| BackgroundChina is a country with a high incidence of esophageal cancer,especially esophageal squamous cell carcinoma.Since the early 1970s.whole-population tumor surveillance and registration sites have been established,including Cixian county in Hebei province,Yanting in Sichuan Province,Yangcheng in Shanxi Province,etc.Since 2006,a program for early diagnosis and treatment of upper digestive tract tumors in rural areas with high incidence has been implemented,significantly improving the five-year survival rate of patients.With the popularization of endoscopic examination,the number of patients with early esophageal cancer and precancerous lesions increases,especially for precancerous lesions that have not reached endoscopic surgery,the intervention of traditional Chinese medicine has a prospect.However,there are no specific symptoms at this stage,so it is difficult for TCM diagnosis and treatment.In this study,tongue screening was conducted in high incidence areas to explore the characteristics of tongue image in early esophageal cancer and precancerous lesions,providing a basis for the prevention and treatment of traditional Chinese medicine,and exploring the internal biological mechanism of esophageal cancer based on biopsy specimens.Part Ⅰ:Tongue image distribution and TCM pathogenesis of early esophageal squamouscell carcinoma and precancerous lesions ObjectiveTongue screening and endoscopic screening were combined to analyze the characteristics oftongue under different physiological states in the process of esophageal carcinoma,and to explore the characteristics of tongue image in the transformation from precancerous lesions of esophagus to early esophageal squamous cell carcinoma and the pathogenesis of traditional Chinese medicine.MethodsA total of 18.954 patients who completed endoscopy screening and tongue image screeningfrom 2017 to 2021 in Cixian County,Yanting County,and Yangcheng County were enrolled.Twelve tongue image features were extracted by Daosheng Tongue Diagnostic Instrument(DS01-B)under a unified standard light source environment.Data were analyzed using SPSS 24(SPSS Inc.,Chicago,IL,USA),and multiple confounding factors were controlled for by multivariate Logistic regression and propensity matching score to compare the differential tongue features between precancerous lesions,early esophageal cancer and pathologic normal subjects.ResultsTongue distribution analysis showed that the proportion of purple tongue in early esophageal cancer and precancerous lesions of esophagus was significantly increased compared with normal pathological group,and the OR value was 1.82(1.45-2.28,P<0.001)and 2.14(1.51-3.05,P<0.001),respectively.The proportion of red tongue and fractured tongue was mainly increased in precancerous lesions of esophagus.OR values were 1.44(1.25-1.66,P=0.003)and 1.49(1.30-1.72,P<0.001),respectively.After incorporating other statistically significant tongue features and risk factors into multivariate Logistic regression analysis,purple tongue showed the same pattern.Red tongue and cracked tongue had statistical difference only in precancerous lesions.In addition,after balancing the baseline data between groups by the method of propensity matching score,the analysis result was the same.In addition,the distribution of red tongue,purple tongue and cracked tongue among the risk factors of esophageal cancer was analyzed.Smoking and drinking could easily lead to an increase in the proportion of red tongue,purple tongue and cracked tongue.Purple tongue was more common in males.In addition,red tongue and cracked tongue showed an increasing trend with age.ConclusionsPurple tongue showed an increasing trend in the process from precancerous lesions to early esophageal cancer,while red tongue and crackled tongue showed an increasing trend first and then decreasing,reflecting the pathogenesis of the transformation from Yin deficiency and hot to blood stasis in the process of esophageal cancer.Part Ⅱ:Tongue image distribution and TCM pathogenesis of Barrett’s esophagus and early esophageal adenocarcinomaObjectiveThe tongue image distribution of Barrett’s esophagus was compared with that of pathologically normal people to explore the characteristics and TCM pathogenesis of Barrett’s esophagus in precancerous lesions of esophageal adenocarcinoma.At the same time,early esophageal adenocarcinoma was included to analyze the characteristics of tongue image and pathogenesis of esophageal adenocarcinoma.MethodsPatients who completed screening and were pathologically diagnosed with Barrett’s esophagus from 2017 to 2021 were compared with the pathologically normal population using the same screening method as study I.Data were analyzed using SPSS 24(SPSS Inc.,Chicago,IL,USA).Multiple confounding factors were controlled by multiple Logistic regression and propensity matching score.In addition,early esophageal adenocarcinoma was included to analyze the tongue characteristic.ResultsAccording to the analysis,the proportion of purple tongue in Barrett’s esophagus was 21.6%,significantly higher than 6.5%in pathological normal group,OR=3.94(2.01-7.72.P<0.001).After the confounding control by multi-factor Logistic regression and propensity score matching,purple tongue was still the main characteristic of Barrett’s esophagus.OR=2.67(1.35-5.27,P=0.005).In addition,purple tongue and cracked tongue are the main features of early esophageal adenocarcinoma,which are more significant than Barrett’s esophagus.In addition,different from esophageal squamous cell carcinoma,the increase of body mass index was significantly correlated with the occurrence of Barrett’s esophagus and early esophageal adenocarcinoma.ConclusionsPurple tongue and cracked tongue are the main tongue features of Barrett’s esophagus and early esophageal adenocarcinoma,especially purple tongue,reflecting Yin deficiency and blood stasis are the core TCM pathogenesis of Barrett’s esophagus and early esophageal adenocarcinoma,and blood stasis is more significant in early esophageal adenocarcinoma than Barrett’s esophageal.Part Ⅲ:Correlation analysis of differential TRANSCRIPTION of RNA and tongue features in early esophageal carcinomaObjectiveBy comparing the differential RNA expression between the pathological tissues of patients with mild,moderate and severe atypical hyperplasia of esophageal squamous epithelium and normal pathology,the molecular biological mechanism of esophageal carcinoma was explored,and the molecular biological mechanism of the transformation from Yin deficiency and heat to blood stasis was discussed in combination with study Ⅰ and Ⅱ.MethodsThree patients with mild,moderate and severe atypical hyperplasia of esophageal squamous epithelium and normal pathological diagnosis were selected,and were compared with each other by NanoString nCounter analysis technology to search for differential gene expression.At the same time,differential genes of characteristic tongue images were compared.DAVID database was used for functional enrichment,KEGG database was used for pathway enrichment,and STRING database was used for PPI protein interaction network analysis.ResultsThe number of different genes in mild,moderate and severe atypical hyperplasia of esophageal squamous epithelium was 48,128 and 1 54,respectively.The common differential genes included HLA-C,GOT2,UBE2C,CXCL14.HDAC4,TYMP,CDC20,LAMB3,CENPF,TGFBR2,IFI16,SLC1A5 and COL5A1.Differential gene enrichment analysis revealed that in addition to extensive activation of cancer network,activation of inflammatory and immune-related signaling pathways was the main feature of this pathological stage,including cytokine receptor signaling pathway.TNF signaling pathway,cell adhesion molecule signaling pathway,chemokine signaling pathway,etc.Characteristic tongue image differential gene enrichment analysis and PPI protein interaction analysis showed that red tongue and crackled tongue had a wide range of inflammatory responses,immune responses and immunosuppression,especially the activation of JAK-STAT signaling pathway and PI3K-Akt signaling pathway mediated by cytokine receptor.Both of them are important components of the cancer network activated by esophageal precancerous lesions and interact with a variety of cancer transformation and immunosuppression pathways.ConclusionsThe extensive activation of JAK-STAT signaling pathway and PI3K-Akt signaling pathway mediated by cytokines and cytokine receptors may be the core biological mechanism of the transformation from Yin deficiency and heat to blood stasis in the early stage of esophageal cancer. |
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