Esophageal Cancer Secondary to Achalasia: A Case Series Study

Abstract

Introduction

Achalasia is a primary motility disorder affecting the esophageal body and lower esophageal sphincter. Although the linkage between achalasia and elevated esophageal cancer risk is already known, the precise mechanisms remain poorly elucidated due to the disease’s relative scarcity. We aim to summarize the clinical characteristics of esophageal cancer (EC) secondary to achalasia and improve the understanding of achalasia combined with EC and further reduce the risk of ECs.

Case Presentations

Retrospective statistics were conducted on patients with ECs secondary to achalasia in our hospital from 2009 to 2023. We categorized all achalasia cases with their initial treatment and recorded subsequent interventions when the symptoms recurred. Additionally, we performed detailed analyses of both EC characteristics and therapeutic regimens. We present a case series comprised of 5 patients with achalasia who presented with EC. Three of the patients diagnosed with achalasia were treated by endoscopy or operation to improve symptoms. One patient was treated by pneumatic dilation. All were histologically diagnosed as squamous cell carcinoma. The validity period of endoscopic treatment has been lost in all patients. The erosions were all distributed over the thoracic esophagus.

Conclusion

The high relative risk of ECs was demonstrated in achalasia patients, even in the treated achalasia patients. Therefore, surveillance endoscopy may be recommended regularly in the treated patients.

Introduction

Achalasia is an uncommon esophageal motility disorder with undetermined etiology despite it having historical records spanning three centuries [1]. Clinical epidemiology studies have identified a broad spectrum of achalasia incidence, with estimates extending from 0.3 to 2.3 occurrences per 100,000 population each year [2]. The most common symptoms of achalasia are dysphagia, vomiting, and chest pain. Besides, achalasia is widely considered as one of the risk factors of esophageal cancer (EC) [3]. Recent investigations have revealed potential pathogenic mechanisms whereby the esophageal microbiome promotes carcinogenesis in achalasia, both by perpetuating local inflammation and generating oncogenic compounds, processes that concurrently disrupt normal sphincter physiology [4].

However, the rarity of this disease makes it hard to estimate the real-world effect on the incidence of EC. In China, where esophageal squamous cell carcinoma accounts for 90% of esophageal malignancies, the interplay between achalasia and region-specific carcinogens (e.g., nitrosamine-rich diets, thermal injury from hot beverages) remains underexplored [5]. Epidemiological analyses reveal that achalasia is associated with a markedly higher cancer susceptibility, showing risk elevations between 7 and 33 times the baseline population rates [6].

Yet, critical gaps persist in Chinese clinical practice. The 2020 China Consensus on esophageal achalasia guidelines recommend follow-up at 3, 6, and 12 months after the therapy of achalasia, including Eckardt score, quality-of-life score, endoscopic examination, HRM, and esophageal imaging and 24-h pH monitoring of the esophagus. Meanwhile, due to the long cycle of progression to EC, guidelines recommend that follow-up should typically begin at least 10 years after the onset of AC symptoms and be conducted every 3 years.

Here, we collected 5 cases of EC secondary to achalasia from January 2009 to June 2023 in the First Affiliated Hospital of Zhejiang University (see CARE Checklist in online suppl. material 1; for all online suppl. material, see https://doi.org/10.1159/000548622). Through this case series and literature analysis, we aim to (1) characterize the clinicopathological progression patterns in Chinese achalasia-associated ECs, (2) evaluate the real-world adherence to posttreatment surveillance, and (3) emphasize the necessity of endoscopic follow-up even after achalasia treatment.

Case Series

Case 1

The first case involved a 73-year-old female with a medical history of achalasia for 30 years (Table 1), and the patient reported that she had undergone Heller’s myotomy for 25 years and 15 years previously. She presented complaining of dysphagia to solid foods for 30 years and of cough for 2 days. Chest CT (Fig. 2a) revealed thickening of the upper and middle esophageal walls, considering tumor. Multiple enlarged lymph nodes in the mediastinum, with enlarged lymph nodes on both sides of the neck, especially on the right side. Upper endoscopy (Fig. 1a) was also performed, which showed an irregular lump in the shape of cauliflower around the esophageal wall at a distance of 30 cm from the incisor. The biopsy indicated squamous cell carcinoma (SCC) pathologically. The patient was treated by chemotherapy subsequently.

