Abstract
Background/Aim: Despite the global rise in the incidence of human papillomavirus (HPV)-positive oropharyngeal carcinoma (OPC) in recent years, its prevalence and oncological outcomes in patients living in rural areas of Northern Japan has not been explored and should be investigated. Patients and Methods: A total of 105 patients with oropharyngeal squamous cell carcinoma who underwent HPV screening and received first-line treatment were included in this study. The annual changes in the number of patients, survival rates, and clinical factors affecting prognosis were examined. Results: The HPV-positive rate in patients with OPC was low, with the lowest rate of 10.0% in 2013 and the highest rate of 46.7% in 2020. The number of HPV-negative cases remained almost unchanged, whereas the overall number of cases increased with the increasing number of HPV-positive cases. Additionally, HPV-positive cases exhibited a fairly good prognosis. Conclusion: The number of OPC cases increased not only in urban areas, but also in rural areas. HPV-positive cases had better outcomes than HPV-negative cases.
Oropharyngeal carcinoma (OPC) has attracted increasing attention in recent years because of its increasing prevalence and association with human papillomavirus (HPV) infection (1). The staging system has been revised to account for the clarified understanding that HPV-positive cases exhibit better treatment responsiveness than HPV-negative cases (2, 3). When diagnosing squamous cell carcinoma of the oropharynx, head and neck surgeons and oncologists should consider the HPV status of the tumor while making treatment decisions (4). Herein, we report an analysis of the observable trend of OPC in our hospital and revealed an increasing incidence of OPC, particularly in rural areas, as well as of the positive outcomes observed in patients with HPV-positive OPC.
Patients and Methods
Patients. In this study, we enrolled 105 patients with oropharyngeal squamous cell carcinoma who underwent HPV testing and received first-line treatment at our hospital between July 2011 and June 2020 (Table I). We examined the survival rates and clinical factors affecting the prognosis of these patients. Survival rates of the patients were calculated based on the results of the prognostic studies. All patient information was recorded in a digital medical record system and updated whenever a clinical event occurred. The database was regularly updated. In our hospital, the HPV status of OPC cases was examined by p16 immunohistochemistry (IHC) and HPV in situ hybridization (ISH).
Characteristic features of the study patients.
Study design. This study was conducted in accordance with the ethical guidelines of the responsible committee on human experimentation (institutional and national) and adhered to the principles outlined in the Declaration of Helsinki of 1975, as revised in 2008 (5). This study was approved by our institutional review board (MH2020-209). Written informed consent was obtained from all treated patients. This study was designed as a retrospective review of the patients’ medical records.
Treatment methods. Our treatment plans for the initial OPC therapy included surgery and chemoradiotherapy (CRT). For early-stage primary tumors, the transoral approach was the preferred method for tumor resection (6). In surgical cases, postoperative chemoradiotherapy (POCRT) was performed if clinical and pathological assessments indicated a high-risk of recurrence, such as a close margin between normal tissues and the tumor or extracapsular invasion of metastatic lymph nodes (7). With the advent of the HPV concept, an evident trend emerged, prioritizing the active adoption of CRT as the first choice of treatment to preserve function capabilities. The concurrent CRT regimen included administration of CDDP (cisplatin, 100 mg/m2) every 3 weeks (8) or modified TPF (docetaxel, 50 mg/m2 day2, Cisplatin 60 mg/m2 day2, 5-FU 600 mg/m2 day1-5) every 4 weeks in combination with radiotherapy (60-70 Gy/30-35 fr) (9, 10). The POCRT regimen included administration of CDDP (Cisplatin, 80-100 mg/m2) every 3 weeks in combination with radiotherapy (60-70 Gy/30-35 fr). Intensity-modulated radiotherapy, mainly used as concomitant and postoperative radiotherapy, was administered on a daily basis. The regimen content was selected based on clinical stage, HPV status, age, and laboratory data. Induction chemotherapy was considered if a time interval existed before treatment initiation.
Statistical analysis. Statistical analysis was performed using the Kaplan–Meier method to evaluate patients’ survival rates, and a log-rank test was used to examine significant differences between the HPV-positive and HPV-negative cases. Differences were considered statistically significant at p-values <0.05.
Results
The mean and median observation periods following the treatment were 34.6 and 28.0 months. In our department, the HPV-positive rates among patients with OPC were previously lower; the lowest rate recorded was 10.0% in 2013 and the highest rate was 47.6% in 2020 (Figure 1). The number of HPV-negative OPC cases remained almost unchanged, whereas the overall number of cases increased with the increasing number of HPV-positive OPC cases. Recently, the HPV-positive rate has approached the average rate in Japan. In line with the conventional trend, both the number of cases and the HPV-positive rates were the highest for OPC originating from the side wall.
