Clinical Case Summary

This case presents a 64-year old man with verrucous carcinoma of the esophagus (VCE), a rare variant of squamous cell carcinoma. The patient has a history of type 2 diabetes and tobacco abuse, and presented in September 2019 with complaints of dysphagia. Upper endoscopy revealed reflux-, and candida esophagitis, and a proximal stenosis. Treatment was initiated with proton pump inhibitors, antifungal therapy, and dilatations. Over three years, multiple endoscopies were conducted, almost all revealing extensive white hyperkeratotic and exophytic lesions. Histopathology reports described fungal threads and no dysplasia, leading to a diagnosis of therapy-resistant candida esophagitis due to poorly regulated diabetes. After two times failure of intravenous antifungal therapy, in February 2023, the patient was referred to our center, a tertiary hospital. Targeted bite on bite biopsies revealed candida aggregates, parakeratosis, and squamous cell proliferation, highly suggestive of well-differentiated VCE. A PET-CT showed no signs of metastatic disease; therefore, considering the early stage and endoscopic extent of the lesion, a laparoscopic esophagostomy was performed.

The prolonged interval from clinical presentation to VCE diagnosis is thought to result from the hyperkeratotic growth pattern, which causes inadequate material for histologic confirmation of underlying neoplastic tissue. Additionally, the presence of fungal threads and white lesions results in diagnosis of candida esophagitis, misleading physicians and causing diagnostic delay. In patients with therapy-resistant candida esophagitis and atypical hyperkeratotic esophageal lesions VCE should be considered, enabling early diagnosis and treatment.

References

Figures that will be presented when accepted:
Figure 1: upper GI endoscopy during initial presentation showing white/yellow keratotic plaques and a proximal stenosis.
Figure 2: upper GI endoscopy at time of VCE diagnosis at our center 4-years after the initial presentation, showing a circumferentially narrowed esophagus, with white, granular and keratotic plaques and lesions at white light endoscopy
Figure 3: upper GI endoscopy at time of VCE diagnosis at our center 4-years after the initial presentation, with NBI showing a circumferentially narrowed esophagus, and diffusely irregular mucosa with white plaques and keratotic lesions.

References:
1. Sweetser S, Jacobs NL, Wong Kee Song LM. Endoscopic diagnosis and treatment of esophageal verrucous squamous cell cancer. Dis Esophagus. 2014;27(5):452-6.
2. Egeland C, Achiam MP, Federspiel B, Svendsen LB. Verrucous Squamous Cell Cancer in the Esophagus: An Obscure Diagnosis. Case Rep Gastroenterol. 2016;10(2):466-71.
3. Tabuchi S, Koyanagi K, Nagata K, Ozawa S, Kawachi S. Verrucous carcinoma of the esophagus: a case report and literature review. Surg Case Rep. 2020;6(1):35.

Introduction

Patients with Barrett’s Esophagus (BE) undergo regular endoscopic surveillance to timely intervene in the development of esophageal adenocarcinoma (EAC). The current European Society of Gastrointestinal Endoscopy (ESGE) guideline recommends stopping BE surveillance at the age of 75 years, based on average life expectancy. However, clinical studies to support this recommendation are lacking.

Aims & Methods

Therefore, this study aims to determine the optimal age to discontinue surveillance by analyzing incidence and mortality rates in a real-life cohort study. We analyzed data from a multicenter, prospective cohort of BE patients in the Netherlands with a segment length of ≥2 cm, all of whom underwent endoscopic surveillance between 2004 and 2023, in accordance with American College of Gastroenterology guidelines. Patients were linked with the Netherlands Cancer Registry (NCR) to optimize data completeness. Vital status and cause of death of patients were verified with their general practitioner and through the Central Statistical Office (CBS). The cumulative incidence of EAC was calculated, and standardized incidence (SIR) and standardized mortality rate (SMR) were analyzed using a Poisson regression model.

