Impact of HPV Status on Oropharyngeal Cancer Detection via Gastrointestinal Endoscopy: A retrospective study

doi:10.21203/rs.3.rs-4705545/v1

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Impact of HPV Status on Oropharyngeal Cancer Detection via Gastrointestinal Endoscopy: A retrospective study

https://doi.org/10.21203/rs.3.rs-4705545/v1

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Gastrointestinal endoscopy (GIE) performed by gastroenterologists is an important modality for early pharyngeal cancer detection. Human papillomavirus (HPV) is one of the causes of oropharyngeal squamous cell carcinoma (OPSCC). However, the prevalence of HPV-related OPSCC detected by GIE is currently unknown. We retrospectively analyzed 207 OPSCC from 2018 to 2022, where HPV infection was diagnosed by p16 immunohistochemistry. We compared detection modalities and evaluated the proportion of lesions detected by GIE in both p16-positive and p16-negative cases. Out of the 207 patients, 92 (44.4%) were p16-positive. p16-positive cases had significantly lower rates of alcohol use, smoking, and history of esophageal or head/neck squamous cell carcinoma (all p < 0.001). Only 4.3% of p16-positive cases were detected by GIE, compared to 44.3% of p16-negative cases (p < 0.001). p16-positive patients were often diagnosed at advanced stages and underwent transoral resection less frequently (2.2% vs. 31.3%, p < 0.001). In cT1 cases, GIE or laryngoscopy revealed that p16-positive lesions were typically protruding and white to normal-colored, while p16-negative lesions were predominantly flat and erythematous.

In conclusion, HPV-related OPSCC cases are rarely detected by GIE, and few cases are treated with minimally invasive transoral resection, indicating a need for improvement in early detection.

Health sciences/Gastroenterology

Health sciences/Oncology/Cancer/Head and neck cancer

Early detection of cancer

Endoscopy

Human papillomavirus

Oropharyngeal neoplasms

In 2020, pharyngeal cancer, including oropharyngeal squamous cell carcinoma (OPSCC) and hypopharyngeal squamous cell carcinoma (HPSCC), accounted for approximately 183,000 new cases of cancer and 87,000 deaths globally¹. More than 90% of pharyngeal cancers are diagnosed at an advanced stage², and their prognosis is not promising^3,4. Traditional treatments such as surgical resection and chemoradiotherapy (CRT) are highly invasive, and they can severely affect quality of life because of complications such as dysphagia and voice impairment. Detecting pharyngeal cancer at an early stage allows minimally invasive endoscopic resection, which preserves organ function.

Gastrointestinal endoscopy (GIE) performed by gastroenterologists plays a crucial role in the early detection of pharyngeal cancer^5,6. Previously, we reported that 164 cases (31.4%) were detected by GIE among 522 pharyngeal cancers at our institution between 2011 and 2018⁷. Detailed endoscopic observation using narrow band imaging (NBI) has facilitated the early detection of pharyngeal cancer in cases with risk factors^8–11. Common risk factors for both OPSCC and HPSCC, similarly as reported for esophageal squamous cell carcinoma (ESCC), include smoking, alcohol consumption, and a history of ESCC or head and neck squamous cell carcinoma (HNSCC)^12–15. However, in contrast to HPSCC and ESCC, human papillomavirus (HPV) infection significantly contributes to tumorigenesis in OPSCC. Recently, the incidence of OPSCC has increased globally, and HPV is considered to be one of the causes of this problem¹⁶. Although the incidence of HPV-related OPSCC is increasing, accounting for approximately half of all OPSCCs^17,18, there are few reports comparing detection modalities, including GIE, between HPV-related and non-HPV-related OPSCC. Hence, this retrospective study aims to investigate the differences in detection modalities between HPV-positive and HPV-negative OPSCC cases, and to compare these two groups in terms of patient characteristics, early detection rates, treatment methods, and GI endoscopic findings.

Patients

This retrospective study assessed the clinical records of consecutive patients with OPSCC. We included patients who underwent detailed examinations, including definitive diagnosis by pathologists and staging based on the TNM classification, at our hospital between January 2018 and December 2022.

