Introduction
Esophageal cancer (EC) is a heterogeneous malignancy arising from the esophageal epithelium, with distinct histological subtypes including esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). The distribution of these subtypes varies substantially across geographic regions. ESCC remains the predominant histological type in East Asia, particularly in China, whereas EAC is more frequently observed in Western countries[
1–
2]. According to the Global Cancer Statistics 2020, approximately 604,000 new cases and 544,000 deaths from EC were reported worldwide, with China accounting for a substantial proportion of the global burden[
3]. The marked geographic variation and high disease burden highlight the importance of early detection and prevention strategies. With the rapid development of endoscopic techniques, esophageal precancerous lesions can be increasingly identified before malignant transformation, providing a critical opportunity for risk assessment, early intervention, and cancer prevention[
4].
From the perspective of traditional Chinese medicine (TCM), EC is traditionally categorized within the disease concepts of “Ye Ge” (dysphagia and obstruction). Classical TCM theories have described swallowing disorders associated with dysfunction of Qi movement, phlegm accumulation, blood stasis, and impairment of gastrointestinal function. Over time, a relatively systematic theoretical framework for the prevention and management of EC has been established, emphasizing the principles of “preventing disease before its occurrence” and “preventing progression after disease onset”. Since the 1970s and 1980s, Chinese oncology specialists have conducted extensive clinical studies exploring the application of TCM in EC prevention and treatment, contributing to the development of integrative approaches.
Although advances in surgery, radiotherapy, chemotherapy, targeted therapy, and immune checkpoint inhibitors have improved outcomes for patients with advanced EC, current clinical strategies remain primarily focused on established cancer rather than the precancerous stage. Esophageal precancerous lesions represent a critical transitional phase preceding invasive cancer development[
5], but their management involves diverse pathological entities, including ESCC-related squamous intraepithelial neoplasia and Barrett’s esophagus-associated dysplasia, which have different biological characteristics, risk factors, and progression patterns[
6–
7]. Current clinical guidelines mainly emphasize Western medicine-based screening, endoscopic diagnosis, and treatment, while evidence-based recommendations integrating TCM and Western medicine for the prevention and management of esophageal precancerous lesions remain lacking. Therefore, there is an urgent need to develop a multidisciplinary, evidence-based guideline that incorporates both conventional medical strategies and TCM approaches[
8]. This guideline aims to establish standardized recommendations for risk assessment, screening, diagnosis, treatment, and surveillance of esophageal precancerous lesions, thereby improving early prevention, individualized management, and long-term clinical outcomes.
Guideline formulation and process of guideline development
The development of this guideline was initiated by the China Association of Chinese Medicine. Following the completion and approval of the guideline development proposal, the guideline working group proceeded with the preparation of the formal guideline document. The overall development process is illustrated in Figure 1.
Guideline project approval
This guideline was registered and developed as a group standard project approved by the China Association of Chinese Medicine. The guideline is entitled Evidence-Based Clinical Practice Guideline for Integrative Chinese and Western Medicine in the Prevention and Management of Esophageal Precancerous Lesions (project number: 20241220-BZ-CACM).
Guideline development group
The guideline development group consisted of guideline coordinators, writing group members, senior reviewers, and consensus panel members. The detailed list of members and their affiliations is provided in the Supplementary Appendix 1.
Scope of the guideline
This guideline focuses on the early identification, standardized diagnosis, integrative Chinese and Western medicine interventions, and surveillance of esophageal precancerous lesions. It addresses key clinical issues across different stages of esophageal carcinogenesis and summarizes currently available evidence-based and clinically applicable strategies for the prevention and management of these lesions. The guideline is intended to support clinical decision-making for healthcare professionals involved in the management of esophageal precancerous lesions, including those working in oncology hospitals, primary healthcare institutions, TCM hospitals, general hospitals, and integrative medicine departments.
This guideline applies to individuals at high risk for EC, patients with ESCC-related precancerous lesions, patients with EAC-related precancerous lesions, and individuals at increased risk of recurrence after treatment for early EC. The scope of this guideline includes the identification of risk and protective factors associated with EC development, screening and risk stratification of high-risk populations, diagnosis and TCM-based pathological evolution of esophageal precancerous lesions, integrative management and surveillance of squamous and glandular precancerous lesions, and TCM-based interventions for recurrence prevention after treatment of early EC.
This guideline is primarily intended for oncologists, endoscopists, gastroenterologists, TCM physicians, integrative medicine practitioners, primary healthcare providers, and researchers involved in the screening, diagnosis, treatment, surveillance, and prevention of esophageal precancerous lesions. It may also serve as a reference for healthcare institutions in establishing clinical pathways, designing clinical research, and implementing quality management strategies for the integrative management of esophageal precancerous lesions.
Formulation of clinical questions
During the initial phase of guideline development, clinical questions were formulated through a combination of two rounds of questionnaire surveys, in-depth expert interviews, and multidisciplinary expert consensus meetings. The clinical questions were developed based on the key issues encountered in the prevention, diagnosis, treatment, and surveillance of esophageal precancerous lesions. Subsequently, comprehensive literature searches were conducted to identify relevant evidence for each clinical question. The detailed search strategies are provided in Supplementary Appendix 2. The following six clinical questions were identified:
Clinical question 1: What are the risk factors associated with the development of EC, and what protective factors may reduce the risk?
Clinical question 2: What are the appropriate strategies for screening and risk prediction among individuals at high risk for EC?
Clinical question 3: What are the diagnostic approaches for esophageal precancerous lesions, and how can the TCM-based pathological evolution of these lesions be characterized?
Clinical question 4: What are the appropriate integrative Chinese and Western medicine strategies for the treatment and surveillance of ESCC-related precancerous lesions?
Clinical question 5: What are the appropriate integrative Chinese and Western medicine strategies for the treatment and surveillance of EAC-related precancerous lesions?
Clinical question 6: What TCM-based interventions are available for preventing recurrence after treatment of early EC?
Evidence quality grading
The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Evidence was evaluated across five domains: risk of bias, inconsistency, indirectness, imprecision, and publication bias. Based on these criteria, the certainty of evidence was categorized as high (A), moderate (B), low (C), or very low (D). Evidence profiles and summary of findings tables were generated to summarize the available evidence, with the grading criteria presented in Table 1[
9].
Recommendation formulation
Recommendations and consensus statements were developed using the Nominal Group Technique (NGT). The multidisciplinary expert panel considered multiple factors, including the certainty of evidence, the balance of desirable and undesirable effects, clinical applicability, patient preferences and values, and expert judgment, to reach consensus and formulate the final recommendations. The strength of recommendations was categorized as Grade 1 (strong recommendation) or Grade 2 (conditional recommendation), with the grading criteria and decision framework presented in Tables 2 and 3.
Clinical questions and recommendations
Etiology
Clinical question 1: What are the risk factors associated with the development of EC, and what protective factors may reduce the risk?
Recommendation: Primary prevention of EC should focus on both the identification of risk factors and the implementation of protective interventions[
10–
12]. Key risk factors include advanced age, unhealthy dietary habits, nutritional deficiencies, exposure to mycotoxins, infectious factors, and lower socioeconomic status (Evidence level: A; strong recommendation). Preventive strategies, including increased intake of fresh fruits and dietary fiber, improvement of dietary patterns, smoking cessation and alcohol control, weight management, and appropriate management of gastroesophageal reflux-related disorders, are recommended to reduce the risk of EC and precancerous lesions (Evidence level: A; strong recommendation). From the perspective of TCM, the development of esophageal precancerous lesions is closely associated with dietary imbalance, emotional disturbances, excessive exposure to tobacco and alcohol-related pathogenic factors, aging-related deficiency, and dysfunction of the spleen and stomach. The pathological progression is considered to involve a gradual transition from Qi stagnation, phlegm accumulation, and blood stasis to the formation of phlegm-blood stasis and toxic accumulation. Following the TCM principle of “preventive treatment of disease” (Zhi Wei Bing), preventive strategies should emphasize emotional regulation, dietary moderation, preservation of spleen and stomach function, resolution of phlegm and dampness, promotion of blood circulation, and individualized constitution-based interventions to reduce the occurrence and progression of EC and precancerous lesions (Evidence level: B; strong recommendation).
