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MINISTRY OF EDUCATION AND TRAINING MINISTRY OF HEALTH HANOI MEDICAL UNIVERSITY PHAM MINH ANH STUDY OF THE APPLICATION OF HISTOPATHOLOGICAL CLASSIFICATION AND THE EXPRESSION OF SOME PROGNOSTIC MOLECULAR MARKERS IN GASTRIC CARCINOMA Specialized Code : Anatomical Pathology and Forensic Medecine : 9720101 SUMMARY OF DOCTORAL THESIS HANOI – 2023 THE SCIENTIFIC WORK WAS COMPLETED AT HANOI MEDICAL UNIVERSITY Scientific instructor: Ass.Prof PhD Le Trung Tho Counter-argument 1: Ass.Prof PhD Nguyễn Phúc Cương Counter-argument 2: PhD Trần Ngọc Dũng Counter-argument 3: Professor Lê Văn Quảng The thesis will be protected before the school-level Doctoral thesis review board held at Hanoi Medical University Organizing time: hours .days Month 2023 The thesis can be found at: - Vietnam National Library - Library of Hanoi Medical University INTRODUCTION Stomach cancer is by far one of the most common cancers and is a major public health problem It is the fifth most common cancer and the third leading cause of cancer death worldwide According to WHO histopathological classification updated in 2019, gastric cancer is divided into many types with their own morphological features due to the diversity of cancer lesions The correct diagnosis of histopathological types is extremely important in determining the appropriate treatment method, as well as accurately assessing the clinical stage as well as the prognosis of the disease Currently, along with molecular targeted therapy is opening a new direction in cancer treatment Detecting the expression of Her-2 gene, a proto-oncogene, is very important in deciding whether or not to use targeted therapy in patients with advanced stages In addition, research on PD-L1 and the mechanism by which tumor cells use to fight the body's immune system has been extensively studied, paving the way for the development of therapeutic therapies immunity The expression of P53 and Ki67 in cancer reflects the malignancy of the disease, and is related not only to the pathogenesis but also to the prognosis of the disease Because of the above reasons, we carry out this study for two purposes: Description of histopathological characteristics of gastric carcinoma types according to the classification of the World Health Organization 2019 Determine the expression rate of some molecular markers with prognostic significance in gastric carcinoma * New contributions of the thesis - The topic has given the histopathological types of gastric adenocarcinoma according to the classification of the World Health Organization in 2019 - Study on gastric carcinoma samples that are partially or completely resected in order to accurately assess histopathological type, histological grade as well as tumor stage - Using immunohistochemistry markers (04 markers) to evaluate the relationship of anatomical characteristics of gastric adenocarcinoma * The practical value of the thesis - The study helps to accurately classify the histopathological type, histological grade as well as the stage of the tumor in order to avoid under- or over-treatment, and improve the survival rate for patients - Correct diagnosis and treatment not only reduce the mortality rate, reduce side effects of chemotherapy, radiotherapy but also contribute to saving costs for the state and the patient's family * Structure of the thesis: Thesis has 104 pages: problem statement pages; 31-page document overview; research objects and methods 13 pages; research results 24 pages; discussion 31 pages; conclusion pages; page recommendation; 34 tables, 05 charts; 15 pictures, 07 page appendices (20 photos) with 134 Vietnamese and English references Chapter 1: OVERVIEW DOCUMENT 1.1 Histological classificaion Histopathological classification of gastric carcinoma (according to WHO 2019) • Adenocarcinoma, NOS o Papillary adenocarcinoma, NOS o Tubular adenocarcinoma o Mucinous adenocarcinoma o Poorly cohesive carcinoma (including ring cell carcinoma and variants) o Mixed carcinoma o Carcinoma with lymphoid stroma o Hepatoid adenocarcinoma o Micropapillary carcinoma, NOS o Carcinoma of the basal gland type o Some