Expression of tumor-associated antigen (DF3) in atypical hyperplasias and in situ carcinomas of the human breast

The monoclonal antibody (MoAb) DF3 prepared against a membrane-enriched fraction of human breast carcinoma has previously shown a differential reactivity to cytoplasmic antigen in carcinomas versus antigen concentrated on apical borders in benign lesions of the breast. In the present report the cytoplasmic reactivity of MoAb DF3 within a spectrum of benign and malignant breast lesions was studied to define whether the DF3 antigen is expressed in the cytoplasm of potentially premalignant lesions, i.e., atypical hyperplasias, or early malignant lesions, i.e., in situ carcinomas. Biopsy specimens of breast lesions from 108 women, including 28 patients with invasive carcinoma, 12 with in situ carcinoma, 17 with atypical hyperplasia, 25 with proliferative lesions without atypia, and 26 with nonproliferative lesions, were examined for DF3 antigen expression with the use of an indirect immunohistochemical method. Atypical hyperplasias were less reactive with MoAb DF3 than invasive carcinomas (P = .05 by Wilcoxon rank sum test). No significant statistical differences were observed, however, between invasive carcinomas and in situ carcinomas or between in situ carcinomas and atypical hyperplasias on the basis of cytoplasmic DF3 reactivity. Invasive carcinomas, in situ carcinomas, and atypical hyperplasias, however, demonstrated significantly higher reactivity with MoAb DF3 in the cytoplasm than proliferative lesions without atypia and nonproliferative lesions (P less than .01). These studies demonstrate that atypical hyperplasias express elevated levels of a given tumor-associated antigen and thus provide further immunologic evidence that these lesions are premalignant.     

Increasing oxidative damage and loss of mismatch repair enzymes during breast carcinogenesis

This study examined the expression of oxidative damage markers 8-hydroxydeoxyguanosine (8-OHdG), 4-hydroxy-2-nonenal (HNE) and nitrotyrosine using immunohistochemical techniques. In addition, DNA topoisomerase II binding protein 1 (TopBP1) and mismatch repair proteins 2 and 6 (MSH2 and MSH6) were immunostained in a series of 80 stage I invasive breast tumours, 26 in situ breast carcinomas and 12 benign breast hyperplasias. 8-OHdG, HNE and nitrotyrosine expression were considerably weaker in hyperplasias than in in situ lesions, which, in turn, showed less oxidative damage than T1N0 tumours. Hyperplasias and in situ tumours were all, at least moderately, positive for MSH2, and nearly all were positive for MSH6. Nitrotyrosine expression was associated with HNE (P<0.0005) and 8-OHdG (P=0.041) in the T1N0 cohort. To conclude, there is increasing oxidative stress during the early steps of breast carcinogenesis. On the other hand, a significant reduction in expression of mismatch repair proteins occurs during the progression of in situ lesions to invasive tumours.     

Clinicopathological significance of stromal myofibroblasts in invasive ductal carcinoma of the breast.

The purpose of this study was to investigate the distribution of CD34-positive fibroblasts and alpha-smooth muscle actin (alpha-SMA)-reactive myofibroblasts in the stroma of benign and malignant breast lesions and, secondly, to determine whether the presence of stromal myofibroblasts is associated with some of the clinicopathological characteristics of patients with invasive ductal carcinoma. The presence of stromal CD34-positive fibroblasts and myofibroblasts was investigated (as defined immunohistochemically) in 8 normal breast tissue samples, 58 invasive ductal carcinomas, 9 ductal carcinomas in situ and 16 specimens with benign lesions of the breast (fibroadenomas, ductal hyperplasias). We further studied the correlations between the presence of stromal myofibroblasts with 7 clinicopathological parameters in 58 invasive ductal carcinomas. The results indicated that the stroma of normal breast tissues contained CD34-positive fibroblasts. All benign breast lesions exhibited stromal CD34-positive fibroblasts. In contrast, the stroma of ductal carcinomas showed a complete loss of CD34-positive fibroblasts. alpha-SMA expression in stromal fibroblasts (myofibroblasts) was not detected in normal tissue samples or benign lesions except in 1 case of fibroadenoma, whereas positive myofibroblasts were found in 44.4% of ductal carcinomas in situ and 56.9% of invasive breast carcinomas. Comparison of clinicopathological parameters between invasive ductal carcinomas with and without stromal myofibroblasts revealed significant differences in lymph node metastasis, high histological grade and high microvessel density. These results suggest that CD34 loss and the presence of myofibroblasts favor the diagnosis of breast carcinoma. In invasive ductal carcinoma, the presence of stromal myofibroblasts correlated significantly with pathological parameters associated with a poor prognosis.     