Risk factors
Age
The risk of developing EC and precancerous lesions increases with advancing age, with age over 45 years recognized as an important risk factor. The increased susceptibility among older individuals may be attributed to cumulative exposure to carcinogenic factors, impaired mucosal repair capacity, persistent chronic inflammation, and the accumulation of genetic and epigenetic alterations over time.
Unhealthy dietary habits
From the perspective of TCM, long-term dietary irregularities, excessive consumption of rich and greasy foods, spicy and roasted foods, preserved or mold-contaminated foods, and overheated foods may impair spleen and stomach function, disrupt gastric descending function and fluid metabolism, and contribute to the pathological basis underlying the development of esophageal precancerous lesions.
(1) Processed meat products. Long-term consumption of preserved, smoked, dried, and processed meat products is associated with an increased risk of EC. This association may be related to the formation of carcinogenic compounds during food processing, including N-nitroso compounds, polycyclic aromatic hydrocarbons, heterocyclic amines, and excessive sodium content, which may induce chronic irritation, oxidative stress, and DNA damage in the esophageal mucosa.
(2) Preserved vegetables. Preserved vegetables may contain elevated levels of nitrites and nitrosamine precursors generated during preparation and storage. Long-term consumption may increase the risk of precancerous alterations in the esophageal mucosa. Poor storage conditions, incomplete fermentation, or fungal contamination may further enhance the potential carcinogenic risk.
(3) Consumption of excessively hot foods and beverages. Regular intake of very hot foods or beverages can cause repeated thermal injury to the esophageal epithelium, resulting in chronic inflammation, epithelial hyperplasia, and impaired mucosal repair, thereby increasing the risk of precancerous lesions. Thermal injury may have synergistic effects when combined with other risk factors, including alcohol consumption, smoking, and spicy food intake.
(4) Carcinogenic N-nitroso compounds and their precursors. N-nitroso compounds are important chemical carcinogens involved in esophageal carcinogenesis. After entering the body, these compounds can be metabolically activated to form DNA adducts, leading to genetic mutations and abnormal proliferation of esophageal epithelial cells.
(5) Mold-contaminated foods and mycotoxin exposure. Mold-contaminated grains, nuts, corn, and fermented foods may contain mycotoxins. Long-term exposure to these toxins may induce oxidative stress, chronic inflammation, and genetic damage in the esophageal mucosa, thereby contributing to carcinogenic transformation.
(6) High-salt diet. Long-term intake of high-salt foods may directly damage the esophageal mucosal barrier, promote inflammatory responses, and impair epithelial repair processes. High-salt diets frequently coexist with increased consumption of preserved foods, and these factors may jointly contribute to the development of esophageal precancerous lesions.
(7) Rapid eating habits. Eating too quickly may increase mechanical and thermal irritation of the esophageal mucosa, caused by coarse, hot, or irritating foods. It may also reduce adequate chewing and the protective buffering effects of saliva, thereby increasing mucosal injury.
Nutritional deficiencies
Insufficient intake of essential nutrients, including vitamins A, C, and E, folate, riboflavin, selenium, and zinc, may impair antioxidant capacity, DNA repair mechanisms, and the integrity of the esophageal mucosal epithelium. Selenium is an essential component of antioxidant enzymes, such as glutathione peroxidases, and its deficiency may increase oxidative stress and tissue damage. Riboflavin participates in energy metabolism and redox regulation, and long-term deficiency may impair epithelial turnover and mucosal repair. Nutritional deficiencies are often associated with inadequate consumption of fresh fruits and vegetables, limited dietary diversity, and lower socioeconomic status.
Mycotoxin exposure
Aflatoxin is a well-established potent carcinogenic mycotoxin, primarily derived from mold-contaminated grains, corn, peanuts, and related products. Chronic exposure to aflatoxin may induce DNA damage, oxidative stress, and abnormalities in cell cycle regulation, thereby contributing to esophageal mucosal injury and malignant transformation.
Infectious factors
Infectious agents may contribute to the development of EC through mechanisms involving chronic inflammation, alterations in the immune microenvironment, and dysregulation of epithelial cell proliferation. However, the associations between specific pathogens and different histological subtypes of EC remain heterogeneous, and current evidence is inconclusive.
(1) Helicobacter pylori. The relationship between H. pylori infection and EC risk remains complex and may vary according to tumor histological subtype, gastric acid secretion status, gastroesophageal reflux conditions, and geographical differences. Some studies suggest that H. pylori may influence the esophageal mucosal environment through chronic gastritis, alterations in gastric acid secretion, and disruption of the gastrointestinal microbiota. However, current evidence is insufficient to establish H. pylori infection as an independent and definitive risk factor for esophageal precancerous lesions.
(2) Human papillomavirus (HPV). HPV infection may contribute to the development of ESCC through viral oncoprotein-mediated disruption of cell cycle regulation, impairment of tumor suppressor gene function, and promotion of abnormal epithelial cell proliferation.
Socioeconomic factors
Individuals with lower socioeconomic status have been reported to have a higher risk of EC and precancerous lesions. This increased risk may be associated with multiple factors, including limited dietary diversity, inadequate intake of fresh fruits, vegetables, and high-quality proteins, increased exposure to preserved and mold-contaminated foods, inadequate oral hygiene, insufficient health awareness, and limited access to endoscopic screening services.
Protective factors
Fresh fruit intake
Fresh fruits contain abundant bioactive components, including vitamins, dietary fiber, polyphenols, and carotenoids, which may enhance antioxidant capacity and reduce oxidative stress and chronic inflammatory damage in the esophageal mucosa. Regular consumption of fresh fruits may help maintain mucosal barrier integrity and reduce the risk of developing esophageal precancerous lesions.
Nutritional supplementation
Appropriate supplementation of essential vitamins, trace elements, and antioxidant nutrients may contribute to reducing the risk of esophageal precancerous lesions, particularly selenium, zinc, riboflavin, folate, and vitamins A, C, and E. Nutritional supplementation may improve redox homeostasis, promote DNA repair, maintain normal epithelial differentiation, and enhance immune function. However, nutritional supplementation should be based primarily on dietary improvement, and long-term, high-dose, or non-individualized supplementation should be avoided.
Dietary pattern modification
Increasing the intake of fresh vegetables, fruits, whole grains, legumes, and high-quality proteins while reducing consumption of preserved, smoked, mold-contaminated, high-salt, and excessively hot foods may decrease long-term exposure to potential carcinogens affecting the esophageal mucosa. A balanced dietary pattern can improve nutritional status, enhance mucosal repair capacity, and reduce exposure to nitrosamines, mycotoxins, and other potential carcinogenic substances.
Smoking cessation and alcohol control
Smoking and alcohol consumption are major modifiable risk factors for EC, and their combined exposure may exert synergistic carcinogenic effects. Smoking cessation and alcohol control can reduce continuous exposure of the esophageal mucosa to harmful substances, including acetaldehyde, tobacco-specific nitrosamines, and polycyclic aromatic hydrocarbons, thereby decreasing chronic inflammation, epithelial dysplasia, and progression of precancerous lesions.
High dietary fiber intake
Dietary fiber may improve the gastrointestinal microbiome and metabolic environment, facilitate the elimination of harmful metabolites, and indirectly reduce inflammation and oxidative stress. Higher dietary fiber intake is often associated with increased consumption of vegetables, fruits, whole grains, and legumes, contributing to an overall improvement in dietary quality.
