Introduction

Transnasal endoscopy by ultrathin endoscope with image-enhanced endoscopy and high image quality has contributed greatly to the diagnosis of superficial cancers of the pharynx due to its ease of use. Its role in the diagnosis of p16-positive pharyngeal carcinoma which is closely associated with HPV infection, and has been recently reported to be increasing, is not clear.

Aims & Methods

We retrospectively investigated the clinical, pathological and endoscopic features of the cases of oropharyngeal cancer at our hospital, who underwent upper gastrointestinal endoscopy in the period between January 2019 to December 2023. All pathological specimens were stained with p16 immunohistochemistry.
(Study 1) Patient background, age, history of alcohol consumption and smoking, and the presence of multiple primary cancers in other organs were compared between the p16-positive oropharyngeal squamous cell carcinoma (p16+OPSCC) group and the p16- negative squamous cell carcinoma (p16-OPSCC) group.
(Study 2) The endoscopic features of the p16+OPSCC lesions were compared with those of the p16-OPSCC lesions.

Results

Sixty patients were included in this study, with a male/female ratio of 48:12 and a mean age of 63.7 years. The mean age of the female patients was 58.5 years, which was significantly younger than that of the male patients (65.0 years).
(Study 1) The p16+OPSCC group consisted of 25 patients with a male/female ratio of 19:6 and a mean age of 58.3 years, and the proportion of female patients was higher than that of the p16-OPSCC group (35 patients, 29:6, 67.5 years). The number of patients without a history of alcohol consumption nor smoking was significantly higher in the p16-OPSCC group (11 and 6, respectively), and 6 patients (24%) had neither. Multiple primary cancers were more frequent in the p16-OPSCC group (17 cases, 49%) than in the p16+OPSCC group (3 cases,12%), mainly found in the hypopharynx and the esophagus.
(Study 2) p16-OPSCC lesions showed brownish areas (BAs) with dotted vasodilatation under narrow band imaging, whereas p16+OPSCC lesions had a unique appearance of subepithelial mass-like, enlarged tonsil-like, or submucosal mass-like with ulceration or nodular elevation. These lesions were accompanied by BA in only 8 cases (32%), and in some cases, the lesions were difficult to even detect by transnasal endoscopic observation.

Conclusion

p16+OPSCC is a new clinical entity that may affect young patients who are not at risk for alcohol consumption and smoking. Our study showed that the endoscopic features of the tumor are not appropriate for BA-based diagnosis. Gastrointestinal endoscopists need to renew their awareness of the disease.

Introduction

Thanks to instrumental advances and accumulation of understandings of endoscopic features of early oropharyngeal neoplasia, we often encounter diminutive pharyngeal lesions. However, whether follow-up is permissible or therapeutic intervention is preferable for these lesions is uncertain. Accurate endoscopic diagnosis is pivotal for the decision-making process. This study aimed to assess the accuracy of endoscopic diagnosis for pharyngeal microlesions.

Aims & Methods

We evaluated pre-treatment endoscopic images of 121 lesions 3 mm or less in that pharyngeal neoplasia was endoscopically diagnosed with magnifying narrow-band imaging observation and resected by cold forceps biopsy. Two endoscopists, one with over 15 years of experience and another with 5 to 10 years (study A), made endoscopic diagnosis of each image and categorized the images into non-dysplasia, low-grade dysplasia, or squamous cell carcinoma (SCC)/high-grade dysplasia, and the accuracy of the endoscopic diagnosis was evaluated with the pathological findings of resected tissues. To assess interrater agreement, another physician joined to each experience group (study B), and the kappa coefficient was calculated.

