| Part1Clinical and Pathological Study of Ductal Carcinoma In Situ of Breast with and without Paget’s DiseaseBackgroundsIn refer to the origin of Paget’s cells of Paget’s disease of breast lying in the epithelial, there are two theories including a.Paget’s cells are derived from the dermis cells (such as suboriferous cell) and b.Paget’s cells derived from the underlying breast cancer, including invasive breast cancer and intraductal carcinoma in situ. Recently, more evidence favor the latter.At present, the diagnosis and treatment of Paget’s disease depend on the pathological classification of underlying breast cancer.And the international guidelines on the treatment of invasive breast cancer tend to be more consistent and mature.But the international opinion on the treatment of breast intraductal carcinoma is controversial which leads the treatment of Paget’s disease accompanied with DCIS are controversial, especially about Herceptin treatment in CerbB2 positive patients.Oncogene CerbB2 over expression in 90-100%　of Paget’s disease. As well as in its underlying DCIS And all its expression are due to CerbB2 gene amplification. And CerbB2 positive breast cancer patient show poorer prognosis who often manifest a negative hormone receptor expression. These patients are not sensitive to postoperative adjuvant therapy including hormone therapy and chemotherapy. In recent years, with the invent of CerbB2 gene targeting therapy drug Herceptin, CerbB2 positive breast cancer patients benefit a lot. but it is mainly used in advanced breast rather than early breast cancer. Studies have demonstrated that Her-2 overexpression of Paget’s disease can induce movement of the cancer cell to epidermal layer which may be via binding to a-regulate protein and mediated or strengthened by waveform protein, and by blocking Her-2 receptor can significantly reduce the induction movement. What’s more, waveform protein in breast cancer has been related with high tumor grade, hormone receptor negative expression and P53 positive expression. All above provided the foundation for clinical application in Paget’s disease.In conclusion, the study the expression of Her-2 and other breast immunohistochemical index in the Paget’s disease associated with DCIS, can deep our understanding of the molecular pathological mechanism, and give us hints in clinical treatment, even provide us with clinical evidence in application of Herceptin in early breast cancer, so eventually benefit more breast cancer patients.ObjectiveTo retrospectively analyze the medical records of Paget’s disease with DCIS in Breast surgery department of Qilu hospital affiliated to Shandong University and study on patient demographic characteristics, clinical pathology characteristic in order to provide clinical evidence for the treatment of Paget’s.Methods277 cases of DCIS were collected between January 1,2010 to December 31, 2014. They were diagnosed and treated at the department of Breast Surgery, Qilu Hospital of Shandong University. A detailed study on patient demographic characteristics, clinical pathology characteristic were made.All the data was managed by Microsoft Office Excel 2013 analyzed by IBM SPSS Statistics 17.Chi-square test and independent t-test are used, And statistically significant is confirmed when P< 0.05.Resultsa. There were 7224 inpatients in breast surgery department from 2010 to 2014, including 4591 breast cancer patients that accounted for 63.55%of inpatients in our department; And 277 intraductal cancer in situ patients that was 6.03%of breast cancer patients.There were 191 solitary DCIS cases and 19 DCIS with Paget’s disease cases (6.859%), 67 other type DCIS.b. There is no significant statistical difference in age, family history, BMI (body mass index) between the two groups, though PDCIS tend to be older than solitary DCIS patients with the average age of 52 and 49 respectively(P= 0.197).However, PDCIS patients readily had a longer in the chief complaint duration, which is 9.8 months in average (P= 0.019) and more common in postmenopausal women (63.15% VS37.57%, (P=0.03)) than solitary DCIS patients.c. PDCIS patients tend to show a higher pathological grade, which is 82.35%VS 53.80%with P is 0.023and more common in postmenopausal women (63.15% VS37.57%, (P=0.03)) than solitary DCIS patients. However, there is no significant statistical difference in lymph node metastasis rate which was 5.26%and 5.32% respectively (P= 