| 1 Background and objectiveEsophageal cancer(EC)is one of the most common malignant tumors in the world.About half of the new esophageal cancer patients in the world each year occur in China,and more than 90%of them are diagnosed with esophageal squamous cell carcinoma(ESCC).With the persisting improvement and advancement of national attention and various diagnosis and treatment technologies,the survival rate of patients with ESCC has gradually increased,but the overall prognosis is still not satisfactory.The fundamental reason is that there are complex factors affecting the prognosis of patients with ESCC.Among them,the degree of tumor differentiation is considered to be one of the crucial independent factors affecting the prognosis of ESCC.Therefore,if the factors that affect tumor differentiation can be found and targeted induction,it may play a huge help in improving the prognosis of patients.Layered keratides can be found in the center of the cancer nest of well-differentiated squamous cell carcinoma,as known as keratin pearls or carcinoma pearls.Keratin pearls is a typical structure of well-differentiated squamous cell carcinoma,which is extremely proliferative in epithelial tissue.So far,there have been few studies on the role of keratin pearls in the development and outcome of patients with esophageal cancer.Therefore,the relationship between keratin pearls and various clinicopathological features and prognosis of patients with esophageal squamous cell carcinoma is explored to improve the operation of patients.The post-survival rate is of great significance in guiding clinicians to choose a rationaltreatment prognosis plan.IVL(Involucrin)is a cross-linked envelope protein precursor in cytokeratin(CK),and is a marker of early differentiation of epidermal keratin pearls.IVL is mainly distributed in the cytoplasm of keratin pearls in the epidermis and other stratified squamous epithelium,and is also regarded as a marker of the end of differentiation of squamous epithelial cells.However,at this stage,there were no research to analyze the relationship between the expression of IVL protein and the formation of keratin pearls in esophageal squamous cell carcinoma and various clinicopathological characteristics.Therefore,this study compares whether there were keratin pearls in patients with esophageal squamous cell carcinoma and the expression of IVL protein in the presence or absence of keratin pearls and different types of keratin pearls,and explored the prognosis of esophageal squamous cell carcinoma patients.The impact of esophageal squamous cell carcinoma patients is expected to provide new ideas for personalized treatment plans,better long-term survival and quality of life after surgery.2 Materials and methods2.1 Object of studyA total of 5,219 patients with esophageal squamous cell carcinoma were included in this study.All data in this study came from the clinical information database of more than 500,000 cases of esophageal and cardia cancer in the State Key Laboratory for prevention and treatment of esophageal cancer jointly established by the provincial and Ministry of the First Affiliated Hospital of Zhengzhou University.All patients were treated with simple radical resection of esophageal cancer,and had complete clinicopathological data and pathological sections.And according to the pathological section of the patient,the patients with keratin pearls were divided into simple keratin pearls,fused keratin pearls,and keratotic necrosis.2.2 Methods①Through retrospective analysis of the clinical diagnosis and treatment data of 5,219 patients with esophageal squamous cell carcinoma,the differences in clinicopathological characteristics of esophageal squamous cell carcinoma patients with or without keratin pearls and different types of keratin pearls,mainly including patients gender,diagnosis age,high or low incidence area,the location of the tumor,the length of the tumor,the depth of tumor invasion,whether the tumor has lymph node metastasis or distant metastasis,and explore the relationship between these clinical features and the prognosis of patients with esophageal cancer keratin pearls.②Select 4,974 cases of esophageal squamous cell carcinoma to perform immunohistochemical staining to detect the expression of IVL,and analyze the difference in IVL expression in patients with esophageal squamous cell carcinoma with or without keratin pearls and the differences between different types of keratin pearls and the relationship between prognosis.