The expression pattern of MUC1 (EMA) is related to tumour characteristics and clinical outcome in 'pure' ductal carcinoma in situ of the breast

AIMS: To classify MUC1 according to five predefined expression patterns in ductal carcinoma in situ (DCIS) and related clinicopathological parameters, coexpression of other biological markers and prognosis. METHODS AND RESULTS: With a manual tissue arrayer, 92% (n = 80) of the 87 DCIS samples were successfully targeted. Immunohistochemistry was carried out for MUC1, oestrogen receptor (ER), progesterone receptor (PR), Her2/Neu, p53 and cyclin D1. Entire membrane expression was related to Her2/neu negativity (P =0.042). Apical membrane expression was associated with low grade (P = 0.027), Her2/neu negativity (P = 0.014) and PR positivity (P = 0.005). Focal cytoplasmic expression was related to high grade (P = 0.006). Diffuse cytoplasmic expression was associated with high grade (P = 0.004), large tumour size (P = 0.046), Her2/neu positivity (P =0.042) and cyclin D1 positivity (P = 0.002). On the basis of these analyses the four patterns were reclassified as membranous or cytoplasmic expression. On multivariate analysis, cytoplasmic MUC1 expression (hazard ratio 8.5, 95% confidence interval 1.0, 73.0; P = 0.04) was the only independent predictor of local recurrence. CONCLUSIONS: Four patterns of MUC1 expression are recognized in DCIS that suggest a relationship to functional differentiation and can be simplified into two types that are clinically relevant and could therefore be helpful in the distinction between different subgroups of DCIS.     

p27KIP-1, cyclin A and cyclin D1 protein expression in ductal carcinoma in situ of the breast: p27KIP-1 correlates with hormone receptor status but not with local recurrence

Using whole sections of formalin-fixed paraffin-embedded material the expression of p27(KIP-1), cyclin A and cyclin D1 was examined in 60 cases of ductal carcinoma in situ (DCIS) using routine immunohistochemistry with a median follow up of 95 months (range 10-139 months) to identify any association with disease recurrence. Fifty-six patients were treated by local excision and radiotherapy and four by mastectomy without radiotherapy. There was a highly significant positive association between p27(KIP-1) and estrogen receptor/progesterone receptor (ER/PR) status (P = 0.002, P = 0.02) and with p27(KIP-1) and cyclin D1 expression (P = 0.002). A trend between cyclin A and PR status (P = 0.08) was also identified. These findings mirror those described in invasive ductal carcinoma, but there were no associations of any biomarker with histological parameters such as nuclear grade or with local recurrence on univariate analysis, which was present in four of the 56 locally excised group (7.1%). Further examination of a larger cohort may be worthwhile to explore the possible role as adjunctive predictive markers to aid clinical decision making.     

Association of nuclear localization of SHP2 and YAP1 with unfavorable prognosis in non-small cell lung cancer

Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) is ubiquitously expressed in cytoplasmic localization, which in turn confers tumor malignancy and poor prognosis in various human cancers. YAP1 interacts with SHP2 to promote translocation of SHP2 to nucleus, which consequently promotes Wnt target activation. However, the oncogenic role of the nuclear localization of SHP2 in human cancers remains unclear. We hypothesized that nuclear SHP2 localization, in combination with nuclear YAP1 expression, could be associated with poor overall survival (OS) and relapse free survival (RFS) due to an increase in cyclin D1 and c-Myc mRNA expression following activation of Wnt/ß-catenin signaling. Immunohistochemical analysis of SHP2 and YAP1 protein expression in 102 tumors resected from patients with NSCLC revealed that nuclear SHP2 expression was well correlated with nuclear YAP1 expression (P?<?0.001). Evaluation of cyclin D1 and c-Myc mRNA levels by the real-time reverse-phase polymerase chain reaction (RT-PCR) revealed that patients with high cyclin D1 and high c-Myc mRNA expressing tumors more commonly showed high nuclear YAP1 and high nuclear SHP2 (high/high) rather than the high/low, low/high, or low/low combinations (P?<?0.001 for cyclin D1 and c-Myc). Kaplan-Meier and Cox-regression models showed OS and RFS to be poorer in patients in the high/high subgroup than in the low/low subgroup (OS: HR?=?2.85, 95% CI, 1.52–5.35, P?=?0.001; RFS: HR?=?2.55, 95% CI, 1.37–4.72, P?=?0.003). No prognostic significance was observed for the other two subgroups (low/high and high/low) when compared to the low/low subgroup in this study population. Therefore, we suggest that the prognostic value of SHP2 could reflect the nuclear localization of SHP2 and its interaction with nuclear YAP1, which led to subsequent upregulation of cyclin D1 and c-Myc mRNA expression via activation of the Wnt/ß-catenin signaling pathway.     

