Human epidermal growth factor receptor 2 (HER2) protein overexpression and/or HER2 gene amplification is found in about 20% of invasive breast cancers. It is a sole predictive marker for treatment benefits from HER2 targeted therapy and thus, HER2 testing is a routine practice for newly diagnosed breast cancer in pathology. Currently, HER2 immunohistochemistry (IHC) is used for a screening test, and in situ hybridization is used as a confirmation test for HER2 IHC equivocal cases. Since the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines on HER2 testing was first released in 2007, it has been updated to provide clear instructions for HER2 testing and accurate determination of HER2 status in breast cancer. During HER2 interpretation, some pitfalls such as intratumoral HER2 heterogeneity and increase in chromosome enumeration probe 17 signals may lead to inaccurate assessment of HER2 status. Moreover, HER2 status can be altered after neoadjuvant chemotherapy or during metastatic progression, due to biologic or methodologic issues. This review addresses recent updates of ASCO/CAP guidelines and factors complicating in the interpretation of HER2 status in breast cancers.
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BACKGROUND Squamous cell carcinoma of the breast is very rare and it is considered to arise from metaplastic change of ductal carcinoma. Metaplastic squamous cell carcinoma (MSC) of the breast includes pure squamous cell carcinoma, metaplastic adenosquamous carcinoma and low grade adenosquamous carcinoma. Most of the cases of MSC of the breast were reported to have lymph node metastasis and this has a worse prognosis than that of conventional invasive ductal carcinoma. METHODS We collected 17 cases of MSC of the breast from 1,173 cases of breast cancer and analyzed the clinicopathological characteristics. RESULTS The age range was 31 to 69 years (mean age: 47.2).
The mean tumor size was 3.6 cm. Twelve cases (70.6%) had a negative nodal status. The majority of the cases were of a high nuclear grade (grade III: 76.5%), and a high histologic grade (grade III: 88.2%). All the cases had no amplification of HER2, and they were negative for hormonal receptors, except for 2 cases with weak positivity. All the cases showed positivity for EGFR (3+: 14 cases, 1+: 3 cases).
Clinical relapse was found in 3 patients on follow up and two of them expired due to lung and bone metastasis. CONCLUSIONS MSC is associated with high nuclear and histologic grades, a high EGFR expression and they are triple negative for ER, PR, and HER2. The EGFR immunopositivity of MSC suggests a basal-like subtype.
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Eccrine ductal and acrosyringeal metaplasia in breast carcinomas: report of eight cases Tibor Tot Virchows Archiv.2019; 474(3): 383. CrossRef
Significance of Foxp3 Positive Regulatory T Cell and Tumor Infiltrating T Lymphocyte in Triple Negative Breast Cancer Hanna Kang, Harin Cheong, Min Sun Cho, Heasoo Koo, Woon Sup Han, Kyung Eun Lee, Byung In Moon, Sun Hee Sung The Korean Journal of Pathology.2011; 45(1): 53. CrossRef
Recently, p53, c-erbB-2 and nm23 proteins have been studied in breast cancer. The expression of p53 protein indicates the mutation of p53 gene known as a tumor supressor gene, and c-erbB-2 gene amplification has been considered an indicator of poor prognosis and nm23 a metastsis suppressor gene. In order to elucidate the roles and relations of these proteins in the develpoment, progression and metastasis in breast cancer, we studied 89 cases of invasive breast cancer and 32 cases of lymph node metastasis for the expression of p53, c-erbB-2 and nm23 proteins using an immunohistochemical method. The results were as follows: 1) The expression rates of p53, c-erbB-2, and nm23 proteins in breast cancer were 40.4%, 34.8% and 55.1%, respectively. Co-expression of p53 protein and c-erbB-2 protein was found in 20.2% of cases, showing the highest incidence in poorly differentiated type (40%). 2) p53 protein expression was increased in poorly differentiated type but was not statistically significant.
On the other hand, the expression of nm23 protein was decreased in poorly differentiated type, which was statistically significant (p<0.05). 3) The correlation of p53 protein expression with c-erbB-2 protein expression was statistically significant (p<0.05) but that with nm23 protein was not. 4) In the cases with lymph node metastasis, discordant expression of p53, c-erbB-2 and nm23 proteins between primary tumor and the lymph node metastatic tumor was found in 9.4%, 3.1% and 18.8% of cases, respectively.
The above results suggest that overexpression of p53 and c-erbB-2 proteins and downregulation of nm23 protein are associated with the tumor progression in the breast cancer.
BACKGROUND PTEN is a novel tumor suppressor gene located at chromosome 10q23.3. Loss of PTEN function has been implicated in the progression of several types of cancer.
Angiogenesis is a critical factor in tumor growth and metastasis. We investigated PTEN expression in invasive breast cancers and described its role in the regulation of angiogenesis related to vascular endothelial growth factor (VEGF). METHODS Forty-five, surgically resected, formalin-fixed and paraffin embedded breast cancer tissue samples were analyzed for PTEN and VEGF expressions by immunohistochemistry and for microvessel density (MVD) by CD34 immunostaining. RESULTS Loss of PTEN expression was found in 35.6% (16/45) of the breast cancer tissues, all of which showed positive VEGF expression. Among 29 cases with normal PTEN expression, 15 (51.7%) were VEGF positive. MVD was significantly higher in tumors with a loss of PTEN expression than in those with normal PTEN expression. CONCLUSION A loss of PTEN expression might increase the VEGF-related angiogenesis in breast cancer. There was no correlation between PTEN expression and clinicopathologic parameters. Detection of the loss of PTEN expression may serve as a useful biologic marker for progression in invasive breast cancer.
