Clinical Characteristics Of Multiple Primary Malignancies Associated With Esophageal Squamous Carcinoma From High- And Low- Incidence Areas And Expression Of P53 In The Two Groups And It's Clinical Significance

1.Background and objectiveMultiple primary malignancies(MPMs)is a common clinical phenomenon,which refers to the occurrence of two or more primary malignant tumors simultaneously or successively in one or more organs of the same individual.Among them,those with a diagnostic interval of no more than 6 months are called simultaneous multiple primary malignancies(SMPMs),and those more than 6 months are called metachronous multiple primary malignancies(MMPMs).Because of gene mutation,polymorphism,cell cycle disorder,harmful environmental factors and lifestyle,patients with primary malignant tumors are more susceptible to neoplasticdisease,and the risk of new malignant tumors is significantly higher than that of the general population.In recent years,with the rapid development of medicine and the wide implementation of standardized diagnosis and treatment of cancer,the survival time of patients with malignant tumor has been prolonged,and the incidence of MPMs has gradually increased.Esophageal squamous cell carcinoma(ESCC)is one of the common malignant tumors of the digestive system.China has the highest incidence and mortality of ESCC.The significant regional distribution difference is one of the prominent epidemiological characteristics of esophageal cancer in China,and the incidence of esophageal cancer in high-and low-incidence areas is very different.The phenomenon of ESCC complicated with MPMs is also very common,which has been reported by scholars at home and abroad for a long time.However,because of the difficulty of data collection,there is a lack of large sample studies to comprehensively and systematically understand multiple primary malignancies associated with esophageal squamous cell carcinoma(ESCC-MPMs).Because of the significant differences in the incidence of esophageal cancer between high-and low-incidence areas,it is not clear whether the incidence and clinical characteristics of ESCC-MPMs are affected by regional differences.Understanding their clinical characteristics is helpful to the early diagnosis and treatment of ESCC-MPMs,to prevent the occurrence of ESCC-MPMs,and to provide new ideas for the future development of prevention and treatment of ESCC.Although a lot of researches have been done by scholars at home and abroad,our understanding of MPMs is still very limited,and the pathogenesis is still not very clear.Studies have shown that p53 expression is closely related to the occurrence of MPMs associated with breast cancer and bladder cancer.However,the relationship between p53 expression and ESCC-MPMs is rarely reported.In this study,all information came from the database of 500,000 cases of esophageal/gastric cardia cancer in Henan Key Laboratory for Esophageal Cancer Research,the First Affiliated Hospital of Zhengzhou University.By collecting and collating the data of ESCC-MPMs,the clinical characteristics,p53 expression and clinical significance of ESCC-MPMs in high-and low-incidence areas were explored,which provided a scientific theoretical basis for the prevention and treatment of ESCC-MPMs.2.Materials and methods2.1 Object of study.In this study,136,279 patients with ESCC were from 500,000 cases of esophageal/gastric cardia cancer in Henan Key Laboratory for Esophageal Cancer Research,the First Affiliated Hospital of Zhengzhou University.The diagnostic time was from January 1970 to May 2017.There were 85,881 males,aged from21~95(60�9)years old and 50,398 females,aged from20~99(61 �9)years old.The ratio of males to females is 1.70:1.2.2 Collection,verification and supplement of clinical diagnosis,treatment and pathological information.The clinical diagnosis and treatment information of all patients was collected by hospital collection,household investigation,telephone follow-up and so on.The relevant information included basic information,detailed family address,contact,contact information,pathological diagnosis and so on.And by the laboratory graduate students to the corresponding treatment hospital to verify and supplement the clinical diagnosis and treatment information and pathological information to ensure that the information is accurate.2.3 Methods.(1)The clinical data of 88,614 cases from high incidence area and 47,665 cases from low incidence areas of ESCC were analyzed retrospectively.The incidence,location,interval time,occurrence time and age distribution of ESCC-MPMs in patients with ESCC in high-and low-incidence areas were analyzed.