1.000).d. The immunohistochemical results analysis shows that lower expression of ER(15.79%VS60.99%, P= 0.000) and PR(10.53%VS52.36%, P= 0.000)), higher Her-2 expression (63.16%VS38.76%,P= 0.040), higher Ki67 expression rate(89.47%VS 52.05%, P = 0.002) were found in PDCIS group than that of solitary DCIS group; However, there is no significant statistical difference in P53 expression (66.67%VS46.61%P = 0.143).e. Correlation in the Her-2 expression and other immunohistochemical markers.In DCIS group, negative expression of ER (37.68%and 37.68%, P= 0.000)and PR(31.88%,69.44%, (P= 0.000), higher Ki67 expression rate(81.54%,33.33%P= 0.000), positive rate of P53(59.09%,38.89%,P= 0.034)were found in Her-2 positive group than that of Her-2 negative group. While in PDCIS group, no significant statistical difference were found.Conclusiona.Breast intraductal carcinoma in situ of the breast cancer show tumor heterogeneity with low incidence which can be solitary DCIS, DCIS with Paget’s disease and with others.The average age of the two group are both above 40 years old, and its had no obvious correlation with obesity and family history.b.PDCIS patients readily had a longer in the chief complaint duration, which is 9.8 months in average and is more common in postmenopausal women.c.PDCIS patients tend to show a higher pathological grade, than solitary DCIS patients. However, there is no significant statistical difference in lymph node metastasis rate.d.The immunohistochemical results analysis shows that lower expression of ER higher Her-2 expression, higher Ki67 expression rate in PDCIS group than that of solitary DCIS group;Part2Clinical study of HPV infection in Paget’s disease of BreastBackgroundResearch conducted in the past more than lOOyears has confirmed that HPV is one of the major carcinogenic agent in cervical cancer. In recent years, studies found that HPV is associated with many kinds of cancer, such as, penile cancer, and vulvar cancer, cancer of lung, head and neck cancer, gastric cancer, esophageal cancer, prostate cancer, colon cancer and skin cancer and so on. Over the past few decades, many studies have found HPV infection in breast cancer, rates of HPV infection is between 0-61%.The type of HPV infection including low-risk type:HPV6, and high-risk type:HPV16,18,31,33,35, etc., some of the studies found that its potential carcinogenesis or effect on tumor progress in breast cancer. Paget’s disease,as a special kind of breast cancer,study on the relationship between HPV infection and its development is rare. In recent years, few research and literature detected HPV L1 protein in the breast cancer and mammary Paget’s disease, HPV as a potential carcinogenic factor,its potential carcinogenesis or effect on tumor progress in, Paget’s disease of the breast cancer remain controversial. Until now, its potential carcinogenesis or effect on tumor progress in mammary Paget’s disease cannot be ruled out.Nipple and cervical are similar referring to histological formation:the surface of the nipple and cervical are squamous epithelium, underlying duct of breast and cervical inner lining cells are glandular epithelium, they are exposed to outside world. Nipples and cervical surface can present erosion changes. And Paget’s disease is the only one kind of breast cancer which possibly is derived from squamous cell cancer, and HPV is a carcinogenic factor that causes variety of squamous cell cancers. It is of value to research the potential carcinogenesis in Paget’s disease of the breast.Koilocytes is characteristic cells indicated HPV infection in cervical tumor and pathological change in cervical infected by HPV, studies have confirmed that Koilocytes is a morphology change caused by E5/E6 protein of HPV DNA inserting with host, Koilocytes founded in cervical tissue cells has been the direct morphological evidence of HPV infection in clinic. Recently JS Lawson also observed Koilocytes-like morphology change in breast cancer tissue samples. If Koilocytes-like cells exist in the Paget’s disease:(a) indicating the interested area may infected by HPV; compared with PCR, gene sequencing and other methods of molecular level, Koilocytes can suggests the presence of HPV infection on cytology level and the accurate infected site (glandular epithelium, squamous epithelium); (b) Koilocytes-like morphology change Caused by HPV can indicate the carcinogenesis of HPV in Paget’s disease more efficiently; (c) it