For patients with multiple lesions detected metachronously during the study period, the first detected lesion was included in the analysis. If multiple lesions were detected simultaneously, the most advanced lesion was considered. This study was approved by the ethical committee of the institutional review board of Kumamoto University Hospital (approval number 1851) and performed in accordance with the ethical principles outlined in the Declaration of Helsinki. Due to the retrospective nature of the study, the institutional review board waived the need of obtaining informed consent.

Definitions

A history of alcohol consumption was defined as the current or past consumption of one cup of sake (180 ml), a medium bottle of beer (500 ml), 80 ml of shochu (35% alcohol), one double shot of whiskey (60 ml), or two glasses of wine (240 ml) per day on at least 3 days per week. That would be 20 g of alcohol consumptions. Smoking history was calculated as the number of cigarettes smoked per day multiplied by the number of years of smoking¹⁹, and a value of at least 400 indicated a history of smoking.

The oropharynx was divided into four subsites: (1) anterior wall (base of the tongue), (2) superior wall (inferior surface of the soft palate and uvula), (3) lateral wall (tonsils, tonsillar fossa, and pillars), and (4) posterior wall (Supplemental Fig. 1).

Treatment was categorized into transoral resection, surgical resection involving lymph node dissection and/or laryngectomy, CRT, radiotherapy (RT) and others. Transoral resection included endoscopic submucosal dissection (ESD)²⁰, endoscopic laryngo-pharyngeal surgery (ELPS)²¹, and transoral videolaryngoscopic surgery (TOVS)²².

We divided the detection modalities into two groups: GIE and non-GIE (detected by means other than GIE, such as rhino-laryngoscopy or direct visualization by otolaryngologists, dentists, and general physicians). The macroscopic type of cT1 (including cTis) cases was classified according to the Japan Esophageal Society classification²³ as follows: 0-I (protruding type), 0-II (flat type), and 0-III (excavated type). Types 0-I and 0-II were further subclassified into 0-Ip (pedunculated type), 0-Is (sessile [broad-based] type), 0-IIa (slightly elevated type), 0-IIb (flat type), and 0-IIc (slightly depressed type). The macroscopic type and color tone of the lesion were assessed by two experienced gastrointestinal endoscopists based on endoscopic images of GIE and laryngoscopy.

Immunohistochemistry

According to the American Joint Committee on Cancer and Union for International Cancer Control classification 8th edition, p16 immunostaining has become essential for diagnosing HPV-related OPSCC^24,25.

For immunohistochemistry, 4-µm-thick sections from formalin-fixed, paraffin-embedded blocks were incubated with a mouse monoclonal antibody against p16 (E6H4, ready to use; Ventana Medical Systems, Tucson, AZ, USA). Immunohistochemistry was performed on a Benchmark ULTRA instrument (Ventana Medical Systems). p16 expression was considered positive if more than 75% of the specimens exhibited strong and diffuse staining in both the nucleus and cytoplasm²⁴.

Analysis of clinical characteristics and detection modalitise in p16-positive and p16-negative OPSCC

In this study, we compared p16-positive and p16-negative OPSCC by examining age, sex, history of alcohol consumption and smoking, history of ESCC and HNSCC, T stage, treatment modality, tumor subsites and detection modality. In additionally, we performed similar analyses based on the presence or absence of a history of ESCC and HNSCC. We compared the proportion of cases detected by GIE for each tumor subsite and examined macroscopic types and coloration in cT1 lesions between p16-positive and p16-negative OPSCC.

Statistical analysis

Continuous data were compared using the Mann–Whitney U test. Pearson’s χ² test or Fisher’s exact test was used to analyze the categorical data and compare proportions between the groups. SPSS version 29.0 (IBM Corporation, Armonk, NY, United States) was used for all statistical analyses. p < 0.05 (two-sided) denoted statistically significant differences.

Patient characteristics

From January 2018 to December 2022, 222 patients with OPSCC were examined in our hospital. Of them, 15 patients with non-squamous cell carcinoma, an unknown alcohol or smoking history, or an unknown p16 status were excluded. Thus, 207 patients with OPSCC were enrolled in this study (Fig. 1).

The demographic and clinical characteristics of the study population are detailed in Table 1. Out of the 207 cases, there were 53 cT1 cases (25.6%), and 38 cases (18.4%) underwent oral resection. Additionally, 55 cases (26.6%) were detected by GIE. Furthermore, 92 (44.4%) OPSCC were p16-positive, and 115 patients were p16-negative.

