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*

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

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

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

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 evaluate the immunophenotype conversion of fibroblasts and its clinical significance in the process of breast tumor stromal remodeling.

METHODSCD34, FAP-α, p63 and a-SMA were detected by immunohistochemistry in 273 breast biopsies, including 60 normal breast tissues, 46 atypical ductal hyperplasia (ADH), 60 ductal carcinoma in situ (DCIS), 47 DCIS microinvasive carcinoma (DCIS-MI) and 60 invasive ductal carcinoma (IDC).

RESULTSThe positive expression rates of CD34, FAP-α and α-SMA in the stromal fibroblasts of normal breast tissues were 93.3%, 6.7% and 18.3%, respectively. Those in the stromal fibroblasts of ADH tissues were 95.7%, 4.3% and 10.9%, respectively. Those in the stromal fibroblasts of DCIS tissues were 95.0%, 8.3% and 15.0%, respectively. Those in the IDC tissues were 35.0%, 85.0% and 93.3%, respectively. The expressions of CD34, α-SMA and FAP-α in the stromal fibroblasts of normal, ASH and DCIS breast tissues did not show significant differences (χ(2) = 1.142, P = 0.896). The main immunophenotype of stromal fibroblasts in the tumor-host interface at the invasive front of ADH and DCIS lesions was CD34(+)α-SMA(+)FAP-α(+). There were statistically significant differences in the expression of CD34, α-SMA and FAP-α between IDC and ADH, DCIS and normal breast tissues (χ(2) = 8.351, P < 0.001). The immunophenotype of stromal fibroblasts in the IDC and DCIS-MI breast tissues was CD34(-) α-SMA(+) FAP-α(+).

CONCLUSIONSImmunophenotype conversion from CD34(+) α-SMA(-) FAP-α(-) to CD34(-) α-SMA(+)FAP-α(+) may be a sensitive indicator to judge whether DCIS has microinvasion. Detection of the immunophenotype conversion of stromal fibroblasts may be helpful to determine the presence of microinvasion, and to improve the diagnostic accuracy rate of DCIS.

Breast ; Breast Neoplasms ; immunology ; pathology ; Carcinoma in Situ ; Carcinoma, Ductal, Breast ; Carcinoma, Intraductal, Noninfiltrating ; Fibroblasts ; immunology ; Gelatinases ; metabolism ; Humans ; Hyperplasia ; Immunohistochemistry ; Immunophenotyping ; Membrane Proteins ; metabolism ; Serine Endopeptidases ; metabolism

OBJECTIVETo study the clinicopathologic features, immunophenotype and differential diagnosis of cystic hypersecretory lesion (CHL) of the breast.

METHODSClinicopathologic and follow-up data of six cases of breast CHL in 2010-2013 were collected and reviewed.Immunohistochemical and mucinous staining was performed.

RESULTSAll six patients were female, age ranged from 37 to 71 years (average 49.3 years). Three cases were cystic hypersecretory hyperplasia (CHH), the other three cases were cystic hypersecretory carcinoma (CHC). Clinically the lesions presented as either breast mass or mammographic calcification.Grossly, the cystic hypersecretory lesions were poorly circumscribed, with multiple colloid containing cysts on the cut surface. Microscopically, the remarkable feature was numerous enlarged cysts which contained densely eosinophilic homogeneous secretion similar to the colloid seen in thyroid follicles, and calcification was seen in the cyst in one case. The secretion was D-PAS and mucicarmine positive. The lining epithelium of the cysts was uniformly flat, cuboid or columnar, and arranged in a monolayer. The cells may be arranged in turfs, solid or micropapillary patterns in CHH.In cases with dysplasia, the epithelium showed cytological and structural atypia, but the usual morphology of atypical dutal hyperplasia such as arcades, rigid bridges or cribriform pattern was less common. The three CHC included two invasive ductal carcinomas (IDC) and one ductal carcinoma in situ (DCIS).In CHL, there was immunoreactivity to S-100 protein, CK5/6 and CK14.Of the three CHCs, ER and PR were expressed in only one IDC.No HER2 expression was identified in the two invasive CHCs.One patient was lost to follow-up, and the rest were uneventful at 18 months.

