Impact of Multiple Primary Cancers on the Prognosis of Early-stage Oropharyngeal and Hypopharyngeal Squamous Cell Carcinoma: A Single-center Retrospective Study

Abstract

Background/Aim

The oropharynx, hypopharynx, and esophagus share similar epithelial characteristics, rendering them highly susceptible to the development of synchronous or metachronous multiple primary cancers. As endoscopic technologies, including Narrow Band Imaging (NBI) and high-resolution imaging systems, have advanced, early-stage pharyngeal cancers are increasingly detected during routine endoscopic evaluations or follow-up examinations for other head and neck or esophageal malignancies. This study aimed to retrospectively evaluate the clinical features, treatment modalities, occurrence of synchronous/metachronous multiple primary cancers, and prognoses in patients with early-stage (Tis, T1, T2/N0) oropharyngeal and hypopharyngeal squamous cell carcinoma who underwent initial treatment between January 2016 and December 2021.

Patients and Methods

Seventy-six patients with early-stage oropharyngeal or hypopharyngeal squamous cell carcinoma were included in the analysis. Parameters evaluated included patient demographics, tumor classification and localization, detection methods, therapeutic interventions, presence and type of multiple primary cancers, and clinical outcomes.

Results

While the disease-specific survival (DSS) rates were generally favorable across T stages, overall survival (OS) rates were comparatively lower, with many deaths attributable to the progression of multiple primary cancers, especially those involving the upper gastrointestinal tract. Detection of Tis and T1 lesions often occurred incidentally during gastrointestinal endoscopy performed for other indications. In contrast, T2 lesions were predominantly detected following the onset of pharyngeal symptoms and ENT examination. Multiple primary cancers were highly prevalent, particularly esophageal and gastric carcinomas.

Conclusion

Despite favorable DSS outcomes in early-stage oropharyngeal and hypopharyngeal cancers, OS remains compromised due to secondary malignancies. These findings underscore the critical need for early, isolated detection of pharyngeal carcinoma through interdepartmental collaboration, particularly with gastroenterologists and screening physicians, to enhance comprehensive cancer control and improve patient survival.

Introduction

Head and neck squamous cell carcinomas (HNSCCs), particularly those arising in the oropharynx and hypopharynx, frequently coexist with malignancies of the upper aerodigestive tract, such as esophageal carcinoma, due to their shared exposure to common carcinogens, including tobacco and alcohol (1,2). These sites are all lined with squamous epithelium, which contributes to their susceptibility to the phenomenon of “field cancerization”, a concept that describes the multifocal development of neoplasms within a contiguous field of epithelium subjected to chronic carcinogenic stimuli (3).

Among these, hypopharyngeal squamous cell carcinoma (HPSCC) has been reported to be accompanied with particularly high rates of synchronous and metachronous malignancies, especially within the upper gastrointestinal tract (4). This is clinically significant, as the presence of multiple primary cancers may not only complicate diagnostic and therapeutic strategies but also substantially influence long-term outcomes. Previous studies have estimated the incidence of synchronous cancers in hypopharyngeal cancer to be approximately 20-30%, with metachronous lesions being observed in as many as 8-30% of cases, depending on the duration of follow-up (4-6).

In recent years, advances in endoscopic imaging technology -including Narrow Band Imaging (NBI) and high-resolution endoscopy- have dramatically improved the early detection of superficial mucosal cancers in the pharynx and esophagus (7,8). Gastrointestinal endoscopy, in particular, has shown superior sensitivity for detecting early-stage (Tis and T1) pharyngeal carcinomas compared to laryngopharyngeal fiberoptic examination performed by otolaryngologists (9,10). This shift in diagnostic landscape has led to an increase in incidental detection of early-stage pharyngeal cancers during screening or surveillance for gastrointestinal malignancies.

Despite improvements in local control through surgical or radiotherapeutic interventions for early-stage pharyngeal cancer, overall survival remains limited in a significant proportion of patients due to the subsequent emergence or progression of other malignancies (11). Thus, the clinical management of early-stage oropharyngeal and hypopharyngeal SCC must be integrated with robust strategies for early detection and surveillance of secondary tumors.

The objective of this study was to clarify the clinical characteristics, therapeutic approaches, prevalence, and patterns of multiple primary cancers, as well as their prognostic implications. Particular emphasis is placed on the importance of interdepartmental collaboration for the early detection and comprehensive oncologic management of this patient population.

Patients and Methods

This retrospective cohort study included 76 patients with early-stage (Tis, T1, T2/N0) oropharyngeal or HPSCC who underwent primary treatment at the Department of Otolaryngology-Head and Neck Surgery, Kindai University, between January 2016 and December 2021.

