[Neuroendocrine tumors of digestive system: morphologic spectrum and cell proliferation (Ki67 index)].

This review deals with the analysis of up-to-date concepts ofdiferent types of human neuroendocrine tumors of the digestive system. It summarizes the information on the specifics of recent histological classifications and criteria of morphological diagnosis accounting histological, ultrastructural and immunohistochemical parameters. Current issues of the nomenclature as well as various systems of grading and staging are discussed. In the light of these criteria the results of the own research clinical value of the determination of cell proliferation in primary and metastatic gastroenteropancreatic neuroendocrine neoplasms on the basis of evaluation of the Ki67 antigen expression are also presented.

[Immunohistochemical study of epidermal growth factor receptor expression in esophageal squamous cell carcinoma].

Primary tumors from 31 patients with esophageal squamous cell carcinoma (ESCC) were immunohistochemically studied for the expression of markers of ESCC in order to define the clinical value of the levels of EGFR and HER-2 in the tumors. EGFR and HER-2 hyperexpression in the tumors of patients with ESCC was ascertained to be an important marker for the analysis of the clinical features of ESCC. There was an association of the elevated levels of EGFR and HER-2 in the tumors of ESCC patients with the presence of vascular tumor invasion (p = 0.006) and that with the poor outcome of the disease (p = 0.004). The findings suggest that estimation of changes found in EGRF and HER-2 expression in the tumors of patient with ESCC is of great interest for the individual prediction of the disease course and for the development of new approaches to treating these tumors, including targeted therapy against these tyrosine kinase receptors.

[Expression of matrix metalloproteinases 2 and 9 and their tissue inhibitors 1 and 2 in papillary thyroid cancer: an association with the clinical, morphological and ultrastructural characteristics of a tumor].

Papillary thyroid cancer (PTC) was ascertained to be characterized by a significant expression of matrix metalloproteinases (MMP-2 and 9) and a TIMP-2 inhibitor and decreased TIMP-1 accumulation in the cytoplasm of tumor cells; at the same time a combination of high cytoplasmic MMP-9 expression with no TIMP-1, as well as triple positive co-expression of MMP-2, MMP-9, and TIMP-2 are poor immunohistochemical indicators. The results of the performed study suggest that the detection of the types of expression of MMP-9+/TIMP-1 and MMP-2+/MMP-9+/TIMP-2+ is associated with the possible progression of a tumor process and concurrent with poor clinical and morphological signs, such as the large size of the tumor, the presence of intravascular invasion and regional metastases, organ capsular invasion, and low ultrastructural tumor cell differentiation. Thus, changes in the tumor expression of the extracellular matrix enzymes MMR-2 and MMP-9 and their inhibitors TIMP-1 and TIMP-2 along with the major clinical, morphological, and ultrastructural signs of the disease are important additional indicators for analyzing the malignant potential of PTC.

[Significance of the expression of nucleolar argyrophilic proteins and antigen Ki-67 in the evaluation of cell proliferative activity and in the prediction of minimal (T1) lung cancer].

S u m m a ry. - The subject of the study was 20 cases of non-small-cell lung carcinomas, up to 3 cm in diameter, conventionally designed as minimal lung cancers removed in patients operated on at the N. N. Blokhin Cancer Research Centre, Russian Academy of Medical Sciences in 1986 to 2001. According to survival rates after surgery, the patients were divided into two groups: 1) those who died within the first two years; 2) those who were followed up for 3-5 years. Histological, histochemical, and immunohistochemical studies were performed. The expression of argyrophylic nucleolar organizer site proteins (Ag-NOS-proteins) that characterized the rate of cell proliferation (the duration of a cellular cycle) and the expression of Ki-67 antigen, which reflected the fraction of growth (the number of proliferating cells), were revealed in the tumor cells. Minimal lung cancers were found to be a heterogeneous group of neoplasms showing differences in both the rate of cell proliferation and the count of proliferating cells. The cell proliferation rate is a determinant of the clinical course of minimal lung cancers. Group 1 tumors characterized by the superexpression of Ag-NOS-proteins and, accordingly, the higher cell proliferation rate and the moderate count of proliferating cells had a poor prognosis even in the presence of Stage IA whereas Group 2 tumors with a large quantity of proliferating cells, but with the less rate of cell proliferation were characterized by a much better prognosis. The rate of cell proliferation (expression of Ag-NOS-proteins) and the count of proliferating cells (the expression of Ki-67 antigen) should be simultaneously studied to have more complete information on the proliferative potential of tumor cells and on the prediction of the course of neoplasms.

[Signet ring cancer of the stomach: clinico-morphological features, postsurgical results and prognosis].

Clinico-morphological features of signet ring cancer of the stomach were evaluated in 372 out of 2,308 gastric cancer patients undergoing gastroectomy or stomach resection. Signet ring tumor pathology occurs mostly in young females and younger patients generally. It features high incidence of early cancers, low frequency of metastatic spreading to lymph nodes (T1-T2), high frequency of immediate involvement of perigastric fatty tissues, peritoneum and ovaries and infrequent spreading to the liver. Post-surgical survival rates among patients with T1-T2 were relatively high, yet declining in cases of extension through the serous membrane of the stomach. D2-lymphdissection failure to improve the end-results of surgical treatment of signet ring cancer might be accounted for by the predominance of peritoneal metastases of this morphological pattern. Histochemical assay of mucines might be contribute additional data on prognosis.