BACKGROUND Oncogene expression in Paget's disease of the breast is not well known. To characterize invasive ductal carcinoma associated with Paget's disease, we studied expression of anaphase promoting complex (APC) with its regulatory proteins. METHODS Immunohistochemical stainings were done with 10 cases of invasive ductal carcinoma associated with Paget's disease for APC, pituitary tumor transforming gene (PTTG), cyclin B1, p53, cyclin D1, and c-erbB-2. The expressions of these markers in Paget's disease were compared with those in the associated with carcinoma. RESULTS APC, PTTG, cyclin B1, and c-erbB-2 were positive in all of the cases with both Paget's disease and underlying carcinoma. p53 was expressed in Paget's disease of 6 cases (60%) and in carcinoma of 7 cases (70%). Cyclin D1 was positive in Paget's disease of 8 cases (80%) and in carcinoma of 9 cases (90%). CONCLUSIONS Breast carcinomas with Paget's disease seem to be distinguished by the high expression of APC, cyclin B1, PTTG, c-erbB2, and cyclin D1 in contrast to breast cancers without Paget's disease. Furthermore, the similar expression patterns of APC and APC regulatory proteins in both Paget's disease and underlying breast cancer support the epidermotropic theory as its pathogenetic mechanism.
BACKGROUND It is known that cathepsin D expression in host stromal cells is associated with a more aggressive tumor behavior in breast cancers. METHODS Cathepsin D expression was examined in 222 cases of invasive ductal carcinoma (CA) and 25 cases of ductal carcinoma in situ (DCIS) by the immunohistochemical staining. Cathepsin D expression was evaluated according to the expression site, either in the tumor cells (CD-T) or in the stromal cells (CD-S), and graded according to the immunopositivity. The differences of CD-T and CD-S in each case were evaluated according to the pathologic parameters and estrogen receptor (ER)/progesterone receptor (PR) status. RESULTS The rate of CD-S was significantly higher in the CA than in the DCIS (p<0.0001). In the CA, the rate of CD-S was higher than that of CD-T, while in the DCIS, the rate of CD-T was higher than that of CD-S. In the CA, the rate of CD-S and the tumor grade showed a positive relationship (p=0.0281). There were positive correlations between the ER positivity and CD-S (p=0.0236), and between the PR positivity and CD-T (p=0.0246). For the DCIS, no significant relationships were noted between the pathologic parameters including ER/PR status and CD-T/CD-S. CONCLUSION Cathepsin D expression in the stromal cells seems to be related to the invasiveness and aggressive biological behavior in breast cancers. In addition, there might be some relationship betweeen the ER positivity and CD-S, and between the PR positivity and CD-T.
BACKGROUND Tyrosine kinase receptor (TKR) is an important protein for normal-development, growth and tumorigenesis in human tissues. The purpose of this study was to evaluate the effect of TKR in the progression of breast cancer. METHODS The expressions of EphA2, c-met and c-erbB-2 were examined, by using immunohistochemical methods and RT-PCR, in samples of breast tissue that included 111 samples of normal epithelium, 34 samples of ductal carcinoma in situ (DCIS), and 109 samples of invasive ductal carcinomas (IDC).
The results were compared with the prognostic parameters of breast cancer including the tumor grade, growth pattern, lymph node metastasis and the expressions of ER, PR, p53 and Ki-67. RESULTS The protein expressions of the three TKRs were higher in DCIS and IDC than in normal epithelium. The protein expression of EphA2 was correlated with a tumor grade, a labeling index of Ki-67, and the protein expression of c-met. Overexpression of c-erbB-2 was correlated with lymph node metastasis. The mRNA levels of the three TKRs were correlated with each other in normal tissue and IDC.
The level of c-met mRNA was higher in the low grade tumors. CONCLUSIONS The three TKRs may play roles in the tumorigenesis of human breast cancer. The overexpressions of EphA2 and c-erbB-2 may be a poor prognostic parameter in breast cancers.
This study was conducted to assess the prognostic value of tumor angiogenesis and Cathepsin-D in breast carcinoma, by correlating them with other clinicopathologic prognostic factors. In order to estimate microvessels within the tumor, an immunohistochemical method using monoclonal antibodies for factor VIII-related antigens (DAKO-vWf, F8/86) was used, and they were counted (perx200 field) in the most active areas of neovascularization. For the expression of Cathepsin-D, an immunohistochemical method using monoclonal antibodies (Novocastra, NCL-CDm) was performed. The microvessel count ranged from 8 to 346 per x200 field and the mean (+/-SD) was 72.46+/-54.96. The microvessel count was correlated with the estrogen receptor status, and it was also correlated with the tumor size when it was graded into four groups (1-33, 34-67, 68-100, >100), but was not correlated with other clinicopathologic parameters.
Cathepsin-D was expressed in 40% (46/115) of the cases, but it was statistically correlated with the tumor size only. In conclusion, the expression of Cathepsin D and the degree of angiogenesis in breast cancer showed a correlation with the tumor size only. Therefore, they do not appear to be good prognostic parameters, according to the present study.
