Esophageal Histological Precursor Lesions and Subsequent 8.5-Year Cancer Risk in a Population-Based Prospective Study in China.

INTRODUCTION: Data on the associations between esophageal histological lesions and risk of esophageal squamous cell carcinoma (ESCC) in general populations are limited. We aimed to investigate these associations in a large Chinese general population to inform future Chinese ESCC screening guidelines. METHODS: We performed endoscopic screening of 21,111 participants aged 40-69 years from 3 high-risk areas of China in 2005-2009, and followed the cohort through 2016. Cumulative incidence and mortality rates of ESCC were calculated by baseline histological diagnosis, and hazard ratios of ESCC, overall and by age and sex, were assessed using the Cox proportional hazards models. RESULTS: We identified 143 new ESCC cases (0.68%) and 62 ESCC deaths (0.29%) during a median follow-up of 8.5 years. Increasing grades of squamous dysplasia were associated with the increasing risk of ESCC incidence and mortality. The cumulative ESCC incidence rates for severe dysplasia/carcinoma in situ, moderate dysplasia (MD), and mild dysplasia were 15.5%, 4.5%, and 1.4%, respectively. Older individuals (50-69 years) had 3.1 times higher ESCC incidence than younger individuals (40-49 years), and men had 2.4 times higher ESCC incidence than women. DISCUSSION: This study confirmed that increasing grades of squamous dysplasia are associated with increasing risk of ESCC and that severe dysplasia and carcinoma in situ require clinical treatment. This study suggests that in high-risk areas of China, patients with endoscopically worrisome MD should also receive therapy, the first screening can be postponed to 50 years, and endoscopic surveillance intervals for unremarkable MD and mild dysplasia can be lengthened to 3 and 5 years, respectively.

Endoscopy screening effect on stage distributions of esophageal cancer: A cluster randomized cohort study in China.

Efficacy of endoscopic screening for esophageal cancer is not sufficiently definitive and lacks randomized controlled trial evidence. The present study proved short-term screening efficacy through describing and comparing disease stage distributions of intervention and control populations. Villages from Linzhou and Cixian were cluster randomly allocated to the intervention or to the control group and the target population of 52 729 and 43 068 individuals was 40-69 years old, respectively, and the actual enrolled numbers were 18 316 and 21 178, respectively. TNM stage information and study-defined stage information of esophageal cases from 2012 to 2016 were collected. Stage distributions were compared between the intervention and control groups in the total target population, as well as in the subgroup populations in terms of enrolment and before or after intervention. There were a total of 199 and 141 esophageal cancer cases in the intervention and control groups, respectively. For the target population, distributions of TNM stage were borderline significant between the two groups after intervention (P = .093). However, subgroup analysis of the enrolled population during the after-intervention period had statistical significance for both TNM and study-defined stage. Natural TNM stage distributions were approximately 32%, 41%, 24% and 3% for stages I to IV vs 71%, 19%, 7% and 3% in the intervention population. The natural study-defined stage distributions from early, middle to advanced stages were approximately 18%, 49% and 33% vs 59%, 33% and 8%. Early-stage esophageal cancer cases accounted for a higher proportion after endoscopy screening, and the efficacy in the target population depends on the intervention compliance.

Natural History Analysis of 101 Severe Dysplasia and Esophageal Carcinoma Cases by Endoscopy.

Objectives. Our research is to realize the natural history from dysplasia to carcinoma and to provide evidence for exploring proper screening intervals. Methods. After the onset endoscopy screening, 2093 of the patients participated in the endoscopic follow-up voluntarily. Totally, 101 severe dysplasia and carcinoma cases, either diagnosed in the first endoscopy without treatment or diagnosed in the second endoscopy, were included in our study. We compared the pathologic results of their two endoscopies and calculate the mean and median progression time. Results. Of the 39 severe dysplasia cases diagnosed by the onset endoscopy, only 8 progressed to carcinoma. For severe dysplasia cases diagnosed by the follow-up endoscopy, mean progression times are 55.0, 49.8, and 38.0 months and median progression times are 43, 56, and 31 months for esophagitis, mild dysplasia, and moderate dysplasia, respectively. For superficial carcinoma cases diagnosed by the second endoscopy, mean progression times are 76.0, 57.4, and 47.0 months and median progression times are 77, 63, and 35 months for mild dysplasia, moderate dysplasia, and severe dysplasia, respectively. Conclusions. Population-based severe dysplasia cases may have much lower carcinoma progression rate than specific-selected ones. The progression time for most enrolled cases seems longer than that of the recent screening protocol recommended.