other rare subtypes such as mucinous epidermoid carcinoma, Paneth cell carcinoma , and parietal cell carcinoma • Squamous cell carcinoma, NOS • Adenosquamous carcinoma • Carcinoma, undifferentiated, NOS Gastric carcinoma differentiation: According to WHO in 2019 , the level of differentiation only applies to the subtypes of tubular and papillary carcinomas, not to other subtypes - Highly differentiated tumours: > 95% of tumors have an glandular structure - Moderately differentiated tumours: 50-95% of tumors have an glandular structure - Poorly differentiated tumours: 100 but the maximum value reported is 100 Divided into groups:CPS < 1: no PDL1 expression CPS ≥ 1: PDL1 expression For P53: Evaluation of the expression is based on the intensity of staining of the nucleus and the percentage of stained cells per 100 tumor cells Cell expression is stained when the cell nucleus is reddish brown For Ki67: Evaluation of the expression was based on the intensity of the staining of the nucleus and the percentage of stained cells per 100 tumor cells - Dual-ISH test: The test was performed on the BenchMark IHC/ISH staining machine system at the Center for Pathology - Cytology - Bach Mai Hospital Specimens: from gastric adenocarcinoma tissue of patients previously stained with HMMD have positive results (from 2+ to 3+) 2.3 DATA PROCESSING AND ANALYSIS The collected data were processed using the software SPSS 22.0 Compare the proportions using the χ2 test with 95 % confidence and Fisher's test 2.4 RESEARCH ETHICS The research proposal was approved by the PhD thesis grading committee of Hanoi Medical University, the approval for the study by the Department of Pathology - Hanoi Medical University, the approval of the Board of Directors Director and Scientific Council of Hanoi Oncology Hospital All cases are explained in terms of the requirements of the study The patient does not have to pay for this test at all, but has the right to use this test result when needed All patient information is kept confidential Chapter 3: RESEARCH RESULTS 3.1 Anatomical features of gastric adenocarcinoma 3.1.1 General features Table 3.1 Age distribution by sex in cancer patients Male Female Total Gender Year old n % n % n % < 50 years 16 11.3 5.6 24 16.9 old 50-70 years 60 42.3 26 18.3 86 60.6 > 70old years 21 14.8 11 7.7 32 22.5 old Total 97 68.3 45 31.7 142 100.0 Comment: The mean age of disease was 60.99±11.73 years old; the lowest is 28 years old, the highest is 82 years old; The male/female ratio is 2.16/1 3.1.2 Macroscopic features of the tumor 3.1.2.1 Location and size of the tumor 80 60 40 20 75 56 Cadiac Body Pyloric Many location Chart 3.1 Distribution of patients according to tumor location Comments: Tumor was detected most in antrum with 75 cases (52.8%) Cardiac tumors only had 02 cases (1.4%) There were 09 cases of lesions at many locations, accounting for 6.3% 30.3% 69.7% < cm >= cm Chart 3.2 Distribution of patients according to tumor size Comment: the majority had tumor size < 5cm with 99 cases accounted for 69.7%, cases with tumor size of 5cm accounted for 30.3% 3.1.2.2 Macroscopic morphological features of the tumor Table 3.2 Macroscopic morphology of the tumor General form Quantity Ratio % Plane 15 10.6 Sou 28 19.7 Non-infiltrative ulcer 27 19.0 Infiltrative ulcers 45 31.7 Infiltration 27 19.0 Total 142 100.0 Comment: The most common infiltrative ulcerative lesions accounted for 31.7% Followed by morphological nodules, non-infiltrative ulcers, and infiltrates account for similar proportions Flat morphology was the least encountered with 10.6% 3.1.2.3 Histopathological classification and differentiation Table 3.3 Distribution according to histopathological type Characteristic Quantity Ratio % Pipeline 91 64.1 Pinch 17 12.0 Histopathological slimy 18 12.7 classification according to Poor adhesion 11 7.7 WHO Mixture 2.8 parietal cells first 0.7 Total 108 100.0% 12 3.2 CHARACTERISTICS DISCOVER SOME HMMD MARKET OF Stomach Cancer 3.2.1 Expression rate of HMMD markers of gastric adenocarcinoma Table 3.8 Expression rate of HMMD markers of gastric adenocarcinoma Imprints HER2 PD-L1 Ki67 P53 Reveal 1+ 2+ 3+ (-) (+) (-) (+) (-) (+) Quantity 