Stereotactic vacuum-assisted breast biopsy in 2874 patients: a multicenter study

BACKGROUND: Vacuum-assisted breast biopsy (VAB) can replace surgical biopsy for the diagnosis of breast carcinoma. The authors evaluated the accuracy and clinical utility of VAB in a multicenter setting using a strict quality assurance protocol. METHODS: In the current study, VABs were performed successfully for 2874 patients at 5 sites. Benign lesions were verified by follow-up. Surgery was recommended for malignant and borderline lesions. VAB was performed on patients with lesions rated as highly suspicious (6%), intermediate to suspicious (85%), or probably benign (9%). Fifty-eight percent of the lesions were < 10 mm and 70% had microcalcifications. RESULTS: The authors identified 7% of patients with invasive carcinomas, 15% with ductal carcinomas in situ (DCIS), 5% with atypical ductal hyperplasias (ADH), and 0.6% with lobular carcinomas in situ. The results of the VAB necessitated an upgrade of 24% of patients with ADH to DCIS or DCIS and invasive carcinoma. Twelve percent of patients with DCIS proved to have invasive carcinoma. Seventy-three percent of the patients had benign lesions. Only 1 false-negative result was encountered (negative predictive value, 99.95%). Minor side effects were reported to occur in 1.4% of patients and 0.1% of patients required a subsequent intervention. Scarring relevant for mammography was rare among patients (i.e., 0.3% of patients had relevant scarring). CONCLUSIONS: Quality-assured VAB was found to be highly reliable. VAB effectively identified patients with benign lesions and assisted therapeutic decisions. Most important, only a single case of malignancy was missed. A close interdisciplinary approach assured optimal results.     

A large 6q deletion is a common cytogenetic alteration in fibroadenomas, pre-malignant lesions, and carcinomas of the breast.

To assess whether early breast lesions are the precursors of invasive carcinomas, three classes of breast lesions, namely benign tumors (including fibroadenomas), putative premalignant lesions (including cases of atypical hyperplasia), and invasive carcinomas, were compared at the cytogenetic and molecular cytogenetic levels. Genetic relatedness was clearly demonstrated by the sharing of several anomalies, among which 6q deletions outnumbered all of the other alterations detected. Indeed, deletions of the long arm of chromosome 6, most likely occurring in epithelial cells, were present in 83.9% of benign breast tumors, 64% of putative premalignant lesions, and 77.4% of analyzable carcinomas. Furthermore, the interval between 6q24 and qter appeared to be the common region of deletion in all three classes of breast lesions, whereas the minimal common region of deletion was 6q27-qter. Interestingly, the latter region was reported previously to be deleted in benign ovarian tumors and recently found to harbor a gene (SEN6) that is important for SV40-mediated immortalization of human cells.     

Expression of endothelial and inducible nitric oxide synthase in benign and malignant lesions of the breast and measurement of nitric oxide using electron paramagnetic resonance spectroscopy

BACKGROUND: Nitric oxide (NO) is present in various human solid tumors and tumor cell lines, and it is believed that NO plays an important role in tumor growth. An increased NO concentration catalyzed by NO synthase (NOS) is cytotoxic and can promote apoptosis. The expression of endothelial NOS (e-NOS) and induced NOS (i-NOS) was examined in various breast tumors. METHODS: Immunohistochemical staining with a monoclonal antibody (Ab) against e-NOS and a polyclonal Ab against i-NOS was performed on paraffin embedded tissues from 41 benign breast lesions, 9 in situ breast lesions, and 54 invasive breast lesions. Functionality was confirmed by detection of NO using spin-trapping electron paramagnetic resonance (EPR) spectroscopy. RESULTS: e-NOS expression was found in 2 benign lesions (5%; 1 fibroadenoma and 1 proliferative mastopathy), in 5 in situ lesions (56%), and in 33 invasive lesions (61%). None of the benign lesions was positive for i-NOS, but 6 in situ lesions (67%) and 33 invasive lesions (61%) showed tumor cell staining. In particular, capillaries that were embedded in lymphocytic stroma showed a positive reaction for e-NOS. The functionality of NOS was demonstrated by direct NO formation using the EPR spin-trapping method. Tumors that were positive for e-NOS were observed more often in younger patients (P = 0.05). These tumors more frequently were highly differentiated or moderately differentiated and more often showed invasive ductal subtypes and a lower proliferation rate. Tumors that were positive for both e-NOS and i-NOS were more likely to be lymph node negative tumors. Both i-NOS-expressing lesions and e-NOS-expressing lesions showed strong coexpression (P = 0.00001). CONCLUSIONS: NOS is detected predominantly in in situ lesions and invasive breast lesions but rarely in benign lesions. NOS is found more frequently in invasive carcinomas with low malignancy. Using the spin-trapping EPR method, this study demonstrates direct NO formation in human breast tumors for the first time.     