BACKGROUND The proto-oncogene c-kit encodes a transmembrane tyrosine kinase growth factor receptor.
Studies have shown that c-kit is highly expressed in normal breast epithelium, but expression is decreased in primary breast cancer. Cyclooxygenase-2 (COX-2) is an inducible enzyme that converts arachidonic acid to prostaglandins.
Expression of COX-2 has been reported in malignant tumors including breast cancer. We evaluated the expression of c-kit and COX-2 in benign and malignant lesions of the breast to assess the roles of these proteins in cancer initiation and progression. METHODS We characterized 20 benign lesions, 20 intraductal carcinomas and 70 invasive breast carcinomas.
Immunohistochemical staining for c-kit and COX-2 was performed. RESULTS Expression of c-kit was detected in 75% of the benign breast lesions, 40% of the intraductal carcinomas and 10% of the invasive carcinomas. COX-2 expression was observed in 80% of the benign lesions, 70% of the intraductal carcinomas and 52% of the invasive carcinomas.
Expression of c-kit was significantly correlated with tumor size (p=0.02). COX-2 expression was significantly correlated with negative expression of estrogen receptor and progesterone receptor (p=0.02, p=0.04), Her-2/neu expression (p=0.008) and the high proliferation index (p=0.0002). CONCLUSIONS Our results suggest that c-kit and COX-2 might be involved in malignant transformation of the mammary epithelium and tumor progression. It is suggested that c-kit and COX-2 can be used as predictive markers and therapeutic targets.
BACKGROUND S Phase Kinase Associated Protein 2 (Skp2), an F-box protein necessary for DNA replication, has recently been demonstrated to be an oncogene. The purpose of this study was to examine the Skp2 expression and to investigate its association with expressions of estrogen receptor (ER), androgen receptor (AR) and HER-2, as well as clinicopathological variables including tumor recurrence. METHODS The expressions of Skp2, ER and AR were examined by immunohistochemistry and HER-2 amplification by chromogenic in situ hybridization (CISH) in 117 cases of breast carcinoma. RESULTS Skp2 was expressed in 26 patients (22.2%) and was significantly correlated with tumor type (p=0.031), tumor grade (p=0.017) and ER expression (p=0.038). Twenty four (20.5%) of 117 patients had a tumor recurrence, and 6 patients (5.1%) died of multifocal metastases. Tumor recurrence was significantly correlated with histological grade (p=0.041) and lymph node status (p<0.001). CONCLUSIONS Although Skp2 expression was statistically insignificant in association with tumor recurrence, it might be useful as a biologic predictor in breast cancer. The simple and reliable immunohistochemical assay presented in this study can be a routine part of breast cancer evaluation and may influence patient management.
Transformation and progression of breast cancer are thought to be caused by an accumulation of complex genetic alterations, but little is known about specific changes.
In this study, the author has undertaken a genome-wide screening to detect genetic changes in 20 cases of breast cancer among Koreans, including 16 infiltrating ductal carcinomas, 2 medullary carcinomas, 1 invasive lobular carcinoma, and 1 borderline phyllodes tumor. Comparative genomic hybridization (CGH) was used to screen for DNA sequence gains and losses across all human chromosomes.
Simultaneous immunohistochemical staining for c-erbB-2 (Her-2/neu), c-myc, cyclin D1, and p53 protein was done to make comparisons with nuclear grade and that with CGH results.
Biotin-labeled tumor DNA and digoxigenin-labeled normal DNA were hybridized to normal metaphase cells. The fluorescence signals were captured by fluorescence microscope after detection by avidin-FITC and anti-digoxigenin rhodamine. Then, the ratio of fluorescence was calculated by an image analyzer.
The immunohistochemical staining was done in paraffin-embedded tissue with an LSAB kit and avidin-biotin complex (ABC) method. The CGH results showed gains on chromosomes 8q (40%), 1q (30%), 17q (15%), 20q (15%), 18q (15%), 5p (15%), and 13q (15%). Deletions were on chromosomes 17p (45%) and 22q (20%). High-level amplifications (green/red ratio >1.5) were noted on chromosomes 1p31, 1q, 3q25-qter, 5p, 7q31-qter, 8q, 9p22-qter, 10p, 11p, 11q22-qter, 12p, 12q24, 14q21-qter, 15q23-qter, 17q, 18p, 18q12-qter, 20p, and 20q. By comparison with infiltrating ductal carcinoma, the two medullary carcinomas showed high-level amplification on chromosomes 1p31, 1q, 8q, 10p, 11p and 12p. c-erbB-2, c-myc, cyclin D1, and p53 protein expression was immunohistochemically detected in 9 of 20 (45%), 8 of 20 (40%), 10 of 20 (50%), and 13 of 20 (65%), respectively. The results indicate that the amplification on chromosome 8q, 1q and the deletions on chromosomes 17p and 22q are the most frequent genetic alterations in breast cancers among Koreans. The results reveal a different pattern of genetic alteration from previous studies. The CGH results were not correlated with the immunohistochemical profiles. The amplification pattern of medullary carcinomas was quite different from the pattern of infiltrating ductal carcinomas. The CGH was thought to be very useful in the screening of genetic alterations of solid tumors.