Expression of p21Waf1, p27Kip1 and cyclin D1 proteins in breast ductal carcinoma in situ: Relation with clinicopathologic characteristics and with p53 expression and estrogen receptor status

p21Waf1 (p21), p27Kip1 (p27) and cyclin D1 have recently been reported as useful prognostic markers for patients with breast carcinoma. However, studies on these cell cycle regulators in ductal carcinoma in situ (DCIS) have been extremely limited. Therefore, we studied the immunohistochemical expression of p21, p27 and cyclin D1 proteins in 49 DCIS cases and compared the findings with the clinicopathologic parameters (age, tumor size, gross type, histologic type, histologic grade, necrosis and mitotic index), p53 and estrogen receptor (ER) status. A significant correlation was found between positive p21 immunoreactivity (67.3% of the cases) and well-differentiated histologic grade, non-comedo type, ER-positive and p53-negative (p53-) status. DCIS with p21+/p53- is likely to be the non-comedo type. The overexpression of cyclin D1 (59.2% of the cases) correlated positively with the ER expression (P = 0.001). The p27 protein expression (46.9% of the cases) correlated with the cyclin D1 immunopositivity (P = 0.0003) and ER expression (P = 0.005). No significant associations were seen in the p27 or cyclin D1 expression and other clinicopathologic parameters. Our results suggest that p21 might be more related to the useful biologic markers in DCIS than p27 or cyclin D1. The significant positive association between p21, p27 or cyclin D1 and ER status, and close association of p27 and cyclin D1 expression might be implicated in the tumor biology of DCIS.     

Oestrogen receptor negativity as a marker for high-grade ductal carcinoma in situ of the breast

AIMS: To compare the morphological and immunohistochemical characteristics of oestrogen receptor (ER)-negative and ER-positive ductal carcinoma in situ (DCIS) of the breast, in an attempt to establish more objective criteria for the classification of DCIS. METHODS AND RESULTS: Sections of 64 cases of in-situ carcinoma of the breast were stained for ER, progesterone receptors (PgR), androgen receptors (AR), c-erbB-2 and p53, using the immunoperoxidase technique. The cases included 60 DCIS and four lobular carcinoma in situ (LCIS). Four DCIS lesions were associated with foci of microinvasion. The 60 DCIS cases included 31 high grade, 23 intermediate grade and six low grade. Twenty-four DCIS cases (40%) were ER-negative and 36 were positive. ER negativity was significantly associated with high nuclear grade (88% versus 27% for ER-positive cases, P < 0.001), PgR negativity (100% versus 25%, P < 0.001), c-erbB-2 positivity (79% versus 14%, P < 0.001) and p53 positivity (58% versus 6%, P < 0.001). There was no difference between ER-negative and -positive DCIS as regards AR expression, with 91% of cases in each group being AR-positive. Of the four cases of DCIS with microinvasion, three were ER- and PgR-negative, all four were c-erbB-2-positive and AR-positive and one was p53-positive. None of the four LCIS was ER, PgR or AR-negative and none was c-erbB-2- or p53-positive. CONCLUSIONS: There is a highly significant direct relationship between ER negativity in DCIS and high nuclear grade, PgR negativity and c-erbB-2 and p53 positivity. We suggest that immunohistological assessment of ER status may help in providing a more objective way of classifying DCIS.     