Results

In study A, the overall accuracy rate of the endoscopic diagnosis was 60.7%. However, for SCC/high-grade dysplasia, the sensitivity was 12.5% (95% confidence interval [CI]: 3.5-29.0), specificity was 94.3% (95% CI: 90.2-97.0), positive predictive value was 25.0% (95% CI: 7.3-52.4), and negative predictive value was 87.6% (95% CI: 82.6-91.6). Nearly 90% of malignant or high-grade dysplastic lesion were not correctly diagnosed by endoscopic observation even with magnifying narrow-band imaging. Although the concordance rate between study A and B was low (κ coefficient 0.07, 95% CI: -0.15-0.30), study B also exhibited low sensitivity (31.2%, 95% CI: 16.1-50.0), specificity (83.3%, 95% CI: 77.6-88.1), positive predictive value (22.2%, 95% CI: 11.2-37.1), and negative predictive value (88.8%, 95% CI: 83.6-92.9) for SCC/high-grade dysplasia.

Conclusion

The accuracy of endoscopic diagnosis of diminutive malignant pharyngeal lesions was very low regardless of proficiency of endoscopist. Thus, given that such diminutive lesions can be resected with minimally invasive cold forceps biopsy, proactive excision for diagnostic treatment is recommended.

Introduction

In Japan, the standard treatment for resectable locally advanced esophageal squamous cell cancer (ESCC) is neoadjuvant triplet chemotherapy (fluorouracil, cisplatin, and docetaxel [DCF]) followed by surgery, based on the results of the phase III randomized controlled study (JCOG1109). Some reports suggest that preoperative endoscopic evaluation of the primary tumor may predict postoperative outcomes. Given the increasing importance of endoscopic evaluation of response to neoadjuvant therapy in primary tumor, the 12th edition of the Japanese Classification of Esophageal Cancer introduced a new endoscopic sub-classification “RR (Remarkable Response)”, which was defined as showing remarkably shrink to nearly T1 depth after treatment. However, its clinical significance remains unclear.

Aims & Methods

The aim of this study is to determine the clinical significance of a new endoscopic sub-classification “RR” by evaluating its association with both histological response in surgical specimens and postoperative prognosis. We retrospectively analyzed the patients with resectable locally advanced ESCC (cT2-3/N0-3/M0-1, UICC-TNM 8th edition) who were performed with ≥1 cycle of neoadjuvant DCF therapy followed by surgery at our institution between April 2015 and March 2020. Exclusion criteria were: 1) JCOG1109 participants, 2) not evaluated the primary lesion by endoscopy before or after DCF therapy due to esophageal stricture, 3) >56 days from DCF therapy completion to surgery, or 4) pathologically non-curative resection (R1-2). Two endoscopists retrospectively evaluated pre- and post-DCF therapy endoscopic images with masked prognostic information and classified the cases into three groups: 1) RR, 2) non-RR and 3) PD (Progressive disease). Histological response data were retrospectively collected from medical records. According to the 12th edition of the Japanese Classification of Esophageal Cancer, all surgically resected specimens containing visible primary tumor tissue underwent histological examination in cases where preoperative treatment has been administered. Histological response was graded according to the Japanese Classification of Esophageal Cancer, on a four-point scale ranging from grade 0 (ineffective) to grade 1 (slightly effective), grade 2 (moderately effective), and grade 3 (markedly effective). We evaluated the proportions of cases achieving histological response of grade 2-3 in each group, and also calculated 3-year RFS and OS rates in each group.

Results

Of 114 eligible patients (median age 66.5 years [range 42-76], 91 males), clinical stage distribution was IIB/IIIA/IIIB/IVA/IVB: 1/0/58/15/40. 97/0/17 patients received 3/2/1 cycles of neoadjuvant DCF therapy. By endoscopic evaluation, 63 patients were classified as RR, 51 as non-RR, and 0 as PD. Among RR cases, 45 patients (71.4%) showed histological response of grade 2-3, while among non-RR cases, 5 patients (9.8%) showed grade 2-3. During the median follow-up of 42.6 months, 3-year RFS rates for RR/non-RR groups were 62.2%/49.0% (P=0.098), and 3-year OS rates were 76.9%/53.0% (P=0.026).