The number of human papilloma virus (HPV)-positive and HPV-negative oropharyngeal squamous cell carcinoma (OPC) cases over a period of 10 years. The graph highlights a rising trend in the number of HPV-positive OPC cases.
Regarding the treatment choice, the number of patients who underwent CRT was slightly higher than that of those who underwent surgery, and POCRT was performed in approximately 30% of the surgical cases.
Smoking rates tended to be higher among HPV-negative OPC cases. Nevertheless, it remained notably high exceeding 80%, regardless of HPV status.
The 3-year overall survival rates of patients with stages I (n=22), II (n=29), III (n=10), IVA (n=28), IVB (n=9), and IVC (n=3) tumors were 85.7, 83.5, 76.2, 54.8, 31.3, and 33.3%, respectively (Figure 2). The 3-year overall survival rates of the patients were almost the same for stage I and II OPCs. The survival rate significantly decreased as the stage progressed, with patient in earlier stages exhibiting better survival rates. The 3-year disease-specific survival rates of patients with stages I (n=22), II (n=29), III (n=10), IVA (n=28), IVB (n=9), and IVC (n=3) tumors were 94.7, 91.6, 76.2, 60.3, 31.3, and 33.3%, respectively (Figure 3). The 3-year disease-specific survival rates for stage I and II OPCs were higher than the overall survival rates. Regarding HPV status, HPV-positive cases exhibited a fairly good prognosis (Figure 4, Figure 5). Notably, 70% of the HPV-positive patients in this study had a smoking history, and intriguingly, smoking had little effect on survival among HPV-positive patients. However, it is important to highlight that HPV-negative patients with no history of smoking were not observed in this study.
Kaplan–Meier analysis of the overall survival rates for the patients in different clinical stages. The horizontal axis represents the time (months) from treatment and the vertical axis represents the survival rate. Open circle: Stage I. Closed circle: Stage II. Open square: Stage III. Closed square: Stage IVA. Open triangle: Stage IVB. Closed triangle: Stage IVC. The 3-year survival rates of patients with stages I (n=22), II (n=29), III (n=10), IVA (n=28), IVB (n=9), and IVC (n=3) tumors are 85.7, 83.5, 76.2, 54.8, 31.3, and 33.3%, respectively. There are significant differences between stages I and IVA (p<0.05), I and IVB (p<0.0005), I and IVC (p<0.0005), II and IVA (p<0.01), II and IVB (p<0.0001), II and IVC (p<0.0005), III and IVB (p<0.05).
Kaplan–Meier analysis of disease-specific survival rates for the patients in different clinical stages. The horizontal axis represents the time (months) from treatment and the vertical axis represents the survival rate. Open circle: Stage I. Closed circle: Stage II. Open square: Stage III. Closed square: Stage IVA. Open triangle: Stage IVB. Closed triangle: Stage IVC. The 3-year survival rates of patients with stages I (n=22), II (n=29), III (n=10), IVA (n=28), IVB (n=9), and IVC (n=3) tumors are 94.7, 91.6, 76.2, 60.3, 31.3, and 33.3%, respectively. There are significant differences between stages I and IVB (p<0.05), II and IVA (p<0.05), II and IVB (p<0.0005), II and IVC (p<0.01).
The overall survival rates of the patients categorized by human papilloma virus (HPV) status. The horizontal axis represents the time (months) from treatment and the vertical axis represents the survival rate. Open circle: Patients with HPV-negative tumor (n=63). Closed circle: Patients with HPV-positive tumor (n=38). The 3-year survival rates of the patients with HPV-positive tumor and HPV-negative tumor are 89.0% and 60.2%, respectively.
The disease-specific survival rates of the patients categorized by human papilloma virus (HPV) status. The horizontal axis represents the time (months) from treatment and the vertical axis represents the survival rate. Open circle: Patients with HPV-negative tumor (n=63). Closed circle: Patients with HPV-positive tumor (n=38). The 3-year survival rates of the patients with HPV-positive tumor and HPV-negative tumor are 96.3% and 62.6%, respectively.