Table 1.

Patient characteristics for EC cases in achalasia

​	Sex	Disease evolution, years	Age at diagnosis of EC, years	Treatment for achalasia	Preoperative diagnosis			Window period, years	Treatment for EC	Pathology	Tumor location	Length, cm
					CT	Esophagram	GE
Case 1	F	30	73	Heller’s myotomy twice	√	×	√	15	Chemotherapy	SCC	Mt	30
Case 2	M	11	69	Heller’s myotomy once	√	√	√	7	Chemoradiotherapy	SCC	Mt	28
Case 3	M	20	65	POEM once	√	×	√	4	Radical operation	SCC	Lt	40
Case 4	M	25	60	None	√	√	√	–	Operation and chemotherapy	SCC	Mt	25
Case 5	F	12	58	PD thrice	√	×	√	10	Chemotherapy	SCC	Ut	20

√: the test is completed. ×: the test is not completed. Window period: time from last achalasia treatment to diagnosis of EC. GE, gastroendoscopy; POEM, peroral endoscopic myotomy; PD, pneumatic dilation; EC, esophageal cancer; SCC, squamous cell carcinoma; Ut, upper thoracic; Mt, middle thoracic; Lt, lower thoracic.

Fig. 2.

The manifestation of esophageal lesions on CT imaging in case 1 (a), case 2 (b), and case 3 (c); on CT imaging (d) and on barium radiography (e) in case 4; and on CT imaging in case 5 (f).

Fig. 1.

Endoscopic manifestations of lesions in case 1 (a), case 2 (b), case 3 (c), case 4 by narrow band imaging (NBI) (d), and case 5 (e).

Case 2

The second case was a 69-year-old male with a medical history of achalasia for 11 years and chronic obstructive pulmonary disease (COPD) (Table 1), the patient had been operated for Heller’s myotomy 7 years ago. He complained of dysphagia for 30 years, worsening for 1 month. Chest CT (Fig. 2b) revealed esophageal dilation and broadening entirely, consistent with achalasia, and the local thickening of the upper esophageal wall. A mass with irregular shape in the middle esophagus was observed by gastroendoscopy (Fig. 1b), diagnosed as SCC by biopsy. Chemoradiotherapy was performed for the patient after comprehensive evaluation in our hospital.

Case 3

The third case was a 65-year-old male with a medical history of achalasia for 20 years (Table 1), who had operation of POEM by endoscopy for 4 years. The patient presented with complains of dysphagia for 20 years, worsening for over a month. Gastroendoscopy (Fig. 1c) was further performed, which showed mucosal exfoliation at a distance of 40 cm from the incisor, with a rough and uneven surface, measuring approximately 2.5 × 2.0 cm in size, diagnosed as SCC by biopsy. Chest CT (Fig. 2c) revealed complete esophageal dilation. Radical operation was performed, and the surgical section revealed ulcerative highly differentiated SCC pathologically.

Case 4

The fourth case was a 60-year-old male with a medical history of achalasia for 25 years (Table 1). The patient presented with complains dysphagia for 25 years, worsening for 6 months. He had not received regular treatment for achalasia before. Chest CT (Fig. 2d) and esophagram (Fig. 2e) only indicated dilation of the upper and middle esophageal lumen. Gastroendoscopy (Fig. 1d) revealed erosion of esophageal mucosa and chyme retention in the esophagus and multiple ulcers in the gastric antrum and duodenum. The biopsy predicated SCC pathologically. Also, we operated the esophageal manometry, which was diagnosed as achalasia II. Fortunately, the patient had surgery and chemotherapy 4 times and recovered well during follow-up.

Case 5

The fifth case was a 58-year-old female with a medical history of achalasia for 12 years with PD treatment 3 times (Table 1). The patient was referred to the hospital for neckache. Chest CT (Fig. 2f) revealed esophageal dilation and esophageal upper thoracic mass. Gastroendoscopy (Fig. 1e) also revealed an irregular mass in the shape of a cauliflower occupying two-thirds of the esophageal wall at a distance of 20 cm from the incisor. Biopsy indicated SCC. Furthermore, the patient was treated by chemotherapy.