Conclusion

The newly introduced “RR (Remarkable Response)” of sub-classification for endoscopic evaluation after neoadjuvant chemotherapy may be useful for predicting histological response and stratifying prognosis in locally advanced ESCC.

Introduction

Polypoid lesions in Helicobacter pylori (Hp)-naive stomachs are generally fundic gland polyps (FGPs), which have a smooth surface and typically do not require treatment. However, some lesions with different appearances, such as foveolar-type adenomas that present with a reddish color and papillary surface structure, may also be observed. These lesions can be difficult to diagnose accurately with biopsy alone. An efficient and safe diagnostic and therapeutic approach for these lesions is needed.

Aims & Methods

We devised outpatient underwater cold snare polypectomy (uCSP) as a diagnostic alternative to biopsy for reddish polypoid lesions in Hp-naive stomachs that differ from the typical appearance of FGPs. We retrospectively analyzed the clinicopathological characteristics and outcomes of cases in which outpatient uCSP was performed for solitary lesions ≤10 mm in size, after obtaining informed consent. Hp-naive was defined by the absence of endoscopic and histological atrophic changes, no history of eradication therapy, and negative results from at least two different diagnostic tests for H. pylori infection.

Results

Between April 2021 and March 2025, 35 cases underwent uCSP (16 males, 19 females; mean age: 55.9 years). The mean lesion size was 3.7 mm, with 21 lesions located in the upper part of stomach and 14 in the middle part of stomach. In all cases, lesions were obtained including surrounding mucosa with minimal crush artifact to the deep mucosal layer or superficial muscularis mucosae. Histopathological diagnoses included foveolar-type adenoma in 28 cases, foveolar hyperplastic polyp in 3, FGP with dysplasia in 2, oxyntic adenoma in 1, and inflammatory polyp in 1. Among the 31 neoplastic lesions, only the oxyntic adenoma case had a positive vertical margin, yet no residual or recurrent lesion was detected during 1-year follow-up. The remaining 30 cases had negative lateral and vertical margins. No postoperative bleeding or other adverse events were observed, regardless of proton pump inhibitor use or clip closure following resection.

Conclusion

Outpatient uCSP appears to be a minimally invasive, safe, and effective diagnostic and therapeutic option for solitary polypoid neoplastic lesions ≤10 mm in Hp-naive stomachs.

Introduction

Recent improvements in endoscopic diagnostic techniques have made it possible to detect early-stage superficial laryngopharyngeal cancer, and endoscopic resection has become one of the standard treatments in Japan1). However, it is not fully known to what extent endoscopic treatment alone is curative.

Aims & Methods

To clarify the relationship between depth and lymph node metastasis in superficial laryngopharyngeal cancer. From August 1996 to April 2023, we experienced 501 cases of 810 lesions of superficial laryngopharyngeal cancer. Of these, 396 cases with 652 lesions (462 in the hypopharynx, 149 in the oropharynx, and 41 in the larynx) that were resected orally without prior treatment and followed for more than 1 year were included to investigate the relationship between depth and late lymph node metastasis.