Results

A total of 1,378 BE patients (median age at inclusion 62 years; 73% male) were included for analysis. Median follow-up time was 6.3 years, and median age at cessation of surveillance was 75 years. In total, 57 EAC cases were identified at a median age of 69 years, of which 89% under active surveillance. The majority of cancers was diagnosed at an early stage (47% Stage I, 12% stage II, 3.5% stage III). The cumulative incidence after 10 years of follow-up was 4.4.% in the complete cohort, which was lower in the age group >75 (1.7%). The incidence rate per 1,000 person years was highest amongst patients aged 65-69 years. The SIR was 19.2 in the complete cohort, decreasing to 12.1 in patients >75 years. A total of 350 patients died during follow-up, of which 15 (4.3%) due to EAC. Median age at death was 79 years. The most frequent causes of death were cardiovascular disease (25%), and other malignancies (27%). The mortality rate per 10,000 person years was 10 for EAC-related death and 240 for other causes. The risk of other cause mortality was 24 times higher than EAC-related mortality. The overall SMR for EAC-related death was 3.9, decreasing to 2.5 in patients > 75 years of age.

Conclusion

Our findings support the ESGE guideline recommendation to discontinue surveillance in BE patients older than 75 years, as the cumulative incidence, SIR, and SMR all declined notably in this age group. Although the SIR was still high in patients aged 75 and above, patients in this cohort were 24 times more likely to die from other causes than from EAC.

Introduction

Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy often detected through surveillance esophagogastroduodenoscopy (EGD). Despite regular screening, some cases still progress to advanced stages, including invasion into the muscularis mucosa (pT1a-MM) or deeper layers. The detection of interval ESCC during surveillance presents a clinical challenge, as these lesions can impact long-term prognosis.

Aims & Methods

This study aimed to investigate the characteristic endoscopic features and prognosis of post-EGD ESCC (PEESCC), defined as ESCC that progressed to pT1a-MM or deeper within two years of a prior surveillance EGD that did not identify neoplasia or carcinoma. We retrospectively analyzed 225 superficial ESCC lesions from 215 patients treated with endoscopic submucosal dissection (ESD) at the Hiroshima University Hospital between April 2010 and March 2023. Among them, 29 lesions in 28 patients were classified as the post-EGD ESCC (PEESCC) group, defined as cases where EGD performed 24 months before diagnosis did not detect neoplasia or carcinoma. The remaining 196 lesions in 188 patients were the control group. Subsequently, endoscopic findings [the presence of multiple Lugol-voiding lesions (LVLs), cancer location, circumferential involvement, direction, tumor size, macroscopic type, submucosal tumor (SMT)-like elevation, tumor color, intrapapillary capillary loop (IPCL), and clinical depth of invasion] and prognosis were compared. For accurate endoscopic findings and prognostic evaluation, patients with concurrent pT2 or deeper ESCC, those who had undergone treatment for pT2 or deeper ESCC, and those with a history of esophagectomy were excluded.

Results

In the PEESCC group, the proportions of cases with the presence of multiple-LVLs (69.0% vs. 39.3%, p < 0.01), cervical esophageal lesions (17.2% vs. 3.1%, p < 0.01), lesions localized between the 11 o’clock and 1 o’clock positions (20.7% vs. 7.7%, p = 0.037), and SMT-like marginal elevations (20.7% vs. 7.7%, p = 0.037) were significantly higher, whereas the proportion of red-colored lesions (24.5% vs. 44.9%, p = 0.027) was significantly lower compared to the control group. Additionally, the tumor size in the PEESCC group was significantly smaller than that in the control group (21.6±12.3 mm vs. 34.0±18.3 mm, p<0.01). From the multivariate analysis using the stepwise method, the presence of multiple-LVLs (OR=3.2, 95%CI:1.3-8.5, p<0.01), cervical esophageal lesions (OR=9.9, 95%CI:2.2-45.6, p<0.01), small tumor diameter(≦30mm)(OR=3.3, 95%CI:1.2-10.6, p=0.017), and SMT-like elevation (OR=3.8, 95%CI:1.1-12.0, p=0.034) were significanty identified as characteristic endoscopic findings of PEESCC. No statistically significant findings were detected in the multivariate analysis of patients without ESD history. But in the multivariate analysis limited to non-CRT cases to exclude the influence of CRT, the presence of multiple-LVLs (OR=6.5, 95%CI:2.1-23.4, p<0.01), cervical esophageal lesions (OR=15.7, 95%CI:3.1-86.8, p<0.01), tumor circumferential involvement: <1/3(OR=8.5, 95%CI:1.6-46.1, p=0.013), and SMT-like marginal elevation(OR=6.5, 95%CI:0.8-9.8, p=0.015) were identified as independent risk factors for PEESCC.The PEESCC group had a lower 5-year disease-specific survival (93.1% vs. 98.5%, p=0.039) and recurrence-free survival (69.0% vs. 83.7%, p=0.0245).