③R(version 4.0.3)software for statistical analysis was used.The software packages used include but were not limited to basic package,openxlsx package,dplyr package,Matchlt package,ggplot2 package,survminer package,etc.The survival period is in years.The Kaplan-Meier method and log-rank test were used for univariate analysis,and the Cox proportional hazard model was used for multivariate analysis.The test level was α=0.05.3 Results3.1 The effect of keratin pearls on clinicopathological characteristics and survival of patients with esophageal squamous cell carcinomaAmong the 5,219 patients with esophageal squamous cell carcinoma included in this study,2,902 patients didn’t have keratin pearls,accounting for 55.6%,and 2,317 patients had keratin pearls,accounting for 44.4%.The male to female ratio of patients without keratin pearls is 1.75:1,which is equal to the 1.75:1 male to female ratio of patients with keratin pearls.There are statistical differences in the distribution of keratin pearls in family history,degree of invasion,and lymph node metastasis.It is particularly noteworthy that the lymph node metastasis majority for patients without keratin pearls were positive(51.4%).Patients with keratin pearls were mostly negative for lymph node metastasis(60.5%).For the 2,317 esophageal squamous cell carcinoma patients with keratin pearls,910 cases(39.3%)were simple keratin pearls,345 cases(14.9%)with fused keratin pearls,and 1,062 cases(45.8%)with keratotic necrosis.For patients with these three types of keratin pearls,lymph node metastasis is mainly negative,but the proportions are statistically different(simple keratin pearls 63.3%,fused keratin pearls 64.3%,keratotic necrosis 56.8%,χ2=11.26,P=0.0036).The overall survival of patients with keratin pearls esophageal squamous cell carcinoma was better than that of patients without keratin pearls,and the overall survival of patients with simple keratin pearls and fused keratin pearlswas better than keratotic necrosis patients.The age of diagnosis of patients with esophageal squamous cell carcinoma,high or low incidence area,family history of the patient’s tumor,degree of invasion,lymph node metastasis,and the type of keratin pearls were independent factors that affect the survival of the patient.Patients with diagnosis age≥60,patients from high-incidence areas,positive family history of tumor,degree of invasion above T3,positive lymph node metastasis,and keratin pearls classified as keratotic necrosis were independent risk factors for poor survival of esophageal cancer patients.3.2 Expression of IVL protein and production of keratin pearls in esophageal squamous cell carcinoma and its influence on survivalAmong the 4,974 patients with esophageal squamous cell carcinoma who underwent IVL immunohistochemical staining were further included in this study,there were 2,211 patients with keratin pearls,1,851 patients had positive IVL expression,and the positive expression rate of IVL protein was 83.7%;A total of 2,763 patients without keratin pearls with 1,442 cases had positive IVL expression.The positive expression rate of IVL protein was 52.2%.There was a statistically significant difference in the expression rate between the two(P<0.0001).In this study,876 cases of simple keratin pearl,314 cases of fused keratin pearls,and 1,021 cases of keratotic necrosis were included.In the three different types of keratin pearl,the positive rates of IVL protein were 82.1%,88.9%,and 83.5%,respectively.The difference in the positive expression rate of the three typical keratin pearls was statistically significant(P=0.02).For patients with IVL negative or positive esophageal squamous cell carcinoma,the short-term survival of IVL-negative patients was significantly better than that of IVL-positive patients,but the long-term survival was basically equal.The survival of IVL-negative patients with keratin pearls was better than that of IVL-positive without keratin pearls,and this was statistically different(P<0.0001).4 Conclusions①The overall survival of patients with keratin pearls is better than that of non-keratin pearls patients;②Different types of keratin pearls are independent factors affecting the prognosis of patients;③The overall survival of patients with simple keratin pearls and fused keratin pearls is better than that of patients with keratotic necrosis;④The independent risk factors for poor survival prognosis of patients include:age at diagnosis≥60 years,patients from high-incidence areas,positive family history of tumors,degree of invasion above T3,positive lymph node metastasis,and keratin pearls classified as keratotic necrosis.⑤The expression of IVL protein will promote the production of keratin pearls;⑥The expression of IVL protein can promote the production of all different types of keratin pearls;⑦The survival of IVL-negative patients is better than that of IVL-positive patients;⑧The survival of IVL-negative patients with simple keratin pearls is significantly better than that of IVL-positive patients with keratotic necrosis. |
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