Expression and clinical significance of E-cadherin, β-catenin and E-cadherin-catenins complex in breast cancer and precancerous lesions简

Objective： The aim of our study was to observe the expressions and clinical Significance of E-cadherin, β-catenin and E-cadherin-catenins complex in breast cancer and precancerous lesions, and analyze the relationship between the expressions and clinicopathological features in breast cancer. Methods： Immunhistochemical UltraSensitiveTM S-P method was employed to detect the expression of E-cadherin, β-catenin and E-cadherin-catenins complex in 128 cases of invasive ductal carcinomas, 89 cases of ductal carcinoma in situ and 57 cases of atypical ductal hyperplasia, 53 cases of usual ductal hyperplasia breast tissues were selected as a control group. The express of E-cadherin, β-catenin and their relationship with mult biological parameters including histological grade, region lymph node metastasis, distant metastasis and recurrence on files were also assessed. Results： （1） The staining patterns character of E-cadherin, β-catenin and E-cadherin-catenins complex： In UDH breast tissues, E-cadherin and a-catenin were expressed on cell membrane of ductal and acinic cells, showing cellular contour and border among cells. The abnormal expression of the three proteins occurred in breast invasive ductal carcinomas, ductal carcinoma in situ and atypical ductal hyperplasia tissues, showing cytoplasmic or nuclear staining, decrease and loss of cytomembrane staining. （2） The abnormal expression rates of E-cadherin, β-catenin and E-cadherin-catenins complex in invasive ductal carcinomas were 53.91%, 65.63% and 81.25%, which were significantly higher than that in ductal carcinoma in situ, atypical ductal hyperplasia, usual ductal hyperplasia tissues （P 〈 0.01）. Compared with usual ductal hyperplasia breast tissues group, the abnormal expression rates of E-cadherin, β-catenin and E-cadherin-catenins complex were significantly decreased （P 〈 0.01） in the breast cancer group. However, there was no significance of the abnormal expression rate between ductal carcinoma in situ and atypical ductal hyperplasia tissues groups （X2 = 0.76, P = 0.38; x2 = 0.14, P = 0.70; x2 = 0.81, P = 0.37; X2 = 2.19, P = 0.14） （P 〉 0.05）. （3） There was a significantly difference in the mean E-cadherin, β-catenin and E- cadherin-catenins complex frequency between estrogen receptor ＆ progesterone receptor positive IDC group and negative group, epidermal growth factor receptor type 2 （HER2/neu） positive and negative groups, Ki-67 proliferation index 〈 14% and 〉 14% groups, histological grade （I ＋ II） and grade III invasive ductal carcinomas groups, with lymph node metastasis, distant metastasis and recurrence groups （P 〈 0.05） and without groups （P 〈 0.05）. However, there was no difference in the mean E-cadherin, β-catenin and E-cadherin-catenins complex frequency between age （_〈 50 years vs 〉 50 years）, tumor diameter （〈 2 cm vs 〉 2 cm） （P 〉 0.05）. Conclusion： In breast cancer, the expressions of E-cadherin, β-catenin and E-cadherin-catenins complex are abnormally decreased and are correlated with pathology grade, differentiation disturbance and metastasis. E- cadherin and β-catenin may be as the predictors for prognosis. Combined detection may improve accuracy and sensitivity of predicting metastasis and prognosis of breast Cancer.     