Weight management
Maintaining an appropriate body weight may help reduce the risk associated with gastroesophageal reflux, chronic inflammation, and metabolic disorders. In individuals with esophageal precancerous lesions, including Barrett’s esophagus and associated dysplasia, overweight and obesity may increase the risk of disease progression by elevating intra-abdominal pressure, promoting gastroesophageal reflux, and enhancing inflammatory responses. Weight control through dietary management, regular physical activity, and lifestyle interventions is recommended for individuals at high risk for EC.
Long-term use of PPIs, NSAIDs, and statins
For individuals with gastroesophageal reflux disease, Barrett’s esophagus, or EAC-related precancerous lesions, long-term and appropriate use of proton pump inhibitors (PPIs) may reduce continuous acid-induced irritation of the esophageal mucosa and potentially decrease the risk of inflammation and dysplasia progression. Aspirin/nonsteroidal anti-inflammatory drugs (NSAIDs) and statins may exert potential protective effects through anti-inflammatory pathways, regulation of cyclooxygenase signaling, improvement of lipid metabolism, and modulation of cellular proliferation and apoptosis. However, these medications may be associated with adverse effects, including gastrointestinal bleeding, hepatic or renal impairment, and cardiovascular risks, and therefore should not be routinely recommended for cancer prevention in the general population.
Anti-reflux surgery
For patients with inadequate symptom control despite medical therapy, confirmed pathological gastroesophageal reflux, or reflux-associated precancerous lesions, anti-reflux surgery may reduce acid and bile reflux exposure and alleviate chronic inflammatory injury to the esophageal mucosa. This approach should be considered only in appropriately selected patients after comprehensive evaluation and should not replace endoscopic surveillance or long-term monitoring of precancerous lesions. Postoperative management should continue to incorporate individualized surveillance strategies based on the presence of Barrett’s esophagus, degree of dysplasia, and overall risk profile.
TCM etiology, pathogenesis, and principles of primary prevention for EC
From the perspective of TCM, esophageal precancerous lesions are categorized within the disease concepts of Ye Ge (dysphagia and obstruction), Ye Shi (difficulty in swallowing), and Ge Sai (esophageal obstruction). The development of these lesions is considered to be associated with multiple factors, including dietary imbalance, emotional disturbances, excessive consumption of tobacco and alcohol-related pathogenic factors, overexertion, aging-related deficiency, and exposure to pathogenic toxins. The primary site of disease is considered to involve the esophagus, with close associations with dysfunctions of the liver, spleen, stomach, and kidney systems.
In the early stages of disease development, emotional disturbances may impair liver regulation, while improper dietary habits may weaken spleen transportation and transformation functions, resulting in impaired gastric descending function, stagnation of Qi movement, and disturbance of fluid distribution. These processes may lead to patterns characterized by disharmony between the liver and stomach and obstruction by phlegm and Qi. With disease progression, prolonged Qi stagnation may lead to blood stasis, and the interaction between phlegm and blood stasis may gradually develop. Further exposure to pathogenic factors such as heat toxin, dampness toxin, and toxic accumulation may contribute to the formation of blood stasis and toxin retention. In older adults or patients with prolonged disease course, deficiencies of the spleen and stomach, Qi and Yin deficiency, and kidney essence deficiency may coexist, resulting in a pathological state characterized by deficiency of healthy Qi with concurrent accumulation of pathogenic factors.
Primary prevention of EC from the TCM perspective follows the principle of “preventing disease before its onset and preventing progression after disease occurrence” (Zhi Wei Bing). Key preventive strategies include: (1) regulating emotional states and avoiding prolonged emotional stress; (2) maintaining appropriate dietary habits and avoiding excessive intake of overheated, rapidly consumed, high-salt, preserved, and mold-contaminated foods; (3) reducing tobacco and alcohol exposure and avoiding excessive intake of heat-inducing and irritating substances; (4) preserving spleen and stomach function and maintaining normal Qi movement and fluid metabolism; (5) maintaining regular daily routines and engaging in appropriate physical activity; and (6) implementing individualized health management based on age, constitution, symptoms, tongue characteristics, and pulse manifestations.
For high-risk individuals with constitutional imbalance or prominent TCM patterns, individualized interventions involving dietary regulation, exercise, emotional adjustment, and syndrome-based management may be considered under the guidance of qualified TCM practitioners. However, TCM-based preventive interventions should complement rather than replace endoscopic screening, pathological evaluation, and evidence-based medical management.
Screening
Clinical question 2: What are the appropriate strategies for screening and risk prediction among individuals at high risk for EC?
Recommendation: Screening strategies for EC should focus on individuals at high risk[
13]. Priority should be given to individuals aged ≥ 45 years with additional risk factors, including residence in areas with a high incidence of EC, family history of EC, unhealthy lifestyle behaviors, or a history of esophageal-related diseases. Upper gastrointestinal endoscopy is recommended as the preferred screening modality (Evidence level: A; strong recommendation). The interval of screening and surveillance should be determined according to individual risk stratification, endoscopic findings, pathological characteristics, and the grade of lesions (Evidence level: A; strong recommendation).
High-risk populations for EC
The target population for EC screening should primarily include individuals at high risk. Screening is recommended for individuals aged ≥ 45 years who meet any of the following risk criteria:
(1) Residence in high-incidence areas or long-term residence in regions with a high burden of EC;
(2) A family history of EC in first-degree relatives;
(3) Long-term exposure to unhealthy lifestyle or dietary factors, including consumption of very hot foods or beverages, high-salt diets, preserved or mold-contaminated foods, smoking, and heavy alcohol consumption;
(4) A history of esophageal-related disorders, including chronic esophagitis, reflux esophagitis, Barrett’s esophagus, esophageal diverticulum, achalasia, and benign esophageal strictures;
(5) A history of diagnosis or treatment of esophageal precancerous lesions, including low-grade or high-grade squamous intraepithelial neoplasia (HGIN) and Barrett’s esophagus-related dysplasia;
(6) Other factors potentially associated with increased EC risk, such as long-term nutritional deficiencies, lower socioeconomic status, poor oral hygiene, and previous malignancies of the head and neck or upper gastrointestinal tract.
Screening decisions should be based on a comprehensive assessment of age, geographic risk, family history, lifestyle factors, previous medical history, and accessibility to endoscopic examination. In general, the screening population may include individuals aged 45–74 years without a previous history of upper gastrointestinal malignancies, without contraindications to endoscopy, and with the ability to understand and undergo endoscopic procedures.
For individuals with confirmed esophageal precancerous lesions, Barrett’s esophagus-related dysplasia, a history of treatment for early EC, or a first-degree family history of EC, screening should be considered even if they do not fully meet the general age criteria. In these populations, earlier screening initiation or shorter surveillance intervals should be considered based on individualized risk assessment, clinical symptoms, and physician evaluation.
Screening methods for EC
Preferred screening modality
Endoscopic examination should serve as the primary approach for EC screening. For individuals at high risk for EC, upper gastrointestinal endoscopy is recommended as the preferred screening method. During endoscopic examination, targeted biopsy and pathological evaluation should be performed based on mucosal morphology, staining characteristics, and the presence of suspicious lesions.
Endoscopy not only enables the detection of early EC and precancerous lesions but also allows lesion localization, the assessment of lesion extent, pathological sampling, and evaluation of suitability for endoscopic treatment of selected early-stage lesions. Therefore, upper gastrointestinal endoscopy remains the most important and reliable first-line approach for EC screening and early detection and treatment.
(Detailed procedures are described in the Technical Protocol for Population Screening and Early Diagnosis and Treatment of Upper Gastrointestinal Cancers issued by the National Health Commission of China on June 18, 2019, and the Chinese Consensus on Screening for Early Esophageal Cancer and Precancerous Lesions.)