Immunocytochemical detection of estrogen and progesterone receptors in 124 human breast cancers

Monoclonal antibodies to human estrogen receptor (ER), and rabbit progesterone receptor (PR), also recognizing human PR, were used to detect the receptors by peroxidase immunocytochemistry in frozen sections of 124 primary breast carcinomas. Both ER and PR were almost exclusively located in carcinoma cell nuclei, with heterogeneous distribution and intensity. The staining results were evaluated semiquantitatively (histoscore), based on the percentage of positively stained carcinoma cells and nuclear staining intensity. The receptor status thus determined was as follows: ER+PR+ in 50 patients, ER+PR- in 23, ER-PR- in 26, and ER-PR+ in 3 patients. There was a 79% (ER) or 70% (PR) agreement in the positivity/negativity between the immunocytochemical and steroid-binding assay (in 102 patients) with a highly significant correlation. The histoscore values increased significantly with cytosol receptor levels (ER, r = 0.623, P less than 0.001; PR, r = 0.366, P less than 0.01).     

Cyclin D1 in invasive breast carcinoma: favourable prognostic significance in unselected patients and within subgroups with an aggressive phenotype

Aims: To study the clinicopathological and prognostic value of cyclin D1 overexpression in patients with breast carcinoma. Methods and results: Immunohistochemistry was performed on paraffin‐embedded tissue specimens from 290 invasive breast carcinomas to detect the proteins cyclin D1, oestrogen receptor (ER), progesterone receptor (PR), p53, c‐erbB2, and topoisomerase IIα (topoIIα). Cyclin D1 staining was quantified using a computerized image analysis method. Cyclin D1 overexpression characterized smaller, ER‐positive and PR‐positive tumours (P = 0.017, P < 0.0001, and P < 0.0001, respectively), of a lower histological and nuclear grade (P = 0.011 and P < 0.0001, respectively), and with reduced expression of topoIIα (P = 0.001) and p53 (P < 0.001). Cyclin D1 was found to have an independent favourable impact on the overall survival of both the unselected cohort of patients (P = 0.011) and of patients with ER‐negative and lymph node‐positive tumours (P = 0.034 and P = 0.015, respectively). In triple‐negative tumours, cyclin D1 overexpression was found to have independent favourable impacts on both overall and relapse‐free survival (P = 0.002 for both). Conclusions: This is the first immunohistochemical study to dissociate the advantageous prognostic effect of cyclin D1 overexpression from its association with ER expression, and to provide evidence that cyclin D1 overexpression may be a marker of prolonged survival in patient subgroups with aggressive phenotypes.     

乳腺导管内增生性病变中ER、Ki-67和cyclin D1的表达

目的 探讨ER、Ki-67和cyclin D1在乳腺导管内增生性病变中的表达及意义。方法 采用免疫组化和免疫荧光双标记法对56例乳腺导管内增生性病变进行ER、 Ki-67和cyclin D1染色标记。结果 正常乳腺组织中仅有散在的少数上皮细胞呈ER阳性表达。在普通型导管增生（usual ductal hyperplasia,UDH）中ER表达比正常乳腺组织增加,但ER阳性细胞呈不连续分布,阳性细胞间有较多的阴性细胞。非典型性导管增生（atypical ductal hyperplasia,ADH）和低级别原位导管癌（ductal carcinoma in situ,DCIS）中ER表达比UDH明显增加（P〈0．05）,ER阳性细胞呈连续的片状分布,阳性细胞间较少或没有ER阴性细胞。ADH和低级别DCIS中ER表达较高级DCIS显著（P〈0．01）。DCIS中Ki-67和cyclin D1表达高于UDH（P〈0．05）,并与UDH、ADH和DCIS的组织学分组呈正相关（r=0．352,P〈0．05和r=0．390,P〈0．05）。正常乳腺组织中上皮细胞内无ER和Ki-67同时表达。在UDH中有极少数上皮细胞ER和Ki-67同时表达,而在ADH和DCIS中ER和 Ki-67同时表达的细胞明显增加。结论 从正常乳腺组织到UDH、ADH、低级DCIS的恶性转化过程中伴有ER表达的逐渐增高。ER过度表达及ER和Ki-67在上皮细胞内同时表达可能是某些乳腺癌发生过程中的早期事件。     

Patterns of episialin/MUC1 expression in endometrial carcinomas and prognostic relevance