Expression of HIF-1α in breast cancer and precancerous lesions and the relationship to clinicopathological features简

Objective： The aim of this study was to observe the expressions and clinical significance of HIF-1a in breast cancer and precancerous lesions, and analyze the relationship between the expressions and clinicopathological features in breast cancer. Methods： We analyzed the HIF-1a expression in 128 cases of invasive ductal carcinomas, 146 precancerous lesions patients including 89 cases of ductal carcinoma in situ and 57 cases of atypical ductal hyperplasia. 53 cases of usual ductal hyperplasia breast tissues were selected as a control group. The specimens were evaluated for HIF-1a, estrogen receptor （ER） ＆ progesterone receptor （PR）, epidermal growth factor receptor type 2 （HER2/neu） and Ki-67. Immunoreactivity was semi-quantitatively evaluated in at least 1000 cells examined under the microscope at 40 x magnification and recorded as the percentage of positive tumor cells over the total number of cells examined in the same area. The percentage scores were subsequently categorized. The express of HIF-1a and their relationship with multiple biological parameters including ER ＆ PR, HER2/neu and Ki-67, the biomarkers levels of CA153, CA125 TSGF, and CEA in blood serum and nipple discharge, histological grade, region lymph node metastasis, distant metastasis and recurrence on files were also assessed. Results： Compared with usual ductal hyperplasia, the positive expression rate of HIF-1a in atypical ductal hyperplasia, ductal carcinoma in situ and invasive ductal carcinomas group was significantly increased （P 〈 0.01）. The positive rates of HIF-1a in invasive ductal carcinomas were 68.75%, which were significantly higher than that in ductal carcinoma in situ （43.8%）, atypical ductal hyperplasia （31.6%）, usual ductal hyperplasia （9.4%; X2 = 13.44, 22.27, 52.79, respectively, P 〈 0.01）. Statistical analysis showed that difference of abnormal expression rate of HIF-1a between ductal carcinoma in situ and usual ductal hyperplasia （X2 = 18.37, P = 0.00）, atypical ductal hyperplasia and usual ductal hyperplasia （x2 = 8.14, P = 0.00） was significant （P = 0.00）. However, no significant difference in the positive expression rate of HIF-1a was found between atypical ductal hyperplasia and ductal carcinoma in situ tissue （X2 = 2.19, P = 0.14）. There was a significantly difference in the mean HIF-1a frequency between ER ＆ PR positive invasive ductal carcinomas group and negative group, epidermal growth factor receptor type 2 （HER2/neu） positive and negative groups, Ki-67 proliferation index 〈 14% and 〉 14% groups, histological grade （I ＋ II） and grade III invasive ductal carcinomas groups, with lymph node metastasis, distant metastasis and recurrence groups （P 〈 0.05） and without groups （P 〈 0.05）. However, there was not difference in the mean HIF-1a between age （〈 50 years vs 〉 50 years）, tumor diameter （〈 2 cm vs 〉 2 cm; P 〉 0.05）. The nipple discharge and serum levels of CA153, TSGF, CA125 and CEA in invasive ductal carcinomas HIF-1a positive patients were significantly higher than those in the negative patients （P 〈 0.05）. Conclusion： In breast cancer, HIF-1a expressibn was abnormally increased. The aberration of HIF-1a may play a key role during oncogenesis （atypical ductal hyperplasia or ductal carcinoma in situ） and promote breast cellular transformation into malignancy, a finding useful for further understanding of tumorigenesis. The abnormal expression of HIF-1a may be as an early event in the development of breast tumor. The over-expression of HIF-1a might be important biological markers for invasion, metastasis and recurrence of breast cancer.     

Expression of urokinase plasminogen activator, its receptor and type-1 inhibitor in malignant and benign prostate tissue

The plasminogen activation (PA) cascade participates in degradation of extracellular matrix during cancer invasion. We have studied the expression of urokinase-type plasminogen activator (uPA) mRNA, uPA receptor (uPAR) mRNA and immunoreactivity, and type-1 plasminogen activator inhibitor (PAI-1) mRNA and immunoreactivity in 16 prostate adenocarcinomas and 9 benign prostate hyperplasias. uPA mRNA and uPAR mRNA expression were found in 9 and 8 of the adenocarcinomas, respectively, and in 7 and 6 of the benign hyperplasias, respectively. In both malignant and benign lesions, expression of these 2 mRNAs was predominantly seen in cells identified as macrophages, which in most of the carcinomas (approximately 90%) were located in the interstitial tissue between the tumor cell islands, while in most of the benign hyperplasias they were located in the lumen of the glands and were in only a few cases (approximately 30%) found in the interstitial tissue. uPAR immunoreactivity correlated with the mRNA expression and was, in addition, found in neutrophils. PAI-1 mRNA was detected in 13 of the 16 carcinomas and in 8 of the 9 benign hyperplasias, located in scattered fibroblast-like cells in both groups, in some vascular structures and in a few macrophages located in the interstitial tissue of both malignant and benign lesions. A similar expression pattern was found for PAI-1 immunoreactivity. In 8 of the 16 carcinomas, all 3 components were present, and in several areas colocalization was observed in stromal cells in close proximity to cancer cell islands. No immunoreactivity and/or mRNA expression of uPA, uPAR or PAI-1 was observed in cancer cells or in other epithelial cells in any of the cases.     

