The characteristic genetic abnormality of neuroendocrine neoplasms (NENs), a heterogeneous group of tumors found in various organs, remains to be identified. Here, based on the analysis of the splicing variants of an oncogene Focal Adhesion Kinase (FAK) in The Cancer Genome Atlas datasets that contain 9193 patients of 33 cancer subtypes, we found that Box 6/Box 7-containing FAK variants (FAK^6/7) were observed in 7 (87.5%) of 8 pancreatic neuroendocrine carcinomas and 20 (11.76%) of 170 pancreatic ductal adenocarcinomas (PDACs). We tested FAK variants in 157 tumor samples collected from Chinese patients with pancreatic tumors, and found that FAK^6/7 was positive in 34 (75.6%) of 45 pancreatic NENs, 19 (47.5%) of 40 pancreatic solid pseudopapillary neoplasms, and 2 (2.9%) of 69 PDACs. We further tested FAK splicing variants in breast neuroendocrine carcinoma (BrNECs), and found that FAK^6/7 was positive in 14 (93.3%) of 15 BrNECs but 0 in 23 non-NEC breast cancers. We explored the underlying mechanisms and found that a splicing factor serine/arginine repetitive matrix protein 4 (SRRM4) was overexpressed in FAK^6/7-positive pancreatic tumors and breast tumors, which promoted the formation of FAK^6/7 in cells. These results suggested that FAK^6/7 could be a biomarker of NENs and represent a potential therapeutic target for these orphan diseases.
Female ; Humans ; Alternative Splicing ; Breast Neoplasms/metabolism* ; Carcinoma, Pancreatic Ductal/pathology* ; Focal Adhesion Protein-Tyrosine Kinases/therapeutic use* ; Nerve Tissue Proteins/genetics* ; Neuroendocrine Tumors/genetics* ; Oncogenes ; Pancreatic Neoplasms/metabolism*

PURPOSE: The aims of this study were to compare the expression of sarcosine metabolism-related proteins between invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) and to determine the implications of these results. MATERIALS AND METHODS: Tissue microarrays were constructed, containing 30 samples from normal breast tissue, 114 samples from patients with ILC, and 692 samples from patients with IDC. Immunohistochemical staining was performed to examine the expression of sarcosine metabolism-related proteins [glycine N-methyltransferase, sarcosine dehydrogenase, and l-pipecolic acid oxidase (PIPOX)]. RESULTS: The sarcosine metabolic phenotype differed between ILC and IDC (p<0.001). In IDC, sarcosine metabolic phenotype was distributed as null type (61.7%)>low sarcosine type (30.4%)>high sarcosine type (5.0%)>intermediate type (2.9%). However, in ILC, the sarcosine metabolic phenotype was distributed as low sarcosine type (61.4%)>null type (32.5%)>intermediate type (5.3%)>high sarcosine type (0.9%). PIPOX showed higher expression in ILC than in IDC (p<0.001) and correlated with androgen receptor (AR) positivity (p=0.001) in ILC. CONCLUSION: Expression of sarcosine metabolism-related proteins differed between ILC and IDC. Low sarcosine type was the majority sarcosine metabolic phenotype of ILC. PIPOX expression was predominant in ILC and correlated with AR positivity.
Adult ; Breast/pathology ; Breast Neoplasms/*metabolism/pathology ; Carcinoma, Ductal, Breast/*metabolism/pathology ; Carcinoma, Lobular/*metabolism ; Female ; Humans ; Immunohistochemistry ; Middle Aged ; Multivariate Analysis ; Phenotype ; Proportional Hazards Models ; Regression Analysis ; Retrospective Studies ; Sarcosine/genetics/*metabolism ; Tissue Array Analysis

OBJECTIVETo study the relationship between fibrotic focus (FF) and carbonic anhydrase (CA) IX in invasive ductal carcinomas (IDC) of the breast.

METHODSIn 167 cases of IDC, the FF was assessed morphologically, and expression of ER, PR and CA IX was evaluated using MaxVision immunohistochemistry.