[Immunohistochemical study of E-cadherin, beta-catenin and CD-44v6 expression in the cells of primary colon cancer and its metastases].

129 primary colon carcinomas, 35 metastases to the lymph nodes and 92 metastases to the liver are studied. Reduction or complete absence of E-cadherin was more frequently observed in cases with liver metastases (64/ 84 - 76%) than in patients without metastases (14/45 - 31%) (p = 0,014). Also, beta-catenin expression was more frequent in cases with metastases. These results of E-cadherin and beta-caterin expression, changes may be considered as factors of unfavourable prognosis. No links between CD44v6 expression and metastases was found.

[The features of expression of cellular adhesion molecules in primary colorectal cancer and its metastases].

Features of expression, distribution and interaction of E-cadherin, beta-catenin and CD-44v6 were immunologically assayed in samples from primary colorectal tumors (129) and their metastases to the lymph nodes (35) and liver (92). Reduction or total absence of E-cadherin expression was significantly more typical of tumors metastasizing, at different stages, to the liver (64/84, 76%) than in metastasis-free ones (14/45, 31%) (p=0.014). Enhanced cytoplasmic immunoreactivity and beta-catenin nuclear translocation occurred in 80% of disseminated tumors. Such alterations of E-cadherin, beta-catenin expression may be regarded as unfavorable prognosis factors involved in colorectal cancer. No significant correlation between CD-44v6 expression and tumor cell ability to metastasize was recorded.

[Comparative electron microscopic study of cancer cell differentiation in the primary tumor and the metastases]. / Sravnitel'noe élektronno-mikroskopicheskoe issledovanie differentsirovki rakovykh kletok v pervichnoi opukholi i metastazakh.

Comparative ultrastructural analysis of primary carcinomas of the lung, mammary gland, colon, stomach and some other sites and their metastases into the lymph nodes and inner organs is presented. It is established that the main ultrastructural specific features of differentiation typical for the cells of primary tumours are, as a rule, retained in their metastases to various organs and tissues. Carcinoma cells in the metastases repeat most frequently (81% of cases) the types of differentiation of a primary tumour. However, the reduction of a number of differentiated cell types (5%) or appearance of a new ultrastructural cell type (14%) may be found in the secondary tumour deposits. Besides, the retention (74%), decrease (10%) or increase (16%) of the degree of differentiation may be observed in metastases as compared to the primary tumour. The data obtained may be the ground for a proper identification of malignant tumours on the basis of the electron microscopic study of their metastasis.

[Electron microscopic study of cellular differentiation in metastases of cancer of the large intestine in man]. / Elektronno-mikroskopicheskoe issledovanie differentsirovki kletok raka tolstoi kishki cheloveka v metastazakh.

A comparative ultrastructural study study of the stage and type of differentiation of cancer cells in the primary large intestine human adenocarcinoma and its metastases in the lymph nodes, ovaries, and greater omentum is described. Metastatic cells have been found to retain the features of specific differentiation and be represented by the same groups and main ultrastructural types as in the primary tumor. The main directions of cell differentiation in metastases and in the primary tumor were similar. The role of microenvironment of different organs appeared to be insignificant in the process of cell differentiation in metastases.

[Expression of nm23 and c-erbB-2 proteins in cells of primary colorectal cancer and its metastases]. / Ekspressiia belkov nm23 i c-erbB-2 v kletkakh pervichnogo kolorektal'nogo raka i ego metastazov.

Expression of proteins nm 23 and c-erbB-2 is observed in many human carcinomas and is associated with the disease progression. Immunohistochemical study of nm23 and c-erbB-2 expression was performed on 64 primary tumours, 19 metastases in the lymph nodes and 37 liver metastases. More pronounced expression of these proteins in the primary tumour cells is observed in cases with liver metastases. Expression of nm 23 was observed in 66% and that of c-erbB2 in 59% of liver metastases. Thus, expression of these proteins may reflect biological behaviour of the tumour and may appear to be an important factor in development of colorectal cancer metastases.

[Results of the electron microscopic diagnosis of human tumors (an analysis of 1000 cases)]. / Itogi élektronno-mikroskopicheskoi diagnostiki opukholei cheloveka (analiz 1000 nabliudenii).

A review of electron-microscopic diagnostic investigations made on biopsy specimens from 1000 patients showed the range of tumors requiring ultrastructural diagnosis to be fairly broad, encompassing virtually all major tumor sources including soft tissues (37% of the cases), epithelium (31.8%), hematopoietic organs (21.3%), pigment-forming tissues (4.9%), and bones (3.3%). The tissue and cellular origin of the tumor was identified, i.e. a differential diagnosis was correctly made and/or the histogenetic (cytogenetic) type of the tumor was established, in most (83.0%) of the cases, whereas the organ of tumor origin was identified in only 6.0%. Electron-microscopically, the histological diagnosis was confirmed in 45.3% of the cases, made more precise in 19.0%, and discarded in 5.1%; in 5.8%, electron microscopy confirmed as correct one of the diagnoses presumed on histologic grounds, while in 3.9% the diagnosis could not be verified because the tumors consisted of undifferentiated cells in their entirety. Historic material (formalin-fixed or from paraffin blocks) and stained histologic sections were used for the ultrastructural diagnoses.