Assessment of apoptosis in human breast tissue using an antibody against the active form of caspase 3: relation to tumour histopathological characteristics.

Apoptosis is of important significance in the pathogenesis of cancer. Many methods are available for the measurement of apoptosis but the 'gold standard' is to identify apoptotic cells by their morphological features using microscopy. Caspase 3 is a cytosolic enzyme that is activated only in cells committed to undergo apoptosis. The activation of caspase 3 precedes the development of the classical morphological features of apoptosis. Using immunohistochemistry with an antibody against the active form of caspase 3, the apoptotic index (AI) was measured in 116 samples of human breast tissue (22 normal/benign and 94 invasive carcinomas). The AI obtained by measuring caspase activation has a strong correlation with the AI derived by morphological assessment (r = 0.736, P < 0.01). The AI is higher in the invasive group than in the benign group (P = 0.008), and in invasive cancer high AI is associated with high tumour grade (P = 0.013), positive node status (P < 0.001) and negative steroid receptor status (P = 0.001 for ER; P = 0.004 for PR). No significant association is observed between AI and tumour size. Measurement of apoptosis by immunohistochemistry using an antibody against the active form of caspase 3 is therefore reliable and correlates strongly with morphological assessment.     

Utility of an upright-type 11-gauge stereotactic vacuum-assisted biopsy device （Mammotome@） for the diagnosis of breast microcalcifications

Objective

The aim of this study was to evaluate the utility of an upright-type 11-gauge stereotactic vacuum-assisted biopsy device (Mammotome®) for the diagnosis of breast microcalcifications

Methods

Between May 2001 and October 2005, 154 biopsies in 152 patients with microcalcifications were performed using the upright-type 11-gauge stereotactic vacuum-assisted biopsy device. Patients in whom this biopsy was diagnosed as carcinoma or a borderline lesion, had a subsequent surgical excision of the lesion. Histopathological and radiological features of the two specimens were then compared with each other.

Results

Microcalcification was identified on specimen mammograms and microscopic slides in 97.4% of cases. Of 154 Mammotome biopsies 98 (63.6%) were benign, 51 (33.1%) were malignant, 3 (1.9%) showed atypical hyperplasia, and 2 (1.3%) were indeterminate, respectively. Of the 48 cases that received surgical excision, 6 of 36 ductal carcinomas in situ (16.7%) upstaged to invasive ductal carcinoma and 1 of 2 atypical ductal hyperplasias was upstaged to ductal carcinoma in situ. The positive predictive value of the 11-gauge Mammotome for the diagnosis of invasion in breast cancer was 100%. Linear calcification and pleomorphic calcification linear/segmental distribution was reliable indications of malignancy. The mean follow-up time of the benign lesions was 22 months, and without evidence of lesion growth. Complications included vasovagal reactions (6.3%), bleeding (0.6%) and hematoma (2.6%).

Conclusion

The upright stereotactic 11-gauge Mammotome procedure is an effective and reliable method for the diagnosis of breast microcalcifications. It has minimal side effects. For lesions diagnosed as ADH or DCIS with the 11-gauge Mammotome, subsequent surgical excision should be performed.     

Coordinate expression of apoptosis-associated proteins in human breast cancer before and during chemotherapy.