The data collected encompassed: patient demographics (sex and age), tumor classification (T-stage based on UICC 8th edition), anatomical subsite, circumstances and methods of tumor detection, treatment strategies, presence of multiple primary malignancies, and clinical outcomes. Multiple primary cancers were defined as malignancies originating in different organs. Synchronous cancers were defined as those diagnosed simultaneously or within six months of the index tumor, and metachronous cancers as those diagnosed after six months.

For the statistical significance test, continuous variables were assessed using the Mann-Whitney U-test, and categorical variables were assessed using Fisher’s exact test. Overall survival (OS) was calculated using the Kaplan-Meier method and was compared using the log-rank test. All statistical analyses were performed with the statistical software ‘EZR’ (Easy R) (Saitama Medical Center, Jichi Medical University, Saitama, Japan) (12).

Results

Patient characteristics. Among 76 patients, 18 had oropharyngeal SCC and 58 had hypopharyngeal SCC. The median age was 69 years for oropharyngeal and 71 years for hypopharyngeal cases. Most patients were male (83.3% and 96.6%, respectively). Median follow-up was 4 years and 10 months for oropharyngeal cancer, and 4 years and 1 month for hypopharyngeal cancer. The majority of hypopharyngeal tumors were located in the piriform sinus, while oropharyngeal tumors were most frequently on the posterior wall (Table I).

Table I. Patient demographics and tumor characteristics.

Detection and diagnosis. Tis lesions were almost exclusively detected incidentally during upper gastrointestinal endoscopy conducted for other reasons such as health screening. T1 lesions followed a similar pattern in oropharyngeal cancer, while hypopharyngeal T1 lesions were more frequently detected during follow-up for other cancers. In contrast, T2 lesions were typically diagnosed after the onset of pharyngeal symptoms. Across both cancer types, detection was more commonly achieved via upper GI endoscopy than by laryngopharyngoscopy, especially in earlier stages (Table II, Table III, Figure 1, Figure 2).

Table II. Clinical presentation, diagnostic modalities, and treatments in patients with oropharyngeal cancer by T classification.

TOVS: Transoral videolaryngoscopic surgery; ELPS: endoscopic laryngo-pharyngeal surgery; RT: radiotherapy; CRT: chemoradiotherapy; BRT: bioradiotherapy.

Table III. Clinical presentation, diagnostic modalities, and treatments in patients with hypopharyngeal cancer by T classification.

TOVS: Transoral videolaryngoscopic surgery; ELPS: endoscopic laryngo-pharyngeal surgery; RT: radiotherapy; CRT: chemoradiotherapy; BRT: bioradiotherapy.

Figure 1.

Routes of detection for early-stage oropharyngeal and hypopharyngeal cancers. Patients were diagnosed either during follow-up for other cancers, through symptomatic presentation, or incidentally. Diagnostic modalities included laryngopharyngeal fiberscopy and upper gastrointestinal (GI) endoscopy. Most detected cases were Tis, T1, or T2 stage. While most T1 cancers (excluding symptomatic cases) were identified via upper GI endoscopy, T2 cancers were more frequently detected using laryngopharyngeal fiberscopy.

Figure 2.

Detection methods and staging distribution of oropharyngeal and hypopharyngeal cancers. Both laryngopharyngeal fiberscopy and upper GI endoscopy were employed for diagnosis. Notably, hypopharyngeal cancers were predominantly detected using upper GI endoscopy, whereas oropharyngeal cancers were more often identified using laryngopharyngeal fiberscopy compared to hypopharyngeal cancers.

Treatment modalities. Tis lesions were all treated surgically using either transoral video-laryngoscopic surgery (TOVS) or endoscopic laryngo-pharyngeal surgery (ELPS), with no recurrence observed. T1 lesions were managed using surgery and/or radiotherapy. For T2 lesions, chemoradiotherapy and radiotherapy alone became the dominant treatments (Table II, Table III).

Multiple primary cancers. Synchronous cancers were identified in 33.3% (oropharynx) and 22.4% (hypopharynx); metachronous cancers occurred in 11.1% and 31.0%, respectively. Among these, the most common sites were the esophagus and stomach, suggesting a predominance of upper gastrointestinal involvement (Table IV).

Table IV. Sites and frequency of synchronous and metachronous cancers.

Outcomes. The 3-year disease-specific survival (DSS) rate was 100% for all Tis, T1, and T2 of oropharyngeal cancers, and 100% for Tis and T1, and 83.9% for T2 hypopharyngeal cancer. While the overall DSS was favorable at 96.7%, the OS rate was lower due to deaths related to multiple primary malignancies, particularly esophageal cancer and pneumonia (Figure 3).

Figure 3.

Overall survival (OS) (A) and disease-specific survival (DSS) (B) in patients with early-stage oropharyngeal and hypopharyngeal cancers. While the 3-year DSS rate is 96.7%, reflecting favorable outcomes associated with early detection and treatment of these malignancies, the OS rate is lower due to deaths related to multiple primary malignancies.