CONCLUSIONSCHL of the breast is a rare pathological entity. Multiple colloid-filled cysts is a unique histological feature. The epithelium of CHL may show usual hyperplasia, dysplasia or carcinoma.

Adult ; Aged ; Breast ; pathology ; Breast Neoplasms ; metabolism ; pathology ; surgery ; Carcinoma, Ductal, Breast ; metabolism ; pathology ; surgery ; Carcinoma, Intraductal, Noninfiltrating ; metabolism ; pathology ; surgery ; Epithelium ; pathology ; Female ; Fibrocystic Breast Disease ; metabolism ; pathology ; surgery ; Humans ; Hyperplasia ; Immunohistochemistry ; Keratin-14 ; metabolism ; Keratin-5 ; metabolism ; Keratin-6 ; metabolism ; Lymphatic Metastasis ; Middle Aged ; S100 Proteins ; metabolism

OBJECTIVETo evaluate the efficacy and safety of trastuzumab plus different chemotherapy regimens in treatment of patients with HER-2-positive advanced breast cancer.

METHODS132 patients with advanced HER-2-positive breast cancer were treated with trastuzumab plus different regimens. The clinical characteristics, efficacy and toxicity of the 132 patients were retrospectively analyzed.

RESULTSFive patients had complete response (CR), 61 patients had partial response (PR), 39 patients had stable disease (SD), and 27 patients had progressive disease (PD). The objective response rate was 50.0% and the disease control rate was 79.5%. The median progression-free survival was 9.3 months. The median overall survival time was 46.2 months. The 1-, 2-, 5- year survival rates were 98.3%, 81.9% and 40.2%, respectively. Trastuzumab combined with chemotherapy is superior to trastuzumab monotherapy (51.2% vs. 33.3%). The number of metastatic sites, efficacy, different previous treatment lines were independent prognostic factors of PFS (P = 0.002, P < 0.0001 and P < 0.0001, respectively). Visceral metastases, pathological grade, and PFS were independent prognostic factors of OS (P = 0.041, P = 0.001, P = 0.025, P < 0.001, P < 0.0001 and P < 0.0001, respectively). Regarding the toxicities, one case discontinued treatment due to the decrease of left ventricular ejection fraction to 47%, two cases had heartbeat tachycardia, 6 cases had palpitation, 17 cases had a fever during first input trastuzumab. No other serious cardiac toxicity was observed. The most common toxicities were chemotherapy-related hematological and non-hematological toxicities.

CONCLUSIONSTrastuzumab combined with chemotherapy is superior to trastuzumab monotherapy. Patients may get benefits for early use of trastuzumab. Trastuzumab plus chemotherapy is effective and well tolerated in patients with advanced HER-2 positive breast cancer. No heart failure occurred in this series of patients, and cardiac safety seems better than that in Caucasians because of younger age at the onset in Chinese advanced breast cancer patients.

Adult ; Antibodies, Monoclonal, Humanized ; adverse effects ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; adverse effects ; therapeutic use ; Breast Neoplasms ; drug therapy ; metabolism ; pathology ; Carcinoma, Ductal, Breast ; drug therapy ; metabolism ; pathology ; Disease Progression ; Disease-Free Survival ; Female ; Fever ; chemically induced ; Follow-Up Studies ; Humans ; Middle Aged ; Neoplasm Grading ; Neutropenia ; chemically induced ; Receptor, ErbB-2 ; metabolism ; Remission Induction ; Retrospective Studies ; Survival Rate ; Taxoids ; administration & dosage ; Trastuzumab ; Vinblastine ; administration & dosage ; analogs & derivatives ; Vomiting ; chemically induced

OBJECTIVETo explore different therapies and affecting factors in breast cancer patients ≥ 65 years old.

METHODSTo retrospectively analyze the clinical characteristics, treatments, comorbidity and survival rate of 126 female breast cancer patients over 65 years old who underwent surgical operation in our hospital from January 2009 to December 2010. To compare and analyze the differences in the treatment patterns, and find out the affecting factors.