PURPOSE: Induction of apoptosis is a key factor in the response of tumors to chemotherapy. Laboratory studies have established many of the factors that regulate and execute apoptosis, but the significance of these in human tumors is poorly understood. Therefore, the relationship between key components of this machinery was examined in primary human breast carcinomas before and 24 h after the initiation of chemotherapy. EXPERIMENTAL DESIGN: Apoptosis was measured using the terminal deoxynucleotidyl transferase-mediated nick end labeling assay, and proliferation was assessed using the anti-Ki67 antibody MIB-1. Monospecific polyclonal antibodies were used for immunohistochemical detection of Bcl-2, Bax, XIAP, activated (cleaved) caspase 3 and 6, and cleaved DNA Fragmentation Factor-40 (DFF40) using paraffin-embedded tissues. RESULTS: Before treatment, a significant correlation was found between apoptosis and proliferation (r = 0.64, P < 0.0001), between caspases 3 and 6 (r = 0.49, P = 0.004) and between cleaved DFF40 and active caspases 3 (r = 0.66, P < 0.0001) or 6 (r = 0.47, P = 0.006). Before treatment, expression of inhibitor of apoptosis protein, XIAP, also correlated positively with cleaved caspase 3 (r = 0.64, P < 0.0001), caspase 6 (r = 0.36, P = 0.04), and DFF40 (r = 0.61, P = 0.0001). At 24 h after chemotherapy, significant increases in apoptosis and decreases in proliferation were observed, with the degree of increase in apoptosis inversely associated with decrease in proliferation. Chemotherapy-induced increases in Bax were correlated with increases in cleaved DFF40 (r = 0.54, P = 0.0008), but no other variables showed significant change at 24 h after initiation of chemotherapy. CONCLUSION: The pretreatment biomarker relationships suggest parallel cleavage and activation of these executioner proteins in breast cancer and that XIAP may maintain cell survival in the face of caspase activation. The findings provide in vivo evidence in human breast cancer that chemotherapy induces an apoptotic program characterized by up-regulation of Bax and cleavage of caspase substrate DFF40.     

乳腺X线立体定位空芯针活检的临床应用

目的评价乳腺X线立体定位空芯针活检在乳腺疾病诊治中的价值.方法采用计算机辅助乳腺X线立体定位系统、弹射式自动活检枪和14-gauge的空芯针.结果对影像学诊断发现异常的71个病灶进行X线立体定位空芯针活检.对照手术或1年以上(13～45个月)的随访结果,该组的诊断特异性和敏感性分别为100％和92％.有73％的良性病灶经空芯针活检明确诊断后免除了手术活检.结论 X线立体定位空心针活检是用于乳腺X线发现的临床摸不到肿块的病灶的一种安全有效的微创活检方法,并使大量良性病变免除手术活检并节省了医疗开支.     

CD133+细胞在乳腺良恶性病变中的分布特点及其临床病理意义

研究CD133+细胞在乳腺普通型增生、乳腺不典型增生、乳腺原位癌、浸润性乳腺癌中的分布特点及其与乳腺癌临床病理特征的关系。方法:采用免疫组织化学方法对45例正常乳腺组织、41例普通型增生乳腺组织、39例不典型增生乳腺组织、51例乳腺原位癌组织、121例乳腺癌组织中CD133+的表达进行检测,分析CD133+细胞在乳腺良恶性病变中的分布特点。结果:CD133+在正常乳腺组织中不表达,在乳腺普通型增生、不典型增生、原位癌、浸润性癌的表达率逐渐增高,分别为31.7%（13/41）、48.7%（19/39）、64.7%（33/51）、74.4%（90/121）,有显著性差异（P<0.01）。CD133+的表达率随乳腺癌组织学分级［Ⅰ级63.6%（21/33）、Ⅱ级72.2%（26/36）、Ⅲ级82.7%（43/52）,P<0.05］和TNM分期［Ⅰ期57.1%（12/21）、Ⅱ期69.4%（34/49）、Ⅲ期68.7%（11/16）、Ⅳ期94.3%（33/35）,P<0.001］的增高而增高;有淋巴结转移或远处转移者分别高于无转移者、无远处转移者（P<0.05）;有复发者高于无复发者（P<0.05）;与患者年龄、月经状态、肿瘤的组织学类型、肿瘤大小、ER、PR、Her-2的表达无显著相关（P>0.05）。结论:CD133+细胞可能在乳腺增生与癌变过程中起重要作用;CD133+的乳腺癌细胞与乳腺癌的侵袭、转移和复发密切相关,CD133+是提示乳腺癌恶性程度和预后的指标之一。      

Gamma-glutamyl transpeptidase immunoreactivity in benign and malignant breast tissue