Conclusion

PEESCC lesions are associated with distinct endoscopic features and poor prognosis than non-PEESCC lesions.

Introduction

Squamous dysplasia is the histopathological precursor of esophageal squamous cell carcinoma (ESCC). The optimal management for distinct squamous dysplasia grades remains unclear because the corresponding risk of developing ESCC is unknown. In this study, we aimed to assess the ESCC risk in patients with esophageal squamous dysplasia in a Western country.

Aims & Methods

This nationwide cohort study included all patients with esophageal squamous dysplasia, diagnosed between 1991 and 2020 in the Dutch nationwide histopathology registry (PALGA). Squamous dysplasia was divided in mild-to-moderate dysplasia (consisting of mild, low-grade, and moderate dysplasia) and higher-grade dysplasia (high-grade dysplasia, severe dysplasia, and carcinoma in situ). The primary endpoint was diagnosis of prevalent (within 6 months) and incident (after more than 6 months after squamous dysplasia) ESCC, identified in PALGA and the Netherlands Cancer Registry.

Results

873 patients (55% male, mean age of 68 years SD±13.2) were diagnosed with esophageal squamous dysplasia, comprising mild-to-moderate dysplasia (n=456), higher-grade dysplasia (n=393) and dysplasia not specified (n=24). 57% of the patients with mild-to-moderate dysplasia received endoscopic re-assessment after 12 weeks (IQR 6-29). During first endoscopic-reassessment, ESCC was detected in 5.1%, 1.8% and 12.8% of patients with baseline mild, low-grade, and moderate dysplasia, respectively. In total, ESCC was diagnosed in 77 (17%) patients with mild-to-moderate dysplasia (49 prevalent, 28 incident ESCC) and in 162 (41%) patients with higher-grade dysplasia (128 prevalent, 34 incident ESCC) (Table 1). After excluding prevalent ESCC, the annual risk of ESCC was 4.0% (95% CI: 2.7-5.7%) in patients with mild-to-moderate and 8.5% (95% CI: 5.9-11.7%) per patient-years and higher-grade dysplasia.

Table 1. The proportion of patients with distinct grades of baseline squamous dysplasia diagnosed with prevalent and incident ESCC.

Conclusion

All patients with squamous dysplasia, including those with mild, low-grade, and moderate dysplasia, have a substantial risk of developing ESCC. Consequently, endoscopic surveillance of the esophageal mucosa is recommended for patients with mild-to-moderate dysplasia in Western countries.

Introduction

A confirmed diagnosis of low-grade dysplasia (LGD) on two endoscopies is currently considered a predictor for neoplastic progression in patients with Barrett’s esophagus (BE), and, therefore, ablation therapy is offered to these patients. However, recent studies show that aberrant expression of the p53 tumor suppressor protein might be a stronger risk factor for neoplastic progression than dysplasia status.

