DISTRIBUTION AND DEMOGRAPHIC CHARACTERISTICS OF DUCTAL INVASIVE BREAST CARCINOMA SUBTYPES IN GEORGIAN POPULATION.

The analysis of prevalence of each specific subtypes of the ductal invasive breast carcinoma according to age group categories showed that Luminal A subtype is observed in every age group as dominant subtype, although in different intensity: two peaks were demonstrated in group III and group IV, and in relatively less amount, in V group as well. Its considerable that Her2(+)/ER subtype was second most prevalent subtype in almost all age groups. It also must be noted that there was no direct correlation found between pre- or post-menopausal period and HER2+ state, except for group IV (60-69 year old range), where it was almost 2 times less frequently found than Basal-like subtype. The frequency of Her2(+)/ER tumor subtype was identical to Luminal A subtype frequency. In age group I (30-39 year old) and all others its frequency was found to be markedly decreasing along with the frequency of Luminal A subtype (if in age group I their frequency was 1.2, in the age group IV it accounted for 9.4, which means that Her2(+)/ER subtype prevalence decreases with increasing age until the age group V (70-79 year old), after which it increases again (age group V and VI demonstrated the frequency of 2.0 and 5.0 respectively). Basal-like tumor was not found in age groups I and VI, and its frequency was gradually increasing except for age group II, where it was approximately 1.5 less frequent than in other age group categories. Triple-negative subtype was not found in age groups I and VI, however, its frequency was gradually increasing with increasing age. The prevalence of triple-negative tumor in age group V was 4.5 times higher than in age group II. The frequency of Luminal B subtype tumor was almost 2 times decreased in age group III, while in age group V it was almost 3 times increased. However, it disappeared in age group VI completely. Consideration of the age-related specificities of ductal invasive breast carcinoma subtypes (phenotypes) is important both for diagnostic aspect and treatment strategy selection, as well as adequate planning of breast cancer screening programs. Thus, in all age groups of the studied population, IIIA and B stages of tumor were identified, with tumor sizes ranging between 2.8-4.7mm. There was no stable direct correlation between breast cancer and family history, as the presence of such data requires additional research with more focus on anamnesis details.

MOLECULAR BASIS OF EPIDERMAL GROWTH FACTOR RECEPTOR AND CYCLIN E EXPRESSION INTERDEPENDENCE IN BASAL-LIKE SUBTYPE OF INVASIVE BREAST CARCINOMA.

Aim of the study was the simultaneous assessment of EGFR and Cyclin E in "basal-like" carcinoma group, in order to establish their interactivity in the aspect of the age and grade of the tumor, taking into account the common parallel HER2+ samples. The study involved postoperative and/or biopsy material (paraffin blocks) of 237 patients from archived data, who were operated due to breast cancer (National Cancer Center of Tbilisi, 2008-2012 years). In TNBC group and "basal-like" tumor subgroup expression of ESFR, Cyclin E and Cytokeratins 5/6 and 17 were shown advanced activity of processes and high dependence to patients age. Taking into account all above mentioned, the immunohistochemical profile of "basal-like" type of breast cancer is defined mostly by sensitivity to cytokeratins CK5,6/17 and EGFR. In addition, the defected synthesis and activity of the latter, which is actually observed in "basal-like" carcinoma, leads to increased malignancy grade and mitotic activity, which creates the phenotypic and group characteristics for this type of carcinomas overall.

BILATERAL ADRENOCORTICAL CARCINOMA: CASE REPORT AND REVIEW OF LITERATURE.

Adrenocortical carcinoma is a very rare and aggressive endocrinological malignancy arising from the adrenal cortex. The estimated incidence is 1 per million people, with an estimated 5-year survival rate of 16-47%. It can be bilateral in roughly 2-10% of cases, but the data is scarce and there is no conclusive evidence whether the contralateral mass is an independent tumor or a metastasis from the other adrenal gland cancer. Radical surgical excision is the only curative treatment. Therefore, careful pre- and intraoperative surgical planning is critically important. Open adrenalectomy has historically been the gold standard approach for surgical treatment of adrenocortical carcinoma. Laparoscopic adrenalectomy has emerged as a minimally invasive alternative, but its oncological safety and effectiveness has long been under debate. Current evidence suggests that in experienced hands laparoscopic adrenalectomy is as safe and effective as its open counterpart in the treatment of localized adrenocortical carcinoma and the adrenal masses ≤10 cm. Urologists have been tempted to apply laparoscopy also to bilateral disease, although the need to reposition the patient and a longer operative time can be limitations. Given the rarity of adrenocortical carcinoma and the lack of quality evidence for the bilateral disease, we used the conventional narrative strategy to review the available literature. We also report a case of nonfunctioning bilateral adrenocortical carcinoma in a 65-year old man, who was operated on with simultaneous bilateral laparoscopic adrenalectomy for suspected localized (stage 2) disease, which proved to be bilateral locally advanced carcinoma (stage 3). Postoperatively, the disease rapidly progressed to the fatal outcome. The case once again highlights the importance of detailed operative planning and the need of imaging studies as close as possible to the date of planned surgery.