Effectiveness of endoscopic gastric cancer screening in a rural area of Linzhou, China: results from a case-control study.

In China, a large burden of gastric cancer has remained, and endoscopic screening was expected to reduce gastric cancer mortality. Therefore, a population-based case-control study was conducted to evaluate the screening effect. The gastric cancer screening program was initiated in Linzhou in the year 2005, and endoscopic examination with indicative biopsy, for residents aged 40-69 years, was used to detect early cancer and precancerous lesion. In this study, cases were defined as individuals who had died of gastric cancer, which were selected from Linzhou Cancer Registry database. Controls were residents (six per case), who had not died of gastric cancer, from the same area as the case, and matched by gender and age (±2 years). The exposure status, whether cases and controls ever attended the screening or not, was acquired by inspecting the well-documented screening records. Conditional logistic regression model was used to estimate the odds ratios (OR) and their 95% confidence intervals (95% CI). A total of 313 cases and 1876 controls were included in our analysis. Compared with subjects who never participated in screening, the overall OR for individuals who ever participated in screening was 0.72(95% CI: 0.54-0.97). The OR for lag time 4 years or longer was 0.68(95% CI: 0.47-0.98) and the OR for those who were aged 50-59 years were 0.56 (0.37-0.85). The results suggest a 28% reduction in risk of gastric cancer mortality by endoscopic screening, which may have significant implications for gastric cancer screening in rural areas of China.

Evaluation of routine biopsies in endoscopic screening for esophagogastric junction cancer.

AIM: To explore whether routine biopsies at the high incidence spot of esophagogastric junction (EGJ) cancer are justified in endoscopic screening. METHODS: This was a multicenter population-based study conducted in eight high-risk areas in China. A total of 37396 participants underwent endoscopic examination. Biopsies were obtained from visible mucosal abnormalities or from normal-appearing mucosa at the high incidence spot of esophagogastric junction cancer when no abnormality was detected. Specimens showing high-grade intraepithelial neoplasia (HIN) or higher grade lesions were deemed as pathologically "positive". The ratios of positive pathologic diagnosis between participants with abnormal and normal-appearing mucosa were compared using the Pearson χ(2) test. Odds ratios and 95% confidence intervals, adjusted for potential confounders, were calculated using logistic regression. RESULTS: A total of 37520 individuals participated in this study and 37396 (99.7%) participants had full information and were suitable for analysis. During endoscopic examinations, 9.11% (3405/37396) participants were found to have visible mucosal lesions. Of the participants who had normal-appearing mucosa at the EGJ, only 0.28% (94/33991) were diagnosed with HIN or higher grade lesions, whereas 6.05% (206/3405) of participants with abnormalities at the EGJ had a positive pathologic result. After controlling for other variables, visible abnormal mucosa detected under endoscopy strongly predicted a positive pathologic result (OR = 32.51, 95%CI: 23.96-44.09). The proportion of participants with "positive" pathologic diagnoses increased as the total number of endoscopic examinations performed by the doctors increased (< 5000 cases vs 5000-10000 cases vs > 10000 cases, Z = -2.7207, P = 0.0065, Cochran Armiger trend test). The same trend was found between the proportion of participants with positive pathologic diagnoses and the total number of years the doctors performed endoscopy (< 5 years vs 5-10 years vs > 10 years, Z = -10.3222, P < 0.001, Cochran Armiger trend test). CONCLUSION: Additional routine biopsies from the high incidence spot of EGJ cancer are of limited value and are unjustified.

[Long-term outcomes of endoscopic argon plasma coagulation (APC) therapy for early esophageal cancer and precancerous lesions].