Aims & Methods

The aim of this study was to evaluate the value of p53 expression compared to confirmed LGD in predicting neoplastic progression in BE patients. Data was analyzed from a large prospective cohort study of 1031 BE patients (73% males, median age 61 years) with index diagnosis of non-dysplastic BE (NDBE), indefinite for dysplasia (IND), and LGD. Confirmed LGD was defined as a LGD diagnosis on 2 separate occasions, each LGD diagnosis was confirmed by two pathologists. P53 immunohistochemistry staining was performed on biopsies of 1545 endoscopies from 655 (64%) patients; both overexpression and loss of expression were considered aberrant. Neoplastic progression was defined as high-grade dysplasia (HGD) and/or esophageal adenocarcinoma (EAC). Cox regression analysis was used to determine neoplastic progression risk.

Results

During a median follow-up of 8.4 (IQR 5.3-12.9) years, 68/655 (10%) patients developed HGD/EAC. Neoplastic progression was found in 20/411 (5%) NDBE patients, 25/149 (17%) patients with a single diagnosis of LGD, and 24/95 (24%) patients with confirmed LGD. P53 expression was aberrant in 28/411 (7%) NDBE patients, 50/149 (34%) single LGD patients, and 51/95 (54%) confirmed LGD patients. Aberrant p53 expression was strongly associated with an increased risk of neoplastic progression after adjusting for age, gender, segment length, esophagitis, and grade of dysplasia (HR 13.5, 95% CI 7.1-25.8). In NDBE patients, the absolute neoplastic progression risk increased from 2% with normal p53 expression to 50% with aberrant p53 expression. In patients with a single diagnosis of LGD, the progression risk increased from 6% to 35% when p53 expression was aberrant. Similar risks where found in patients with confirmed LGD, with a neoplastic progression risk of 2% with normal p53 expression and 43% with aberrant p53 expression.

Conclusion

Aberrant p53 expression is a strong predictor for neoplastic progression in BE patients. The predictive value of aberrant p53 expression is independent of the grade of dysplasia. Aberrant P53 expression may be a better parameter than (confirmed) LGD to identify patients who need close surveillance or could benefit from ablation therapy.

Introduction

Endoscopic submucosal dissection (ESD) for esophageal squamous cell carcinoma (ESCC) with esophageal varices (EVs) is one of the most challenging endoscopic procedures due to the high risk of bleeding and fibrosis caused by prior treatment of varices. However, due to the small number of such cases, the clinical outcomes of ESD for ESCC with EVs have been reported in only a limited number of cases at single centers^​1-3.

Aims & Methods

We conducted a multicenter, retrospective, cohort study to clarify the safety and efficacy of ESD for ESCC with EVs.Eleven institutions in the Tohoku region of Japan participated in this multicenter, collaborative, retrospective study. We performed endoscopic resection for 3619 patients with esophageal carcinoma at the participating institutions during the period from January 2010 to April 2022. Among those, 30 patients who underwent ESD for ESCC with EVs were recruited for the present study.
Rates of en bloc resection and R0 resection, procedure time and adverse events were evaluated as indicators of the feasibility and safety of ESD. Additional treatment, recurrence and metastasis of the lesions were evaluated as indicators of the long-term efficacy of ESD.

Results

Portal hypertension was caused by cirrhosis, of which alcohol was the most common cause. En bloc resection was achieved in 93.3% and R0 resection in 80.0% of the patients. The median procedure time was 92 minutes. Adverse events included a case of uncontrolled intraoperative bleeding leading to discontinuation of ESD and a case of esophageal stricture due to extensive resection. During the follow-up period of a median for 42 months, a patient with local recurrence and another patient with liver metastasis were observed. One patient died of liver failure after receiving chemoradiotherapy as an additional treatment after ESD. No patient died of ESCC.

Conclusion

This multicenter, retrospective cohort study demonstrated the safety and efficacy of ESD for ESCC with EVs. Further studies are needed to establish appropriate treatment methods for EVs before ESD and additional treatments for patients with insufficient ESD.