has Confirmed that the HPV virus load in breast tissue is far less than in cervical tissue, therefore looking for Koilocytesi in sample is compensate method for PCR, gene sequencing and other molecular methods.HPV (Human papilloma virus), as a kind of DNA virus, includes more than 100 kinds of types.it can be divided into low-risk type (low risk) and high-risk type (high risk), both of them are related with tumorigenesis.The low risk HPV type (LR-HPV) mainly cause benign diseases, such as warts; And high risk type HPV (HR-HPV) main cause malignant diseases, such as cervical cancer, etc. As mentioned above, because of the limit in detection method of HPV, detection rate is very low. Meanwhile detection methods are largely influenced by experimental environment, the consistency among the research is bad. In recent years, with the development of technology, new technique for detecting HR-HPV HC2 (Hybrid Capture2, the second generation of Hybrid capture technology) have been widely used in clinical, providing a new measuring method for HR-HPV detection with high consistency. This method has been used to detect HR-HPV infection rate in breast cancer, and compared with HPV detection gold standard PCR, its detection rate in the mammary gland is consistent with PCR,To sum up, it is similar with the HPV and cervical cancer, we research the HR-HPV infection and its relationship with the occurrence and development Paget’s disease of breast, so detecting HPV infection rate in Paget’s disease by use of HC2 method in the clinical with Koilocytes in the Paget’s disease. Our research has a lot of theoretical and theory basis. We may confirm that HPV infection in Paget’s disease and its possible carcinogenic effects and mechanisms in breast cancer based on the predecessors’study, to provide the proof for HPV carcinogenic mechanism in breast cancer research, to provide new thought the clinical treatment for Paget’s disease.Objectivea.In order to research the HPV infection rate in the special type breast cancer-Paget’s disease and breast cancer patients from Department of Qilu Hospital using HC2 method. Medical records were retrospectively analyzed,;b.to observe Paget cell in the microscope sample of Paget’s diseaseMethods28 cases of Paget’s disease,124 cases of breast cancer and 22 cases of fibroma were collected between January 1,2010 and April 1,2015. They were diagnosed and treated at the department of Breast Surgery, Qilu Hospital of Shandong University. Since 2012 patients in the group were collected fresh tissue samples for detecting HR-HPV infection by HC2. A detailed study on patient demographic characteristics, clinical pathology characteristic and the correlation with HPV infection were made.All the data was managed by Microsoft Office Excel 2013 analyzed by IBM SPSS Statistics 17.Resultsa.HC2 routine detection demonstrate,1 case (20%) of 5Paget’s disease is HPV positive;b.28 Paget’s patients with an average age of 53.96 years,25 cases underwent modified radical mastectomy,3 patients underwent simple mastectomy.23 patients (82.14%) companied with underlying breast cancer.26 cases (78.8%), mainly present eczema changes in nipple areola area,5 cases simple Paget’s disease,21 cases with intraductal carcinoma,12 cases with invasive ductal carcinoma (7 cases of them with axillary lymph node metastasis);besides,12 cases with breast tumors (64%) patients, no simple mammary Paget’s disease,1 case of intraductal carcinoma,11 cases of invasive ductal carcinoma with axillary lymph node metastasis (7 cases), most of the mammary Paget’s disease associated are companied with intraductal carcinoma or invasive ductal carcinoma, the patients with breast lumps, their diagnosis age tend to be young and history is shorter, they are found to be premenopausal women frequently, and histological types is more malignant (most of them tend to be invasive ductal carcinoma), pathological tumor stage is higher, lymph node metastasis rate is higher, with worse prognosis.Conclusiona. HPV infection is found in the Paget’s disease of breast.b. Most of Paget disease is accompanied by breast cancer,including DCIS or IDC.and the main clinical manifestation is the eczematoid changes of nipple and areola complex and mammary mass.C.Paget disease with mass tend to be younger,with shorter history, and more prevelant in premenopausal patients,with poorer pathological type,higher tumor stage,higher lymphonode positivity. |