63 46 27 87 55 41 101 75 sixty seven Ratio % 44.4 32.4 4.2 19.0 61.3 38.7 28.9 71.1 52.8 47.2 Comment: Ki67 had the highest expression rate (71.1%), followed by P53 and PDL1, the lowest expression was HER2 (23.2%) In 06 cases of HER2 2+ with HMMD, 04 cases had HER2 mutations and 02 cases were false positive With 3+ positive HMMD staining cases, 100% have HER2 mutations HMMD test cases with HER2 2+ and 3+ were Dual-ISH staining to confirm HER2 overexpression Thus, there were HER2 mutations in this study, we encountered 31 cases, accounting for 21.8% 3.2.2 The relationship between HER2 overexpression and histopathological features 3.2.2.1 The relationship between HER2 overexpression and histopathological type of gastric adenocarcinoma according to WHO 2019 and the degree of differentiation Table 3.9 The relationship between HER2 overexpression and histopathological type of gastric adenocarcinoma according to WHO 2019 and the degree of differentiation Characteristic n Tubular Histopatholog y Papilary HER2 expression rate (-) (+) 68 23 % 74.7 25.3 n 12 % 70.6 29.4 Tota l p 91 100 17 100 0.38 13 Mucinou s Poor adhesion Mix Parietal cells Well Degree of differentiation Med Poorly n 17 % 94.4 5.6% n % 81.8 18.2 n % 100 n % 100.0 0.0 n % n 81.8 51 18.2 14 % 78.5 21.5 n 20 12 % 62.5 37.5 18 100 11 100 100 100 11 100, 65 100 32 100 0.19 Comment: HER2-expressing positive papillary carcinoma accounted for the highest percentage, followed by ductal carcinoma Mixed body and parietal cells had no HER2 mutations 3.2.2.2 Relationship between HER2 overexpression and gastric wall invasion and lymph node metastasis Table 3.10 Relationship between HER2 overexpression and gastric wall invasion and lymph node metastasis HER2 p Characteristic Level of invasion pT1+pT2 pT3+pT4 Lymph node metastasis Total (-) (+) (-) (+) n % n % n % n % 55 84.6 56 72.7 66 83.5 45 71.4 n n 10 15.4 21 27.3 13 16.5 18 28.6 31 0.088 0.083 14 % 21.8 % Comment: Tumors with deep invasion had a higher rate of HER2 overexpression (27.3%) than those with shallow invasion (15.4%) This association was not statistically significant with p=0.088 Tumors with lymph node metastasis had a higher rate of HER2 overexpression than those without lymph node metastasis This association was not statistically significant with p=0.083 3.2.2.5 Association between HER2 overexpression and vascular and neurological infiltrates Table 3.11 Association between HER2 overexpression and vascular and neurological infiltrates HER2 Characteristic (-) Invasion of blood vessels n % n % n % n % n % (+) (-) Nerve invasion (-) 77 78.6 34 77.3 75 77.3% 36 80.0 111 78.2 (+) Total p (+) 21 21.4 ten 22.7 22 22.7% 20.0 thirty first 21.8 0.862 0.719 Comment: The rate of HER2 positive in the group with vascular infiltration was higher than in the group without vascular infiltration Nerve-infiltrating tumors had a higher rate of HER2 overexpression than those with neuroinfiltration 3.2.3 The relationship between PD-L1 expression and histopathological features 3.2.3.1 The relationship between PD-L1 expression and histopathological type of gastric adenocarcinoma according to WHO 2019 and the degree of differentiation Table 3.12: Relationship between PD-L1 expression and histopathological type and differentiation PD-L1 Characteristic Total p (-) Tubular n 51 (+) 40 91 15 100.0 % n 13 17 Papilary 76.5% 23.5% 100.0 % % n 13 18 Mucinou 72.2% 27.8% 100.0 s % % Histopatholog 0.15 n 11 y Poor 54.5% 45.5% 100.0 adhesion % % n 4 Mix 100.0 0.0% 100.0 % % % n first first Parietal 0.0% 100.0 100.0 cells % % % n 11 Well 54.5% 45.5% 100.0 % % n 39 26 65 Degree of 0.94 Med 60.0% 40.0% 100.0 differentiation % % n 19 13 32 Poor 59.4% 40.6% 100.0 % % Comment: Poor adhesion and ductal adenocarcinoma have a high positive rate with 45.5% and 44.0% There was no statistically significant relationship between PD-L1 expression and differentiation 3.2.3.2 Relationship between PD-L1 expression and gastric wall invasion and lymph node metastasis Table 3.13 Relationship between PD-L1 expression and gastric wall invasion and lymph node metastasis % Characteristic 56.0% 44.0% PD-L1 (-) p (+) 16 Level of