AIMS: To investigate episialin/MUC1 expression in the normal, hyperplastic and neoplastic endometrium, and relate patterns of tumour MUC1 reactivity with histopathological characteristics, oestrogen and progesterone receptor (ER and PR) status, bcl-2 and p53 oncoproteins and with clinical behaviour. METHODS AND RESULTS: We studied 42 normally cycling endometria, 45 endometrial hyperplasias of various forms, and 111 endometrial carcinomas of endometrioid and non-endometrioid cell types with specific monoclonal antibodies employing standard immunohistochemical techniques. The follow-up period ranged from 34 to 182 months with a median of 86 months. Epithelial mucin episialin/MUC1 was consistently expressed in the normal endometrium, following a cyclical pattern: "apical membrane staining" in early and mid-proliferative endometrium; "purely cytoplasmic staining" in late proliferative endometrium; and "cytoplasmic staining with intraluminal secretions" in secretory endometrium. Immunostaining patterns in simple and complex hyperplasia were similar to late proliferative endometrium, while atypical hyperplasias and endometrial carcinomas either simulated patterns of proliferative endometrium or lacked MUC1 reactivity. Membranous MUC1 positivity was statistically more frequent in endometrioid carcinomas compared with carcinomas of non-endometrioid type (P = 0.006). Cytoplasmic MUC1 positivity was significantly associated with poor prognosis, while MUC1-negative carcinomas were associated with PR expression and an improved survival (P=0.04). There was no association of MUC1 patterns with bcl-2 and p53 immunoreactivity or with other histopathological variables. CONCLUSIONS: Episialin/MUC1 is an integral component of the normal premenopausal endometrium and is probably hormonally regulated. It is frequently expressed in endometrial hyperplasias and carcinomas. The loss of MUC1 expression from endometrial carcinomas is associated with a favourable prognosis.     

Immunophenotypic analysis of inflammatory breast cancers: identification of an 'inflammatory signature'

Inflammatory breast cancer (IBC) is a rare but very aggressive form of breast cancer. Its definition is based on clinical criteria, but a molecular definition could be useful when data are incomplete or features are missing. Recently, the identification of overexpression of E-cadherin in IBC has improved understanding of the molecular basis of this disease. Consequently, the aim of this study was to try to determine an immunophenotypic 'signature' of IBC. A series of 80 cases of IBC were compared with 552 non-IBC control cases and a model was elaborated to evaluate the probability of an inflammatory carcinoma being present in any clinical situation. Tissue microarrays (TMAs) were used to determine the immunohistochemical profile of eight proteins including E-cadherin, EGFR, oestrogen and progesterone receptor (ER and PR), MIB1, ERBB2, MUC1, and P53. All the parameters tested were differentially expressed between IBC and control cases in univariate analysis (p < 0.001). The five variables that were significantly associated with IBC in multivariate analysis were E-cadherin > or = 300 [HR = 5.64 (2.92-10.87)], ER negative [HR = 3.00 (1.67-5.51)], MIB1 > 20 [HR = 3.54 (1.87-6.71)], MUC1 cytoplasmic staining [HR = 2.72 (1.49-4.96)], and ERBB2 positive 2+ or 3+ [HR = 2.46 (1.26-4.78)]. The probability that a breast cancer with this full phenotype at diagnosis was an IBC was 90.5%. If any one of the five parameters was missing, this probability dropped to 75% and was less than 50% when one, two, or three parameters were present. The 5-year overall survival (OS) and 5-year disease-free survival (DFS) of patients with IBC were not significantly different from those of the non-IBC control group that expressed four or five parameters (nIBC-1), but this nIBC-1 control group had a significantly worse outcome than the non-IBC control group (nIBC-2) with only 0-3 parameters (p = 0.0049 for OS and p < 0.0001 for DFS). In conclusion, an immunophenotypic signature was suggested for IBC. This could help to determine the worst cases, independent of clinical criteria.     