Antiestrogen tamoxifen (TMX) is thought to elicit its therapeutic effect by competing with endogenous estrogens for the estrogen receptor. Several more recent studies asserted that the antitumor effect of TMX is not due solely to the inhibition of estrogen receptor-mediated action, but due partly to its capacity to inhibit angiogenesis and impair neovascularization. Despite extensive research and clinical experience with this drug, its exact mode of action in inducing tumor regression is still not clear. The present study is aimed toward the investigation of the effects of TMX on dimethylbenzanthracene- induced rat mammary carcinomas with respect to the tumor response to the drugs, histological changes, cell proliferative acitivity and angiogenesis inhibition, and if TMX has antiangiogenic action, to compare it with that of pentosan polysulfate (PPS), an already known antiangiogenic substance. Female Sprague-Dawley rats, aged 50 days, were divided into normal control, test control (tumor induction by dimethylbenzanthracene), TMX (TMX administration after tumor induction), and PPS (PPS administration after tumor induction) groups. Tumor response to the drug administration was classified according to changes of tumor volume as follows; complete response (CR), partial response (PR), no response (NR), and progressive disease (PD). The response rate of rat mammary carcinomas to the drug administration was significantly higher (p<0.05) in the TMX and PPS groups as compared with the test control group. There was, however, no statistical significance between the TMX and PPS groups.
Necrosis was considerably frequent in tumors of the TMX and PPS groups. Hyaline change of the stroma was strikingly more common and marked in the TMX group and it was associated with atrophy of epithelial cells of the tumor glands.
Proliferating cell nuclear antigen (PCNA)- labeling index of the tumors was significantly higher (p<0.05) in the tumors with NR and PD of the TMX group when compared with those with PR of the same group, which suggested a higher cell proliferative activity in these response groups. In the PPS group, however, there was no significant difference in PCNA index according to response. Microvessel density of the tumors was significantly lower (p<0.05) in the PPS group as compared with the test control and TMX groups and it was not related with response. The TMX group, however, did not show any significant difference in microvessel density when compared with the test control group. Microvessel density was significantly higher (p<0.05) in tumors with PD than those with PR in all 3 groups, which suggested a positive relation of increase in tumor size and angiogenesis. Based on these results it is thought that TMX and PPS inhibit growth of chemically-induced rat mammary carcinomas. It seems that the antitumor action of PPS is related with its antiangiogenic capability, but that of TMX does not have a relationship with angiogenenesis inhibition.
This study was performed on 50 cases of primary breast cancer removed surgically during the period 1990~1991 and compared the results of four morphologic methods developed for the detection of estrogen receptors, progesterone receptors, monoclonal antibody PCNA immunoreactivity, and the mean number of argyrophilic nucleolar organizer regions(mAgNORs) to ascertain the prognostic significance and also to detect highly malignant heterogenous cancer. To determine the validity of these measurements, a variance analysis was done with Kruskal-Wallis 1-way ANOVA. The results showed that the significant correlation between histologic grade and ER/PR status(P=0.005/P=0.015), the borderline significant correlation between mAgNORs and ER/PR status(P=0.08), and between AgNORs and stage(P=0.07), PCNA has no correlation with ER/PR status(P=0.25), clinical stage and histologic grade. In follow up, four cases of invasive ductal carcinoma with ER/PR, developed early and rapid metastasis within 2 years, three of them were classified as histologic grade 3 and another case was grade 2, whereas two of them were classified ans stage III(+) and the rest were in stage IIB(+) and stage IIA(-). The mAgNOR count of these four cases were ranged from 3.32 to 4.29 which were in the aneuploid category most likely. One of them had rather stormy rapid course with multiple organ metastases resulting death within one year. These results indicated that ductal carcinoma(>2cm size) with ER-/PR- and high mAgNOR level or high PCNA grade, and hihg histologic grade had h highly malignant course, marked by rapidly developing metastases.
Thus we concluded that the status of ER/PR alone in tumor tissue is an important information for selecting hormone treatment btu, for the ultimate prognosis, is a weak indicator. Therefore for early detection of such heterogenous tumor, besides ER/PR, AgNORs or PCNA, histologic grade and tumor size are very useful as biological indicators of prognosis. The status ER/PR in combination with these indicators are more accurate and provide better basis on which to base a decision for early implementation of chemotherapy from which to give probably benefit by inhibition of rapid progress.