Classification of endoscopic techniques
Endoscopic techniques applicable for EC screening include conventional white-light endoscopy, Lugol chromoendoscopy, electronic chromoendoscopy, magnifying endoscopy, and transnasal endoscopy. Conventional white-light endoscopy serves as the fundamental examination modality. Lugol chromoendoscopy may improve the detection of esophageal squamous epithelial dysplasia and early squamous cell carcinoma by highlighting iodine-unstained lesions. Electronic chromoendoscopy and magnifying endoscopy enable detailed assessment of mucosal microvascular patterns and surface structures, thereby improving the identification of suspicious lesions. Transnasal endoscopy is characterized by better patient tolerance, relatively convenient operation, and may serve as an alternative screening option in selected populations.
Emerging endoscopic technologies
In medical institutions with appropriate equipment, technical expertise, and quality control systems, emerging technologies, including confocal laser endomicroscopy, artificial intelligence-assisted endoscopy, and esophageal capsule endoscopy, may be explored to improve the detection of subtle lesions, the assessment of lesion extent, and screening efficiency. However, these technologies should currently be considered complementary approaches to conventional endoscopic screening and cannot replace standard upper gastrointestinal endoscopy or pathological diagnosis.
Principles of screening
The screening process should follow the principles of “endoscopic detection, pathological confirmation, risk stratification, and standardized surveillance”. Suspicious lesions identified during endoscopy should undergo standardized biopsy and pathological evaluation. For patients diagnosed with low-grade squamous intraepithelial neoplasia (LGIN), HGIN, Barrett’s esophagus-related dysplasia, or early EC, subsequent treatment and surveillance strategies should be developed based on lesion extent, pathological grade, overall health status, and patient preferences.
Frequency of EC screening and surveillance
The frequency of EC screening and surveillance should be determined based on comprehensive assessment of individual risk stratification, endoscopic findings, pathological characteristics, lesion grade, and previous treatment history. The primary objectives of screening and surveillance are to detect esophageal precancerous lesions at an early stage, dynamically assess the risk of disease progression, and identify individuals requiring further endoscopic intervention or pathological reassessment.
(1) High-risk individuals without detected esophageal precancerous lesions
For individuals at high risk for EC but without identified precancerous lesions, upper gastrointestinal endoscopy is generally recommended every 5 years. For individuals with multiple risk factors, the screening interval may be shortened according to individualized risk assessment. (Risk factors are described in Section 3.1 of this guideline.)
(2) Patients with esophageal LGIN
For patients with esophageal squamous LGIN, endoscopic surveillance is recommended every 1–3 years. The specific surveillance interval should be determined according to lesion extent, morphological characteristics, pathological findings, and individual risk factors. For patients with LGIN accompanied by the high-risk endoscopic features, annual endoscopic examination is recommended for 5 consecutive years. During surveillance, disease progression, lesion enlargement, or upgrading of pathological grade should prompt repeat multi-site biopsy, pathological reassessment, and evaluation for endoscopic treatment indications.
High-risk endoscopic features include irregular lesion margins, rough mucosal surface, erosion, nodular changes, prominent iodine-unstained areas on Lugol chromoendoscopy, or lesion diameter > 1 cm.
(3) Patients with Barrett’s esophagus
For patients with Barrett’s esophagus, surveillance strategies should be determined according to the presence and grade of dysplasia. For patients without dysplasia, endoscopic surveillance every 3–5 years is recommended. For patients with low-grade dysplasia, surveillance every 1–3 years is recommended. For patients with uncertain pathological diagnosis, severe inflammation, long-segment Barrett’s esophagus, or other high-risk features for progression, repeat endoscopy after standardized anti-reflux therapy may be considered, and the surveillance interval may be shortened to 6–12 months when clinically appropriate.
Surveillance of esophageal precancerous lesions should integrate endoscopic evaluation with pathological assessment. During each surveillance examination, lesion location, extent, morphology, chromoendoscopic or electronic chromoendoscopic features, and biopsy results should be systematically documented and compared with previous findings. For cases with discordance between pathological diagnosis and endoscopic appearance, increased risk for progression, or suspected HGIN/early EC, multidisciplinary pathological review and further diagnostic and therapeutic evaluation should be performed.
Diagnosis
Clinical question 3: What are the diagnostic approaches for esophageal precancerous lesions, and how can the TCM-based pathological evolution of these lesions be characterized?
Recommendation: Diagnosis of esophageal precancerous lesions should be established based on a comprehensive assessment of clinical symptoms and signs, laboratory examinations, imaging studies, and endoscopic pathological evaluation[
14–
15]. These assessments enable the determination of pathological classification, including histological subtype, molecular pathological characteristics, and clinical staging when applicable (Evidence level: A; strong recommendation). From the perspective of TCM, syndrome differentiation should be performed based on clinical manifestations, tongue characteristics, and pulse findings through comprehensive evaluation using the four diagnostic methods (Si Zhen He Can). The pathological evolution of esophageal precancerous lesions is considered to progress gradually from patterns characterized by liver–stomach disharmony and phlegm–Qi obstruction to phlegm–blood stasis accumulation and blood stasis–toxin retention (Evidence level: C; conditional recommendation).
Clinical symptoms
Esophageal precancerous lesions are often asymptomatic in the early stages and lack specific clinical manifestations. Some patients may experience mild symptoms, including difficulty in swallowing, the sensation of food sticking, retrosternal discomfort, epigastric or retrosternal fullness and tightness, acid reflux, belching, and a foreign body sensation in the throat. These symptoms are typically intermittent, mild, and fluctuating, and may be associated with dietary stimulation, emotional changes, gastroesophageal reflux, and chronic esophagitis.
(1) Patients with esophageal squamous epithelial precancerous lesions may present with discomfort or obstruction when swallowing coarse or solid foods, as well as retrosternal burning or dull pain.
(2) Patients with Barrett’s esophagus and EAC-related precancerous lesions commonly present with reflux-related symptoms, including acid regurgitation, heartburn, belching, and retrosternal burning sensations.
(3) The absence of symptoms does not rule out the presence of esophageal precancerous lesions. Individuals with relevant risk factors should undergo endoscopic screening according to their risk profile.
Physical examination findings
Patients with esophageal precancerous lesions generally lack specific positive physical signs. Some individuals with long-term inadequate nutritional intake or prolonged disease courses may present with weight loss, signs of anemia, or malnutrition. Patients with concomitant gastroesophageal reflux may exhibit chronic pharyngeal congestion, throat discomfort, or related upper airway symptoms.
Ancillary examinations
Laboratory examinations
Laboratory examinations are primarily used to evaluate patients’ baseline health status, nutritional status, anemia, liver and renal function, coagulation status, and treatment safety. Depending on clinical needs, tests including complete blood count, liver and renal function tests, electrolyte levels, coagulation parameters, nutritional indicators, and inflammatory markers may be performed. For patients scheduled for endoscopic treatment or those with relevant comorbidities, appropriate preoperative assessments should be completed. Laboratory examinations cannot replace endoscopic evaluation and pathological diagnosis.
Endoscopic examination
Upper gastrointestinal endoscopy is the cornerstone for the detection and evaluation of esophageal precancerous lesions. Conventional white-light endoscopy allows assessment of mucosal abnormalities, including changes in morphology, color, erosion, nodularity, roughness, depression, and elevation. Lugol chromoendoscopy facilitates the identification of esophageal squamous epithelial dysplasia and early squamous cell carcinoma. Electronic chromoendoscopy and magnifying endoscopy enable further evaluation of mucosal microvascular patterns and surface structures, thereby improving the recognition of suspicious lesions.
Suspicious lesions identified by endoscopy should undergo targeted biopsy, with multi-site biopsy and pathological reassessment considered when necessary. Endoscopic reports should systematically document lesion location, distance from the incisors, lesion size and extent, morphological characteristics, staining findings, biopsy sites, and the presence of multifocal lesions.