invasion pT1+pT2 pT3+pT4 Lymph node metastasis Total (-) (+) n % n % n % n % n % forty six 70.8% 41 53.2% 53 67.1% 34 54.0% eighty seven 61.3% 19 29.2% 36 46.8% 26 32.9% 29 46.0% 55 38.7% 0.033 0.111 Comment: Tumors with T3+pT4 invasion had a higher rate of PD-L1 overexpression (46.8%) than tumors with pT1+pT2 invasion (29.2%) This association is statistically significant with p=0.033 The mass with lymph node metastasis had a higher rate of PD-L1 overexpression of 46.0% compared with the block without lymph node metastasis (32.9%) This association was not statistically significant with p=0.111 3.2.3.3 The relationship between PD-L1 expression and vascular invasion and nerve invasion Table 3.14 The relationship between PD-L1 expression and vascular invasion and nerve invasion PD-L1 p Characteristic (-) (+) n 64 34 (-) % 65.3% 34.7% Invasion of 0.140 blood vessels n 23 21 (+) % 52.3% 47.7% (-) n 58 39 % 59.8% 40.2% Nerve 0.597 invasion (+) n 29 16 % 64.4% 35.6% 80 n 55 seven Total % 61.3% 38.7% Comment: Tumors with vascular invasion had a higher rate of PD-L1 expression than those without vascular infiltration This association was not statistically significant with p=0.140 Tumors without nerve infiltration had a higher rate of PD-L1 expression (40.2%) and tumors with nerve infiltration (35.6%) This association was not statistically significant with p= 0.597 17 3.2.4 The relationship between Ki67 and P53 expression with histopathological features 3.2.4.1 Relationship between Ki67 and P53 expression with histopathological type of gastric adenocarcinoma according to WHO 2019 and the degree of differentiation Table 3.15 Relationship between Ki67 and P53 expression with histopathological type of gastric adenocarcinoma according to WHO 2019 and the degree of differentiation Characteristic n Tubular % n Papilary % Mucinou n s % Histopathology n Poor adhesion % n Mix % Parietal n cells % n Well % Degree of n differentia Med % -tion n Poorly % Ki67 Low High 21 70 23.1 76.9 47.1 52.9 ten 44.4 55.6 27.3 72.7 first 25.0 75.0 first 0.0 100.0 36.4 63.6 17 48 26.2 73.8 24 25.0 75.0 p 0.236 0.749 p P53 (-) (+) 45 49.5 52.9 11 61.1 63.6 75.0 0.0 36.4 37 56.9 13 40.6 forty six 50.5 47.1 38.9 36.4 first 25.0 first 100.0 63.6 28 43.1 19 59.4 0.702 0.203 Comment: There was no statistically significant relationship between Ki67 and P53 expression and histopathology and tumor differentiation 3.2.4.2 Relationship between Ki67 and P53 expression with gastric wall invasion and lymph node metastasis Table 3.16 Relationship between Ki67 and P53 expression with gastric wall invasion and lymph node metastasis Characteristic Ki67 Disclosure Rate Low Hig character h p P53 (-) (+) p 18 Level of invasion Lymph node metastasi s pT1+pT pT3+pT Are not Have Total n % n % n % n % n % 26 40.0 15 19.5 30 38.0 11 17.5 41 28.9 39 40 25 60.0 61.5 38.5 0.007 0.056 62 35 42 80.5 45.5 54.5 49 49 30 62.0 62.0 38.0 0.007 0.014 52 26 37 82.5 41.3 58.7 101 75 67 71.1 52.8 47.2 Comment: Gastric cancer has a higher rate of Ki67 expression, which is higher in cases of more invasive tumor lesions and lymph node metastases These differences are statistically significant with p=0.007 Tumors with lymph node metastasis had a higher positive rate of P53 with 58.7%, tumors without lymph node metastasis had a positive rate of P53 of 38.0% The difference between the two groups was statistically significant with p=0.014 3.2.4.5 Relationship between Ki67 and P53 expression with vascular and nerve invasion characteristics Table 3.17 Relationship between Ki67 and P53 expression with vascular and nerve invasion characteristics Characteristic Invasion of blood vessels Nerve invasion Total NO YES NO YES n % n % n % n % n % Ki67 Disclosure Rate Low High 29 69 29.6 70.4 twelfth 32 27.3 72.7 34 63 35.1 64.9 38 15.6 84.4 41 101 28.9 71.1 p 0.778 0.017 P53 (-) 54 55.1 21 47.7 57 58.8 18 40.0 75 52.8 p (+) 44 44.9 23 52, 40 41.2% 27 60.0 67 47.2 0.416 0.037 Comment: The percentage of positive Ki67 and p53 was higher in the group with vascular infiltration as well as in the group with nerve infiltration Statistically significant difference of both markers with nerve penetration