Table 1

The demographic and clinical characteristics of the study population
	Total n = 207
Median age, years	69 (34–91)
Sex, male/female	173 (83.6%)/34
Alcohol history, yes/no	109 (52.7%)/98
Smoking history, yes/no	135 (65.2%)/72
History of ESCC, yes/no	49 (23.7%)/158
History of HNSCC, yes/no	56 (27.0%)/151
Location
Anterior	40 (19.3%)
Superior	23 (11.1%)
Lateral	125 (60.4%)
Posterior	19 (9.2%)
Clinical T1/2–4	53 (25.6%)/154
Treatment
Transoral resection	38 (18.4%)
Surgical resection	26 (12.6%)
CRT/RT	143 (69.0%)
Other	20 (9.7%)
Detection by GIE/non-GIE	55 (26.6%)/152
p16 status, positive/negative	92 (44.4%)/115
ESCC: Esophageal squamous cell carcinoma, HNSCC: Head and neck squamous cell cancer, CRT: Chemoradiotherapy, RT: Radiotherapy, GIE: Gastrointestinal endoscopy.

Comparison of characteristics between p16-positive and p16-negative lesions

We compared the characteristics of p16-positive and p16-negative cases in Table 2. The proportion of patients with alcohol and smoking histories, as well as histories of ESCC and HNSCC, were significantly lower among p16-positive cases (all p < 0.001). cT1 lesions were significantly less prevalent in the p16-positive cases. Among p16-positive cases, only two underwent transoral resection (both TOVS), while in p16-negative cases, 36 underwent transoral resection (ELPS/ESD 26 cases and TOVS 10 cases) (p < 0.001). Comparing p16-positive and p16-negative cases, there was a significant difference in lesion subsites. In p16-positive cases, the lateral wall was the most common subsite at 72.8%, followed by the anterior wall at 22.8%, with very few lesions observed in the superior and posterior walls. In contrast, for p16-negative cancers, the lateral wall was the most common subsite at 50.4%, with the frequencies of lesions in the anterior, superior, and posterior walls being approximately equal. Additionally, only four p16-positive cases (4.3%) were detected by GIE, whereas 51 p16-negative cases (44.3%) were detected by GIE (p < 0.001).

Table 2

Comparison of characteristics between the p16-positive and p16-negative cases
	p16-positive cases n = 92	p16-negative cases n = 115	p value
Median age, years	62 (34–86)	72 (50–91)	< 0.001
Sex, male/female	68 (73.9%)/24	105 (91.3%)/10	0.001
Alcohol history, yes/no	36 (39.1%)/56	73 (63.5%)/42	< 0.001
Smoking history, yes/no	47 (51.1%)/45	88 (76.5%)/27	< 0.001
History of ESCC, yes/no	3 (3.3%)/89	46 (40%)/69	< 0.001
History of HNSCC, yes/no	5 (5.4%)/87	51 (44.3%)/64	< 0.001
cTis-1/2–4	13 (14.1%)/79	40 (35.0%)/75	0.001
Treatment
Transoral resection	2 (2.2%)	36 (31.3%)	< 0.001
Other	90 (97.8%)	79 (68.7%)
Location			< 0.001
Anterior	21 (22.8%)	19 (16.5%)
Superior	3 (3.3%)	20 (17.4%)
Lateral	67 (72.8%)	58 (50.4%)
Posterior	1 (1.0%)	18 (15.7%)
Detection modality
GIE/non-GIE	4 (4.3%)/88	51 (44.3%)/64	< 0.001
ESCC: Esophageal squamous cell carcinoma, HNSCC: Head and neck squamous cell cancer, GIE: Gastrointestinal endoscopy.