References

1. Sawaguchi M, Jin M, Matsuhashi T, et al. The feasibility of endoscopic submucosal dissection for superficial esophageal cancer in patients with cirrhosis (with video). Gastrointest Endosc 2014;79:681-5.
2. Choi YK, Noh JH, Kim DH, et al. Outcomes of endoscopic submucosal dissection for superficial esophageal neoplasms in patients with liver cirrhosis. Clin Endosc 2022;55:381-9.
3. Zhang S, Liu YD, Chai NL, et al. Endoscopic submucosal dissection for early cancers or precancerous lesions of the upper gastrointestinal tract in cirrhotic patients with esophagogastric varices: Ten-year experience from a large tertiary center in China. Gastrointest Endosc 2023 Online ahead of print.

Disclosure

The authors declare that they have no conflicts of interest.

Introduction

Patients with multiple Lugol-voiding lesions (mLVLs) in esophageal squamous cell carcinoma (ESCC) were known to have an increased risk of metachronous ESCC or pharyngeal and laryngeal squamous cell carcinoma (PLSCC) following endoscopic resection (ER), necessitating intensive endoscopic surveillance. The Japan Esophageal Cohort study, a multicenter prospective study evaluating the cumulative incidence of metachronous ESCC after esophageal ER, demonstrated that ER was selected as the initial treatment for most newly detected metachronous ESCC (72/74 patients). However, in clinical practice, ESCC or PLSCC outside the indications for ER are occasionally detected. Additionally, patients with mLVLs are known to have a high risk of developing other secondary primary cancers, nonetheless, the long-term clinical course in this population remains unclear.

Aims & Methods

The aim of this retrospective study was to evaluate the long-term prognosis of patients with mLVLs after endoscopic submucosal dissection (ESD) for superficial ESCC. This study included patients with mLVLs who underwent ESD for primary ESCC at our institution between April 2008 and August 2016. The exclusion criteria were patients with non-curative resection after ESD requiring additional treatment, such as submucosal invasion, positive vertical margins (pVM1), or lymphovascular invasion (LVI), and patients with a follow-up period of less than one year. After esophageal ESD, endoscopic surveillance was conducted every six months to one year, and metachronous cancers were considered for treated if detected. The cumulative incidence of metachronous ESCC and PLSCC, as well as the cumulative incidence of metachronous major ESCC and PLSCC, and overall survival (OS) were evaluated. Major ESCC were defined as lesions outside the indications for ER or those in which ER was performed resulting in a non-curative resection. Major PLSCC were defined as lesions outside the indications for ER or endoscopic laryngopharyngeal surgery (ELPS), or those in which ER or ELPS were performed resulting in pVM1 or LVI.

Results

A total of 140 patients were included, with a median age of 69 years (range: 47-86), and 30 patients (21.4%) had a history of head and neck cancer. During the median follow-up of 8.8 years (range: 1.2–15.5), 85 patients (60.7%) developed metachronous ESCC, all of whom were initially treated with ER, and 81 (95.3%) managed with ER alone, including repeated ER. Meanwhile, 35 patients developed metachronous PLSCC, 30 (85.7%) of whom were managed with ELPS alone. The cumulative incidence of metachronous ESCC and PLSCC at 5/10 years was 47.5%/67.1% for ESCC, and 13.8%/35.4% for PLSCC, respectively. The cumulative incidence of metachronous major ESCC and PLSCC at 5/10 years was 0.8%/2.8% for ESCC, and 1.5%/1.5% for PLSCC. Additionally, 30 (21.4%) patients died during follow-up, including progression of superficial metachronous ESCC (n=1) and superficial metachronous PLSCC (n=2) under observation after detection due to poor performance status, recurrences of previously treated PLSCC (n=7), aspiration pneumonia (n=4), hematological malignancies (n=3), tongue cancer (n=2), and others (n=11). The 5- and 10-year OS rates were 92.4%/ 79.5%.

Conclusion

In patients with mLVLs, endoscopic surveillance including pharyngo-laryngeal area following ESD for ESCC enabled early detection of metachronous lesions, the majority of which were successfully treated with ER. However, deaths from other causes were not negligible, highlighting the importance of careful long-term systemic monitoring.