| BACKGROUDDuctal carcinoma in situ(DCIS)is a malignant lesion of ductal epithelium,but it has not yet broken through the basement membrane covered by myoepithelial cells Pathologically,it is included in the category of ductal intraepithelial neoplasia(DIN 1C?3).The detection rate of DCIS is increasing year by year.In the United States,DCIS comprises about 20%of breast cancer.About 1/33 of women will be diagnosed as carcinoma in situ in their lifetime,and about 83%of them are DCISDCIS will have different outcomes.Studies based on autopsy data found that some DCIS can be maintained in situ for a lifetime,while others will progress to invasive ductal carcinoma(IDC).This poses a huge challenge to the management of DCIS.Clinicians need to balance the health damage caused by over treatment and the risk of recurrence caused by under treatment.Therefore,identification subpopulation of DCIS with malignant potential is valuable for the management.With the development of gene chip technology,some differential genes between DCIS and IDC have been screened out,which are believed to be helpful to identify the malignant potential of DCIS,but the results are not conclusive at present.The difference of phenotypes between DCIS and IDC is also helpful to find the risk factors predicting infiltration for DCIS.However,there are still some disputes in previous researches.1.The significance of HER2 overexpression in DCIS is still unclear.Some studies believe that the overexpression of HER2 in DCIS indicates that it is more likely to develop into invasive cancer,while others believe that the state of HER2 has little to do with the infiltration.Some studies even suggest that overexpression of HER2 in DCIS is a protective factor for local invasive recurrence.2.Estrogen and progesterone receptor can promote gene transcription,DNA synthesis and proliferation of tumor cells through various ways.However,the role of estrogen and progesterone receptor in the progression of invasion is still uncertain.3.It is believed that the progression of breast cancer follows the process of "DCIS-DCIS with microinvasion(DCIS-Mi)-invasive cancer".In order to study the risk factors of invasion,previous studies focused on the differences between DCIS and the early stage of invasive cancer(including DCIS-Mi).However,there are still differences in the clinicopathological characteristics between microinvasive carcinoma and invasive carcinoma.At present,few researches have explained the significance of these differences in the development of breast cancer and the impact of these differences on predicting the risk factors for invasion.On the other hand,DCIS is also considered to be the precursor of Paget's disease(PD).PD is a rare disease located in the epithelial cells of the nipple,accounting for about 1-3%of breast cancer.Because of its low incidence rate,previous researches are relatively limited.It is believed that the expression rates of estrogen and progesterone receptor in PD are generally lower than that in other types of breast cancer,but there are still controversies.Few studies have evaluated the expression of Ki67 in PD and underlying breast cancer.The clinicopathological differences of breast cancer with or without PD are still unclear,and the significance of these differences in the occurrence and development of PD is still unclear.We intend to take DCIS as a clue to study the differences of clinicopathological and immunohistochemical characteristics in different breast cancer(DCIS,PD,DCIS-Mi,DCIS-IDC),so as to help identify the risk factors of invasion,further understand the mechanism of invasion,and explore the roles of HER2 and hormone receptors in the invasion of DCIS and the histogenesis of PD.Part ? Clinicopathological differences of ductal carcinoma in situ(DCIS),DCIS with microinvasion,and DCIS with invasive ductal carcinoma and the role of HER2,estrogen and progesterone receptors in the invasionPurpose:To investigate the clinicopathological characteristics of DCIS,DCIS with microinvasion(DCIS-Mi)and DCIS with invasive ductal carcinoma(DCIS-IDC),analyze the differences among the three pathological types of breast cancer in terms of clinicopathology,immunohistochemical phenotype and molecular subtype,identify the risk factors of DCIS with microinvasion/infiltration,further understand the development process of DCIS to invasive carcinoma,and explore the roles of HER2 and hormone receptors in this process.Methods:A retrospective study were conducted.DCIS,DCIS-Mi and DCIS-IDC cases were collected from the breast cancer patients who were diagnosed and treated by the department of breast surgery of Qilu Hospital of Shandong University from January 1,2008 to January 1,2018.The clinicopathological data and immunohistochemical results were recorded.The differences of histopathological and immunohistochemical expression were analyzed by Pearson chi square test,Kruskal Wallis test,Mann Whitney U test and McNemar test.Univariate regression analysis and multivariate regression analysis were performed to determine the risk factors of DCIS coexisting with microinvasion or IDC,and the risk factors of DCIS-Mi progression to DCIS-IDC.Results:Totally 810 sides of 801 cases with mammary ductal carcinoma were reviewed,including 453 sides of DCIS,88 sides of DCIS-Mi,and 269 sides of DCIS-IDC.1.Analysis of clinicopathological differences