RESULTSThe expression of CA IX in IDC with and without FF was 56.3% (45/80) and 28.7% (25/87) respectively, with significant difference (P=0.001). In IDC with FF, the CA IX expression of tumor cells in tumors with CA IX-positive fibroblasts (35/40, 87.5%) was significantly (P<0.001) higher than that in tumors with CA IX-negative fibroblasts (10/40, 25.0%). In IDC with FF, the CA IX expression of fibroblasts of FF in grade 3 IDC (23/33, 69.7%) was significantly (P=0.006) higher than that in grade 1+2 tumors (17/47, 36.2%). The ER and PR expression of tumor cells in tumors containing CA IX-negative fibroblasts was 72.5% (29/40) and 65.0% (26/40) respectively, whereas the ER and PR expression of tumor cells in tumors containing CA IX-positive fibroblasts was 50.0% (20/40) and 42.5% (17/40) respectively; the difference was statistically significant (for both ER and PR, P=0.04). The age of patients with tumors containing CA IX-negative fibroblasts was significantly (P=0.002) older than those containing CA IX-positive fibroblasts. The FF diameter/tumor diameter in tumors containing CA IX-positive fibroblasts was significantly larger than those containing CA IX-negative fibroblasts. (3) For the groups of tumor size≤2 cm and tumor size between 2 cm to 5 cm, the diameter of the fibrotic focus was significantly (P<0.01) smaller than the fibrotic focus size of tumors>5 cm in size.

CONCLUSIONSCA IX expression is correlated with FF, and that in fibroblasts of FF correlated with patients' age, tumor grade, hormone receptors and FF diameter/tumor diameter. CA IX expression in FF might be a marker for poor prognosis in patients with breast cancer.

Age Factors ; Antigens, Neoplasm ; Breast Neoplasms ; metabolism ; pathology ; Carbonic Anhydrase IX ; Carbonic Anhydrases ; Carcinoma, Ductal, Breast ; enzymology ; pathology ; Female ; Fibroblasts ; metabolism ; Humans ; Immunohistochemistry ; Neoplasm Grading ; Neoplasm Proteins ; Receptors, Estrogen ; metabolism ; Receptors, Progesterone ; metabolism

OBJECTIVETo investigate the expression of high-molecular-weight keratins CK5/6, CK14, estrogen receptor (ER) and progesterone receptor (PR) in differential diagnosis of simple ductal hyperplasia (UDH), atypical ductal hyperplasia (ADH) and low-grade ductal carcinoma in situ (low-grade DCIS) .

METHODSThe clinicopathological data of twenty cases of atypical ductal epithelial hyperplasia (ADH) with focal cancerization changed into low-grade DCIS diagnosed at Tianjin Medical University Cancer Institute and Hospital between January 2013 and February 2014 were reviewed and analyzed. The expressions of CK5/6, CK14, ER and PR were detected by immunohistochemistry.

RESULTSPositive expressions of CK5/6 and CK14 were seen in UDH showing a mosaic pattern, while negative expression in ADH and low-grade DCIS. In addition, CK5/6 and CK14 were positively expressed in the myoepithelial cells of UDH, ADH and low-grade DCIS. Positive expressions of ER and PR were observed in UDH, ADH and low-grade DCIS. But they presented diffuse and homogeneous strong positive expression in ADH and variable positive expression in UDH.

CONCLUSIONIn the intraductal proliferative lesions of the breast, the use of combined detection of the expression of CK5/6, CK14, ER and PR is of practical significance in the differential diagnosis of UDH, ADH and low-grade DCIS.