Imaging examinations
Imaging examinations are mainly applied to patients with suspected advanced lesions, early EC, or those requiring pre-treatment staging. Appropriate imaging modalities, including contrast-enhanced CT of the chest and abdomen, endoscopic ultrasound (EUS), magnetic resonance imaging (MRI), and positron emission tomography‑computed tomography (PET‑CT), may be selected according to clinical conditions.
For patients with isolated low-grade precancerous lesions, imaging examinations are generally not required for diagnostic confirmation. However, in patients with suspected HGIN, early cancer, or endoscopic features suggestive of invasion, imaging evaluation should be combined with endoscopic and pathological findings to assess lesion depth, lymph node involvement, and the risk of distant metastasis.
TCM-based examinations
TCM-based examinations should follow the principle of comprehensive assessment using the four diagnostic methods (Si Zhen He Can), including inspection, auscultation and olfaction, inquiry, and palpation. The evaluation should focus on swallowing function, retrosternal symptoms, dietary status, emotional conditions, tongue characteristics, and pulse manifestations, providing a basis for TCM syndrome differentiation and pathogenesis assessment.
(1) Inspection (Wang Zhen). Inspection includes evaluation of body constitution, facial appearance, mental status, and nutritional condition, with attention to signs such as weight loss, pale complexion, and fatigue. Tongue examination is an important component, including assessment of tongue color (pale red, red, dark red, or purple), the presence of petechiae or ecchymosis, and tongue coating characteristics, such as thin white, yellow greasy, white greasy, scanty, or peeled coating. Patients with esophageal precancerous lesions commonly present with dark red or purple tongue manifestations, sometimes accompanied by petechiae or ecchymosis, while greasy tongue coating is frequently observed.
(2) Auscultation and olfaction (Wen Zhen). Changes in voice, breathing patterns, and the odor of vomitus should be assessed when clinically relevant.
(3) Inquiry (Wen Zhen). Clinical inquiry should focus on swallowing-related symptoms and associated manifestations, including the food sticking sensation, dysphagia, retrosternal fullness or pain, acid reflux, heartburn, belching, hiccups, vomiting of phlegm or saliva, and foreign body sensation in the throat. The relationship between symptoms and emotional changes, temperature and characteristics of food intake, spicy food consumption, tobacco and alcohol exposure, eating speed, and reflux symptoms should be evaluated. Additional information regarding appetite, dry mouth or bitter taste, bowel and urinary function, sleep quality, body weight changes, previous esophageal diseases, and history of diagnosis or treatment of precancerous lesions should also be collected.
(4) Palpation (Qie Zhen). Pulse examination is an important component of TCM syndrome differentiation and may provide information regarding the status of Qi, blood, body fluids, and organ function. In the early stages of esophageal precancerous lesions, phlegm and blood stasis accumulation is considered a common pathological pattern; therefore, wiry, slippery, or choppy pulse manifestations may be observed.
Western medicine-based diagnosis
The diagnosis of esophageal precancerous lesions should be established based on endoscopic examination and histopathological evaluation. Esophageal squamous epithelial precancerous lesions mainly include LGIN and HGIN. EAC-related precancerous lesions primarily include Barrett’s esophagus and associated dysplasia. The pathological subtype, lesion grade, lesion extent, anatomical location, and the presence of multifocal lesions should be systematically evaluated and documented to guide subsequent treatment and surveillance strategies.
TCM-based diagnosis
In TCM, esophageal precancerous lesions can be categorized within the disease concepts of Ye Ge (dysphagia and obstruction), Ye Shi (difficulty in swallowing), Ye Sai (esophageal obstruction), Ge Sai (diaphragmatic obstruction), and Ge Qi (Qi obstruction). The primary site of disease is considered to involve the esophagus, with close associations with impaired gastric Qi descending function and dysfunction of the liver, spleen, and kidney systems.
Although patients in the early stages may not present with obvious dysphagia, symptoms such as the sensation of food obstruction, retrosternal fullness, belching, acid regurgitation, and throat discomfort may occur, suggesting that impaired Qi movement and dysfunction of esophageal transportation are important pathological foundations.
TCM diagnosis should be performed through syndrome differentiation based on TCM examinations (see Section 3.3.3.4) and the stage of disease progression. In the early stages, common patterns include liver–stomach disharmony and phlegm–Qi obstruction. With disease progression, patterns such as phlegm–blood stasis accumulation, blood stasis–toxin retention, and fluid deficiency with heat accumulation may develop. In patients with prolonged disease courses or after treatment-related damage to healthy Qi, deficiency patterns or mixed deficiency–excess patterns may occur, including spleen and stomach deficiency, Qi and Yin deficiency, and spleen and kidney Yang deficiency.
Evolution of TCM-based pathogenesis
The evolution of TCM-based pathogenesis in esophageal precancerous lesions can be summarized as “Qi stagnation as the initial process, phlegm accumulation as the pathological basis, progressive formation of blood stasis and toxin accumulation, with deficiency of healthy Qi throughout the disease course”.
In the early stages, the development of esophageal precancerous lesions is considered to be associated with emotional disturbances, dietary irregularities, excessive exposure to tobacco, alcohol, and overheated foods, as well as dysfunction of the spleen and stomach. These factors may lead to impaired liver regulation and gastric descending function, resulting in stagnation of Qi movement, abnormal fluid distribution, endogenous phlegm formation, and obstruction of the esophagus by phlegm and Qi.
With disease progression, prolonged Qi stagnation may result in blood stasis, and the interaction between phlegm and blood stasis may gradually occur. Over time, heat transformation and toxin accumulation may develop, with pathogenic toxin retention potentially contributing to progression from precancerous lesions to HGIN and malignant transformation. In advanced or prolonged disease courses, deficiency of healthy Qi may become prominent, leading to the pathological pattern characterized by the coexistence of deficiency and excess.
(1) Liver–stomach disharmony with phlegm–Qi obstruction
Clinical manifestations: Patients commonly present with impaired swallowing, mild sensation of food sticking, retrosternal discomfort or fullness, frequent belching, acid regurgitation, and a foreign body sensation in the throat. Symptoms may fluctuate with emotional changes. The tongue may appear pale red with a thin or slightly greasy coating, and the pulse may be wiry or wiry-slippery.
Pathogenesis characteristics: This pattern is commonly observed in the early stages of disease development and is considered to be associated with impaired liver regulation, dysfunction of gastric Qi descending, stagnation of Qi movement, and obstruction of the esophagus by phlegm and Qi.
(2) Phlegm–blood stasis accumulation
Clinical manifestations: Patients may experience aggravated swallowing obstruction, retrosternal fullness or fixed stabbing pain, impaired food intake, increased phlegm or saliva production, and localized discomfort. The tongue may appear dark or purple with petechiae or ecchymosis, accompanied by a white or yellow greasy coating. The pulse may be wiry-slippery or choppy.
Pathogenesis characteristics: This pattern is considered to result from prolonged Qi stagnation and phlegm accumulation, leading to impaired blood circulation and interaction between phlegm and blood stasis, which obstructs the esophageal collaterals. It represents an important stage of disease progression.
(3) Blood stasis–toxin retention
Clinical manifestations: Patients may present with marked dysphagia or the food sticking sensation, retrosternal pain with a fixed location, dry mouth or bitter taste, sputum with blood streaks, and progressive weight loss. The tongue may appear dark purple or dark red, with a yellow greasy or scanty coating. The pulse may be wiry-choppy or thin-choppy.
Pathogenesis characteristics: This pattern is considered to develop from long-standing phlegm and blood stasis, with transformation into heat and accumulation of pathogenic toxins. The interaction of heat toxin, phlegm toxin, and blood stasis is considered to contribute to internal toxin accumulation and malignant transformation.
(4) Fluid deficiency with heat accumulation
Clinical manifestations: Patients may experience dry and difficult swallowing, retrosternal burning sensation, dry mouth and throat, constipation, tidal fever, night sweating, and progressive weight loss. The tongue is typically red with reduced fluid, scanty or peeled coating, and the pulse may be thin and rapid.