Expression of autophagy related proteins in invasive lobular carcinoma: comparison to invasive ductal carcinoma

The aim of this study is to compare the expression of autophagy related proteins in invasive lobular carcinoma (ILC) with that of autophagy related proteins in invasive ductal carcinoma (IDC), and to determinate its implication. Tissue microarray containing 114 ILC and 692 IDC was constructed, and immunohistochemistry was performed for autophagy related protein (beclin-1, LC3A, LC3B, p62) and Ki-67. No significant difference in expression of autophagy-related proteins between pleomorphic type (n = 12) and classic type (n = 102) of ILC was observed, whereas ILC and IDC showed distinguished features that tumoral beclin-1, stromal LC3A, tumoral LC3B, tumoral p62 were highly expressed in IDC and tumoral BNIP3 was highly expressed in ILC (P < 0.001). Beclin-1 expression was correlated with ER negativity (P = 0.016) and TNBC type (P = 0.024). BNIP3 expression was correlated with ER positivity (p = 0.040). Using multivariate Cox analysis, shorter overall survival was associated with tumoral beclin-1 positivity (hazard ratio: 21.19, 95% CI: 1.098-409.1, P = 0.043). In conclusion, ILC and IDC showed different expression pattern of autophagy-related proteins in tumor and stroma that demonstrated by higher expression of tumoral beclin-1, stromal LC3A, tumoral LC3B, tumoral p62 in IDC, and higher expression of tumoral BNIP3 in ILC.     

Combination of MUC5ac and WT‐1 immunohistochemistry is useful in distinguishing pancreatic ductal carcinoma from ovarian serous carcinoma in effusion cytology

Malignant ascites may be the first presentation of an unsuspected cancer. Pancreas and ovary are among the organs that are usually evaluated as a source of primary. The purpose of this study is to investigate a panel of immunohistochemical stains to help differentiate pancreatic from ovarian carcinoma. We evaluated the immunohistochemical staining of eight commercially available antibodies MUC1, MUC2, MUC5ac, Wilm's tumor susceptibility gene 1 (WT1), cytokeratin 7 (CK7), CK20, CA125, and CA19.9 in 25 effusion specimens with evidence of metastatic carcinoma including 14 ovarian serous carcinomas, 9 pancreatic adenocarcinomas, and 2 unknown primaries. Primary ovarian serous carcinomas were positive for WT‐1 (100%), CK7 (93%), CK20 (43%), CA125 (100%), CA19.9 (50%), MUC1 (100%), MUC2 (0%), and MUC5ac (0%). Primary pancreatic carcinomas were positive for MUC5ac (100%), MUC1 (100%), CA19.9 (100%), CK7 (78%), CK20 (22%), CA125 (89%), WT‐1 (0%), and MUC 2 (0%). The combination of MUC5ac positivity/WT‐1 negativity was seen in 100% of pancreatic carcinoma, whereas MUC5ac negativity/WT‐1 positivity in 100% of ovarian serous carcinoma. It appears that the combination of MUC5ac and WT‐1 stains is useful in distinguishing pancreatic ductal from ovarian serous carcinoma in body fluid cytology. Diagn. Cytopathol. 2010. © 2009 Wiley‐Liss, Inc.     

乳腺浸润性导管癌中ER、PR、Her-2、Ki-67表达与病理特征及预后的相关性

目的 探究Ki-67、ER、PR、Her-2等基因在乳腺浸润性导管癌（IDC）组织中的表达,分析其与患者临床病理特征及预后的相关性。方法 收集2013年1月~2014年12月广东医科大学附属医院病理科乳腺包埋石蜡块IDC组织74例。采用免疫组织化学法检测ER、PR、Her-2、Ki-67在IDC组织中的表达,分析其与患者年龄、组织学分级、TNM分期、淋巴结转移及预后的相关性。结果 ①不同年龄、组织学分级、淋巴结转移及TNM分期的IDC患者ER、PR表达情况比较,差异均无统计学意义（P＞0.05）;未发生淋巴结转移的IDC患者Her-2表达低于转移患者,差异有统计学意义（P＜0.05）;不同年龄、组织学分级、TNM分期的IDC患者Her-2表达比较,差异无统计学意义（P＞0.05）;不同TNM分期的IDC患者Ki-67表达情况比较,差异有统计学意义（P＜0.05）,不同年龄、组织学分级、淋巴结转移的IDC患者Ki-67表达比较,差异均无统计学意义（P＞0.05）。 ②Spearman相关性分析显示,ER与PR正相关,ER与Her-2、PR与Her-2负相关,ER、Ki-67和PR、Ki-67负相关,Her-2与Ki-67正相关。③Ki-67阳性表达的IDC患者病死率高于Ki-67阴性表达的患者,差异有统计学意义（P＜0.05）;不同ER、PR、Her-2表达情况的IDC患者病死率比较,差异无统计学意义（P＞0.05）;Ki-67阴性表达患者的总生存时间（OS）高于阳性表达患者,COX多因素分析显示,Ki-67阳性表达是影响IDC患者OS的独立因素（95%CI:0.212~0.865,P=0.018）。结论 Ki-67可作为乳腺浸润性导管癌危险评估的分子标志物,其阳性表达可影响乳腺癌患者的预后。ER、PR、Her-2的表达对乳腺浸润性导管癌患者的预后没有明显影响。     