OBJECTIVE: To evaluate the long-term outcomes of endoscopic argon plasma coagulation (APC) therapy for early esophageal cancer and precancerous lesions. METHODS: One-hundred and seventy-one cases with early esophageal cancer (intramucosal carcinoma) and precancerous lesions were treated by APC from 1994 to 2005, and all the cases were followed up. One-hundred and sixty-eight (98.2%) cases were follow-up by endoscopic examination for several times. On average, each patient was endoscopically examined 2.8 times. The follow-up rate was 100%. RESULTS: The precancerous lesion group had 160 patients. They were followed up for 5 years. 11 patients died of causes unrelated to cancer. The lesions developed into esophageal squamous cell carcinoma in five patients ( 2 died and 3 underwent esophagectomy). The remaining 144 cases survived without cancer. In this group, the esophageal cancer incidence rate is only 3.1% (5/160). The early cancer (i.e. intramucosal cancer) group had 11 patients. During the 5-year follow-up period, two patients died of causes unrelated to cancer,six patients had recurrence (4 patients died and 2 patients underwent esophagectomy), and only 3 patients survived without cancer. Therefore, the 5-year survival rate was only 27.3% (3/11). CONCLUSIONS: The APC therapy for precancerous lesions of the esophagus is effective and successful. Indications should be carefully considered when treating early esophageal cancer such as intramucosal carcinoma by APC therapy.

Population-based study of DNA image cytometry as screening method for esophageal cancer.

AIM: To explore the DNA image cytometry (DNA-ICM) technique as a primary screening method for esophageal squamous precancerous lesions. METHODS: This study was designed as a population-based screening study. A total of 582 local residents aged 40 years-69 years were recruited from Linzhou in Henan and Feicheng in Shandong. However, only 452 subjects had results of liquid-based cytology, DNA-ICM and pathology. The sensitivity and specificity of DNA-ICM were calculated and compared with liquid-based cytology in moderate dysplasia or worse. RESULTS: Sensitivities of DNA-ICM ranging from at least 1 to 4 aneuploid cells were 90.91%, 86.36%, 79.55% and 77.27%, respectively, which were better than that of liquid-based cytology (75%). Specificities of DNA-ICM were 70.83%, 84.07%, 92.65% and 96.81%, but the specificity of liquid-based cytology was 91.91%. The sensitivity and specificity of a combination of liquid-based cytology and DNA-ICM were 84.09% and 85.78%, respectively. CONCLUSION: It is possible to use DNA-ICM technique as a primary screening method for esophageal squamous precancerous lesions.

[Natural progression of early esophageal squamous cell carcinoma].

OBJECTIVE: The survival time of untreated advanced esophageal squamous cell carcinoma is about 8 - 9 months. The objective of this study was to observe the natural progression of untreated early esophageal squamous cell carcinoma for 20 years. METHODS: 4800 subjects from a high risk area of esophageal cancer in Lin-zhou city, Henan province, were examined by endoscopy from 1985 to 1990. Among them, 132 cases were diagnosed as early esophageal cancer. Based on the criteria, the lesions were endoscopically diagnosed as superficial mucosal lesions and histopathologically confirmed by biopsy as carcinoma in situ, intramucosal carcinoma or squamous cell carcinoma. 48 of the 132 patients, who refused treatment, were followed up to the end of 2005. There were 43 death and 5 alive. 40 patients were re-examined for 1 - 4 times by endoscopy during the following up. RESULTS: A total of 48 patients have been followed up for 20 years. 38 (79.2%) cases died of esophageal squamous cell carcinoma, 5 (10.4%) died of non-cancer diseases and 5 (10.4%) were surviving. 37 patients had survived for over 5 years. The 5-, 10-, 15- and 20-years survival rates were 77.1%, 39.6%, 25.0% and 10.4%, respectively. CONCLUSION: The natural history of esophageal squamous cell carcinoma takes a long time to progress from early to advanced stage. It is very helpful for early diagnosis and selection of opportunity for treatment. The leading time bias by natural history of this disease should be considered when evaluate therapeutic effect on early stage esophageal cancer.

[A prospective study of the origin of esophageal squamous cell carcinoma in the esophageal mucosa:result from a high risk area of esophageal cancer in China during a 15-year follow up (1987 - 2002)].