Assessment of the proportion of cases detected by GIE for each subsite

We present the proportion of GI endoscopic detection of OPSCC stratified by tumor subsites. In p16-positive OPSCC, the proportion of lesions detected by GIE was low regardless of the subsite (10.5% in the anterior wall, 0% in the superior wall, 3.0% in the lateral wall, and 0% in the posterior wall) (Fig. 2a). On the other hands, in p16-negative OPSCC, the proportions of lesions detected by GIE were 35.7% in the anterior wall, 60.0% in the superior wall, 31.0% in the lateral wall, and 88.9% in the posterior wall, respectively (Fig. 2b). The proportion of lesions detected by GIE was significantly higher in the posterior wall compared to the anterior wall (p < 0.001) and the lateral wall (p < 0.001). Similarly, lesions in the superior wall were more frequently detected by GIE compared to both the anterior wall (p = 0.034) and the lateral wall (p = 0.022).

Comparison of detection modalities and indications for examination between p16-positive and p16-negative OPSCC

We explored the indications for the examination and modality of detection in Table 3. Eighty-two out of 92 (89.1%) p16-positive OPSCC cases were detected through non-GIE examinations conducted to investigate presenting symptoms. In contrast, 37 out of 115 (32.2%) p16-negative OPSCC were predominantly detected by GIE follow-up for ESCC and HNSCC.

Table 3

Comparison of detection modalities and indications for examination between p16-positive and p16-negative oropharyngeal squamous cell carcinoma
Detection modality	Opportunity for examination	p16-positive cases n = 92	p16-negative cases n = 115
GIE n = 55	Investigation of symptoms	1 (1.1%)	6 (5.2%)
	Follow-up for ESCC and/or HNSCC	1 (1.1%)	37 (32.2%)
	Incidental GIE	2 (2.2%)	8 (7.0%)
Non-GIE n = 152	Investigation of symptoms	82 (89.1%)	54 (47.0%)
	Follow-up for ESCC and/or HNSCC	2 (2.2%)	7 (6.1%)
	Other	4 (4.3%)	3 (2.6%)
GIE: Gastrointestinal endoscopy, ESCC: Esophageal squamous cell carcinoma, HNSCC: Head and neck squamous cell cancer.

Comparison of characteristics between p16-positive and p16-negative OPSCC, with or without a history of ESCC/HNSCC

We compared the characteristics of p16-positive and p16-negative cases, with or without a history of ESCC/HNSCC in Table 4. In p16-negative OPSCC, the proportion detected by GIE was significantly higher in patients with a history of ESCC/HNSCC compared to those without (57.7% vs. 29.4%, p < 0.001). Furthermore, among those with such history, a significantly higher proportion of cases were detected at cTis-1 stage (52.1% vs. 6.8%, p < 0.001), resulting in a higher proprtion of cases treated with transoral resection (45.1% vs. 9.1%, p < 0.001).

Table 4

Comparison of characteristics between p16-positive and p16-negative OPSCC, with or without a history of ESCC/HNSCC
	p16-positive cases n = 92			p16-negative cases n = 115
	With history of ESCC/HNSCC n = 7	Without history of ESCC/HNSCC n = 85	p value	With history of ESCC/HNSCC n = 71	Without history of ESCC/HNSCC n = 44	p value
Median age, years	69 (51–71)	62 (34–86)	0.397	71 (50–88)	73.5 (61–91)	0.019
Sex, male/female	6 (85.7%)/1	62 (72.9%)/23	0.672	63 (88.7%)/8	42 (95.5%)/2	0.313
Alcohol history, yes/no	4 (57.1%)/3	32 (37.6%)/53	0.426	48 (67.6%)/23	25 (56.8%)/19	0.243
Smoking history, yes/no	5 (71.4%)/2	42 (49.4%)/43	0.435	56 (78.9%)/15	32 (27.2%)/12	0.450
cTis-1/2–4	2 (28.6%)/5	11 (12.9%)/74	0.257	37 (52.1%)/34	3 (6.8%)/41	< 0.001
Treatment
Transoral resection/Others	0 (0%)/7	2 (2.4%)/83	1.000	32 (45.1%)/39	4 (9.1%)/40	< 0.001
Location			-			0.087
Anterior	5 (71.4%)	16 (18.8%)		11 (15.5%)	8 (18.9%)
Superior	0 (0%)	3 (3.5%)		17 (24.0%)	3 (6.8%)
Lateral	2 (28.6%)	65 (76.5%)		31 (43.7%)	27 (61.4%)
Posterior	0	1 (1.2%)		12 (16.8%)	6 (13.6%)
Detection modality
GIE/non-GIE	1 (16.7%)/6	3 (3.7%)/82	0.275	41 (57.7%)/30	10 (29.4%)/34	< 0.001
OPSCC: oropharyngeal squamous cell carcinoma, ESCC: Esophageal squamous cell carcinoma, HNSCC: Head and neck squamous cell cancer, GIE: Gastrointestinal endoscopy.

