Oliveira et al. (21), RT alone was the most used treatment in OSCC cases. The oropharynx is not easy to access, and OPSCC usually presents as an advanced disease. Chemoradiotherapy was the main choice of treatment, being employed in approximately 40.2% of our cases, and confirming previous reports from Brazil (8) and another from the United Kingdom (20). It is important to emphasise that lip SCC exhibited a better survival curve in our study, with a 5-year OS rate of 66.3%, which agreed with reports in the US (15) and Germany (25) (28) found that the 5-year OS rate was slightly better than the report from the US, at 54.5%. The worst outcomes were reported in southern Taiwan (29) and Uganda (22) .00) with advanced-stage (stages III-IV) tumours were more likely to die than patients with early-stage disease, which was an important independent determinant of OS, corroborating the findings reported in earlier studies (7,8,15,22,27). Pathology laboratories provide cancer diagnostic services and key prognostic factors that guide patient treatment decision. In Brazil, the university oral pathology laboratories performed an important role in oral cancer diagnosis and the national public health system (SUS) (33). In our study, patients with OPSCC diagnosed by public laboratories/hospitals (SUS) presented higher mortality rates (HR: 2.45; 95% CI, 1.66-3.62). However, these findings for patients with OPSCC can be attributed to several reasons and may include lack of awareness of cancer signs and symptoms, the patient, who can often take a long time to seek care, and the access to the public health service for the biopsy which can be difficult, especially in public tertiary health centers, including oncology hospitals. Therefore, most cases are diagnosed in advanced-stages and, consequently, the potential curability of OPSCC decreases considerably (1,34).
The delay between diagnosis and the start of treatment at over 60 days was associated with a high mortality hazard for OSCC (HR: 1.27; 95% CI, 1.14-1.41) and OPSCC (HD: 1.19; 95% CI, 1.08-1.31) patients. In Australia (17), the median time between diagnosis and treatment was 30 days for OSCC, and in Brazil, the median time was up to 3-times higher (34), which was similar to our findings (75 days). Finally, according to Felippu et al. (34), this delay was associated with factors such as the low intellectual and social status of most patients, as well as the shortcomings of the public health care system. Patients treated with surgery alone presented higher survival rates compared to patients treated with combinations of RT and CT. Fukumoto et al. (16), Bai et al. (7), and Farhood et al. (27) found similar results. However, the treatment must be done carefully, as advancedstage disease usually requires more complex treatments with the use of RT and/or CT. Furthermore, the protocols used and the patient's collaboration can also influence the choice of treatment.

Conclusions
Based on this robust analysis of 12,099 cases of lip SCC, OSCC, and OPSCC derived from the FOSP database, this report highlights a marked male predominance, mainly affecting patients over 60 years old and with less than or equal to 8 years of education, presenting as an advanced-stage (stages III-IV) disease. The independent prognostic factors varied according to tumour site in multivariate analysis, except for tumour stage, which was a significant determinant of survival for all three sites. In addition, OSCC and OPSCC presented worse 5-year OS rates, whereas lip SCC had a high OS rate. However, an improvement in OS was observed for patients diagnosed in the more recent years of study (2013)(2014)(2015).