EXPRESSION OF CYCLIN E IN BASAL-LIKE BREAST CARCINOMA.

Results of study under 362 patients biopsy materials in Tbilisi National Cancer Center were shown that basal-like type breast carcinoma is characterizes by different reaction on Cyclin E, CK5/17 and ER/PR immunoreactivities. Basal-like tumor immunoreactivity on Cyclin E differs based they clinical stage and seen maximum correlation with III-IV stage and poor prognosis.

Features of CD44+/CD24-low phenotypic cell distribution in relation to predictive markers and molecular subtypes of invasive ductal carcinoma of the breast.

Breast cancer is the most widespread pathology among women. Despite the current progresses in research and treatment of metastatic breast cancer, mortality caused by this disease is still high, because above mentioned therapy is limited due to existence of cells resistant to therapy . Cancer stem cells are the only cells with ability of unlimited proliferative activity and cancerous potential, thus, they participate in the growth, progression and dissemination of cancer. Cancer stem cells are resistant to various forms of therapy, including chemotherapy and radiotherapy . Results of examination showed that 50% of all cases are positive on so called markers of stem cells, thus 45% of cases are negative. CD44+/CD24-low cases (cases that reveal stem cell-phenotype) in the group of invasive ductal carcinoma of Luminal A molecular subtype are almost as many as CD44+/CD24+ and CD44-/CD24+ phenotype cancers. In this group non-stem phenotype cases are 65%, so 5 times more than stem cell phenotype cancers. 1324 postoperative breast materials studied through 2008-2012 at the laboratory of "Pathgeo-Union of Pathologists" LTD and Academician N. Kipshidze Central University Clinic were used as test materials and specimens from 393 patients with invasive ductal carcinoma were selected. CD44/CD24 markers' expression in phenotypically different cancers and clinic-pathologic parameters as well as various biological features was conducted by the Pearson's correlation analysis and using X2 test. Statistical analysis of obtained numeral data was held using SPSS V.19.0 program. Confidence interval of 95% was considered statistically significant. Stem cell phenotype positive cases are with the highest percentage represented in Luminal B and basal-like molecular subgroup that to our minds is associated with their aggressive behavior and resistance to chemotherapy. Relatively good prognosis and response to chemotherapy of Luminal A molecular subtype cancers are to be stipulated by lower percentage of cases with stem cells phenotype. With regard to the dimension of cancer the analysis of stem cell phenotype cancers showed that frequency of stem cell phenotype (CD44+/CD24-low) dramatically increases from T1 to T4 cancers. High density of stem cell phenotype cancers in cancers with metastatic lymphatic nodes proves that presence of mentioned phenotype plays a role in progression and dissemination. On the one hand, little amount of stem cells phenotype cancers (CD44+/CD24-low), on the other hand absence of negative cases for markers of stem cell in Her2 subtype makes us consider that come phenotype, close to stem-cell phenotype, plays the leading role in Her2 positive cases.

[Epidermal growth factor receptor expression and epidermal growth factor blood plasma content in simple and complex endometrial hyperplasia].

The goal of our study was to concurrently determine the prognostic significance of Epidermal Growth Factor Receptor (EGFR) expression in endometrium and Epidermal Growth Factor (EGF) blood content in simple and complex hyperplasia. In order to detect EGFR expression, immunohistochemical examination of endometrial scarp from 35 patients was done along with HPLC (High performance liquid chromatography) method, for measuring EGF blood plasma content. The numerical data obtained were processed statistically using computer program SPSS-12. According to the results: 1. A significant/marked increase in EGF blood plasma level together with pronounced EGFR expression in simple endometrial hyperplasia (without atypia) suggests that simple hyperplasia is likely to transform into complex form, while unchanged level of EGF against the background of mild EGFR expression is probably indicative of not very bad prognosis. 2. Normal indices of EGF blood plasma level in simple endometrial hyperplasia (without atypia), accompanied by mild EGFR expression is suggestive of good prognosis. 3. A sharp or extremely sharp increase in EGF blood plasma level with pronounced EGFR expression in complex endometrial hyperplasia (without atypia) is likely to indicate poor prognosis that may lead to the transformation into atypical form. However, unchanged EGF blood plasma level against the background of mild EGFR expression in complex endometrial hyperplasia (without atypia) is likely to point to not very bad prognosis. 4. A marked increase in EGF blood plasma level with a pronounced EGFR expression in complex endometrial hyperplasia (without atypia) is likely to indicate poor prognosis that may lead to the transformation into atypical form. Because it is evident that drastic increase in EGF blood plasma level is not necessary, other factor should be suspected to play the major role, i.e the substance that will (or will not) withstand neoplasia.

[Expression of epidermal growth factor receptor and plasmatic level of melatonin in simple and complex endometrial hyperplasia].

