[Neuroendocrine neoplasms of the breast]. / Neuroendokrine Neoplasien der Mamma.

Neuroendocrine neoplasms (NEN) of the breast are specific tumor entities. According to the literature up to 5% of breast neoplasms are malignant epithelial neoplasms of the breast. They are defined by a neuroendocrine (NE) architecture and cytology combined with an expression of the neuroendocrine vesicle markers chromogranin A and/or synaptophysin. The diagnosis is supplemented by the receptor status and the proliferative activity. According to the World Health Organization (WHO) classification of 2012 the following groups of NEN are distinguished: (1) invasive breast carcinoma with NE differentiation, (2) well-differentiated neuroendocrine tumor (NET) and (3) poorly differentiated small cell carcinoma (NEC). This review article focuses on (1) the definition and basic principles of diagnostics, (2) the history, nomenclature and WHO classification from 2003 and 2012, (3) the frequency of breast NEN, (4) the hereditary background and functional activity, (5) the expression of receptors and (6) the possible clinical implications. In addition, the first results of a retrospective single center study (n = 465 patients with breast cancer over a time period of 4 years) on the frequency of NEN of the breast at the Breast Center of the University Hospital Düsseldorf are presented. In this study a frequency of 4.5% of NEN was found based on a diagnostic cut-off of > 50% Chromogranin A and/or synaptophysin positive tumor cells.

Prognostic significance of vascular endothelial growth factor expression in ovarian cancer patients: a long-term follow-up.

The purpose of the study was to determine vascular endothelial growth factor (VEGF) concentrations in ascites from ovarian cancer and to correlate these data with VEGF expression in ovarian tumors, serum VEGF concentrations, and clinicopathologic characteristics. Ascites, serum, and tumor tissue from 65 ovarian carcinomas and eight borderline tumors were collected. VEGF concentration in peritoneal fluids and sera was determined using enzyme immunoassay. VEGF tumor expression was evaluated immunohistochemically. Significantly higher VEGF concentrations were found in ascites from malignant tumors (median, 2575 pg mL(-1)) compared with borderline tumors (median 181.9 pg mL(-1)) and benign peritoneal fluid (184.5 pg mL(-1)). Both VEGF ascites concentration and tumor expression correlated with advanced tumor stages and ascites volume. Elevated VEGF ascites levels were negatively correlated to patient survival. No differences between VEGF serum levels could be observed between ovarian cancer patients and patients with benign cysts. This study showed for the first time the clinical significance of elevated VEGF ascites level in ovarian carcinomas. VEGF is expressed by ovarian tumor cells and locally released in the malignant peritoneal fluid but is not increased in the serum of preoperative ovarian cancer patients. The enhanced VEGF level support novel therapeutic perspectives by VEGF inhibition.

Micrometastatic bone marrow cells at diagnosis have no impact on survival of primary breast cancer patients with extensive axillary lymph node involvement treated with stem cell-supported high-dose chemotherapy.

BACKGROUND: To determine the impact of micrometastatic bone marrow cells (MMC) on survival in high-risk primary breast cancer (HRPBC) patients treated with high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT). PATIENTS AND METHODS: Ninety-one HRPBC patients (73 patients with > or =10 involved axillary lymph nodes (ALN), 18 premenopausal women with > or =4 involved ALN) received one cycle (eight patients) or two cycles of HDCT and ASCT. Bone marrow aspiration was performed before systemic treatment to search for MMC using a cocktail of four monoclonal epithelial-specific antibodies (5D3, HEA125, BM7 and BM8). The influence of MMC and other prognostic factors on disease-free survival (DFS), distant DFS (DDFS), and overall survival (OS) was analysed. RESULTS: In 23 of 91 patients (25%) we detected a median of three MMC (range, 1-43) among 10(6) mononuclear cells. With a median follow-up of 62 months (range, 10-117), the detection of MMC was not associated with DFS (P=0.929), DDFS (P=0.664) or OS (P=0.642). In multivariate analysis the strongest predictor was nodal ratio for DFS (P=0.012) and expression of p53 for OS (P <0.001). CONCLUSION: The detection of MMC at diagnosis has no impact on survival in HRPBC patients treated with HDCT and ASCT.

Gemcitabine, epirubicin and docetaxel as primary systemic therapy in patients with early breast cancer: results of a multicentre phase I/II study.

Developing primary systemic chemotherapy (PST) regimens that induce higher pathological complete response (pCR) rates remains a challenge in operable breast cancer. We recruited 77 eligible patients into a multicentre phase I/II study to evaluate the maximum tolerated dose (MTD), toxicity and efficacy of preoperative gemcitabine day 1 and 8 (800 mg/m(2) fixed dose), epirubicin and docetaxel on day 1 (doses escalated from 60 mg/m(2)) (GEDoc), repeated 3-weekly for 6 cycles with filgrastim support. MTD for epirubicin was 90 mg/m(2) and for docetaxel 75 mg/m(2). Dose-limiting toxicities (DLTs) included febrile neutropenia and grade 3 diarrhoea. Clinical response rate was 92%, pCR rate was 26%. 79% of patients had breast-conserving surgery. Grade 3/4 leucopenia was the main toxicity, occurring in 55 (87%) of 63 patients treated at the MTD. Non-haematological toxicity caused no serious clinical problems. In conclusion, GEDoc is highly active as PST. Efficacy and toxicity compare favourably with other effective combinations.