Pathogenesis characteristics: This pattern is associated with consumption of Yin fluids due to prolonged disease progression or internal accumulation of heat toxin. Deficiency of body fluids fails to nourish the esophagus, while heat accumulation contributes to obstruction. It is commonly observed in patients with prolonged disease courses and impaired Yin-fluid status.
(5) Spleen and stomach deficiency
Clinical manifestations: Patients may present with impaired food intake, reduced appetite, epigastric fullness, fatigue, shortness of breath, reluctance to speak, loose stools or irregular bowel movements, and weight loss. The tongue may appear pale or pale and swollen, with a thin white coating, and the pulse may be thin and weak.
Pathogenesis characteristics: This pattern is considered to result from deficiency of healthy Qi after prolonged disease, leading to impaired spleen transportation and transformation, insufficient generation of Qi and blood, and inadequate nourishment of the esophagus. It may further contribute to phlegm-dampness accumulation and recurrent disease.
(6) Qi and Yin deficiency
Clinical manifestations: Patients may present with impaired swallowing, dry mouth and throat, fatigue, reduced appetite, irritability, weight loss, and occasionally low-grade fever or night sweating. The tongue may appear red with reduced fluid or pale red with scanty coating, and the pulse may be thin-rapid or thin-weak.
Pathogenesis characteristics: This pattern is considered to result from prolonged consumption of Qi and Yin, leading to deficiency of healthy Qi and depletion of Yin fluids, with inadequate nourishment of the esophagus. It is commonly observed in patients with long-standing precancerous lesions, during recovery after endoscopic treatment, or in individuals with constitutional weakness.
(7) Spleen and kidney Yang deficiency
Clinical manifestations: Patients may present with impaired swallowing, poor appetite, aversion to cold, cold extremities, pale complexion, fatigue, abdominal distension, loose stools, and accumulation of fluid or excessive phlegm. The tongue may appear pale and swollen or pale-purple, with a white slippery coating, and the pulse may be deep-thin or deep-weak.
Pathogenesis characteristics: This pattern is considered to occur when prolonged disease affects kidney function, resulting in deficiency of spleen and kidney Yang and impaired warming and transformation functions. Accumulation of water-dampness may generate phlegm, while phlegm and blood stasis obstruct the esophagus, leading to a condition characterized by deficiency of healthy Qi and persistence of pathogenic factors.
Treatment
Integrative Chinese and Western medicine treatment for ESCC-related precancerous lesions
Clinical question 4: What are the appropriate integrative Chinese and Western medicine strategies for the treatment and surveillance of ESCC-related precancerous lesions?
The recommendations are as follows:
Target population
This section applies to patients with esophageal squamous epithelial precancerous lesions confirmed by upper gastrointestinal endoscopy and histopathological examination. The major pathological categories include LGIN and HGIN.
The term “esophageal squamous epithelial dysplasia” may be used as a pathological descriptive term for precancerous changes. In clinical management, further classification according to pathological grading is required to determine whether the lesion represents low-grade or high-grade disease.
TCM-based treatment strategies for ESCC-related precancerous lesions
(1) LGIN
Recommendation: Zeng Sheng Ping tablet is suggested for patients with LGIN (Evidence level: A; conditional recommendation).
Zeng Sheng Ping Tablet[16] Therapeutic principle: Clearing heat and removing toxins; resolving blood stasis and dissipating masses.
Composition: Sophora tonkinensis (Shan Dou Gen), Polygonum bistorta (Quan Shen), Patrinia scabiosaefolia (Bai Jiang Cao), Prunella vulgaris (Xia Ku Cao), Dictamnus dasycarpus (Bai Xian Pi), and Dioscorea bulbifera (Huang Yao Zi).
Administration: Oral administration, 8 tablets per dose, twice daily. One treatment course consists of 6 months.
Evidence summary: A multicenter, single-blind, randomized, placebo-controlled clinical study evaluated the efficacy of Zeng Sheng Ping in patients with esophageal epithelial hyperplasia. A total of 449 patients were randomly assigned to the treatment group (n = 300) or placebo group (n = 149) and were followed for 6 months. Improvement was observed in 193 patients (64.3%) in the Zeng Sheng Ping group, which was significantly higher than that in the placebo group (P < 0.001).
(2) Esophageal squamous epithelial dysplasia
Recommendation: Liu Wei Di Huang Wan is suggested for patients with esophageal squamous epithelial dysplasia (Evidence level: B; conditional recommendation).
Therapeutic principle: Nourishing Yin and tonifying the kidney.
Composition: Rehmannia glutinosa (Shu Di Huang), Cornus officinalis (Jiu Yu Rou), Paeonia suffruticosa (Mu Dan Pi), Dioscorea opposita (Shan Yao), Poria cocos (Fu Ling), and Alisma orientale (Ze Xie).
Administration: Oral administration, 1 pill per dose, twice daily. After 3 months, the dosage is reduced to once daily, with continuous administration for 2 years.
Evidence summary: A prospective clinical study evaluated the preventive effect of Liu Wei Di Huang Wan in patients with esophageal epithelial hyperplasia. A total of 344 patients were assigned to the treatment group (n = 211) or the observation-control group without intervention (n = 133) and followed for 2 years. The incidence of malignant transformation was 1.9% in the Liu Wei Di Huang Wan group compared with 8.3% in the control group, showing a statistically significant difference between groups (P < 0.005).
Western medicine treatment strategies for ESCC-related precancerous lesions (Evidence level: A; strong recommendation)
(1) LGIN
For patients with histologically confirmed esophageal LGIN who do not exhibit high-grade endoscopic features or pathological risk factors for progression, standardized endoscopic surveillance is recommended as the primary management strategy. Upper gastrointestinal endoscopy is generally recommended every 1–2 years, with targeted biopsy of the original lesion or suspicious areas.
For patients with LGIN accompanied by high-risk endoscopic features, including irregular lesion margins, marked erosion, nodular changes, depression or elevation, prominent iodine-unstained areas on Lugol chromoendoscopy, extensive lesions, or those with potential pathological underestimation and upgrading risk, endoscopic resection may be considered. For patients who do not undergo resection, repeat endoscopy with biopsy is recommended within 3–6 months.
The choice of endoscopic resection technique should be individualized according to lesion size, extent, and technical feasibility. Endoscopic submucosal dissection (ESD) is preferred for esophageal mucosal lesions and precancerous lesions requiring en bloc resection. Endoscopic mucosal resection may be considered for lesions < 15 mm in diameter that are suitable for complete en bloc removal. For lesions with extensive longitudinal involvement, near-circumferential distribution, difficulty achieving en bloc resection, or patients unable to tolerate endoscopic resection, radiofrequency ablation (RFA) or other endoscopic ablative therapies may be considered. However, clinicians should recognize that ablative approaches without tissue resection cannot provide complete histopathological assessment and staging.
(2) HGIN
For patients with histologically confirmed esophageal HGIN, endoscopic resection is recommended as the preferred treatment approach. Before treatment, comprehensive assessment using white-light endoscopy, Lugol chromoendoscopy, electronic chromoendoscopy, magnifying endoscopy, and, when necessary, EUS or CT should be performed to evaluate lesion extent, depth of invasion, and the risk of lymph node metastasis.
For patients with biopsy-confirmed HGIN without evidence of submucosal invasion or lymph node metastasis based on endoscopic or imaging evaluation, en bloc endoscopic resection is recommended to obtain complete pathological specimens. This enables accurate assessment of resection margins, invasion depth, and lymphovascular invasion. ESD is the preferred technique, particularly for lesions requiring complete removal and precise pathological evaluation. Endoscopic mucosal resection (EMR) may also be selected for small lesions that can be completely resected in one piece according to lesion characteristics.