Estrogen receptor(ER) is a soluble form of hormone receptor protein which is located in the nucleus and cytoplasm of a cell is found in 60% of cases of the cells of breast carcinoma. Fifty to sixty percent of ER positive breast carcinoma responds to antihormone therapy wheres the response rate is only 5% in ER negative tumors. Currently, the ER assay has become a standard index in the management and prediction of the prognosis of advanced breast carcinoma. Semiquantitative biochemical assay, dextran-coated charcol(DCC) assay, to measure ER from fresh tissue was first developed by Korenman in 1970 using isotope-labled ertradiol, has been widely utilized. In 1978, Kurzon newly developed immunocytochemical assay(ICA) employing monoclonal antibody against those hormone receptors to detect intracellular localization of ER and progesterone receptor (PR). The results of the assay have been reported by many investigators thereafter. The purpose of this study was to evaluate the hormonal receptors with a monoclonal antibody using an immunoperoxidase procedure to detect both estrogen and progesterone receptors (ER-immunocytochemical assay:ER-ICA and PR-immunocytochemical assay:PR-ICA) in 59 cases of paraffin embedded sections from formalin-fixed and routinely processed breast carcinoma tissue. Concomitantly, fine-needle aspiration biopsy cytology of the breast cancer from 29 women were assayed for ER/PR receptors. Results were compared with quantitative biochemical values determined from dextran-coated charcoal(DCC) assay on the fresh tumor tissue obtained subsequently from the surgery. ER-ICA showed positive result in 22 out of 36 DCC-positive cases(sensitivity, 61.1%) and negative in 23 out of 23 DCC-negative cases (specificity, 100.0%). PR-ICA was positive in 33 out of 35 DCC-positive cases(sensitivity, 94.3%) and negative in 16 out of 24 DCC-negative cases(specificity, 66.7%). The value of ER-ICA or PR-ICA positivity were roughly correlated with the concentration of ER/PR receptors analyzed by DCC method. The results of both methods were correlated with the nuclear grade of the tumor(ICA:p=0.002, DCC: p=0.015) but were not correlated with histologic grade(ICA: p=0.323, DCC: p=0.0164). ER-ICA positivity was correlated with lower incidence of axillary node metastasis (p=0.021) but no significant correlation between PR-ICA positivity and node metastasis(p=0.171). Both ER/PR-ICA positivity were not correlated with age(p=0.924) and tumor size(p=0.663). The score of ICA particularly ER was proportional to DCC level(ER: r=0.5, p=0.000, PR: r=0.2, p=0.000). ICA concordance with DCC of ER and PR were 76.3% and 83.1%, respectively. The concordance of PR-ICA and DCC was proportional but was statistically less significant. In aspiration biopsy cytology the concordance of ER/PR-ICA and DCC were 72.4% and 65.5%, respectively. Immunocytochemical staining to identify ER/PR receptors from the tissue of breast carcinoma would be tested as a mean to substitute for the conventional DCC method.
c-erbB-2 oncogene is a normal cellular proto-oncogene coding transmembrane glycoprotein structurally similar to the epidermal growth factor receptor. Amplification of this oncogene in a variety of human adenocarcinomas has been reported and is particularly well documented in breast carcinoma. It has been suggested that amplification of this oncogene is indicative of poor prognosis and is valuable only second to the lymph node status. Using immunohistochemical staining for the c-erbB-2 protein, overexpression of this protein was analysed in 228 primary breast cancer specimens and the frequency of overexpression and the relationship between overexpression and the other established prognostic variables are evaluated. Ninty three cases out of 228 cases(40.8%) show postive oncoprotein overexpression and using the chi-squared test for a trend, a significant correlation was found between c-erbB-2 protein staining and the histological grade, lymph node status, and estrogen receptor status(P<0.05). No significant association was found between staining and the patient's age and tumor size. Most of the tumors with histological types known to have good prognosis showed negative expression. Above findings strongly suggest that expression of c-erbB-2 oncogene is another independent indicator of poor prognosis in breast carcinoma.
Following results were obtained from the light microscopic and stereomicroscopic observations of the breasts of rats treated with 9, 10-Dimethyl-1,2-Benzanthracene(DMBA). 1) Adenocarcinomas developed in 17 rats (24%) among 70 DMBA-treated rats. 2) Terminal and buds (TEB) were observed longer in DMBA-treated rats than in control group, but they finally disppeared 4 monthes after treatment. 3) Many hyperplastic alveolar nodules (HAN) developed in DMBA-treated rats. 4) There were no transitional lesions between TEB and adenocarcinoma or HAN and adenocarcinoma. 5) The number of lobules was decreased in DMBA-treated rats. On the other hand, terminal ducts were increased in number.
These findings suggest that DMBA stimulate the regression of lobules and induce to form terminal ducts from which adenocarcinomas and HAN develop independently.
BACKGROUND The E2F family (E2F1 to E2F6) of transcription factors plays a key role in cell cycle progression. Some act as oncogenes and others act as tumor suppressor genes (TSG) in a tissue-specific manner. E2F4 may function as a TSG.
However, the role of E2F4 in breast carcinogenesis remains controversial. Also the clinical impact of E2F2 expression on breast cancer remains unknown. METHODS Expressions of E2F4 and E2F2 were assessed immunohistochemically in 113 breast carcinomas and were compared with clinicopathological variables, expressions of G1/S checkpoint proteins (p16, cyclin D1 and Rb), and DNA ploidy to identify their possible role and to assess their prognostic value in breast cancer. RESULTS Expressions of E2F4 and E2F2 were detected in 48 cases (42.5%) and 66 cases (58.4%), respectively.
Expressions of E2F4 and E2F2 were significantly correlated with large tumor size (p<0.001) and lymph node metastasis (p<0.001). There was no correlation between expressions of E2F4 or E2F2 and any other variables, including age, histologic grade, DNA ploidy and expressions of p16, cyclin D1 and Rb. CONCLUSIONS These results suggest that expressions of E2F4 and E2F2 are associated with growth and spread of breast cancer and indicate poor prognosis.
We report a case of secretory carcinoma with axillary lymph node metastasis in a 21-year old woman. She was aware of a mass in her breast for 10 years and noticed a rapid growth of the preexisting mass during the last years.