Breast ; metabolism ; pathology ; Breast Neoplasms ; diagnosis ; metabolism ; Carcinoma, Ductal, Breast ; diagnosis ; metabolism ; Carcinoma, Intraductal, Noninfiltrating ; diagnosis ; metabolism ; Diagnosis, Differential ; Female ; Humans ; Hyperplasia ; diagnosis ; metabolism ; Immunohistochemistry ; Keratin-14 ; metabolism ; Keratin-5 ; metabolism ; Keratin-6 ; metabolism ; Receptors, Estrogen ; metabolism ; Receptors, Progesterone ; metabolism

OBJECTIVE: To study the expression of PTEN, p53 and epidermal growth factor receptor (EGFR) in the molecular subtypes of breast carcinoma and to evaluate the correlations with triple-negative breast cancer.
 METHODS: Immunohistochemical MaxVision(TM) method was used to detect the expression of PTEN, p53, EGFR, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) in 291 cases of infiltrating ductal carcinoma of breast. 
 RESULTS: The positive expression of PTEN, p53 and EGFR protein in breast carcinoma was 57.0%, 57.0% and 38.5%, respectively, which were significantly different from those in benign breast diseases (P<0.05). The expression of PTEN or EGFR in breast cancer was correlated with tumor size, histological grade, lymph node metastasis, TNM stage, ER and HER2 status (P<0.05); the expression of p53 was correlated with tumor size, histological grade and ER status (P<0.05). The difference of positive expression rates of PTEN, p53 and EGFR protein among different subtypes including luminal A, luminal B (HER2-), luminal B (HER2+), HER2 over-expression and triple-negative was statistically significant (P<0.05). There were close correlations among PTEN, p53 and EGFR in the triple-negative subtype (P<0.05).
 CONCLUSION Low expression of PTEN and high expression of EGFR and p53 are observed in triple-negative breast cancer, which may synergistically contribute to the pathogenesis of triple-negative breast cancer.
Breast Neoplasms ; classification ; metabolism ; pathology ; Carcinoma, Ductal, Breast ; metabolism ; pathology ; Female ; Humans ; Lymphatic Metastasis ; PTEN Phosphohydrolase ; metabolism ; Receptor, ErbB-2 ; metabolism ; Receptors, Estrogen ; metabolism ; Receptors, Progesterone ; metabolism ; Triple Negative Breast Neoplasms ; metabolism ; pathology ; Tumor Suppressor Protein p53 ; metabolism

OBJECTIVETo investigate the different expressions of ER and ER gene status between primary and relapsed/metastatic lesions and their clinical significance.

METHODSER and ER gene status of primary and relapse/metastatic breast cancer masked in 70 metastatic breast cancer patients were assessed by determination of methylation status by immunohistochemistry (IHC) and methylation specific polymerase chain reaction (MSP), respectively.

RESULTSPositive rate of ER in the primary breast cancers was 64.3%, and in the relapse/metastatic lesions was 41.4% (P < 0.05). There were six patients whose positive ER status was changed to negative, among them the ER gene status was changed from demethylation to hypermethylation in four cases. Another four patients with negative ER status changed to positive, and their ER gene hypermethylation changed to ER demethylation status.

CONCLUSIONSThe discordance of ER expression status in primary and relapse/metastatic lesions of breast cancer might be related to DNA methylation status.

Adult ; Aged ; Breast Neoplasms ; genetics ; metabolism ; pathology ; Breast Neoplasms, Male ; genetics ; metabolism ; pathology ; Carcinoma, Ductal, Breast ; genetics ; metabolism ; pathology ; secondary ; DNA Methylation ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Immunohistochemistry ; Liver Neoplasms ; genetics ; metabolism ; secondary ; Lung Neoplasms ; genetics ; metabolism ; secondary ; Male ; Middle Aged ; Neoplasm Recurrence, Local ; Receptors, Estrogen ; genetics ; metabolism

OBJECTIVETo investigate the predictive factors affecting sentinel lymph node status in early breast cancer patients.

METHODSClinicopathological data of 1 038 patients with early breast cancer, who underwent sentinel lymph node biopsy in Henan Tumor Hospital between July 2010 and August 2013, were reviewed. Logistic regression analysis was performed to identify the relevance of clinicopathological features with sentinel lymph node metastases.

RESULTSThis group was consisted of 1 038 female patients with an average of 48.6 years. Positive sentinel lymph nodes were found in 22.9% (238/1 038) of the patients. The average number of sentinel lymph nodes removed by surgery was 3.8. Tumor size, tumor location, histopathology, ER/PR status and Ki-67 level were significantly correlated with SLN metastasis(P < 0.05 for all). All the above factors but Ki-67 level were significant independent predictors for SLN metastasis(P < 0.01 for all).