Results

Endoscopic classification of the treated lesions was 81 lesions of type 0-Ⅰ(protruded type), 164 lesions of type 0-IIa(elevated type), 391 lesions of type 0-IIb(flat type), and 16 lesions of type 0-IIc (depressed type). Type 0-IIb was the most frequent.
Histopathologically evaluated 174 cases of intraepithelial carcinoma with 249 lesions showed no metastasis. On the other hand, of the 403 lesions in 295 cases of subepithelial invasive cancer (T1, tumor size less than 2cm: 213 lesions, T2, tumor size 2-4cm or smaller: 159 lesions, T3, tumor size greater than 4cm: 31 lesions), 30 lesions in 28 cases(9.5%) had later lymph node metastasis. Two of 305 lesions (0.65%) with tumor thickness less than 1000 μm were positive for metastasis. By size, 1 of 178 lesions in T1(0.6%), 1 of 111 lesions(0.9%) in T2, and 0 of 16 lesions in T3 were positive for metastasis. On the other hand, 28 of 98 lesions (28.6%) with tumor thickness greater than 1000 μm were positive for metastasis. By size, 6 of 35 lesions in T1(17.1%), 17 of 48 lesions(35.4%) in T2, and 5 of 15 lesions(33.3%) in T3 were positive for metastasis. The frequency of lymph node metastasis by endoscopic type was 20 of 81 lesions(24.7%) for type 0-I, 8 of 164 lesions (4.9%) for type 0-IIa, 1 of 391 lesions(0.25%) for type 0-IIb, and 1 of 16 lesions (6.25%) for type 0-IIc, metastasis was seen more frequently in type 0-I. The observation of brownish areas and brown dots with Image Enhanced Endoscopy is useful for detecting early-stage cancer. When examining the depth of the disease, the Valsalva method is recommended to focus on type 0-I lesions with a thickness of 1 mm or more and a well-stretched pharyngeal mucosa.

Conclusion

Superficial carcinomas with a thickness greater than 1 mm should be noted for late lymph node metastasis.

References

1) Watanabe A, Taniguchi M, Kimura Y, et al. Synopsis of transoral endoscopic laryngopharyngeal surgery for superficial pharyngeal cancers. Head Neck 2017; 39: 1779-1787

Disclosure

The authors have no financial conflicts of interest disclose concerning the study.

Introduction

Twenty-five years have passed since the development of endoscopic submucosal dissection (ESD), and it has become widely used as the first-line treatment for early-stage esophageal and gastric cancers with low risk of lymph node metastasis. However, due to the anatomical complexity and technical difficulty, the application of ESD for hypopharyngeal cancer remains limited.

Aims & Methods

A total of 151 lesions in 106 patients with hypopharyngeal cancer who underwent ESD at the Department of Endoscopy, Saku Central Hospital Advanced Care Center from June 2006 to March 2025 were retrospectively reviewed to evaluate treatment outcomes. Cases of recurrence after chemoradiotherapy were excluded. ESD Procedure
All procedures were performed under general anesthesia with intubation. A hook knife J was used to perform circumferential incisions with the Autocut mode of the VIO 3000 or VIO 3. Submucosal dissection was carried out using Endocut I and spray coagulation. For traction and improved visualization, Clip line technique was used.

Results

The study included 116 patients (109 men, 7 women), with a mean age at diagnosis of 67.7 years (range: 40–92). Synchronous multiple pharyngeal cancers were found in 25 patients and metachronous in 13. A total of 156 lesions were resected: 10 by endoscopic mucosal resection (EMR) and 146 by ESD.
Tumor locations were as follows: oropharynx (7 lesions), hypopharynx (149 lesions), primarily in the piriform sinus (135) and posterior cricoid area (14). Of these, 6 extended to the epiglottis and 5 to the aryepiglottic fold.
Detailed Results

1. Tumor size: mean maximum diameter was 14.5 mm (range: 1–51; resection specimen size: 27.4 mm (5–90). Depth of invasion: EP in 92 lesions (59%) and SEP in 64 (41%). Mean invasion depth from the surface was 712 µm (range: 150–2600). Macroscopic types: 0-I (7), 0-IIa (53), 0-IIb (92), 0-IIc (4). Histology: squamous cell carcinoma (SCC) in 155 lesions, neurofibroma in 1. En bloc resection rate was 100%. Lateral margins: positive in 6, negative in 150. Deep margins: negative in all cases.
2. Adverse events: delayed bleeding (1), aspiration pneumonia (2), and stricture (1).
3. Local recurrence: observed in one SEP case with lymphatic involvement.
4. Pre-ESD metachronous cancers: esophagus: 42, stomach:17, colon:1.
5. Post-ESD metachronous cancers: esophagus:22, hypopharynx:13 and stomach:10.
6. Prognosis: Mean follow-up was 84.9 months (range: 5–222). There were 5 deaths from primary disease, 10 from other diseases, and 8 from other malignancies. All 5 primary disease-related deaths had ly1 and died due to lymph node, pulmonary, or hepatic metastases.
7. Among 11 cases with extension to the aryepiglottic fold or epiglottis, tracheostomy was performed in 8 and nasotracheal intubation in 2 cases.