For lesions with extensive longitudinal extent, near-circumferential involvement, inability to achieve en bloc resection, or patients who cannot tolerate endoscopic resection, RFA or other endoscopic ablative therapies may be considered after comprehensive evaluation. Because ablative techniques without tissue removal cannot provide complete pathological specimens, accurate assessment of resection margins, invasion depth, and pathological staging is limited. Therefore, strict patient selection criteria should be applied, with enhanced post-treatment endoscopic surveillance and pathological evaluation.
Integrative Chinese and Western medicine treatment for EAC-related precancerous lesions
Clinical question 5: What are the appropriate integrative Chinese and Western medicine strategies for the treatment and surveillance of EAC-related precancerous lesions?
The recommendations are as follows:
Target population
This section applies to patients with EAC-related precancerous lesions confirmed by upper gastrointestinal endoscopy and histopathological examination, which mainly include Barrett’s esophagus and Barrett’s esophagus-associated precancerous changes.
TCM-based treatment strategies for EAC-related precancerous lesions
(1) Barrett’s esophagus
Recommendation: Ling Gui Ban Xia Decoction is recommended for the prevention of malignant transformation in patients with Barrett’s esophagus (Evidence level: C; conditional recommendation).
Ling Gui Ban Xia Decoction[18] Therapeutic principles: Regulating liver Qi, relieving emotional stagnation, harmonizing the stomach, and directing rebellious Qi downward.
Composition: Trichosanthes kirilowii (Gua Lou) 24 g, Bupleurum chinense (Chai Hu) 12 g, Curcuma aromatica (Yu Jin) 12 g, Salvia miltiorrhiza (Dan Shen) 12 g, Paeonia veitchii (Chi Shao) 12 g, Poria cocos (Fu Ling) 12 g, Alisma orientale (Ze Xie) 9 g, Trionyx sinensis (Bie Jia) 9 g, Fritillaria thunbergii (Zhe Bei Mu) 9 g, Pinellia ternata (Ban Xia) 9 g, Cinnamomum cassia (Gui Zhi) 9 g, Glycyrrhiza uralensis (Gan Cao) 9 g, and fresh ginger (Sheng Jiang) 6 g.
Administration: One dose daily, decocted with water and administered orally in two divided doses (morning and evening).
Evidence summary: A randomized clinical study enrolled 84 patients with Barrett’s esophagus, who were randomly assigned to the control group (n = 42) or the treatment group (n = 42). Patients in the control group received omeprazole combined with hydrotalcite, whereas patients in the treatment group received Ling Gui Ban Xia Decoction combined with the same conventional therapy. Both groups received treatment for three consecutive courses, with each course lasting 6 weeks.
After treatment, TCM symptom scores were significantly reduced in both groups compared with baseline (P < 0.05), with greater improvement observed in the treatment group (P < 0.05). The overall clinical response rate was significantly higher in the treatment group than in the control group (88.10% vs. 66.67%, P < 0.05). In addition, the expression levels of COX-2 and Ki-67 in esophageal mucosal lesions were significantly decreased after treatment in both groups (P < 0.05), with significantly lower levels observed in the treatment group compared with the control group (P < 0.05).
Western medicine treatment strategies for EAC-related precancerous lesions
EAC-related precancerous lesions mainly include Barrett’s esophagus-associated dysplasia. Treatment strategies should be individualized according to the presence and grade of dysplasia, lesion visibility, presence of nodularity or mucosal irregularity, patients’ overall health status, and treatment tolerance. The general principles of management include control of gastroesophageal reflux, standardized endoscopic assessment, preferential management of visible lesions, and selection of endoscopic eradication therapy or surveillance according to pathological grade[
19–
21].
(1) Barrett’s esophagus without dysplasia (Evidence level: A; strong recommendation)
For patients with Barrett’s esophagus without dysplasia, management should focus on standardized surveillance, reflux control, and lifestyle modification. PPI therapy may be administered according to reflux symptoms and individual risk of disease progression to reduce continuous acid-related injury to the esophageal mucosa.
Routine endoscopic ablation or resection is generally not recommended for nondysplastic Barrett’s esophagus. However, patients with long-segment Barrett’s esophagus, inadequate reflux control, or additional high-risk factors should undergo more intensive endoscopic surveillance.
(2) Barrett’s esophagus with low-grade dysplasia (Evidence level: A; strong recommendation)
For patients with Barrett’s esophagus-associated low-grade dysplasia, endoscopic treatment or close surveillance may be considered after pathological confirmation. Before treatment decisions are made, potential confounding factors, including mucosal inflammation and mucosal erosion, should be excluded. When necessary, repeat endoscopy and pathological reassessment should be performed after optimized PPI therapy.
Endoscopic eradication therapy may be considered for patients with persistent dysplasia, extensive Barrett’s segments, visible lesions, or other high-risk features associated with progression. For visible lesions, including nodular lesions, focal mucosal irregularities, or elevated areas, endoscopic resection should be performed first to obtain complete pathological assessment. Residual Barrett’s mucosa may subsequently be treated with ablative therapies, such as RFA or cryotherapy, to reduce the risk of recurrent dysplasia and disease progression.
(3) Barrett’s esophagus with high-grade dysplasia (Evidence level: A; strong recommendation)
For patients with Barrett’s esophagus-associated high-grade dysplasia, endoscopic therapy is recommended as the preferred treatment approach. Before intervention, comprehensive evaluation of lesion extent, mucosal morphology, depth of invasion, and risk of lymph node metastasis should be performed.
For patients with high-grade dysplasia or intramucosal carcinoma without clear indications or contraindications for esophagectomy, and with lesions suitable for endoscopic treatment, endoscopic eradication therapy is preferred over surgical resection.
Treatment strategies should follow the principle of “resect first, then ablate”. All visible lesions, including elevated lesions, nodular lesions, or areas with irregular mucosal patterns, should undergo endoscopic resection initially to determine pathological grade, invasion depth, margin status, and the presence of lymphovascular invasion. Subsequent ablation of residual Barrett’s mucosa should be performed to achieve complete the endoscopic eradication.
Prevention of recurrence
Clinical question 6: What TCM-based interventions are available for preventing recurrence after treatment of early EC?
The recommendations are as follows:
(1) Postoperative EC
Recommendation: Modified Qi Ge San (Jia Wei Qi Ge San) (Evidence level: B; conditional recommendation), Shidao Tongjie Formula (Evidence level: B; conditional recommendation), and Pingxiao Capsule combined with Chinese herbal medicine (Evidence level: B; conditional recommendation) may be considered as adjunctive interventions for reducing the risk of postoperative recurrence and metastasis in patients with EC.
Therapeutic principles: Moistening dryness, relieving stagnation, resolving phlegm, and directing rebellious Qi downward.
Composition: Glehnia littoralis (Sha Shen) 30 g, Salvia miltiorrhiza (Dan Shen) 15 g, Poria cocos (Fu Ling) 10 g, Fritillaria cirrhosa (Chuan Bei Mu) 10 g, Curcuma aromatica (Yu Jin) 10 g, Amomum villosum (Sha Ren) 6 g, and lotus receptacle (He Ye Di) 10 g.
Administration: One dose daily, decocted with water and administered orally in two divided doses (morning and evening).
Evidence summary: A clinical observational study enrolled 332 patients with ESCC after radical surgical resection. According to patients’ treatment preferences, participants were divided into a control group (n = 204) and a Chinese medicine intervention group (n = 128). Patients in the control group received routine postoperative follow-up after completion of adjuvant chemotherapy, whereas patients in the Chinese medicine group received modified Qi Ge San. Patients with stage I disease started treatment 3 weeks after radical surgery, while patients with stage II–III disease initiated treatment 3 weeks after completion of adjuvant chemotherapy.