Discussion

This study provides an in-depth analysis of early-stage oropharyngeal and HPSCC, with a particular focus on the prognostic implications of synchronous and metachronous multiple primary cancers (MPCs). Our findings demonstrate favorable DSS following standard treatment modalities. However, the OS was diminished, primarily due to the high incidence of secondary malignancies, particularly in the upper gastrointestinal tract.

The observed distribution of MPCs in our cohort is consistent with the theory of field cancerization, originally proposed by Slaughter et al., which posits that chronic exposure to carcinogenic agents such as tobacco and alcohol leads to multifocal oncogenic transformation within a contiguous epithelial field (3). The anatomic contiguity and shared histological features of the oropharynx, hypopharynx, and esophagus, all lined by squamous epithelium, create an environment predisposed to multiple cancers (13).

Among the 76 patients analyzed, MPCs were present in 50.0% of oropharyngeal cancer cases and 49.2% of hypopharyngeal cancer cases. The most frequent sites of secondary malignancies were the esophagus and stomach. This distribution aligns with prior reports identifying the esophagus as the most common site of MPC in patients with head and neck cancer (14,15). Notably, 13.2% of synchronous MPCs and 9.2% of metachronous MPCs in our cohort involved the esophagus, highlighting the clinical necessity of vigilant surveillance in this region.

The frequency of synchronous (25.0%) and metachronous (26.3%) tumors in our study is in line with established data, which report synchronous MPCs in 20-30% and metachronous MPCs in up to 80% of patients depending on the length of follow-up (4-6).

With the increasing use of advanced endoscopic technologies such as NBI, early detection of pharyngeal carcinoma has become more feasible. Gastrointestinal endoscopy, often performed during health screenings or cancer follow-up, proved to be a superior diagnostic modality in detecting superficial Tis and T1 lesions compared to laryngopharyngeal fiberoptic endoscopy. In our study, over 90% of Tis lesions were incidentally discovered via upper gastrointestinal endoscopy, supporting previous findings that NBI-enhanced endoscopy improves the detection of early mucosal abnormalities (16).

From a therapeutic perspective, superficial lesions (Tis, T1) were predominantly managed by transoral endoscopic resection techniques such as TOVS and ELPS, both of which achieved high rates of curative resection. In contrast, T2 lesions were more frequently treated with radiation-based modalities (radiotherapy, chemoradiotherapy, or bio-radiotherapy) due to their depth of invasion or anatomical complexity. Despite high rates of local control, recurrence and secondary tumor progression remained a threat to long-term survival, particularly in patients with metachronous MPCs. This was especially evident in hypopharyngeal cancer cases, where T2 patients had a 5-year DSS of 83.9% but a lower OS due to deaths from secondary malignancies. These findings underscore the necessity of implementing a comprehensive screening strategy that includes upper GI endoscopy and Positron Emission Tomography/Computed Tomography (PET/CT) imaging as part of routine pre-treatment workups for HNSCC. Studies have shown that gastrointestinal endoscopy is superior to PET/CT in detecting early-stage upper GI cancers (17), further justifying its inclusion in standard screening protocols.

In conclusion, while local control of early-stage oropharyngeal and hypopharyngeal SCC is achievable through current therapeutic techniques, survival outcomes remain influenced by the presence of MPCs. Early and isolated detection of these lesions, along with coordinated multidisciplinary management involving otolaryngologists, gastroenterologists, and oncologists, is essential to improve prognosis in this high-risk population.

Conclusion

Although early-stage oropharyngeal and hypopharyngeal SCCs exhibit favorable DSS following appropriate treatment, OS remains suboptimal due to the high incidence of multiple primary cancers. Therefore, efforts must be made to detect these cancers as isolated, treatable lesions through improved interdisciplinary collaboration with gastroenterologists and screening physicians. Strengthening such collaborations is critical to enhancing long-term outcomes in this high-risk patient cohort.

Conflicts of Interest

The Authors declare no conflicts of interest in relation to this study.

Authors’ Contributions

Conceptualization, R.Y; Methodology, D.A and R.Y; Validation, T.K; Investigation, D.A, T.K, S.I, M.O, S.K, M.K, M.U, S.K, M.S, M.K, T.W and R.Y; Writing - Original Draft Preparation, D.A; Writing - Review & Editing, R.Y; Supervision, M.K and T.W; Project, R.Y; Administration, R.Y; Funding Acquisition, R.Y. All Authors have read and agreed to the published version of the manuscript.

Funding

The study was supported by a grant from JSPS KAKENHI Grant Number JP 23K09000 to Ryuji Yasumatsu.

Artificial Intelligence (AI) Disclosure

No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.