Comparison of endoscopic findings in cT1 cases between p16-positive and p16-negative OPSCC

We assessed the GIE or laryngoscopy images in cT1 cases, focusing on their macroscopic appearance and coloration in Table 5. One p16-negative case was excluded from the analysis because of the lack of evaluable endoscopic images. In the macroscopic classification, the protruding type (0-I) was more common in p16-positive cases, whereas the flat type (0-II) was more prevalent in p16-negative cases. In p16-positive cases, lesions more frequently displayed a white to normal color, whereas in p16-negative cases, erythematous lesions were more common. The images of representative cases are presented in Supplemental Fig. 2.

Table 5

Comparison of macroscopic types and coloration in cT1 cases between p16-positive and p16-negative oropharyngeal squamous cell carcinoma
	Clinical T1 p16-positive n = 13	Clinical T1 p16-negative n = 39	p value
Macroscopic type			< 0.001
0-I (0-Is)	12 (92.3%)	5 (12.8%)
0-II (0-IIa, 0-IIb, 0-IIc)	1 (7.7%)	34 (87.2%)
Coloration			0.041
Erythematous	1 (7.7%)	16 (40.0%)
White to Normal	12 (92.3%)	23 (57.5%)
0-I: Protruding type, 0-Is: sessile (broad-based) type, 0-II: flat type, 0-IIa: slightly elevated type, 0-IIb: flat type, 0-IIc: slightly depressed type

In this study, approximately half of p16-negative OPSCCs were detected by GIE, whereas only 4.3% of p16-positive OPSCCs were identified in this manner. Consequently, the proportion of lesions detected at cTis-1 was lower in p16-positive cases, and there were very few cases that could be treated with transoral resection.

The most potential factor in this finding is the accessibility of endoscopic examination. As presented in Table 2, p16-negative OPSCC is more likely to involve risk factors such as histories of alcohol consumption, smoking, ESCC, and HNSCC. Consequently, these patients are categorized as high risk, and they are more frequently subjected to GIE surveillance with image enhancement. Conversely, HPV-related OPSCC is typically diagnosed in younger individuals with less exposure to smoking and alcohol²⁶, which might lead them being perceived as lower risk. As a result, patients with HPV-related OPSCC are less likely to undergo GIE than those with HPV-unrelated OPSCC. Therefore, patients with HPV-related OPSCC are frequently identified at an advanced stage of progression, typically when symptomatic manifestations have become evident. If high-risk cases of HPV-related OPSCC could be identified and actively screened using GIE, it might increase the early detection of HPV-related cancers. Currently, there is no available screening test to detect HPV status in the general population, which makes it impractical to identify high-risk cases. In the future, HPV vaccination history may help stratify the risk of HPV-related OPSCC²⁷, potentially guiding screening strategies and improving early detection.

However, considering that approximately 30% of p16-negative OPSCC without a history of ESCC or HNSCC are detected by GIE, it suggests that factors other than the limited opportunities for undergoing GIE may be responsible for this difference in detection rate. The location of the lesion is also a crucial factor influencing the GI endoscopic detection of OPSCC. Hamada et al. reported that the anterior and lateral walls of the oropharynx are anatomically difficult to observe using GIE²⁸. Consistent with previous reports, our data, as shown in Fig. 2, also indicate that the proportion of lesions detected by GIE was low for anterior wall and lateral wall lesions in p16-negative cancers. Additionally, it has been reported that HPV-related OPSCC is more likely to arise in the anterior and lateral walls of the oropharynx²⁹, and our data showed a similar pattern. Considering these findings, the predilection of p16-positive OPSCC to arise in challenging-to-observe sites makes GIE detection more difficult.