Histologically, the tumor was composed of micropapillary and microcystic or cribriform glandular structures which contained eosinophilic, mucinous, intraluminal secretions.
The center had a dense hyalinized strama with a solid infiltrative growth of tumor cells with intracytoplasmic secretory vacuoles at the periphery. In addition, marked intraductal papillary epithelial proliferations were present at the superficial portions of the tumor near the nipple.
Prognostic factors and their relationship to juvenile papillomatosis are discussed with a review of the literature.
In this study of 64 cases of breast cancer with a clinical follow-up period of more than 5 years, several prognostic factors were evaluated. The purpose of this study was to determine whether any one parameter or group of parameters serves as adequate predictors of tumor behavior and patient's prognosis.
Several prognostic factors included clinicopathological variables (patient's age, histologic grade, status of lymph node (LN) metastasis, and tumor size), expression of estrogen receptor (ER), progesterone receptor (PR), p53, bcl-2 and CD44 by immunohistochemistry, and DNA ploidy pattern. The results showed that the expression of ER and PR had a significant inverse correlation with the histologic grade (ER, p=0.05; PR, p<0.05). The expression of p53 protein showed a significant relationship with high histologic grade of tumor (p<0.05). The expression of bcl-2 protein was preferably seen in low histologic grade of tumor (p<0.05) and significantly associated with ER positive or PR positive tumors (ER, p<0.05; PR, p<0.05). This results suggest that bcl-2 protein might play significant roles in ER and PR. The CD44 expression showed a significant relationship with tumor size (p<0.05). The large size and aneuploidy pattern of tumor had a tendency to be associated with shorter patient survival. Cox's multivariate analysis showed that overall survival was affected by LN metastasis because of the shorter survival in patients with LN metastasis. In conclusion, tumor size, DNA ploidy pattern, and LN metastasis were themselves significant predictors of breast cancer survival rate.
To evaluate correlation between the expression of neu and ras oncoprotein and epidermal growth factor receptor on breast carcinoma and other known prognostic factors, immunohisto-chemical studies were performed. Positive reaction for neu, which appeared as brown granular deposits along cell surface and cytoplasm of the tumor cells, was significantly correlated with the histological grade but not with other prognostic factors such as tumor size, lymph node me-tastasis, local recurrence, and estrogen and progesteron receptor status. Also granular deposits of ras were noted in the carcinoma cells in the cytoplasm, while the epithelaial cells of the normal lobule and duct showed negative reation.
But expression of ras was not significantly associated ras with other prognostic factors. The reaction for EGFR was mostly negative on epithelial cells of both the normal lobule and duct, and was not significantly associated with other prognostic factors. The results suggested that expression of the neu oncoprotein is significantly associated with the histological grade of breast carcinoma, while the ras and the EGFR do not show significant prognostic value.
BACKGROUND Cell cycle progression is governed by cell cycle regulators and inhibitors such as the cyclin dependent kinases (CDK), p27(Kip1), p21(WAF1/Cip1) and p53. The purpose of this study was to correlate expressions of p34(cdc2), p27(Kip1), p21(WAF1/Cip1) and p53 with the various clinicopathologic prognostic parameters of human breast cancers. METHODS The paraffin-embedded tissue sections from 102 patients with human breast carcinomas were examined by performing immunohistochemical staining. The primary antibodies used for immunohistochemical staining were mouse monoclonal antibody to human p34(cdc2), p27(Kip1), p21(WAF1/Cip1), p53, ER and PR. RESULTS The expression rates of p34(cdc2), p21(WAF1/Cip1) and p53 were 29.3%, 40.2% and 49.1% in breast carcinomas, respectively. In normal breast tissues, p34(cdc2), p21(WAF1/Cip1) and p53 were not expressed. The p34(cdc2) was expressed in the cytoplasm of cancer cells. The expression rate of p27(Kip1) was 29.3% in breast carcinomas and 100% in normal breast tissues, so the loss of p27(Kip1) expression in breast cancer was noted. The high expression of p21(WAF1/Cip1) in neoplastic cells was associated with the p53 expression (p=0.03). The expression of p27(Kip1) was correlated with that of the progesterone receptor (PR) (p=0.04) and the expression of p21(WAF1/Cip1) was correlated with that of positivity for estrogen receptor (ER) (p=0.04) and PR (p=0.04). No correlation was demonstrated between the mean patient survival and the expression rate of p34(cdc2), p27(Kip1), p21(WAF1/Cip1) and p53. CONCLUSIONS The loss of the normal cell growth cycle by the abnormal expression of cyclin dependent kinases and their inhibitors and the steroid hormones may play an important role in human breast carcinogenesis. The p53 dependent p21(WAF1/Cip1) pathway, the p27(Kip1) protein loss and the cdc2 overexpression were important in development and progression of human breast cancer.
Expression of the pS2 protein in breast carcinoma is a useful guide to evaluate the prognosis and response to tamoxifen. The pS2 protein is an estrogen-regulated 60 amino acid protein which was originally discovered following the screening of cDNA libraries in MCF-7 breast carcinoma cells and is induced through estrogen-dependent transcription of the pS2 gene. The presence of the pS2 protein in breast cancer is considered as valuable as the receptor status, or even more so, in predicting the response to hormonal therapy. We have investigated the pS2 protein expression in 62 cases of primary breast cancer in order to know the relationship between the expression rate of the pS2 protein and hormonal receptor status using immunohistochemical procedures on formalin-fixed and paraffin-embedded tissues.