The results showed that disease-free survival (DFS) was longer in the Chinese medicine group than in the control group (22.1 ± 1.4 months vs. 14.2 ± 1.0 months). The 1-year recurrence and metastasis rate was lower in the Chinese medicine group than in the control group (9.4% vs. 19.6%), with statistically significant differences between groups (P < 0.05).
(b) Shidao Tongjie Formula[23] Therapeutic principles: Tonifying Qi, breaking blood stasis, resolving toxins, and dissipating masses.
Composition: Codonopsis pilosula (Dang Shen) 15 g, Poncirus trifoliata (Gou Ju Li) 15 g, Scolopendra subspinipes (Tian Long) 9 g, Cardamine impatiens (Ji Xing Zi) 15 g, Salvia chinensis (Shi Jian Chuan) 30 g, processed Arisaema erubescens (Zhi Nan Xing) 15 g, and roasted Terminalia chebula (Wei He Zi) 15 g.
Administration: One dose daily, decocted with water and administered orally in two divided doses (morning and evening).
Evidence summary: Shidao Tongjie Formula was administered to postoperative patients with EC characterized by the TCM pattern of phlegm–Qi obstruction. The study demonstrated that the formula significantly improved treatment-related gastrointestinal adverse reactions, including nausea, vomiting, and diarrhea. In addition, treatment was associated with prolonged median recurrence time and improved 3-year disease-free survival (P < 0.05).
Therapeutic principles: Activating blood circulation and resolving blood stasis, dissipating masses and reducing swelling, detoxifying, and relieving pain.
Composition: Curcuma longa (Yu Jin), Strychnos nux-vomica powder (Ma Qian Zi Fen), Agrimonia pilosa (Xian He Cao), Faeces Trogopterori (Wu Ling Zhi), alum (Bai Fan), sodium nitrate (Xiao Shi), processed Toxicodendron vernicifluum (Gan Qi), and stir-fried Citrus aurantium (Zhi Qiao).
Administration: Administered orally, 4 capsules each time, three times daily.
Evidence summary: A clinical study evaluated the efficacy of combined TCM therapy and Pingxiao Capsule in patients with EC following radical surgery and completion of adjuvant chemotherapy. The results demonstrated that this integrative treatment not only improved patient-reported symptoms and quality of life but also prolonged DFS and reduced recurrence and metastasis rates (P < 0.05).
Comparison with Existing Guidelines
To place the present guideline in an international context, we compared its recommendations with four major guideline systems relevant to the prevention and early management of EC, including the National Comprehensive Cancer Network (NCCN), the European Society for Medical Oncology (ESMO), the Japan Esophageal Society (JES), and Chinese National Guidelines and Screening Programs[
25–
31]. Overall, substantial agreement was observed in the principles of endoscopic assessment, histopathological confirmation, endoscopic treatment of high-grade or superficial neoplastic lesions, and post-treatment surveillance, whereas greater heterogeneity existed in population screening strategies and the management of precancerous lesions (Supplementary Appendix 3).
A descriptive quantitative comparison across the four external guideline systems showed that two of four (50%) provide explicit risk-based screening strategies for populations at increased risk of EC, most clearly in the NCCN recommendations and the Chinese national screening program. In contrast, the ESMO guideline primarily focuses on the diagnosis and treatment of established EC, while the JES guideline emphasizes risk factors and early-stage management without establishing a population-based screening algorithm. All four guideline systems (4/4, 100%) support endoscopic resection as a central treatment strategy for appropriately selected patients with high-grade intraepithelial neoplasia/carcinoma in situ or superficial early EC. Dedicated or explicit management strategies for Barrett’s esophagus and related dysplasia are provided in three of four guideline systems (75%), namely the NCCN, JES, and Chinese guidelines. Specific endoscopic surveillance intervals for precancerous or very early lesions are most clearly defined in the NCCN and Chinese guidance (2/4, 50%). None of the four external guideline systems (0/4, 0%) incorporates TCM pattern differentiation or evidence-based Chinese herbal interventions.
The present guideline is largely consistent with these established recommendations regarding risk-stratified endoscopic evaluation, histopathological confirmation, endoscopic resection of high-grade lesions, and continued surveillance. In particular, the Chinese 2024 National Program closely parallels our recommendations by defining high-risk populations, recommending endoscopy as the primary screening modality, and specifying surveillance intervals for squamous low-grade intraepithelial neoplasia and Barrett’s esophagus[
31]. The NCCN guideline similarly emphasizes risk-based endoscopic screening in selected populations, endoscopic resection for early-stage lesions, and continued endoscopic surveillance after eradication of neoplasia[
25]. ESMO recommends endoscopic
en bloc resection with EMR or ESD for intraepithelial high-grade dysplasia and most T1 tumors[
26], while the JES guideline provides detailed recommendations for cStage 0/I disease and a dedicated framework for the diagnosis and treatment of Barrett’s esophagus and EAC[
28,
29]. The 2025 ESMO interim update primarily addresses locally advanced adenocarcinoma and metastatic squamous-cell carcinoma and therefore does not substantially alter the comparison regarding precancerous and early-stage disease[
27].
Conclusion
This evidence-based clinical practice guideline provides a structured framework for the prevention and management of esophageal precancerous lesions using integrative Chinese and Western medicine. It addresses six major clinical domains, including risk and protective factors, screening and risk stratification of high-risk populations, standardized diagnosis, TCM syndrome differentiation and pathogenesis evolution, management of squamous and adenocarcinoma-related precancerous lesions, and selected TCM-based interventions for recurrence risk management after treatment of early EC. The recommendations were developed through multidisciplinary collaboration and were informed by the available evidence, clinical applicability, patient preferences, and expert consensus.
Upper gastrointestinal endoscopy and histopathological assessment remain the cornerstones of screening, diagnosis, risk stratification, treatment selection, and surveillance. Clinical management should be individualized according to histological subtype, pathological grade, lesion extent and visibility, risk of progression, overall health status, treatment tolerance, and patient preferences. Endoscopic surveillance or intervention should be implemented in accordance with lesion risk, while gastroesophageal reflux control and lifestyle modification are important components of long-term management. TCM interventions may be considered as complementary strategies for selected patients to improve symptoms, regulate TCM patterns, support long-term management, and potentially reduce the risk of lesion progression or postoperative recurrence. However, TCM-based interventions should not replace standardized endoscopic surveillance, pathological reassessment, or established conventional treatment.
Although the recommended TCM interventions have been used in clinical practice, their safety should be carefully considered, particularly during prolonged treatment. Some herbal components may be associated with organ-specific toxicity. For example, Dioscorea bulbifera and Sophora tonkinensis, which are included in Zeng Sheng Ping, have been associated with potential hepatotoxicity, whereas Strychnos nux-vomica contained in Pingxiao Capsule may cause neurotoxicity when used improperly or at excessive doses. Therefore, baseline and periodic liver function assessment should be considered for patients receiving potentially hepatotoxic preparations, while neurological symptoms should be closely monitored in patients receiving preparations containing Strychnos nux-vomica. Medication reconciliation is also recommended to identify potential drug–drug interactions and overlapping toxicities. All TCM preparations should be administered according to approved formulations and dosages and under the supervision of qualified physicians.
The current evidence base, particularly that supporting TCM interventions, remains limited by small sample sizes, heterogeneous diagnostic criteria and treatment regimens, incomplete reporting of safety outcomes, and insufficient data on long-term malignant transformation, recurrence, and survival. Therefore, the recommendations should be implemented with appropriate clinical judgment and regular assessment of effectiveness and safety. Future research should prioritize rigorously designed multicenter randomized controlled trials, standardized TCM formulations and syndrome definitions, patient-important long-term outcomes, comprehensive safety monitoring, and evaluation of implementation feasibility and cost-effectiveness. This guideline should be periodically updated as new evidence emerges to improve the standardization and quality of integrative management for esophageal precancerous lesions.
The Author(s) 2026. This article is published by Higher Education Press at journal.hep.com.cn.
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