characteristics Chapter 4: DISCUSSION 4.1 CHARACTERISTICS OF TREATMENT OF Stomach Cancer 4.1.1 General characteristics of case studies Among 142 cases of gastric carcinoma, the lowest age was 28 years old, the highest was 82 years old, the mean age was 60.99±11.73 years 19 old The disease is most common in the age group of 50-70 years, up to 60.6% The disease is more common in men than women, the male/female ratio is 2.16/1 The average age of men is 61.23 ± 11.13, the age group with the highest incidence is 50 - 70 years old, accounting for 78.4% The average age of women is 60.47 ± 13.06, the age group with the highest incidence is 50 - 70 years old, accounting for 57.8% The results of this study are quite similar to the studies of domestic and foreign authors 4.1.2 Macroscopic features of the tumor 4.1.2.1 Location and size We found that most tumors were detected in the body (52.8%); followed by the position of subjects (39.4%) Other locations are less common This result is also similar to domestic and foreign studies Most of the cases of gastric cancer in our study were detected with the size < 5cm was 69.7%, and the tumor of 5cm was 30.3% This result is similar to the results of other studies Tumor size is an important prognostic factor in malignancies in some organs such as breast and lung There have not been many studies proving that this is an independent prognostic factor of UTI Tumor size is a feature that can be determined quickly and easily during surgery, helping surgeons decide on the area of tumor removal and the stage of lymph nodes to be removed The general trend is that small tumors are detected earlier due to the development of examination methods and medical expertise Later tumor stage also corresponds to larger tumor size 4.1.2.2 General morphology In our study, the most common form of infiltrative ulcer was 31.7% Followed by non-infiltrative and infiltrative forms of warts, ulcers accounted for nearly equal proportions: 19.7%; 19.0%; 19.0%, respectively Flat morphology was encountered less frequently with 10.6% Research results of domestic and foreign authors are quite similar to our study In which, the invasive macroscopic form has the highest rate This is also a form with a poor prognosis, which can affect the treatment strategy of patients, especially those with stage III disease This emphasizes the importance of endoscopic examination and dissection procedure to accurately assess the macroscopic form, in order to improve the quality of diagnosis and treatment of gastric cancer 4.1.2.3 Classification of histopathological type and differentiation 20 In the cases participating in the study (142 people), the most common tubular carcinomas accounted for 64.1%, mucinous and papillary types accounted for 12.7% and 12% The remaining types are less common We encountered case of parietal cell carcinoma In this study, we found that tumors of moderate differentiation were the most common with 65 cases (60.2%) Lesions with low differentiation had 32 cases (29.6%) Highly differentiated lesions were encountered in at least 11 cases (10.2%) From the above results, it can be seen that our study is similar to domestic studies in terms of differentiation In which, the majority of tumors have low and moderate differentiation, and highly differentiated tumors are less common 4.1.2.4 Invasion of gastric wall and lymph node metastasis of tumor Tumors with invasion stage pT4 were the most common at 48.6%, pT3 in our study only encountered 8/142 cases, accounting for 5.6% The proportion of patients without regional lymph node metastasis was 79/142, accounting for 55.6% Among lymph node metastases, the rate of N2 was highest with 23.3%, followed by N1 with 16.9% and N3 with only 4.2% This result has differences with some domestic studies but similar to foreign authors The results of the above studies show that although the ability to detect tumors at an early stage has increased, the number of tumors in the late invasive stage still accounts for the majority Differences between studies may be due to different sampling standards, sample sizes, and sampling locations Regarding the assessment of lymph