in DCIS,DCIS-Mi,DCIS-IDCCompared with DCIS,DCIS-IDC was more associated with high nuclear grade,large tumor size,high Ki67 index and lymph node metastasis(all p<0.05).The expression of steroid receptor in DCIS-IDC was higher than that in DCIS(p<0.05),the expression of HER2 in DCIS-IDC was lower but not significant(p=0.269).Compared with DCIS,DCIS-Mi was more associated with high nuclear grade,large tumor size,comedo-necrosis,absence of hormone receptor,HER2 overexpression,and high Ki67 index(all p<0.05).Compared with DCIS-IDC,DCIS-Mi was still more associated with high nuclear grade,comedo-necrosis,multifocal lesions(all p<0.05),and had the lowest expression rate of hormone receptor(p=0.000),but the highest expression rate of HER2(p=0.003).According to the immunohistochemical surrogate molecular classification,DCIS and DCIS-IDC are mainly classified as luminal type(luminal A and luminal B,respectively),while DCIS-Mi is mainly classified as HER2 overexpression type.2.Analysis of risk factors of infiltrationIn multivariate regression analysis,high nuclear grade(OR=6.345,p=0.002),multifocal lesion(OR=2.185,p=0.014),ER negativity(OR=3.247,p=0.016),and high expression of Ki67(OR=2.443,p=0.015)were independent risk factors for DCIS coexisting with microinvasion,while the moderate/high nuclear grade(moderate nuclear grade,OR=2.430,p=0.004;high nuclear grade,OR=5.290,p=0.000),HER2 negativity(OR=2.564,p=0.001),Ki67 high expression(OR=3.622,p=0.000)were independent predictors of DCIS coexisting with IDC.Further more,ER positivity was independent predictors of expanded invasion for DCIS-Mi(OR=4.691,p=0.005).When hormone receptors and HER2 are the(independent or non-independent)risk factors for DCIS to develop into microinvasion or IDC,they have the opposite predictive value:hormone receptors negativity and HER2 positivity are the risk factors for DCIS to develop into microinvasion,while hormone receptors positivity and HER2 negativity are the risk factors for DCIS to develop into IDC.Conclusion:1.DCIS-Mi is more likely to be negative in estrogen and progesterone receptor and overexpressed in HER2,while DCIS-IDC is more likely to be positive in estrogen and progesterone receptor and negative in HER22.DCIS with high histological grade,multifocal/multicentric growth,ER negativity and high expression of Ki67 is more likely to be associated with microinvasion.3.DCIS-Mi with ER positive is more likely to progress to DCIS-IDC.4.Different expression of hormone receptors and HER2,as well as different risk factors for invasion suggest that DCIS-Mi and DCIS-IDC may originate from different DCIS clones.Part ? Clinicopathological features of Paget's disease and the significance of HER2 in the histogenesis of Paget's diseasePurpose:To understand the clinicopathological and immunohistochemical features of Paget's disease(PD)and underlying breast cancer;to identify the clinicopathological differences of breast cancer with or without PD through the comparative study;to verify the histogenesis of this disease and to explore the role of immunohistochemical indicators in PD.Methods:A retrospective study were conducted.PD cases were collected from the breast cancer patients who were diagnosed and treated by the department of breast surgery of Qilu Hospital of Shandong University from January 1,2008 to January 1,2018.These patients had PD with various stages of breast carcinoma,from ductal carcinoma in situ(DCIS)to infiltrating ductal carcinoma(IDC).Immunohistochemical data were recorded for the PD(dermatological),intraductal and invasive components.McNemar test or Cochran's Q test were performed to evaluate the consistency of immunohistochemistry indexes among the different components.Breast cancer with corresponding histological subtypes without PD were collected for comparison,Chi square test or Fisher exact probability method were used to evaluate the differences between groups.Results:We retrospectively reviewed 36 patients with PD.96.7%of HER2,3.3%of ER,and 16.7%of PR were positive in PD,and HER2 overexpression type is the main molecular type.91.7%(33/36)PD coexist with DCIS,while 44.4%(16/36)PD coexist with invasive/microinvasive ductal carcinoma.The histological grade of PD concomitant breast cancer was middle or high grade(18.8%in middle grade and 81.2%in high grade).There was a good consistency of the immunohistochemical indexes between PD and underlying breast cancer.Compared with breast cancer without PD(except DCIS-Mi group),breast cancer with PD was more likely to be hormone receptor negative and HER2 positive(p=0.000),and its main molecular type was HER2 overexpression type(p=0.000).Whether there was PD or not had no significant effect on the histopathological characteristics and immunohistochemical expression of DCIS-Mi(p>0.05).In addition,DCIS with PD had higher tissue grade(p=0.017)and higher expression level of Ki67(p=0.006).Conclusion:1.High-grade intraductal carcinoma with/without IDC is the most common histological subtype of PD2.Unusually high rates of negative estrogen and progestogen receptor expression and HER2 overexpression are typical features of PD and underlying ductal carcinoma3.DCIS with concomitant PD shows more aggressive characteristics than DCIS alone.4.HER2 overexpression may play an important role in the histogenesis of PD. |
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