Nuclear expression of p53, p21 and cyclin D1 is increased in bronchioloalveolar carcinoma

AIMS: The objectives of this study were: (1) to determine, using immunohistochemistry, the level of expression of the cell cycle factors p53, p21 and cyclin D1 in a group of bronchioloalveolar carcinomas (BACs), and to compare these data to relevant published data for lung carcinoma; (2) to determine if higher expression rates for these factors in BAC were associated statistically with advanced clinical stage, greater tumour size, tobacco abuse, and/or BAC subtype; (3) to seek, using Fisher's exact t-test and paired data groups, any significant associations within the expression data for p53, p21 and cyclin D1. METHODS AND RESULTS: A panel of monoclonal antibodies against p53, p21 and cyclin D1 was applied to 19 bronchioloalveolar carcinomas (17 surgical pathology cases and two autopsies) from the tissue archives of St. Louis University. These immunohistochemical stains were graded on a semiquantitative scale according to the prevalence of nuclear staining within the tumour (< 10% positive cells = 0, 10-25% = 1+, 25-50% = 2+, 50-75% = 3+ and 75-100% = 4+). Six of 19 (32%) of BACs showed 1+ or greater p53 positivity, six of 19 (32%) showed 1+ or greater nuclear cyclin D1 positivity, and nine of 19 (47%) of BACs showed 1+ or greater p21 nuclear positivity. A statistically significant correlation was found between p53 and cyclin D1 expression (P = 0.046, Fisher's exact t-test), but not between p53 and p21, or between p21 and cyclin D1. No statistically significant association was found between the cell cycle factor expression data and subtype of BAC (mucinous vs. nonmucinous), tumour diameter, clinical stage or tobacco-use history. CONCLUSIONS: BACs show p53 immunostain positivity at a frequency similar to that published for p53 mutations in lung adenocarcinomas in general. Cyclin D1 and p21 nuclear expression characterizes a significant proportion of BACs, with cyclin D1 and p53 expression showing a statistically significant association. Aberrations in p53, p21, and cyclin D1 expression may be important in the development of a significant proportion of BACs.     

Comparison of HER-2/neu, ER and PCNA expression in premenopausal and postmenopausal patients with breast carcinoma

We attempted to compare the pattern of HER-2/neu, ER and PCNA in premenopausal and postmenopausal patients with breast carcinoma to identify potential biological differences. Five hundred and forty-eight samples from 318 premenopausal and 230 postmenopausal women with invasive ductal carcinoma of the breast were evaluated for HER-2/neu, ER and PCNA expression by immunohistochemistry. HER-2/neu expression showed 27.4% positivity in premenopausal and 24.8% in postmenopausal women; there was no significant difference between the two groups (p>0.05). In contrast, HER-2/neu expression was found to be significantly associated with ER negativity in the two groups (p<0.05 in premenopausal, p<0.001 in postmenopausal patients). However, it was significantly associated with PCNA expression only in the postmenopausal group (p<0.001). 54.4% showed premenopausal tumor cell ER positivity, whereas 64.3% of the postmenopausal group showed positivity. ER expression showed a significant correlation with patient menopausal status (p<0.05). The prevalence of PCNA positivity in the tumor cell components is slightly higher in postmenopausal compared to premenopausal women (p>0.20). The current study is consistent with reports from other groups regarding the correlation of HER-2/neu with adverse pathologic features and with expression of other markers in carcinoma. We also observed there was no trend toward increased HER-2/neu expression in either premenopausal or postmenopausal patients, i.e. there was similar HER-2/neu expression in the two groups. This suggests that HER-2/neu status could be used to determine assignment to specific intensive adjuvant therapy and evaluation of biological behavior in both pre- and postmenopausal patients with breast carcinoma.     