Conclusion

ESD for hypopharyngeal cancer demonstrated a high rate of local control and was an effective treatment option. Even in cases with extension to the aryepiglottic fold or epiglottis, safe procedures were possible with tracheostomy. For cases with positive lympho-vascular involvement, the risk of lymph node and distant metastases warrants consideration of additional treatment. Metachronous multiple cancers in the hypopharynx, esophagus, and stomach occurred in 40% of patients, emphasizing the importance of postoperative surveillance.

Clinical Case Summary

A 58-year-old woman with no relevant medical history, presenting with progressive dysphagia and odynophagia over a 2-month period. Upper gastrointestinal endoscopy (UGE) revealed a circumferential lesion with a verrucous appearance and exophytic papillomatous component spanning from 20 to 30 cm from the dental arch. These lesions raised suspicion of malignancy; however, biopsies showed only hyperplastic mucosa with chronic inflammation. In an attempt to obtain histological documentation, additional UGE were performed, with repeat biopsies and macrobiopsy of one of the more exophytic components, all without confirmation of neoplasia by multiple pathologists. Immunohistochemistry showed positivity for p16. Additional imaging studies confirmed extensive and locally invasive neoplastic formation with nodal involvement, leading to an empirical diagnosis of verrucous carcinoma of the esophagus (VCE), prompting initiation of neoadjuvant chemoradiotherapy. Subsequently, exploratory thoracoscopy revealed unresectable disease. Palliative chemotherapy was initiated, and a repeat endoscopy shows regression of the lesion.
Discussion: VCE, an extremely rare variant of squamous cell carcinoma, presents with slow growth, local invasiveness, and rare nodal metastases. Although its exact etiology is uncertain, associations with chronic inflammation caused by factors such as smoking, reflux esophagitis, or alcoholism are reported. Human papillomavirus (HPV) infection has also been suggested as a potential contributor. Due to the proliferative nature of VCE, superficial biopsies often show nonspecific inflammatory changes, making diagnosis challenging. Despite the lack of confirmatory histopathology, the unique endoscopic findings, presence of p16 (associated with HPV-related carcinomas), and clinical deterioration led to the empirical diagnosis of VCE. This case highlights the diagnostic complexity and therapeutic challenge associated with this rare variant of esophageal carcinoma.

References

• Minielly, J. A., Harrison, E. G., Fontana, R. S. & Payne, W. S. Verrucous squamous cell carcinoma of the esophagus. Cancer 20, 2078–2087 (1967).
  
• Cappellesso, R. et al. Human papillomavirus infection is not involved in esophageal verrucous carcinoma. Hum Pathol 85, 50–57 (2019).
• Tonna, J. et al. Esophageal verrucous carcinoma arising from hyperkeratotic plaques associated with human papilloma virus type 51. Diseases of the Esophagus 23, (2010).
• Ramani, C., Shah, N. & Nathan, R. S. Verrucous carcinoma of the esophagus: A case report and literature review. World Journal of Clinical Cases : WJCC 2, 284 (2014).
• Osborn, N. K., Keate, R. F., Trastek, V. F. & Nguyen, C. C. Verrucous carcinoma of the esophagus: Clinicopathophysiologic features and treatment of a rare entity. Dig Dis Sci 48, 465–474 (2003).
• Devlin, S., Falck, V., Urbanski, S. J., Mitchell, P. & Romagnuolo, J. Verrucous carcinoma of the esophagus eluding multiple sets of endoscopic biopsies and endoscopic ultrasund: A case report and review of the literature. Canadian Journal of Gastroenterology 18, 459–462 (2004).