[Comparative studies on the biological significance of the marker for proliferation Ki-67-Antigen and PCNA in primary ovarian carcinoma]. / Vergleichende Untersuchungen zur biologischen Bedeutung der Proliferationsmarker Ki-67-Antigen und PCNA in primären Ovarialkarzinomen.

OBJECTIVE: It was shown in experimental and clinical investigations, that the biological behavior of malignant tumors is reflected by their proliferative activity. PCNA and Ki-67-Antigen are two nuclear antigens and considered to represent important markers of proliferation. We investigated their proliferation index in primary ovarian carcinomas and correlated the results with tumor stage, grading, histological type and survival. MATERIAL AND METHODS: The expression of PCNA and Ki-67-Antigen was immunohistochemically evaluated using the monoclonal antibodies MIB-1 and PC 10 on formalin-fixed, paraffin-embedded tissue of 49 patients. Statistical data were calculated by means of Fisher's Exact Test and Pearson's Chi 2 Test, survival was estimated by Kaplan Meier Curves. RESULTS: PCNA-expression was shown in all ovarian carcinomas and Ki-67-Antigen-expression was detected with one exception (98%) in all tumors, too. No correlation could be found between Ki-67-Antigen-expression and the prognostic factors mentioned above, whereas a high PCNA-expression was significantly correlated with the tumor grading (G3), (p < 0.05). Patients with ovarian carcinomas with high PCNA proliferation index showed the tendency of a shorter overall survival. DISCUSSION: Ki-67-Antigen and PCNA-expression could be detected in almost all primary ovarian carcinomas. PCNA compared to Ki-67-Antigen is considered to be more useful for the determination of the proliferative activity of ovarian carcinomas, although there was shown just a tendency of overall survival dependent on PCNA-expression, and there was a significant correlation only between PCNA-proliferation index and tumor grading.

The role of 18F-fluoro-deoxyglucose positron emission tomography (18F-FDG PET) in diagnosis of ovarian cancer.

We evaluated the clinical significance of 18F-FDG PET to detect malignant ovarian neoplasms and tumor spread. 40 patients (median age: 57.5 years) underwent laparotomy because of clinical suspicion of malignant ovarian tumors or recurrent disease. The results of the preoperatively performed PET were correlated with the postoperative histologic diagnosis and the intraoperatively assessed tumor spread. In 10 of 40 patients benign tumors were found, among which a tubo-ovarian abscess was the only one diagnosed as false positive. 4/30 malignant neoplasms did not originate from the coelomic epithelium, but all were correctly recognized as malignant tumors by PET, as was recurrent ovarian cancer in 12 patients. Out of 14 primary ovarian carcinomas, 2 borderline tumors and 1 well-differentiated adenocarcinoma FIGO stage I were not correctly identified. Considering the tumor type, sensitivity, and specificity were 90%, calculating for the positive and negative predictive value 96% and 75%, respectively, and 90% for the diagnostic accuracy. Those statistical parameters were slightly lower for PET detection of lymph node metastasis and peritoneal carcinomatosis. Although its diagnostic accuracy may vary depending on the clinical application, 18F-FDG PET is basically a suitable method for detecting ovarian malignancies, particularly in patients with relapsed ovarian carcinoma.

Expression of CD44(v5-10) splicing variants in primary ovarian cancer and lymph node metastases.

BACKGROUND: This study was designed to detect the expression of CD44v splicing variants in primary ovarian carcinomas and their lymph node metastases, in order to evaluate the possible role in intraperitoneal and lymphogenic metastasization. MATERIAL AND METHODS: Paraffin-embedded tissue of 50 patients with ovarian cancer was available from both the primary tumors and from the lymph node metastases. The expression of the CD44 standard from (CD44s) and of the variant isoforms CD44v5, CD44v6, CD44v7 and 8, and CD44v10 was investigated in the tumor cell regions by immunohistochemistry. RESULTS: 45/50 (90%) primary ovarian carcinomas were found to be immunohistochemically positive for the CD44v5 splicing variant; 10 (20%) tumors expressed both CD44v5 and CD44v6. Apart from an additional v7 stain, all of the ovarian carcinomas studied were negative for the splicing variants v7, v7-8 and v10. No differences were revealed in the pattern of CD44 variants expression investigated in primary tumors and in the lymph node metastases. CONCLUSIONS: In ovarian cancer the expression of CD44v5 as a possible first step, as well as CD44v6, probably plays an important role in intraperitoneal implantation. In view of the comparatively heterogeneous expression patterns of CD44v in individual organs, it may be assumed that there are organ-specific differences in this respect, and that the invasion potential is influenced by both the expression pattern and the extent of expression.