node metastasis, because the number of lymph nodes obtained depends on the qualifications of the surgeon, the person dissecting the specimen, the assessment of lymph nodes based on only one slice inevitably leads to an incomplete assessment Therefore, the rate of lymph node metastasis across studies varied greatly, from 42.3% to 98.6% 4.1.2.5 Vascular and Nerve Invasion Our study found that advanced tumors with vascular invasion (31.0%) or neuroinfiltration (31.7) Vascular and lymphatic infiltration is recognized as an independent prognostic factor, increasing the risk of lymph node metastasis, distant metastasis and reducing the patient's disease-free survival time In a meta-analysis of 24 studies involving 30590 patients with gastric cancer, nerve infiltration was reported as a predictor of recurrence after resection 21 4.1.3 Relationship between histopathological types of gastric adenocarcinoma according to WHO 2019 with some anatomical characteristics 4.1.3.1 The relationship between histopathological types and the degree of invasion and lymph node metastasis The papillary type has the highest rate of superficial invasion of pT1 + pT2: 58.8% Mucous and mixed types have 50.0% of cases with superficial invasion Poor adhesion type has only 27.3% of superficially invasive cases, most of the cases when the tumor is detected has invaded deeply, this shows that the less adherent type usually has a worse clinical prognosis with recurrence rate and shorter survival time than other types Parietal cell type with 01 case when detecting the tumor has invaded the level of deep invasion However, the association of histopathological type with the degree of invasion was not statistically significant with p = 0.607 The association of histopathological type with lymph node metastasis was also not statistically significant with p = 0.257 4.1.3.2 The relationship between histopathological types and vascular and neurological infiltration In this study, the parietal cell type we encountered was not detected at an early stage, with vascular and neurological infiltration observed on microscopic examination Then there is the poor adhesion type: 45.5% have vascular invasion, 54.5% have nerve infiltration However, the association between histopathological types with vascular and neurological infiltration was not statistically significant with p = 0.445 The association of histopathological type with the degree of invasion was also not statistically significant with p = 0.073 4.2 CHARACTERISTICS DISCOVER SOME HMMD MARKET OF Stomach Cancer 4.2.1 Expression rate of HMMD markers of gastric adenocarcinoma Regarding HER2 overexpression: HER2 has an overexpression rate by HMMD staining of 23.2% HMMD test cases with HER2 2+ and 3+ were Dual-ISH staining to confirm HER2 overexpression Results in 06 cases of HER2 2+ with HMMD have 04 cases with HER2 mutations and 02 cases are false positive With 3+ positive HMMD staining cases, 100% have HER2 mutations Thus, there were HER2 mutations in this study, we encountered 31 cases, accounting for 21.8% This result is similar to the 22 study of Le Viet Nho et al (2011) with 22.5% , 25.7%, Bang, YJ (22.1%) Le Thi Thu Nga et al (2012) studied over 70 cases and showed that the rate of HER2 expression at 0, 1+, +, 3+ was 57.1%, respectively; 17, %, 15.7%, 10% , rate The patient had an overexpression of HER2 protein (HMMD 2+/3+) of 25.7 % 114 The results of a multicenter study (ToGA trial) showed that overexpression of HER2 in gastric cancer varied greatly, from 4.4% to 53.4% Regarding the rate of PD-L1 expression: The results showed that in 142 surgical specimens of gastric cancer, 55 samples were positive for PD-L1, equivalent to 38.7 % There are two problems when evaluating PD-L1 expression: the same antibody is expressed differently in different tumors and different antibodies also give inconsistent results in the same tumor 123 This may be the reason why the rate of PD-L1 expression fluctuates in studies In addition, the study subjects (race, stage, have received chemotherapy or not), the way to evaluate positive cells and cut-off also differ in the studies This shows that, in the world, there