Expression of p16 and pRB in invasive breast cancer

We aimed to assess protein expressions of p16 and pRB in breast cancer and explore the clinicopathologic implications. Tissue microarray (TMA) was constructed with 406 cases of breast cancer. The cases were subgrouped into luminal A, luminal B, HER-2, and triple negative breast cancer (TNBC) based on the results of immunohistochemical stains for ER, PR, HER-2, and Ki-67 and fluorescent in situ hybridization (FISH) for HER-2. One hundred and sixty-eight cases were allocated to the subgroup luminal A; 87 cases to the luminal B; 32 cases to the HER-2; and 119 cases to the TNBC. The TNBC group showed the highest negative rate for p16, and the luminal B and HER-2 groups showed the highest positive rate for p16 (P < 0.001). Alteration of p16 was the highest in the luminal B and HER-2 groups, and pRB expression rate was the highest in the HER-2 group and lowest in the luminal A group. In addition, p16(+)/pRB(+) type was the most common in the luminal B group, p16(+)/pRB(-) in the luminal A group, and p16(-)/pRB(+) in the TNBC group (P < 0.001). Altered p16/pRB(+) and non-altered p16/pRB(+) type was the most common in the luminal B, and altered p16/pRB(-) and non-altered p16/pRB(+) type was the most common in the luminal A (P < 0.001). Alteration of p16 was correlated with higher Ki67 labeling index (LI) (P = 0.013), and p16 negativity was correlated with ER negativity (P = 0.002), PR negativity (P = 0.004), and higher Ki67 LI (P < 0.001). pRB positivity was correlated with PR negativity (P = 0.009), HER-2 positivity (P = 0.001), and higher Ki-67 LI (P < 0.001). In luminal group A, p16 alteration was correlated with shorter DFS in univariate analysis (P = 0.024). In conclusion, Expression rates of p16 and pRB differ according to the molecular subgroups of breast cancer and they subsequently correlate with clnicopathologic factors.     

Hormone receptors in non-malignant meningiomas correlate with apoptosis,cell proliferation and recurrence-free survival

AIMS: A retrospective immunohistochemical and statistical analysis of patients with non-malignant meningiomas was undertaken to determine the correlation of steroid hormone receptor status with apoptosis, tumour cell proliferation, clinicopathological characteristics and prediction of recurrence. METHODS AND RESULTS: Paraffin sections from 51 primary intracranial totally resected benign and atypical meningiomas were immunohistochemically evaluated for the expression of progesterone (PR), oestrogen (ER) and androgen (AR) receptors, apoptotic rate, Bcl-2, p53 and Ki67 antigens. In addition to the above parameters, the mitotic index and the patients' clinicopathological data were statistically correlated and entered in a recurrence-free survival analysis. A high level of apoptotic cell death was associated with loss of PR expression by logistic regression analysis (P = 0.016). An inverse correlation existed between the mitotic index and PR counts (P = 0.009), while high Ki67 values correlated with increased ARs (P = 0.041). Atypical meningiomas had a lower ER staining score (P = 0.036). Multivariate analysis indicated that the absence of PR and large tumour size were significant factors for shorter disease-free intervals. CONCLUSIONS: The results suggest that ER expression is lost or reduced in atypical meningiomas, whereas loss of PR expression is an indicator of increased apoptosis and early recurrence. PRs and ARs may also influence tumour cell proliferation.     