CONCLUSIONNegative hormone receptor status, invasive cancer of non-specific histopathological type, tumor size >2 cm, and tumor location in the outer upper quadrat are independent predictive factors of sentinel lymph node metastasis in patients with early breast cancer.

Adult ; Aged ; Aged, 80 and over ; Breast Neoplasms ; metabolism ; pathology ; surgery ; Carcinoma, Ductal, Breast ; metabolism ; pathology ; surgery ; Female ; Humans ; Ki-67 Antigen ; metabolism ; Lymph Node Excision ; Lymph Nodes ; pathology ; Lymphatic Metastasis ; Middle Aged ; Neoplasm Staging ; Receptors, Estrogen ; metabolism ; Receptors, Progesterone ; metabolism ; Retrospective Studies ; Sentinel Lymph Node Biopsy ; Tumor Burden ; Young Adult

OBJECTIVETo explore the feasibility of testing HER-2 expression and gene amplification in fine needle aspiration specimens of advanced breast cancers, and to benefit the patients receiving targeted drug therapy.

METHODSLiquid-based cytology specimens by fine needle aspiration of 49 breast cancer cases were used in this study. The expression of HER-2 protein was detected by immunocytochemistry (ICC) and the gene amplification was assessed by fluorescence in situ hybridization (FISH). All the 49 cases had overexpression of HER-2 protein marked as ++ or +++ in immunohistochemistry (IHC), and had corresponding FISH results in formalin-fixed, paraffin-embedded (FFPE) tissue samples.

RESULTSFNA samples in all the 49 cases were tested by FISH, and showed a complete agreement with the FISH results in the histological specimens (kappa = 1.0). Of the 49 cases, 33 had HER-2 gene amplification in FFPE samples. So do that in FNA samples. Both had an amplification rate of 67.3%. Among the 33 cases with HER-2 gene amplification, 26 had an ICC score of +++ (78.8%). The conformity rate was 78.8%. Of the 33 cases, 29 had an IHC score of +++ (87.9%). Its conformity rate was 87.9%. The difference between the ICC and IHC results was statistically not significant (P = 0.322). Among the 16 cases with negative gene amplification by both ICC and IHC, 15 cases showed HER-2 protein expression as 0/+, and another one case was not counted because there was not enough cells. Of the 16 cases, 15 had an IHC score of ++ and one of +++ . To take the FISH results as gold standard, ICC results had a high sensitivity (87.9%) and specificity (100.0%).

CONCLUSIONSFISH in FNA samples can be used in the clinic to test HER-2 gene amplification and overexpression in breast cancers, with a high sensitivity and specificity in ICC. Our data support the use of FISH and ICC analysis to determine HER-2 status on FNA specimens in patients with advanced breast cancer and recurrence or metastatic tumors. When ICC score is +++ , it indicates that there is a HER-2 gene amplification by FISH.

Adult ; Aged ; Biopsy, Fine-Needle ; Breast Neoplasms ; genetics ; metabolism ; pathology ; Carcinoma, Ductal, Breast ; genetics ; metabolism ; pathology ; Female ; Gene Amplification ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Lymphatic Metastasis ; Middle Aged ; Neoplasm Recurrence, Local ; Neoplasm Staging ; Paraffin Embedding ; Receptor, ErbB-2 ; genetics ; metabolism ; Sensitivity and Specificity

OBJECTIVETo study the expression of fascin-1 protein in breast cancer and to evaluate its correlation with clinicopathologic features of the tumor.

METHODSImmunohistochemical EnVision method was performed to evaluate the expression of fascin-1 in 23 cases of normal breast tissues, 69 cases of benign breast lesions, 58 cases of usual ductal hyperplasia (UDH), 61 cases of ductal carcinoma in situ (DCIS) and 221 cases of breast cancer from March 2007 to December 2011.

