Clinico-morphological analysis of the neuroendocrine neoplasms of the gastroenteropancreatic system.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are unusual and rare epithelial tumors for which the diagnosis of the grade of malignancy and prognostic assessment on the basis ofhistology represent considerable challenges for the pathologist. In this study we conducted a retrospective analysis of the cell proliferation (Ki-67 nuclear antigen) in primary and metastatic GEP NENs of 137 patients as well as the assessment of keratin 19 (CKI9) and progesterone receptors (PR) expression in pancreatic NENs of 57 patients. In 19 (27,1%) GEP NEN metastases was found I,5-4,5-fold increase of Ki-67 index compared with their primaries. Consequently, 6 (21,4%) cases of NETGI and 4 (7,0%) cases of NET G2 were up-graded Pancreatic NETs G2 with Ki-67 index >5% were significantly associated with presence of distant metastases (p =0,007) and decreased survival (p=0,03). Decreased survival also was found in the group of gastrointestinal NET G2 with Ki-67 index > 15% (p=0,005). Further analysis of immunomorphological features and proliferative activity allowed to separate a rare group of tumors - ("NET G3", characterized by decreased survival comparing to NET G2. Expression of CKI9 in pancreatic NETs was significantly associated with higher proliferative activity of primary tumor (p =0,04) and adverse outcome (p=0,003). On other hand, PR expression correlated with lower Ki-67 index (p=0,006), absence of metastases (p=0,004) and favorable outcome (p=0,000). Our results show that Ki67 index is a key parameter of morphological diagnosis of GEP NENs. Thus, the studied markers are important parameters of the morphological diagnostic of GEP NENs, which allow more accurately assess the degree of malignancy, prognosis and treatment of the disease.

Squamous cell carcinoma of the esophagus: evaluation of the status of epidermal growth factor receptors (EGFR and HER-2) by immunohistochemistry and in situ hybridization.

We performed a parallel evaluation of the status of epidermal growth factor receptors EGFR and HER-2 in tumor samples from 31 patients with squamous cell carcinoma of the esophagus. Hyperexpression of proteins was detected by immunohistochemical methods and gene amplification and other chromosome abnormalities were studied using FISH reaction. Evaluation of EGFR status showed that amplification of EGFR gene was present in 25% cases and chromosome 7 polysomy was detected in 29.2% cases positive by protein expression (2+/3+). Immunohistochemically positive EGFR status was confirmed by the results of FISH reaction for gene amplification and chromosome 7 polysomy in 54.2% cases (p=0.002). During evaluation of HER-2 status in the tumor, hyperexpression of the protein detected histochemically was not confirmed by FISH reaction for detection of amplification of the corresponding gene in 16.1% cases. In 22.6% patients, chromosome 7 polysomy was detected; it was not accompanied by amplification of HER-2 gene, but was related to immunohistochemically positive status of the tumor. Hyperexpression of EGFR protein significantly correlated with the presence of intravascular invasion (p=0.006) and increased depth of invasion (p=0.044), while amplification of EGFR gene (≥2.2) correlated with low differentiation degree of the tumor (p=0.006). The outcome of the disease was not associated with EGFR status at the gene and protein levels, whereas clinical course of the disease in patients with immunohistochemically negative expression of HER-2 protein was more favorable than in patients with positive expression (p=0.004). The results of this study suggest that hyperexpression/amplification of EGFR and hyperexpression of HER-2 are important clinical markers for evaluation of disease prognosis and development of new regimens of targeted therapy for patients with squamous cells carcinoma of the esophagus.

Clinical significance of hyperexpression of epidermal growth factor receptors (EGFR and HER-2) in esophageal squamous cell carcinoma.

Immunohistochemical study of marker expression in primary tumors of patients with esophageal squamous-cell carcinoma was carried out in order to evaluate prognostic significance of EGFR and HER-2 levels in the tumors. Hyperexpression of EGFR and HER-2 in the tumors is an important marker for the analysis of prognosis and clinical course of the disease. A relationship between high levels of EGFR and HER-2 in the tumors of patients with esophageal squamous-cell carcinoma and intravascular tumor invasion (p=0.038) and poor outcome of the disease (p=0.019) was detected. The results indicate that evaluation of changes in the expression of EGFR and HER-2 in tumors is essential for individual prediction of the disease course and development of new approaches to the treatment of these tumors, including target therapy aimed at these tyrosine kinase receptors.

Soluble fragment of HER2/neu receptor in the serum of patients with breast cancer with different levels of this protein expression in the tumor.

Serum level of soluble HER2/neu in patients with tumors characterized by high expression of this protein (2+/3+ according to immunohistochemical analysis) was significantly higher than in patients with low expression of HER2/neu and in women with benign diseases of the mammary glands. The level of HER2/neu in the serum decreased after removal of the primary tumor in the majority of patients.