Discussion
In this study, we conducted a comprehensive analysis of OPC cases spanning over 10 years and obtained intriguing results and novel insights. Although some differences existed from year to year, the number of cases and HPV-positive rate of OPCs in our hospital demonstrated a consistent increase, similar to recent global trends (1). Notably, our hospital’s central location within a rural area (Iwate Prefecture) indicated that the rise in OPC cases is not only in urban areas, but also in rural areas. We speculated that this trend was related to the decrease in the smoking rates due to the recent awareness of smoking cessation. However, in cases of OPC, the smoking rate did not exhibit a decrease during these time intervals; therefore, the increase in HPV-positive OPC cases appeared to be unaffected by smoking patterns. In contrast, the HPV-positive rate may be associated with the method employed for HPV detection. The 2014 NCCN Guidelines (Version 2. 2014) recommended p16 IHC as an HPV surrogate marker (11), along with ISH (12). At our hospital, HPV detection was conducted using ISH until 2015, after which p16 IHC was introduced from 2016. Notably, compared to p16 IHC, ISH has been reported to have a higher specificity but a lower sensitivity (13). We hypothesized that the recent standardization of p16 IHC could be one of the factors leading to the consistent detection of HPV.
Our hospital is located in the center of a rural area in Northern Japan and has the characteristics of a region where patients seldom seek medical attention at an earlier stage. Therefore, the patients referred to our hospital presented with more advanced head and neck cancers. However, the staging system underwent drastic change with the introduction of HPV status in OPC within the UICC 8th edition; HPV-positive OPC cases, previously classified as advanced cancer in the UICC 7th edition, were downstaged and reclassified into the early-stage category in the UICC 8th edition. Therefore, we investigated the effects of the staging system on survival rates and the potential for excessive downgrading based on the reclassification. The results demonstrated that overall survival decreased steadily as the stage progressed, and HPV-positive T2 or N1 cases, which were newly downstaged to stage I OPC in the UICC 8th edition, exhibited significantly better survival rates than that of HPV-negative stage I cases. These results affirmed the validity of the new stage classification introduced in the UICC 8th edition.
In our region, encompassing a population of 1.3 million, almost all patients with head and neck cancer, including those with oropharyngeal carcinoma, especially in advanced stages, were referred to our hospital. Chaturvedi et al. (1) reported that the incidence of OPC significantly increased from 1983 to 2002, predominantly in economically developed countries. The incidence of OPC has significantly increased among men in the USA, Australia, Canada, Japan, and Slovakia. However, our data suggested that until the second decade of 2000s, the number of OPC cases in our hospital was low, although it increased during the second decade. The number of HPV-positive OPC cases had markedly increased over the 10 years. This result seemed to correlate with the location of our hospital that is surrounded by a wide range of rural areas, including extensive mountainous areas, coastal areas facing the Pacific Sea, and some rice fields. Considering Chaturvedi et al.’s findings that sexual behaviors contributing to oral HPV exposure can influence geographic variations in this disease, the observed rise in the number of HPV-positive OPC cases in our hospital could be potentially attributed to changes in sexual behavior.
Faraji et al. reported that the number of HPV-positive OPC cases increases regardless of sex or race (14). Their data support our results, indicating an increase in the number of HPV-positive cases extends even to the rural areas of East Asia.
HPV status is also an important prognostic factor, because HPV-positive patients exhibit better prognoses than HPV-negative patients, as shown in our results (15, 16). HPV status should be considered when making treatment decisions. Notably, in our study, smoking did not affect the prognosis of HPV-positive patients. However, smoking may affect the prognosis of HPV-positive patients (17). Recently, Jeong et al. reported that higher expression of PD-L1 might suggest a poorer outcome of HPV positive OPC patients (18). Mendonça et al. reviewed that increased expression of MMPs is associated with cancer progression and poor prognosis in multiple HPV-induced cancers (19). Further investigation is warranted in the future.
Nevertheless, this study has some limitations. This retrospective cohort study included a relatively small number of patients. However, despite these limitations, clear results were obtained regarding the increasing tendency of HPV-positive OPC cases, and the better oncologic outcomes observed in patients with HPV-positive OPC than in those with HPV-negative OPC. Future studies encompassing large patient cohorts and/or prospective approaches may reveal more specific results for patients with OPC within our district.
Acknowledgements
The Authors would like to thank Editage (www.editage.com) for the English language editing.
Footnotes
Authors’ Contributions
Conceptualization, K. S.; methodology, K. S. and K. T.; investigation, T. K.; resources, K. T., K. S., K. K., D. S., S. O., A. I., J. M., T. K., I. K., Y. O., and H. A.; writing – original draft preparation, K. T. and K. S.; funding acquisition, K. S., K. K., and D. S. All Authors have read and agreed to the published version of the article.
Conflicts of Interest
The Authors have no conflicts of interest to declare in relation to this study.
Funding
This study was supported in part by JSPS KAKENHI, Grant Number 26462619.
- Received November 6, 2023.
- Revision received December 5, 2023.
- Accepted December 6, 2023.
- Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