is still no consensus on how to evaluate PD-L1 in gastric cancer with different types of anti-PD-L1 antibodies Regarding the Ki67 exposure rate: Performing HMMD staining on 142 cases, the results showed that the high Ki67 rate was more common in 101 cases, accounting for 71.1%, the low Ki67 rate was 41 cases, accounting for 28.9% Strong positivity of Ki67 is a risk factor for high recurrence rate and poor prognosis However, quantification of cell proliferation based on mitotic counts is not an easy task and often results in variable outcomes among pathologists Regarding the rate of P53 expression: The rate of gastric cancer cases positive for P53 in our study is similar to that in the studies of Nguyen Duc Huan and Wu et al., lower than the studies of the author Zolota et al., Tran Ngoc Anh, Sezer and cs and Seo and cs are presented in the table above 4.2.2 The relationship between HER2 overexpression and histopathological features Among 142 patients who studied the relationship between the rate of HER2 expression and histopathology, cases of HER2-positive papillary carcinoma accounted for the highest rate (29.4%) Our study is similar to the study of author Wang et al (2010) when HER2 expression is highest in ductal adenocarcinoma (28.8%) 131 However, the results of our study 23 are completely different from the results of some other authors Author Tateishi found that out of 179 gastric adenocarcinoma patients, 9/23 (39%) patients with papillary carcinoma were HER2 positive; 12/131 (9.2%) patients with ductal adenocarcinoma were HER2 positive; of undifferentiated carcinoma cases only 4% HER2 was positive with p>0.01 132 Tumors with lymph node metastasis had a higher rate of HER2 overexpression of 30.2% This association was not statistically significant with p=0.081 Wang et al (2007) reported that HER2 expression accounts for 32% of gastric adenocarcinomas, proportional to clinical stage, lymph node metastasis and HER2 expression associated with survival time short In this study, we found that tumors with vascular invasion had the highest rate of HER2 overexpression (25.0%) This association was not statistically significant with p=0.739 This result is similar to the study results of Phan Dang Anh Thu et al showed that the rate of HER2 mutation in the vascular invasive group was 17.5% higher than that in the non-vascular group of 15.2% 134 Tumors with nerve invasion had a higher rate of HER2 overexpression (24.4%) than those without neuroinfiltration This association was not statistically significant with p=0.817 4.2.3 The relationship between PD-L1 expression and histopathological features Parietal cell carcinoma was 100% positive for PD-L1 Poor adhesion and ductal adenocarcinoma have a high positive rate with 45.5% and 44.0% Mixed form did not have any positive cases for PD-L1 There was no statistically significant relationship between PD-L1 expression and histopathology (p=0.159) The rate of PD-L1 expression in highly differentiated tumors was the highest: 45.5%, moderate and low differentiated tumors had approximately the same PD-L1 expression rate of 40, respectively 0%; 40.6% There was no statistically significant relationship between PD-L1 expression and differentiation These results vary between researchers According to our study, there was no difference between the state of PD-L1 expression and the invasion status, as well as vascular and lymphatic invasion This result is different with some other authors Results may vary between studies possibly due to differences in sample selection criteria, antibodies, PD-L1 assessment methods, and vascular penetration assessment methods 24 4.2.4 The relationship between Ki67 and P53 expression with histopathological features The high expression rate of Ki67 was found in mixed and parietal cell carcinomas, followed by ductal, mixed and poorly adherent carcinomas There was no statistically significant relationship between high Ki67 expression and histopathology with p = 0.236 Terada's study showed that the positivity rate of Ki-67 in ring cell carcinoma of the stomach was 100% (30/30) According to our study, the difference was not statistically