GGT 129, a polyclonal antibody directed against gamma-glutamyltranspeptidase (GGT), was used to study GGT expression in formalin-fixedparaffin-embedded tissues from normal breast, 24 benign lesions, 27 in situcarcinomas or atypical hyperplasias, and 79 infiltrating mammary carcinomas.Epithelium of the ducts and ductules in normal breast tissue showedimmunoreactivity along the apical surface. There was a strong correlation (P< 0.01) between the histologic classification of the tissue and GGTexpression. All of the benign breast lesions stained positive for GGT. Amongin situ carcinomas and atypical hyperplasias, 5/27 (19%) werenegative for GGT while 22/27 were immunopositive. Infiltrating carcinomasshowed the greatest deviation from normal tissue with 23/79 (29%)negative for GGT. GGT expression in benign and malignant breast tissue wasnot correlated with the age of the patient, suggesting that menopausalstatus does not influence expression of GGT. Correlation of GGTimmunoreactivity with tubule formation, nuclear pleomorphism, mitoses,grade, size of tumor, lymph node status, and ER/PR status was performed for69 cases of infiltrating ductal adenocarcinoma. There were no statisticallysignificant relationships between the level of GGT immunoreactivity and anyof the parameters. The loss of GGT in some of the cases is evidence thatthis enzyme is not required for mammary tumor development or maintenance.However, as GGT is a component of the pathways that metabolize glutathioneand glutathione-conjugates, the difference in levels of the enzyme ininvasive breast cancers may be one explanation for the variation inchemotherapy response that has been observed in patients treated foradvanced mammary cancer.     

Hypermethylation of 14-3-3 sigma (stratifin) is an early event in breast cancer.

We have identified 14-3-3 sigma (sigma) as a gene whose expression is lost in breast carcinomas, primarily by methylation-mediated silencing. In this report, we investigated the timing of loss of sigma gene expression during breast tumorigenesis in vivo. We analysed the methylation status of sigma in breast cancer precursor lesions using microdissection for selective tissue sampling. We found hypermethylation of sigma in 24 of 25 carcinomas (96%), 15 of 18 (83%) of ductal carcinoma in situ, and three of eight (38%) of atypical hyperplasias. None of the five hyperplasias without atypia showed sigma-hypermethylation. Unexpectedly, patients with breast cancer showed sigma hypermethylation in adjacent histologically normal breast epithelium, while this was never observed in individuals without evidence of breast cancer. Also, samples of periductal stromal breast tissue were consistently hypermethylated, underscoring the importance of selective tissue sampling for accurate assessment of 14-3-3-sigma methylation in breast epithelium. These results suggest that hypermethylation of 14-3-3-sigma occurs at an early stage in the progression to invasive breast cancer, and may occur in apparently normal epithelium adjacent to breast cancer. These results provide evidence that loss of expression of sigma is an early event in neoplastic transformation.     

Mammary lesions diagnosed as "papillary" by aspiration biopsy: 70 cases with follow-up

BACKGROUND: The authors reviewed smears from fine-needle aspiration biopsies (FNAB) diagnosed as "papillary lesions" and correlated the cytologic findings with the final diagnoses at excision. The objective of the current study was to determine the accuracy of FNAB diagnosis of a papillary lesion in distinguishing true papillary from nonpapillary proliferations and to evaluate cytologic criteria for the distinction of papillomas from true papillary malignancies and their cytologic look-alikes. METHODS: The cytopathology database at the New York University Medical Center was searched for women who underwent surgical excision after a breast FNAB diagnosis of a papillary lesion. The FNAB smears and corresponding slides from excisional biopsies were reviewed. The smears were evaluated and graded for the following features: cellularity, architecture, presence of fibrovascular cores, single cells, columnar cells, cellular atypia, myoepithelial cells, foamy histiocytes, and apocrine cells. The F test was used to determine the statistical significance of differences between true benign papillary lesions (papilloma) and adenocarcinomas (in situ and invasive). RESULTS: At the time of excision, 46 (66 %) cases were benign (23 solitary intraductal papillomas, 6 intraductal papillomatosis, 11 examples of fibrocystic change, and 6 fibroadenomas) and 24 (34 %) were malignant (1 low-grade phyllodes tumor [PT], 23 ductal in situ and invasive carcinomas). Of the 23 carcinomas, 3 (13 %) were classified as benign papillary lesions on FNAB and 19 (86 %) were classified as either atypical or suspicious. One case of low- grade PT originally was classified as benign on FNAB. There were four false-negative diagnoses; two were due to sampling and two to interpretative errors. A portion of the lesions classified as papillary were fibroadenomas and examples of fibrocystic change on excision and all of these were correctly classified as benign on FNAB. Of the histologically proven papillomas, 62% were correctly classified as benign on FNAB and none were designated as being positive for malignancy. Statistically significant features of distinction between papillomas and carcinomas included cellularity (P = 0.016), cellular atypia (P = 0.0053), and the presence of cytologically bland columnar cells (P = 0.04). Low-grade ductal carcinoma in situ (cribriform and micropapillary types) and tubular carcinoma represented the most difficult differential diagnostic problems. CONCLUSIONS: A significant portion of lesions displaying a papillary pattern on FNAB are nonpapillary on follow-up. Among benign processes, fibrocystic change and fibroadenoma may closely simulate papilloma on cytology. However, in spite of the overlapping features of true papillary lesions and their cytologic look-alikes, the majority can be classified accurately into benign or atypical (and above) categories by FNAB. Lesions that fall short of a definitive benign diagnosis should be placed into an indeterminate category. This approach will guide the surgeon to provide better patient management.     