The goal of our research was to find the prognostic significance of the epidermal growth factor receptor (EGFR) in the hyperplastic endometrium. Immunohistochemical study of morphological material (endometrial scrap) was conducted in order to reveal the EGFR expression (in 35 patients). The study of consistence of melatonin (universal antiproliferative and anticancerogenic hormone) in patients' blood serum was performed as well (using ELISA method). The numeric data of investigation were processed statistically using the SPSS-12 program and IBM SPSS Statistics, 20. According to received results, the more complicated the type of endometrial hyperplasia is, the stronger EGFR expression is and the more melatonin consistence is reduced in blood plasma. However, sometimes much lower level of melatonin not only in case of complex hyperplasia (with atypia), but also in case of simple hyperplasia (without atypia) was observed. In addition, melatonin consistence is in norm not only in case of simple hyperplasia, but also in case of complex hyperplasia. Also, unimportant reduction of melatonin level is seen in plasma in case of both types of endometrial hyperplasia (without atypia): if, for example, in simple hyperplasia, this slight reduction of melatonin level in plasma is seen in condition of sharp EGFR expression, the same amount reduction of plasmatic melatonin in complex hyperplasia is seen in condition of weak EGFR expression. To sum up: in case of simple endometrial hyperplasia without atypia, reduction of plasma melatonin level should be a bad prognostic indicator and this condition can be followed by transformation of hyperplasia into atypical form; the normal plasmatic level of melatonin in complex endometrial hyperplasia without atypia (in condition of weak EGFR expression) should be a good prognostic indicator; unimportant reduction of plasma melatonin level and in addition, EGFR sharp expression in simple hyperplasia, is probably the sign, that hyperplasia can change and become complex; however, the same indicators of plasma melatonin level (on the background of weak EGFR expression) in complex hyperplasia (without atypia) should not indicate the poor prognosis.

Distribution of cancer stem cells in ductal invasive carcinoma of breast (review).

Despite advances in detection and treatment of breast cancer, mortality from this disease remains high. According to contemporary point of view the reason for this lies in fact, that in addition to intertumor heterogeneity, there is also a high degree of intratumor diversity in cancer cell population. For most cancers it is less clear which cells within the tumor clone possess tumor-initiating cell function. During studying oncogenesis and maligniяation processes a pool of cancer cells with stem characteristics - cancer stem cells (CSC) was identified. Indeed, the specifications of them let us conclude, that exactly these cells comprise the leading substrate for cancer initiation and self-renewal. Breast carcinomas have been reported to contain a subpopulation of CD44(+)/CD24(-)/low cancer cells, which are capable of generating tumors even when implanted in very low numbers. Exactly these cells are considered to be CSCs in different subtypes of breast cancer and cancers with CD44(+)/CD24(-)/low phenotype are confirmed to have a poor prognosis (but some controversies remain concerning this issue). The aim of the review was to assess the current literature published on the breast cancer stem cells. There are not so many studies, revealing the diversity of cancer stem cells in different types, different sizes and different grade of breast cancers. CSC distribution in breast cancer with lymph node involvement, metastasizing and chemoresistant cases, existence of circulating tumor cells in not studied precisely. So the concept of cancer stem cells in breast cancer is still a topic for discussions. This can bring light to a better understanding of the pathological process in breast cancer and ways to target it.

Distribution of CD44/CD24 positive cells in ductal invasive carcinoma of breast of different grade and molecular subtype.

The purpose of our study was to learn the distribution characteristics of cancer stem cell markers (CD24, CD44) in invasive carcinomas with different grade and molecular subtype. For research was used 1324 postoperative breast cancer samples, from which were selected 393 patient with invasive ductal carcinoma samples examined 2008-2012 in Laboratory of "Pathgeo Union of Pathologist" is and N.Kipshidze Central University Hospital. The age range is between 23-73 year. For all cases were performed immunohistochemical study using ER, PR, Her2, Ki67, CK5- molecular markers (Leica Microsystems). For identify cancer stem cells mononuclear antibodies CD24 (BIOCARE MEDICAL, CD44 - Clone 156-3C11; CD24 - Clone SN3b) were used. Association of CD44/CD24 expression in different subtypes of cells, between clinicopathological parameters and different biological characteristics were performed by Pearson correlation and usind X2 tests. Obtained quantitative statistical analyses were performed by using SPSS V.19.0 program. Statistically significant were considered 95% of confidence interval. The data shows, that towards G1-G3, amount of CD44 positive cases increased twice. CD44 positive cases are evenly distributed between Luminal A, Luminal B, HER2+, triple negative basal like cell subtypes and in significantly less (4,8 times) in Her2+ cases. Maximum amount of CD44 negative cases is shown in Luminal A subtype, which could be possible cause of better prognosis and high sensitivity for chemotherapy. For one's part such aggressive subtypes of breast cancer as Luminal B and basal like cell type, are characterized by CD44 positive and antigen high expression, which can be reason of aggressive nature of this types and also reason of chemotherapy resistance. As well as amount of CD24 positive cases according to malignancy degree, also antigen expression features does not show any type of correlation between malignancy degree and CD24 positivity or with CD24 expression features, or presence of stem cells. That can be the reason of tumor aggressivity and chemoresistance. exceptions are Her2 positive tumors because they have different base of carcinogenesis.