(2)The esophageal cancer tissues of 81 ESCC-MPMs patients were selected,and81 ESCC samples from high-and low-incidence areas were matched with esophageal cancer tissues from ESCC-MPMs patients at 1:1,according to sex,age and pathological grade.Immunohistochemical method was used to detect the expression of p53 protein,to analyze the difference of p53 protein expression positive rate between ESCC-MPMs and ESCC patients,and to further explore its clinical significance.(3)Stata15.0 was used for data analysis.The prevalence of ESCC-MPMs and the expression of p53 in high-and low-incidence areas and between men and women were compared by ?2 test,Fisher exact probability method if necessary.Rank sum test was used to compare the interval time between MMPMs and ESCC in the same area or high-incidence area and low-incidence areas.The test level = 0.05.3.Results3.1 Tumorigenesis of ESCC-MPMs.There were 136,279 cases of ESCC,of which 2,050 cases(1.5%)were ESCC-MPMs.There were 1,466 cases(1.7%)in high incidence areas and 584 cases(1.2%)in low incidence areas.there was significant difference in the incidence of ESCC-MPMs between the high-and low-incidence areas(?2 = 38.525,P < 0.001).There were 1,048 males(2.0%)and 418 females(1.2%)in high incidence areas.there was significant difference in the incidence of ESCC-MPMs between male and female in high incidence areas(?2 = 80.224,P < 0.001).There were 443 males(1.4%)and141 females(0.9%)in low incidence areas.there was significant difference in the incidence of ESCC-MPMs between male and female in low incidence areas(? 2 ?15.238,P < 0.001).3.2 Distribution of occurrence sites of ESCC-MPMs.Among 2056 lesions,1470 were from high incidence areas and 586 were from low incidence areas.In high incidence areas,the most common ESCC-MPMs were,in turn,gastric cardia adenocarcinoma,gastric cancer,lung cancer,liver cancer andbreast cancer,in which gastric cardia adenocarcinoma was SMPMs,231/238 gastric cancer,189/190 lung cancer,107/111 liver cancer and 12/14 breast cancer were MMPMs later than ESCC.In low incidence areas,the most common ESCC-MPMs were,in turn,gastric cardia adenocarcinoma,lung cancer,gastric cancer,liver cancer and bone cancer,in which gastric cardia adenocarcinoma was SMPMs,92/95 gastric cancer and other tumors were MMPMs later than ESCC.3.3 Interval time between MMPMs and ESCCThe median interval time between MMPMs(later than ESCC)and the first diagnosis of ESCC in high incidence areas were 2.0 years for gastric cancer,2.4 years for lung cancer and 1.9 years for liver cancer,respectively.The corresponding median interval time in low incidence areas were 2.4 years for gastric cancer,2.3 years for lung cancer and 2.0 years for liver cancer,respectively.3.4 The occurrence sequence of ESCC-MPMs.Among ESCC-MPMs,there were 1116 SMPMs,accounting for the largest proportion,followed by MMPMs later than ESCC,and MMPMs earlier than ESCC were rare.SMPMs were most common in high incidence areas,while MMPMs were most common in low incidence areas later than ESCC.3.5 Diagnostic age distribution of ESCCIn this study,all patients with ESCC-MPMs were grouped by the diagnostic age of ESCC.The proportion of patients aged 60-70 years old in high-and low-incidence areas was the largest,accounting for 43.1% and 44.5%,respectively.3.6 Expression of p53 in patients with ESCC-MPMs and ESCC in high-and low-incidence areasThere was no significant difference in age,sex and pathological stage between ESCC and ESCC-MPMs patients detected by immunohistochemistry in high-andlow-incidence areas.There were 50 cases of p53 positive expression in patients with ESCC-MPMs in high incidence areas,including 2 cases of mosaic type,6 cases of focal type,42 cases of diffuse type and the positive expression rate was 92.6%.There were 31 ESCC patients with p53 positive expression,including 2 cases of mosaic type,4 cases of focal type,25 cases of diffuse type and the positive expression rate of p53 was 57.4%.The positive expression rate of p53 in ESCC-MPMs group was significantly higher than that in ESCC group(?2 = 17.827,P < 0.001).There were 24 cases of p53 positive expression in patients with ESCC-MPMs in low incidence areas,including 1 cases of mosaic type,2 cases of focal type,21 cases of diffuse type and the positive expression rate was 88.9%.There were 14 ESCC patients with p53 positive expression,including 1 cases of mosaic type,3 cases of focal type,10 cases of diffuse type and the positive expression rate of p53 was 51.9%.The positive expression rate of p53 in ESCC-MPMs group was significantly higher than that in ESCC group(?2 = 8.882,P =0.003).4.Conclusions(1)The clinical characteristics of ESCC-MPMs in high and low incidence areas were similar.(2)p53 is an important related protein of ESCC-MPMs.In order to get a more comprehensive and accurate evaluation standard,it is necessary to make a further systematic study of ESCC-MPMs with forward-looking,multi-center,large sample and multi-index.