Association of hormone receptor status with grading,age of onset,and tumor size in <Emphasis Type="Italic">BRCA1</Emphasis>-associated breast cancer

BRCA1-associated breast cancer frequently presents with estrogen-receptor (ERα) and progesterone-receptor (PR) negativity, grade 3, and early onset. In contrast, in BRCA1-deficient mice, ERα is highly expressed in early tumorigenesis. In a retrospective cohort study on 587 breast cancer patients with deleterious BRCA1 mutations, the correlation of ER, PR status, grading, age of onset, and tumor size was investigated. ERα and PR expression decreased from 62% in ductal carcinoma in situ (DCIS) to 20% and 16% in pT3, respectively (p value for ER 0.025 and PR 0.035, Fisher’s exact test). The percentage of grade 1/2 tumors decreased from 44% in DCIS to 17% in pT3 (p value 0.074). Moreover, ER/PR positivity increased with increasing age. Our data suggest that early stage BRCA1-associated breast cancers are more frequently ERα and PR positive and low grade than advanced stages. M. Graeser and K. Bosse contributed equally to this paper.     

乳腺癌cyclin D1、Rb蛋白表达的意义

目的：探讨cyclin D1蛋白和Rb蛋白的表达状况与乳腺癌发生发展的关系。方法：采用S-P免疫组化法检测52例乳腺癌和20例良性乳腺病变组织中cyclin D1蛋白和Rb蛋白的表达。结果：乳腺癌中cyclin D1过表达率为34．60％（18／52），显著高于良性乳腺病变组织的10．00％（2／20），P〈0．05，cyclin D1过表达出现于导管内癌中并持续于浸润、转移等进展过程中，与患者年龄、肿瘤大小、腋窝淋巴结转移及组织学分级均无相关性。乳腺癌中Rb蛋白阴性表达率为76．91％（40／52），显著高于良性乳腺病变组织的15．00％，P〈0．05；Rb蛋白阴性表达与乳腺癌临床病理特征间无相关性，Rb蛋白表达阴性者中，cyclin D1过表达率为20．00％，而Rb蛋白表达阳性者中，其cyclin D1过表达率为83．33％，两者比较有显著差异（P〈0．05）。结论：cyclin D1蛋白和Rb蛋白与乳腺癌发生、发 展密切相关；cyclin D1、P16及Rb通路失活可能与乳腺癌的发生密切相关。     

The prognostic value of cyclin D1, p53, and MDM2 protein expression in uveal melanoma

Malignant uveal melanoma is the commonest primary intraocular tumour in adults. It metastasizes frequently and 50% of patients die within 10 years of diagnosis. The expression of cyclin D1, p53, and MDM2 in uveal melanoma and their relationship to metastasis-free 5-year survival was determined, in order to investigate whether these proteins help to distinguish those patients with a favourable prognosis from those with a poorer one. Ninety-six eyes enucleated for uveal melanomas were immunohistochemically analysed for the protein expression of cyclin D1 and related cell-cycle markers, p53 and MDM2. The evaluation of the specimens was undertaken by two independent pathologists without knowledge of the outcome. Statistical analysis of clinical, morphological, and immunohistological features was performed. A 'favourable outcome' was defined as survival of at least 5 years after diagnosis, without metastases (n=57). An 'unfavourable outcome' was defined as death from metastases within the first 5 years after diagnosis of uveal melanoma (n=39). Cyclin D1 positivity (>15% positive tumour cells) as well as p53 positivity (>15% positive tumour cells) was associated with an unfavourable outcome (for cyclin D1: odds ratio=4. 2, 95% confidence interval 1.5-11.8, p=0.006; for p53: odds ratio=3. 2, 95% confidence interval 1.1-9.3, p=0.03). In addition, cyclin D1 positivity was associated with the presence of extraocular extension of the tumour (p=0.01), with the mixed or epithelioid cell type (p=0. 02), and with the tumour cell MIB-1 positivity (p=0.0001). MDM2 immunoreactivity of the tumour cells showed a potential correlation with clinical outcome (odds ratio=2.1, 95% confidence interval 0.8-5. 8, p=0.13). Multiple logistic regression models showed that cyclin D1 positivity is an independent prognostic factor after control for other prognostic markers. The expression of cyclin D1 in uveal melanoma is associated with a more aggressive course and histologically unfavourable disease. This could serve as a further independent prognostic factor in uveal melanoma.