[Breast cancer with neuroendocrine differentiation]. / Rak molochnoi zhelezy s neiroéndokrinnoi differentsirovkoi.

One rare case of mammary carcinoma with an unusual clinical course and non-typical morphology is described. The diagnosis of mammary carcinoma with neuro-endocrine differentiation was established on the basis of histologic, immunomorphologic and electron-microscopic examination.

[Morphology of dysplasia and small cancer of the breast]. / Morfologiia displazii i malen'kogo raka molochnykh zhelez.

The results of histological study of material from sectoral resection of 285 mammary glands (MG) from 265 patients with fibrocystic disease (FCD) are presented. 112 cases of a nonproliferative FCD and 173 cases with different variants and degree of proliferation and atypia of the duct and lobules epithelium are recorded. Slight proliferation is observed in 66 cases, mild in 43 cases, pronounced proliferation corresponding to the atypical hyperplasia according to the WHO classification of MG tumours (1981) is found in 30 cases; ductal and lobular carcinoma in situ is observed in 16 cases. A long-term follow-up showed the invasive MG carcinoma in the preserved part of MG to develop in 3 of 172 FCD cases (1.7%). A frequent combination of the atypical hyperplasia foci with an intraductal and lobular carcinoma in situ, revealed in 60 cases of the MG small carcinoma (from 3 to 10 mm in size) with a focal invasion, is in favour of the morphogenetic link between dysplasia and MG carcinoma. Electron-microscopic examination of a proliferative FCD (12 observations) and invasive carcinoma (15 observations) established an enhancement of the specific ultrastructural differentiation in parallel with an increase of the epithelial proliferation but did not reveal the ultrastructural signs of malignant transformation.

[Geographic differences in the frequency of chromosome alterations characteristic of cancer of the large intestine]. / Geograficheskie razlichiia v chastote khromosomnykh izmenenii kharakternykh dlia raka tolstoi kishki.

The authors' material (33 tumours) and that from foreign literature (18 to 100 tumours from every country) was used. The following chromosome aberrations were compared: the deletion of a part of chromosome 1 short arm, deletion of chromosome 5 and a part of its long arm, additional chromosomes 7, complete or partial deletion of chromosome 17 short arm, deletion of chromosome 18 and appearance of additional chromosomes 20. Clear-cut differences were revealed between the following three groups of regions: 1) countries of the Eastern and Western Europe (Russia, France, Germany); 2) Northern Europe countries (Denmark, SWeden); 3) USA and China. Geographical differences in chromosome anomalies in hemoblastosis were found in 1970s, the difference in colon carcinoma are presented for the first time. The experimental results suggest that non-homogeneous distribution of the karyotype alterations typical for certain morphological types of malignant tumours are due to different environmental influences.

[An immunohistochemical study using monoclonal antibodies of the antigen of fat globule membranes in human milk]. / Immunogistokhimicheskoe izuchenie antigena membran zhirovykh globul zhenskogo moloka s pomoshch'iu monoklonal'nykh antitel.

Monoclonal antibodies (Mab) IKO-21 and IKO-25 obtained to the membrane antigen of the woman milk lipid globules were tested immuno- and cytochemically on the samples of human normal definitive and embryonal tissues and tumours. Mab IKO-21 are shown to react, apart from epithelial tissues, with a vascular endothelium and blood cells. Mab IKO-25 are specific to the epithelial tissue and malignant epithelial tumours. Their intensive reaction with the cells of malignant tumours of the mammary gland, lung, ovary and the type of their distribution in the organs and tissues enables their use in the differential diagnosis of malignant epithelial and non-epithelial tumours as for revealing metastases both in vitro and in vivo.

[The role of monoclonal antibodies to the epithelial membrane antigen in the diagnosis of human tumors]. / Rol' monoklonal'nykh antitel k antigenu épitelial'nykh membran v diagnostike opukholei cheloveka.

The paper discusses the possibility of the use of the Soviet-made ICO 25 monoclonal antibodies to membrane antigen of lipid globules of the human milk for differential diagnosis of human tumors. ICO 25 monoclonal antibodies reliably detected the above antigens in normal epithelial and breast cancer cells. However, these antigens cannot be considered strictly specific for breast tissue. They were found in various human epithelial tissues, in the majority of epithelial tumors and lymph node metastases. Staining for ICO 25 monoclonal antibodies was negative in non-epithelial tumors. The above antibodies proved a useful marker for the identification of epithelial origin of primary tumors and their metastases showing unclear histology. They can be used to differentiate between epithelial and non-epithelial malignancies as well as to detect micrometastases and areas of microinvasion. Paraffin-embedded samples can be used for immunohistochemical examination.