significant between the Ki67 ratio and the degree of differentiation The study by Seo et al (2019) recorded over 251 cases and found that highly differentiated tumors had 95/100 cases, accounting for 95% with Ki67 positive, with poorly differentiated tumors having 125/151 cases cases accounted for 82.8%, the difference between the two groups in the positive Ki67 rate was statistically significant with p = 0.003 The rate of high-level Ki67 expression was higher in cases of more invasive tumor lesions and lymph node metastases These differences are statistically significant with p=0.007 According to our study, there is a statistically significant difference showing that the high expression rate of Ki67 is higher in cases with nerve infiltration P53 expression was higher in the vascular infiltration group than in the non-vascular group, and there was no statistically significant relationship between these two groups The group with nerve infiltration had a statistically significant higher rate of positive P53 than the group without nerve infiltration with p = 0.037 CONCLUDE Through the study of 142 cases of gastric adenocarcinoma according to WHO subtype in 2019 and the expression of Her2, PDL-1, KI67 and P53 immune markers, we draw the following conclusions: Pathological characteristics of gastric adenocarcinoma according to the classification of the World Health Organization 2019 - General: The most common tumor location is in the antrum with 52.8%; followed by the position of subjects with 39.4% The most common infiltrating ulcerative lesion accounted for 31.7% and the tumor size < 5cm accounted for the most with 69.7% - Histopathology: + Tubular type accounted for the highest rate with 64.1%, followed by mucinous and papillary type (12.7% and 12%) Poor adhesion has 7.7%, mixed type is 2.8%, there is case of parietal cell carcinoma, accounting for 0.7% 25 + Most of the tumors were invasive at the late stage, pT4 was the most common (48.6%), the number of cases of lymph node metastasis accounted for only 44.4% No relationship between histopathological type and invasion, lymph node metastasis, vascular and neurological infiltration was found Determine the rate of expression of markers HER2, PD-L1, P53 and Ki67 in gastric adenocarcinoma and compare with some histopathological features - The rate of overexpression of HER2 by HMMD staining was 23.2%, the rate of HER2 amplification by Dual-ISH staining was 21.8% The rate of PDL1 showing positive was over 38.7% with CPS ≥ The rate of low Ki67 expression was 28.9%, high Ki67 was 71.1% P53 positive rate accounted for 47.2% The rate of HER2 positivity was higher in tumors with deep invasion and lymph node metastasis but was not statistically significant, even with vascular and neurological infiltration - The rate of PDL1 expression in macroscopic infiltrates and warts (59.3% and 46.4%); related to histopathological type, PDL-1 was found in 100.0% parietal cell type, poor adhesion was 45.5%, ductal gland was 44.0% but not statistically significant Also, PDL-1 expression was not associated with lymph node metastasis, vascular and neurological infiltration However, the rate of PDL-1 expression was significantly related to the degree of invasion (p = 0.033) - High rate of Ki67 expression is seen in ductal adenocarcinoma, mixed type and poorly adherent; and had a statistically significant relationship with the depth of tumor invasion, vascular and neurological metastasis - The rate of P53 expression was high in pancreatic cancer (50.5%), papillary gland (47.1%), lowest in mixed form (25.0%) This difference is not statistically significant p=0.702 P53 expression was significantly higher in the group with lymph node metastasis and in the group with nerve infiltration PUBLISHED RESEARCH WORKS RELATED TO THE THESIS Pham Minh Anh, Le Trung Tho Study status of the human epidermal growth factor receptor overexpression with histopathology of gastric cancer Vietnam Medical Journal, 2022; 1: 89-94 Pham Minh Anh, Le Trung Tho Relationship between the expressions of PD-L1 and some of pathological characteristics of gastric adenocarcinoma Vietnam Medical Journal, 2022; 2: 147152