Discussion

Our study collected all the cases of achalasia-related EC from January 2009 to June 2023 in the First Affiliated Hospital of Zhejiang University. These 5 patients were all over 55 years old, and the maximum age was 73 years, including 2 females and 3 males. These findings are consistent with previous studies, which revealed that risk factors associated with the development of EC included increasing age as a well-established independent risk factor.

In this case series study, 2 female patients had reinterventions following primary treatment, and the window periods were over 10 years. Prior studies have demonstrated that secondary procedures after initial therapeutic management of achalasia correlate with elevated risks of esophageal malignancy development [7]. It is thought that a need for reintervention may eventually represent the severity of underlying achalasia for these patients, which may be the underlying reason that they are at greater risk of developing cancer rather than the act of reintervention itself. Although achalasia is more common in young women, achalasia combined with EC is more common in older males [8]. Zendehdel et al. [9] conducted a large-scale retrospective study in Sweden in 2011, which showed a male-to-female ratio of up to 10:1. In this study, males were more than females even in the 5 cases, and the window periods were shorter for the male patients, although they did not get reintervention. Thus, more research is needed for understanding the differences of reintervention following primary achalasia between males and females.

All 5 cancers were in the thoracic esophagus (Ce: 0, Ut: 1, Mt: 3, Lt: 1, Ae: 0), a large database analysis in Japan (SATO) had noted that EC is predominantly distributed over the thoracic esophagus, especially in the middle thoracic esophagus. Multiple lesions and metachronous lesions were also observed. The pathophysiological mechanism behind it is still unclear. Cancers in our study were all single lesion, and only 1 patient had the opportunity to get radical operation, 3 received chemotherapy, and 1 received operation and chemotherapy. Out of the 5 cancers, 3 were macroscopically diagnosed with mass-shaped neoplasm on endoscopy (2 were cauliflower-like neoplasms). However, superficial ECs were successfully treated with endoscopic treatment in the vast majority of cases in a study in Japan [10]. It highlights the importance of surveillance endoscopy in patients with achalasia, even in the patients who had been treated.

The 5 patients were all histologically diagnosed with SCC, and it was reported that most of the ECs secondary to achalasia were SCC in a study in Japan [11], but some studies have reported that Barrett’s esophagus and subsequent adenocarcinoma were more common in Caucasian populations [12], who were treated with pneumatic dilation mostly, and a current hypotheses proposed that pneumatic dilation could exacerbate reflux phenomena, establishing a biochemical environment that fosters epithelial metaplasia and progression to adenocarcinoma.

One patient in our study accepted PD treatment 3 times and was diagnosed with SCC. Therefore, the incidence of adenocarcinoma may be associated with race or ethnicity.

In conclusion, it is still necessary to take regular endoscopic examination in patients with achalasia for cancer surveillance. Although achalasia itself is not a malignant disorder, performing long-term follow-up is needed especially in treated patients.

Statement of Ethics

This study protocol was reviewed and approved by the Clinical Ethics Committee of the First Affiliated Hospital, Zhejiang University School of Medicine, Approval No. 0936. Written informed consents were obtained from all the patients for publication of details of their medical cases and any accompanying images. The authors have read the CARE Checklist (2013), and the manuscript was prepared and revised according to the CARE Checklist (2013).

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This paper was financially supported by the Natural Science Foundation of Zhejiang Province, No. LQ20H030007. The fund was used for polishing the manuscript to improve readability.

Author Contributions

Wenli Xu, Yanqin Long, and Hongtan Chen conceived the study and designed the methodology. Wenli Xu, Bo Li, and Fenming Zhang collected the data acquisition. Wenli Xu drafted the manuscript. Yanqin Long and Hongtan Chen wrote the manuscript and revised it critically for important intellectual content. All authors approved the final version of the paper.

Funding Statement

This paper was financially supported by the Natural Science Foundation of Zhejiang Province, No. LQ20H030007. The fund was used for polishing the manuscript to improve readability.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.