RESULTSOne hundred and twenty-six cases were included in this retrospective study, and they were divided into two groups according to age: 65-74 years old group (71 cases) and >74 years group (55 cases). Most patients in the two groups received modified radical mastectomy (84.5% and 89.1%); 73.2% and 54.5% of patients received adjuvant chemotherapy in the two groups, respectively. 67.6% and 61.8% of the patients had adjuvant endocrine therapy respectively. 19.7% and 7.3% of the patients received radiotherapy, respectively. Chemotherapy in elderly breast cancer patients was correlated with age, pathological types, progesterone receptor (PR) status and comorbidity. Radiotherapy in elderly breast cancer patients was related to age, surgical patterns, TNM stage and lymph node status. Multivariate analysis showed that age, pathological types, PR expression and comorbidity were independent factors affecting choice of chemotherapy in elderly breast cancer patients (P < 0.05 for all). Age and surgical patterns were independent factors affecting choice of radiotherapy (P < 0.05 for all). The 3-year disease-free survival (DFS) rate and overall survival (OS) rate in these patients were 91.3% and 92.0%, respectively. Furthermore, endocrine therapy was related to 3-year DFS rate (P = 0.038) and age was correlated with 3-year OS rate (P = 0.037) in these elderly patients.

CONCLUSIONSBreast cancer in the elderly patients receive similar surgery and endocrine therapy, but the elderly patients are less likely to have chemotherapy and radiotherapy, due to age, PR expression, pathological types, surgical patterns and comorbidity. Only age contributes to the lower 3-year overall survival rate in >74-year old patients.

Adenocarcinoma, Mucinous ; pathology ; surgery ; therapy ; Aged ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Breast Neoplasms ; pathology ; surgery ; therapy ; Carcinoma, Ductal, Breast ; pathology ; surgery ; therapy ; Carcinoma, Intraductal, Noninfiltrating ; pathology ; surgery ; therapy ; Chemotherapy, Adjuvant ; Disease-Free Survival ; Female ; Humans ; Lymphatic Metastasis ; Mastectomy, Modified Radical ; Mastectomy, Segmental ; Neoadjuvant Therapy ; Neoplasm Staging ; Radiotherapy, Adjuvant ; Receptors, Progesterone ; metabolism ; Retrospective Studies ; Survival Rate

OBJECTIVETo analyze the relationship between the expression level of Ki67 and clinicopathological features in breast cancer.

METHODSData of 918 female patients with invasive ductal breast carcinoma treated in the Cancer Hospital, Chinese Academy of Medical Sciences from Jan. to Dec. 2010 were analyzed retrospectively. The correlation of Ki67 expression and other clinicopathological features in the breast cancer was analyzed.

RESULTSAmong the 918 cases, the Ki67 index was 0.9% to 95% (mean value 27.8%). Taking the Ki67 index 14% as the boundary to divide the patients into two subgroups, 263 cases (28.6%) were ≤ 14%, and 655 cases (71.4%) were >14%. There were significant differences between the Ki67 expression and age, tumor size, axillary lymph nodes status, histological grade and the expressions of C-erbB-2, estrogen receptor (ER) and progesterone receptor (PR) (P < 0.05 for all). All the Ki67 indexes of Ki67 expression in luminal B (30.44%), HER-2 overexpression (36.77%) and triple negative (47.40%) subtypes were significantly higher than that in the luminal A subtype (21.36%)(P < 0.01). The expression level of Ki67 in triple-negative subtype (47.40%) was significantly higher than that in the non-triple-negative subtype (24.79%)(P < 0.001).

CONCLUSIONSKi67 index is significantly correlated with the age, tumor TNM stage, axillary lymph node status, histological grading, ER status, PR status and HER-2 status. A high expression level of Ki67 is a poor prognostic factor for breast cancer. The expression level of Ki67 should be detected routinely and it may become a useful prognostic marker in the treatment of breast cancer.

Adult ; Age Factors ; Aged ; Aged, 80 and over ; Breast Neoplasms ; metabolism ; pathology ; Carcinoma, Ductal, Breast ; metabolism ; pathology ; Female ; Humans ; Ki-67 Antigen ; metabolism ; Lymphatic Metastasis ; Middle Aged ; Neoplasm Grading ; Neoplasm Staging ; Prognosis ; Receptor, ErbB-2 ; metabolism ; Receptors, Estrogen ; metabolism ; Receptors, Progesterone ; metabolism ; Retrospective Studies ; Young Adult