OBJECTIVE: The aim of this study was to observe the association between the occurrence of esophageal cancer lesions and esophageal mucosa fold (white ridges), and further identify where is the initial origin of esophageal cancer lesions in the esophagus mucosa. METHODS: This was a cohort study which recruited 551 subjects underwent endoscopic examination in a high risk area of esophageal cancer in Linxian, Henan Province in 1987. 339 subjects with esophageal white ridges, and with red area or erosion lesion at the surface of the white ridges, was studied as exposure group. Other 212 subjects whose esophagus had no white ridges and pathological diagnosis was negative, was studied as control group. The endpoint was occurrence of pathologically confirmed esophageal cancer. After a 15-year follow-up, the results were compared between two groups. RESULTS: Among the 551 subjects, there were 339 cases with esophageal mucosal white ridges in the exposure group. During the period of 15 year follow-up, the incidence of esophageal cancer was 11.8% (9/76) in 76 case with simple mucosal white ridges, 33.5% (88/263) in 263 subjects with white ridges and red area, or erosions on the surface of white ridge. While only 8.0% of subjects (17/212) developed esophageal cancer after the 15-year follow up in the control group. There was a significant difference between the two groups (P < 0.001). CONCLUSION: Esophageal mucosal white ridge, especially white ridge with red area or erosions is closely associated with subsequent esophageal cancer occurrence in the esophageal cancer high risk area in China. It is suggested that esophageal mucosa with white ridge may be the initial origin of esophageal cancer. Further investigations focused on this spot are required.

Cytologic detection of esophageal squamous cell carcinoma and its precursor lesions using balloon samplers and liquid-based cytology in asymptomatic adults in Llinxian, China.

OBJECTIVE: Esophageal squamous cell carcinoma (ESCC) is associated with very high regional mortality rates in several countries. Our initial test of esophageal cytology screening devices found them not sensitive enough for an early detection program. The current study tested a newly designed "mechanical" balloon and a traditional Chinese inflatable balloon, followed by liquid-based cytology, to detect biopsy-proven squamous dysplasia and early cancer. STUDY DESIGN: Participants were randomized to a cytologic sampler, followed by endoscopy with iodine staining. For each patient, the cytologic diagnosis (test) was compared with the worst endoscopic biopsy diagnosis (truth). RESULTS: Seven hundred forty subjects completed both examinations. Approximately 30% showed atypical squamous cells of undetermined significance (ASCUS), and 10% showed squamous intraepithelial lesions. Seven hundred twenty-five subjects (98%) had satisfactory biopsies, and 32% had low grade dysplasia or worse disease. Defining > ASCUS, favor neoplastic, as a positive screening test, the sensitivities/specificities of the mechanical and inflatable balloons were 39%/85% and 46%/84%, respectively, for detecting any squamous dysplasia or cancer. CONCLUSION: These esophageal cell samplers performed equivalently, but the accuracy was still too low for a primary screening test. These results highlight the need to develop new cytologic criteria or molecular markers that can better detect early squamous esophageal disease [corrected]

[A comparative study of endoscopic image stained by iodine and histopathology in early esophageal cancer and precancerous lesions (dysplasia)].

OBJECTIVE: The aim of this study is to evaluate the relationship between the imaging patterns of endoscopy aided by iodine stain and histological diagnosis. METHODS: A balloon cytological screening was conducted in 4000 participants in high-risk area of esophageal cancer in 1997-1998, 1050 out of these 4000 participants were confirmed as abnormal by cytology. Among them, 867 were given endoscopy examination during which mucosal stain with 1.2% iodine solution was used. The stain images were graded as four categories: Grade 1, dark yellow, protruding inlay-like with clear borders and showing pink after discoloration; Grade 2, between grade 1 and grade 3; Grade 3, light yellow, flat lesion with clear but not sharp borders and Grade 4, dark-brown color. According to the above criteria, the lesions were recorded and graded after the examination. The biopsies were taken from the unstained lesions and underwent pathologic evaluation. A comparison between the imaging patterns of endoscopy aided by iodine stain and histological diagnosis was evaluated. The correlation coefficient was estimated using Spearman's Rank Correlation. RESULTS: 94.4% (68/72) of the superficial carcinoma and severe dysplasia, 61.8% (73/118) of moderate dysplasia and 27.7% (35/126) of mild dysplasia were distributed in the grade 1 and grade 2 of iodine stain images of which the patterns conforming to the principle and rule of formation of the image by iodine stain. CONCLUSION: There is close relationship between the imaging patterns of endoscopy aided by iodine stain and histological diagnosis. The magnitude of exposure of the malignant tissue is the pathologic basis of formation of various images by iodine stain. Iodine stain greatly helps of early detection of esophageal cancer.