Concomitantly, both the estrogen receptors (ER) and progesterone receptors (PR) were examined using the immunohistochemical technique. Positive staining for the pS2 was seen in forty-nine cases (79%) of the tumors. Forty three cases (88%) of the pS2 positive tumors were ER positive and forty one cases (84%) of the pS2 positive tumors were PR positive ; forty six cases (93%) of pS2 positive tumors were positive for ER and/or PR. The pS2 status correlated significantly with the ER (p<0.0001) and PR (p<0.001). The results reveal a close association between the pS2 protein and either or both the ER and PR status.
From a retrospective study of 366 cases of breast cancer, following results are obtained. 1) Relative incidence of breast cancer is increased during recent 7 years as compared with total female cancer. 2) Invasive ductal carcinoma and invasive ductal carcinoma with a predominant intraductal component (ICPI) account for 78% of total breast cancer, and its ratio shows little variance during recent 7 years and as compared with previous studies. 3) The incidence of invasive lobular carcinoma is increased as compared with 10 years ago, but it seems more likely that the increase is due to difference in diagnostic criteria rather than due to real increase in incidence. 4) The average patients' age of five major histologic types of breast cancer is 47.3 year. The patient's age of invasive ductal carcinoma is highest and that of ICPI is lowest. 5) Outer upper quadrant is the most frequent site of breast cancer. Left side is slightly more frequent than right side. There is little variance among the histologic types in tumor location. 6) The average symptom duration of patients of major types of breast cancer is 8.4 month. It is longest in invasive ductal carcinoma and shortest in ICPI. 7) Invasive lobular carcinoma is largest in tumor size and intraductal carcinoma is smallest, among the major histological types. 8) Intraductal carcinoma is most freqnently accompanied by nipple discharge and Paget's disease. 9) The rate of axillary lymph node metastasis is highest in invasive lobular carcinoma, followed by invasive ductal carcinoma, medullary carcinoma, and ICPI, in order of freqnency. 10) Distant metastasis is to the bone, lung, liver and brain, in order of freqnency. Medullary carcinoma shows the highest rate of distant metastasis. 11) The important prognostic factors of breast cancer are histologic types, status of axillary lymph node metastasis, size of tumor and histologic grade of malignancy. But there is little difference in prognosis between invasive ductal carcinoma and medullary carcinoma.
In 41 cases of breast cancers, the aneuploidy measured by Image Analyzer was compared with that of flow cytometric analysis, and estrogen and progesterone receptor(ER/PR) and Her-2/neu oncoprotein were immunohistochemically stained and measured by Image Analyzer. In ER/PR, the positive nuclear area(PNA, %) was measured, and in Her-2/neu, the content of oncoprotein was expressed as pg/cell. To assess the usefulness of these parameters as a prognostic factor, the author evaluated the results in relation with tumor size, nuclear grade and lymph node metastasis. The obtained results are summarized as follows: 1) The detection rate (90%) of aneuploidy by image analysis was higher than that (70%) of flow cytometric analysis. The concordance rate of both method was 80%. 2) The positivity of ER was 73% and PR was 34%, and the high PNA of ER and PR was related with high nuclear grade. There was an inverse correlation of the ER PNA with tumor size and PR PNA with negative lymph node. 3) Her-2/neu oncoprotein overexpression was found in only 2 cases and another two showed borderline overexpression. All four cases had DNA tetraploidy. From the above results, it was concluded that the image analyzer could be used in DNA analysis and in quantitation of immunostained ER/PR and Her-2/neu oncoprotein, providing the important information in the management of the breast cancer patients.
The morphologic study of noninfiltrating and infiltrating duct carcinoma of the breast disclosed profound alterations along the parenchymal-stromal junction. But fate of myoepithelial cell, changes of basement membrane and the relationship of fibroblast to myofibroblast remain uncertain. To study the morphologic changes of myoepithelial cell, basement membane and stromal fibroblast, a series of 32 not otherwise specified (NOS) type of infiltrating duct carcinoma of the breast with regional lymph node metastases was examined light microscopically after S-100 protein immunoperoxidase staining by biotinavidin system (BAS) and ultrastructurally. The results were as follows. 1) In 18 out of 32 cases, S-100 protein positive myoepithelial cells were observed individually in the parenchyma at the periphery of some carcinomatous duct-like structures or cancer cell nests. The cells were noted in 7 cases of metastatic regional lymph nodes. In 5 cases contained with 2 cases of infiltrating duct carcinoma with focal sarcomatous metaplasia, S-100 protein positive cells were seen in fibroblast-like spindle cells in stroma adjacent to cancer nests. 2) Ultrastructural features of myoepithelial cells showed significant loss of fine microfilament and hemides-mosomes and relative imcrease of coarse large filaments. Morphologic transformation of myoepithelial cells to neoplastic epithelial cells or stromal fibroblast-like spindle cells were suggested in 3 NOR type and 2 metaplastic type carcinomas. 3) The ultrastructural changes of basement membrane disclosed some variations from case to case and even within a single tumor if large number of blocks were studied. Focal destruction, splitting, segmentation and extensive loss of basement membrane arround cancer nests were noted. On the other hand, basement membrane material surrounded cancer nests or individual cancer cells irregularly. 4) Most stromal fibroblasts in infiltrating duct carcinoma had abundant rough endoplasmic reticulum with enlarged plump cytoplasm. Some of them were transformed to myofibroblasts which had perinuclear rough endoplasmic reticulum and peripheral microfilaments with dense bodies in their cytoplasm.