Development of Androgen-independent Carcinomas from Androgen-dependent Preneoplastic Lesions in the Male Accessory Sex Organs of Rats Treated with 3,2'-Dimethyl-4-aminobiphenyl and Testosterone Propionate

Two kinds of cancer can be induced in rat male accessory sex organs, one a non-invasive carcinoma arising in the ventral lobe and the other an invasive lesion which develops in the dorsolateral and anterior lobe as well as the seminal vesicles. In the present study, one group of male rats were given biweekly s.c. injections of 3,2'-dimethyl-4-aminobiphenyl (DMAB) for 20 weeks for induction of non-invasive carcinomas and the other group received DMAB with 40-week testosterone propionate for induction of invasive carcinomas. Half of the animals in each group were then subjected to bilateral orchiectomy at week 41 to remove testicular androgen, in order to examine the androgen dependence of both types of carcinomas as well as precancerous lesions. Animals were killed at weeks 41, 46 and 60. All parts of the prostate complex showed involution and significant weight reduction after castration, with a complete disappearance of atypical hyperplasias and carcinomas of the ventral prostate. However, in spite of suppression of development of atypical hyperplasias in the anterior prostate and seminal vesicles, the incidence of invasive carcinomas was not changed. Normal epithelial cells and atypical hyperplasias of all parts of the prostate and seminal vesicles and carcinomas of the ventral prostate were immunohistochemically positive for nuclear androgen receptor, while invasive carcinomas that developed in either castrated or non-castrated animals were negative. These findings suggest that in the ventral prostate, both precancerous and cancerous lesions are androgen-dependent, but in the anterior and seminal vesicles, cancerous lesions (invasive carcinomas) are androgen-independent while precancerous lesions are hormone-dependent.     

CD44~+/CD24~-、CD44~-/CD24~+在乳腺良恶性病变中的分布特点和临床病理意义

[目的]探讨CD44+/CD24-细胞、CD44-/CD24+细胞在乳腺癌发生不同阶段中(乳腺良性增生、乳腺不典型增生、乳腺原位癌、乳腺癌)分布规律,及其与乳腺癌临床病理因素之间的关系。[方法]采用免疫组化双染色方法检测45例正常乳腺组织、41例良性增生乳腺组织、39例不典型增生乳腺组织、51例乳腺原位癌组织、121例乳腺癌组织中CD44、CD24的表达情况,分析CD44+/CD24-细胞、CD44-/CD24+细胞在乳腺癌发生不同阶段中的数量和分布特点。[结果]CD44+/CD24-细胞存在于20.0%(9/45)的正常乳腺组织中,在29.3%(12/41)的乳腺良性增生组织、35.9%(14/39)的乳腺不典型增生组织、43.1%(22/51)的乳腺原位癌组织、52.9%(64/121)的浸润性乳腺癌组织中检测到CD44+/CD24-细胞,随着病变的进展,CD44+/CD24-细胞的数量也增加,差异具有显著统计学意义。此外,在33.3%(15/45)的正常乳腺组织中有CD44-/CD24+表达,43.9%(18/41)的乳腺良性增生组织、46.2%(18/39)的乳腺不典型增生组织、68.6%(35/51)的乳腺原位癌组织、86.0%(104/121)的浸润性乳腺癌组织检测到CD44-/CD24+细胞,且阳性细胞百分率随病变程度升高。在浸润性乳腺癌组织中CD44+/CD24-的表达与肿瘤有无淋巴结转移相关(P<0.05),但与病人年龄、月经状态、肿瘤的组织学类型、病理分级、肿瘤大小、ER、PR及Her-2的表达无显著相关(P>0.05),CD44-/CD24+的表达率与乳腺癌患者的各项临床病理特征均无统计学意义(P>0.05)。[结论]CD44+/CD24-、CD44-/CD24+细胞在乳腺增生和癌变过程中可能起重要作用。