RESULTSFascin-1 protein expression rates in normal breast tissues, benign breast lesions, UDH, DCIS and breast cancer were 100.0% (23/23), 89.9% (62/69), 13.8% (8/58), 19.7% (12/61), and 42.1% (93/221), respectively. Fascin-1 expression in normal breast tissues and benign breast lesions was significantly higher than those in UDH, DCIS and breast cancer (P < 0.01); Fascin-1 expression in breast cancer was significantly higher than those in UDH and DCIS (P < 0.01). There was a tendency of increased fascin-1 expression in DCIS compared to UDH, but the difference was not statistically significant (P > 0.05). Fascin-1 positive rates in patients with DCIS grade III (26.8%, 11/41) was significantly higher than that in patients with DCIS grade I-II (1/20, P < 0.05). Fascin-1 protein expression in breast cancer increased with increasing histologic grade and clinical stage (P < 0.01). Fascin-1 protein expression was also significantly higher in tumors with negative estrogen receptor (ER) and progestone receptor (PR) status and > 3 axillary lymph node metastases compared to tumors that were ER and PR positive and ≤ 3 axillary lymph node metastases (P < 0.01 and P < 0.05, respectively). Logistic regression analysis showed that fascin-1 expression correlated positively with high clinical stage (OR = 1.568, 95% CI = 1.029-2.387, P < 0.05) , but negatively with ER expression (OR = 0.149, 95% CI = 0.079-0.281, P < 0.01) .

CONCLUSIONSFascin-1 is highly expressed in normal breast tissues and benign breast lesions, suggesting that it may be a biological marker of mature mammary ductal epithelium. Fascin-1 protein expression shows a significantly increasing trend from UDH, DCIS to invasive breast cancer, suggesting that fascin-1 plays an important role in breast carcinogenesis and may be a potential target for therapy.

Axilla ; Breast ; metabolism ; pathology ; Breast Neoplasms ; metabolism ; pathology ; Carcinoma in Situ ; metabolism ; pathology ; Carcinoma, Ductal, Breast ; metabolism ; pathology ; Carrier Proteins ; metabolism ; Estrogen Receptor alpha ; metabolism ; Female ; Humans ; Hyperplasia ; metabolism ; Lymph Nodes ; metabolism ; Lymphatic Metastasis ; Microfilament Proteins ; metabolism ; Receptors, Estrogen ; metabolism

OBJECTIVETo detect the expression of pan-neuronal marker protein gene product (PGP)9.5 and its clinicopathologic significance in breast cancer.

METHODSThe expression of PGP9.5 was examined by immunohistochemistry EnVision method in 196 cases during 2007 to 2011, including 20 normal tissues, 14 cases of fibroadenoma, 18 cases of ductal carcinoma in situ (DCIS) and 144 cases of invasive ductal carcinoma (IDC) of the breast. The relationship between PGP9.5 expression and clinicopathologic characteristics of IDC was assessed.

RESULTSPGP9.5 expression was localized in the stroma of all normal breast tissues, but there was no expression observed in all fibroadenomas and DCIS. Overall, the expression rate of PGP9.5 in IDC was 61.8% (89/144). PGP9.5 expression increased from grade 1 tumors (29.4%, 10/34) to grade 2-3 tumors (71.8%, 79/110; P = 0.000). In addition, patients with less than 3 years disease-free survival tended to show higher PGP9.5 expression (64.8%, 35/54), compared to patients with equal to and/or more than 3 years disease-free survival (46.7%, 42/90; P = 0.035). However, there was no correlation between PGP9.5 expression and tumor size, tumor stage, lymph metastasis, hormone receptor expression.

CONCLUSIONPGP9.5 expression is correlated with tumor grade and prognosis in IDC of the breast.

Adult ; Aged ; Biomarkers, Tumor ; metabolism ; Breast Neoplasms ; metabolism ; pathology ; Carcinoma, Ductal, Breast ; metabolism ; pathology ; Carcinoma, Intraductal, Noninfiltrating ; metabolism ; pathology ; Disease-Free Survival ; Female ; Fibroadenoma ; metabolism ; pathology ; Humans ; Middle Aged ; Neoplasm Grading ; Ubiquitin Thiolesterase ; metabolism