TROP-2 expression in papillary thyroid cancer: a preliminary cyto-histological study.

OBJECTIVE: TROP-2 (human trophoblast cell surface marker) is a gene-related protein expressed in trophoblastic cells, which is also present in a variety of epithelial cancers and whose overexpression has been found to correlate with a poor prognosis. We analysed the possibility of using the expression of TROP-2 to detect papillary thyroid carcinoma (PTC) on cytological and histological samples, and compared it with Hector Battifora mesothelial antigen-1 (HBME-1). METHODS: From 127 patients, 127 fine needle aspirates (FNAs), in which HBME-1 was detected by immunocytochemistry (ICC), were re-classified according to the Bethesda system for reporting thyroid cytopathology (TBSRTC): 20% were benign, 56% were atypical cells/follicular lesion of undetermined significance (AUS/FLUS), 4% were follicular neoplasm/suspicious for a follicular neoplasm, 5% were suspicious for malignancy and 16% were malignant. Sufficient material to test for TROP-2 was available in 64 FNAs, 22 of which had a histological control. Including six additional cases in which the FNAs were not available, immunohistochemistry (IHC) was carried out with both markers on 94 cases. RESULTS: Among 88 FNAs with histological control, the sensitivity of HBME-1 to predict PTC was 87.5% (28/32) and the specificity was 86% (48/56), whereas, in 22 FNAs, TROP-2 sensitivity was 100% (13/13) and specificity was 89% (8/9). In 94 histological specimens in which IHC was carried out with both markers, the sensitivity and specificity were 82% and 86%, respectively, for HBME-1 and 87% and 89%, respectively, for TROP-2. The difference between the markers was not significant. Concordance between IHC and ICC was 76% for HBME-1 and 91% for TROP-2. CONCLUSION: TROP-2 can be used as well as HBME-1 in thyroid cytology to detect PTC. Positivity for either or both markers could help to stratify the risk of malignancy in indeterminate FNAs. Larger studies are need to analyse its role in the behaviour of PTC and its variants.

Nuclear NHERF1 expression as a prognostic marker in breast cancer.

Our purpose was to investigate whether Na(+)/H(+) exchanger regulatory factor 1 (NHERF1) expression could be linked to prognosis in invasive breast carcinomas. NHERF1, an ezrin-radixin-moesin (ERM) binding phosphoprotein 50, is involved in the linkage of integral membrane proteins to the cytoskeleton. It is therefore believed to have an important role in cell signaling associated with changes in cell cytoarchitecture. NHERF1 expression is observed in various types of cancer and is related to tumor aggressiveness. To date the most extensive analyses of the influence of NHERF1 in cancer development have been performed on breast cancer. However, the underlying mechanism and its prognostic significance are still undefined. NHERF1 expression was studied by immunohistochemistry (IHC) in a cohort of 222 breast carcinoma patients. Association of cytoplasmic and nuclear NHERF1 expression with survival was analyzed. Disease-free survival (DFS) and overall survival (OS) were determined based on the Kaplan-Meier method. Cytoplasmic NHERF1 expression was associated with negative progesterone receptor (PgR) (P=0.017) and positive HER2 expression (P=0.023). NHERF1 also showed a nuclear localization and this correlated with small tumor size (P=0.026) and positive estrogen receptor (ER) expression (P=0.010). Multivariate analysis identified large tumor size (P=0.011) and nuclear NHERF1 expression (P=0.049) to be independent prognostic variables for DFS. Moreover, the nuclear NHERF1(-)/ER(-) immunophenotype (27%) was statistically associated with large tumor size (P=0.0276), high histological grade (P=0.0411), PgR-negative tumors (P<0.0001) and high proliferative activity (P=0.0027). These patients had worse DFS compared with patients with nuclear NHERF1(+)/ER(+) tumors (75.4% versus 92.6%; P=0.010). These results show that the loss of nuclear NHERF1 expression is associated with reduced survival, and the link between nuclear NHERF1 and ER expression may serve as a prognostic marker for the routine clinical management of breast cancer patients.

Angiogenetic axis angiopoietins/Tie2 and VEGF in familial breast cancer.

Angiogenesis leads to the formation of blood vessels from pre-existing ones, allowing tumor growth. Vascular endothelial growth factor (VEGF) and Angiopoietins (Ang-1, Ang-2) have a pivotal role in tumor angiogenesis but few data regarding their role in hereditary breast cancer are available. The aim of the present study was to analyze Ang-1, Ang-2, tyrosine-protein kinase receptor Tie2 and VEGF expression and their correlation in a cohort of familial and sporadic breast cancers in order to verify whether the presence of germline mutations in BRCA may have a role in tumor microenvironment regulation. Tumor samples from a cohort of 41 patients with a first diagnosis and a family history of breast cancer and 19 patients with sporadic breast cancers were enrolled. The expression of Tie2, Ang-1, Ang-2 and VEGF were analyzed by quantitative real-time PCR. Patients harboring BRCA mutations had higher levels of Ang-1 (P=0.05), Ang-2 (P=0.02) and VEGF (P=0.04) mRNA compared with those without BRCA mutations (BRCAX). The same was observed in triple-negative breast cancer (TNBC). Moreover, a positive correlation between Ang-2 and VEGF was found in both the familial breast cancer group (BRCA carriers: r=0.83; P<0.0001 and BRCAX: r=0.58; P=0.008) and in TNBC (r=0.62; P=0.007). The higher levels of Ang-1, Ang-2 and VEGF mRNA found in BRCA carriers and TNBCs suggest that they could be attractive angiogenic therapeutic targets in these breast cancers.