BACKGROUND p27 is a member of the cyclin-dependent kinase (CDK) inhibitors that arrest the progression of the cell cycle; thus, it acts as a tumor suppressor gene. The loss or decrease of p27 protein is frequently seen and this has an independent prognostic potential for many human cancers. p27 is functionally inactivated through accelerated proteolysis and cytoplasmic sequestration. Cytoplasmic mislocalization of p27 by abnormal phosphorylation in the tumor cells doesn't allow it to bind and inhibit nuclear cyclin/CDK targets. METHODS We examined the p27 protein expression in 86 cases of invasive ductal carcinoma of the breast via immunohistochemical staining to evaluate the subcellular localization of p27 and its relationship with the clinicopathologic features and the prognostic factors. RESULTS The nuclear expression of p27 was noted in 48.9% of the tumors, a combined nuclear and cytoplasmic expression was noted in 20.9%, a cytoplasmic expression was noted in 12.8%, and a negative expression was noted in 17.4%. The decreased nuclear expression and/or cytoplasmic mislocalization of p27 were statistically correlated with the nuclear grade (p=0.001), histologic grade (p=0.036), tumor size (p=0.033), lymph node metastasis (p=0.043), ER (p=0.001), and PR (p=0.001) status, while they were not correlated with patient age, stage, HER2, p53, and Ki67. CONCLUSIONS The breast tumors showing both decreased nuclear expression and cytoplasmic mislocalization of p27 are associated with a deranged cell cycle via functional inactivation and also with poor prognostic factors. It is expected that p27 can be a promising anticancer target molecule for the treatment of breast cancer.
The cathepsin D is a lysosomal protease secreted in excess by breast cancer cells. The function of this enzyme is degradation of the extracellular matrix and proteoglycan. It is induced by estrogens in estrogen receptor positive breast cancer cell lines. On the basis of this, cathepsin D expression in breast cancer cells seems to be correlated with the prognosis. But there is debates in its prognostic significance. Relationship between cathepsin D expression and other prognostic factors of breast cancer was studied.
We investigated 51 cases of invasive ductal cell carcinoma of breast removed by open biopsy or mastectomy. All cases were fixed in formalin and embedded in paraffin. We used 46-KD intermediate form of the enzyme for cathepsin D expression on immunohistochemical stain. We observed no significant correlation with age, stage, histologic grade, lymphatic invasion, and estrogen receptor status. Cathepsin D may be an independent factor which is not related with other prognostic factors, especially estrogen receptor status.
BACKGROUND KAI-1 is a metastasis suppressor gene. We have evaluated the correlationbetween KAI-1 protein expression in ductal carcinomas of the breast and axillary lymph nodemetastasis. METHODS The expression of KAI-1 protein was confirmed by immunohistochemistryto examine breast tissues of ductal carcinomas from 50 patients with nodal metastasisand from 53 patients without metastasis. Western blot analysis was performed on fresh frozenbreast tissues from 17 cases with nodal metastasis and from 19 cases without metastasis. RESULTS Immunohistochemical KAI-1 protein expression was decreased or negative in 39out of 50 cases with metastasis (78%), compared with 8 out of 53 cases with no metastasis(15.1%). The difference was statistically significant (p<0.05). Immunohistochemical KAI-1protein expression was significantly decreased in cases with higher modified Black's nucleargrade (p=0.027) and larger tumor size (p=0.039). Western blot analysis showed positivebands at 29.5 kDa in 8 out of 19 cases without metastasis (42.1%), and none of the 17 caseswith metastasis showed positive bands (p=0.0024). CONCLUSION These results suggest thepossibility that KAl-1 might play a major role of a metastasis suppressor gene in addition tothe part it plays in the growth and progression of human breast ductal carcinoma. In addition, the decreased expression of KAI-1 protein in breast ductal carcinomas could be used as afactor suggesting poor prognosis.
Background : Claudins are important components of the tight junctions in the intercellular barriers and cell polarity.
Among them, claudin-7 is down-regulated in breast cancers compared with the normal breast epithelium. The aim of this study was to determine the expression pattern and prognostic value of claudin-7 in breast carcinomas. Methods : Claudin-7 expression was evaluated immunohistochemically in 42 cases of ductal carcinoma in situ (DCIS) and in 142 cases of invasive breast carcinoma (IBC) using a tissue microarray (TMA). Results : Claudin- 7 was strongly expressed in the normal luminal epithelial cells in the breast lobule. The level of claudin-7 expression was significantly lower or absent in 45.2% (19/42) of DCIS and 72.5% (103/142) of IBC. A loss or reduced expression of claudin-7 correlated with the invasiveness (p=0.001) of breast carcinomas and a high nuclear grade (p=0.013) in IBC. Conclusion Claudin-7 is an important tight junction protein in the breast and a loss of expression may assist in the dissociation and invasion of tumor cells.