[Minimal invasive treatment of early esophageal cancer and its precancerous lesion: endoscopic mucosal resection using transparent cap-fitted endoscope].

OBJECTIVE: To explore the effect of endoscopic esophageal mucosal resection using transparent cap-fitted endoscope to treat early esophageal cancer and severe hyperplasia, precancerous lesion of esophageal cancer. METHODS: Endoscopic esophageal mucosal resection were performed with transparent-cap technique on 29 cases of early esophageal cancer and 42 cases of severe hyperplasia, and the residual lesions were treated by Argon plasma coagulation (APC). All patients were followed up by endoscopic examination one month, 4 months, and 12 months after the therapy. RESULTS: (1) Local esophageal mucosa with the size of 21.8 mm +/- 1.02 mm x 18.2 mm +/- 1.02 mm on average was resected from 71 cases, with 88 lesions, using transparent cap-fitted endoscope. 1:1,000 saline-epinephrine at an average dose of 18 ml was injected submucosally for each lesion. (2) After the mucosectomy 5 cases had bleeding which was controlled successfully by compression, local injection of saline-epinephrine, and APC. None case suffered from perforation. Stenosis was found in 4 cases after mucosal resection, in three of which the extent of resected mucosa exceeded 3/4 of the esophageal circumference. Water-balloon dilator was used once a month for 3 - 4 times since one month after mucosal resection. All cases were cured. (3) The lesions of 58 cases (81.2%) were completely resected, and the remaining cases had residual lesions that were treated by APC. Three cases of early cancer and 2 cases of severe atypical hyperplasia were discovered endoscopically 4 months after resection and were cured by APC. (4) All cases survived without any discomfort after a follow-up of 4.6 months on average. CONCLUSION: Safe, simple, minimally invasive and effective on early esophageal cancer and precancerous lesion, endoscopic esophageal mucosal resection (EEMR) is promising clinically.

[Significance of screening by iodine staining of endoscopic examination in the area of high incidence of esophageal carcinoma].

BACKGROUND & OBJECTIVE: In order to improve early detection and visualization of esophageal premalignant lesion and carcinoma, this study was designed to explore significance of the screening by iodine staining of endoscopic examination in the area of high incidence of esophageal carcinoma. METHODS: Three screenings were completed through endoscopic examination for 3164 persons in high-risk population. Esophageal epithelium was stained with iodine in endoscopic examination. According to mucosal color and pathological result, esophageal carcinoma and premalignant lesion were confirmed. RESULTS: After staining, the normal epithelium became brown and precancerous or malignant epithelium manifested yellow with sharp margin. (1) 100% early esophageal cancer was iodine staining positive, all lesions were grade I to grade II. The incidence rates of early esophageal carcinoma and advanced esophageal carcinoma were 1.60%-4.59% and 0.29%-1.09%, respectively. Early detection rate of esophageal carcinoma was all over 75%. (2) 95.6% severe dysplasia were staining positive; 91.3% lesion were grade I and grade II in staining. The incidence rate of severe dysplasia was 4.49%-7.68%. (3) 96.6% moderate dysplasia was positive in iodine staining, 73.3% lesion were grade II and grade III. (4) 92.3% mild dysplasia was positive in iodine staining; most of lesions were grade III. (5) 0.9% esophagitis and 0.4% normal esophageal mucosal were grade I and grade II in iodine staining, most of lesion were negative or grade III. CONCLUSION: The results demonstrated that the screening with endoscopic staining examination could improve early detection of esophageal carcinoma and precancerous lesion. Iodine staining showed highly sensitivity and specificity for identifying these precancerous and early squamous cancer lesions; it may be helpful for diagnosis of early esophageal carcinoma and precancerous lesion.