Furthermore, the progression process of HPV-related OPSCC is likely to contribute to its lower GI endoscopic detection rate. These cancers originate from the basal layer of the tonsillar crypt, they are in deeper areas of the tonsils, and the tumors are usually covered by normal mucosa³⁰. Thus, HPV-related OPSCC is not exposed to the luminal surface in the early stage. A tumor growing within the palatine tonsils might be challenging to detect by GIE. In our data, most of the p16-positive OPSCC cases were protruding lesions, but they were probably difficult to detect because they were subepithelial tumor-like smooth elevations and lacked color variation compared to the surrounding tonsillar tissue, making them difficult to identify. In the present study, only the limited number of p16-positive OPSCC were observed with NBI, so the utility of NBI in detection could not be determined. However, in two cases observed using NBI, as presented in Supplemental Figure (3-b and 3-h), microvessels resembling intrapapillary capillary loops were identified. There are case reports suggesting that the use of NBI with laryngoscopy can be effective for detection of HPV-related OPSCC^31,32. Although the early detection of p16-positive OPSCC remains challenging, NBI observation might potentially be useful.

This study had some limitations. First, this was a retrospective review of a single center. Second, this study includes cases detected by GIE performed at other institutions. Therefore, it is unclear whether the GIE was performed transnasally or transorally, whether image-enhanced endoscopy was used, or the details of the previous endoscopic history. Subsequently, HPV infection was determined only by p16 immunostaining in this study. In clinical practice, the stage of cancer is diagnosed using the results of p16 immunohistochemistry²⁵. The p16 immunostaining was reported as efficient and highly sensitive for HPV infection, but its specificity was insufficient. In a recent report, 7.0%-13.6% of patients were incorrectly diagnosed as HPV-negative^33,34 In situ hybridization is highly specific, and it has been reported to be effective when performed in conjunction with p16 immunostaining³⁵. However, in clinical practice, it is not easy to perform in situ hybridization because of its high cost and complicated procedure. Furthermore, in this study, there was a large difference in the number of detections by GIE between p16-positive and p16-negative cases. Even if 7.0%-13.6% of p16-positive cancers were in fact HPV-negative, we concluded that this result is robust and unlikely to be reversed.

Our study shows that p16-positive OPSCC are significantly less likely to be detected by GIE compared to p16-negative cases. This is likely due to less frequent accessibility of GIE. Anatomical challenges in observing the oropharynx and the growth pattern of HPV-related OPSCC make early detection difficult. Improving screening strategies, particularly for HPV-related OPSCC, could enhance early detection rates. Future research should focus on advanced imaging techniques such as NBI and the role of HPV vaccination history in identifying high-risk cases to improve outcomes.

Additional Information

Conflict of Interests

None.

Informed consent

Due to the retrospective nature of the study, the institutional review board of Kumamoto University Hospital waived the need of obtaining informed consent.

Author Contribution

ST, HM, and MH were involved in the analysis and interpretation of data and drafting of the manuscript. MI, YK SM, DM, and YO participated in study coordination and data acquisition. KW, KM, AY, RG, KN, HN, and FK critically revised the manuscript for important intellectual content. YT approved the final version of the article for publication. All authors approved the final version.

Acknowledgments

We special thank all staff of the Department of Endoscopic Diagnostics and Therapeutics and the Department of Otolaryngology Head and Neck Surgery at Kumamoto University Hospital.

Data Availability

The data that support the findings of this study are available on reasonable request from the corresponding author.

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No competing interests reported.

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Impact of HPV Status on Oropharyngeal Cancer Detection via Gastrointestinal Endoscopy: A retrospective study

Status:

Version 1

Abstract

Figures

Introduction

Materials and Methods

Patients

Definitions

Immunohistochemistry

Analysis of clinical characteristics and detection modalitise in p16-positive and p16-negative OPSCC

Statistical analysis

Results

Patient characteristics

Comparison of characteristics between p16-positive and p16-negative lesions

Assessment of the proportion of cases detected by GIE for each subsite

Comparison of detection modalities and indications for examination between p16-positive and p16-negative OPSCC

Comparison of characteristics between p16-positive and p16-negative OPSCC, with or without a history of ESCC/HNSCC

Comparison of endoscopic findings in cT1 cases between p16-positive and p16-negative OPSCC

Discussion

Conclusion

Declarations

Additional Information

Informed consent

Author Contribution

Acknowledgments

Data Availability

References

Additional Declarations

Supplementary Files

Status:

Version 1