Evolving of HER2 marker in metastatic process of mammary invasive ductal carcinoma

Catedra de histologie, citologie şi embriologie, Laboratorul de morfologie, USMF „Nicolae Testemițanu”, Chișinău, Moldova, Conferința stiințifică „Nicolae Anestiadi – nume etern al chirurgiei basarabene” consacrată centenarului de la nașterea profesorului Nicolae Anestiadi 26 august 2016Introducere. Supraexpresia oncogenei HER2 (receptorul pentru factorul uman de creștere epidermală 2) inhibă apoptoza, stimulând progresia neoplazică. Scop. Analiza comparativă a expresiei receptorului HER2 în carcinomul mamar de tip ductal invaziv versus metastazele limfonodale axilare corespondente. Material şi metode. Studiu imunohistochimic (markerul HER2, clona HER2/polyclonal, Dako), secţiuni la parafină, contracolorare hematoxilina Harris (HHS32, SigmaAldrich)) pe 84 cazuri (tumora primară şi metastaza limfonodală) diagnosticate morfologic drept carcinom mamar ductal invaziv de tip NST (no specific type). Gradul histologic de diferențiere a fost stabilit conform sistemului de gradare Scarff-Bloom-Richardson. Analiza statistică: corelaţie după Pearson (r) şi McNemar-test. Rezultate. Numărul de cazuri după gradul de diferenţiere: G1 – 5, G2 – 45, G3 – 34. În tumora primară: HER2- – 66 cazuri/78,57%; HER2+ – 18 cazuri/21,43%. În metastazele limfonodale: HER2- – 68 cazuri/80,95%; HER2+ – 16 cazuri/19.05%. Statistic: r=0.87, p=0,00001. În 4 cazuri/4,76% statutul HER2 s-a schimbat în procesul metastatic, şi anume: 1caz/1,19% din HER2- în HER2+, 3 cazuri/3,57% din HER2+ în HER2-. Toate aceste cazuri au prezentat grad G2 de diferenţiere. Nu s-au determinat diferenţe statistice la compararea expresiei HER2 de ambele localizări (McNemar-test: χ²=0,2, p=0,65, kappa=0,85). Gradul de diferenţiere nu a corelat cu valoarea markerului Her2, indiferent de localizare. Concluzii. Receptorul HER2 este instabil în evoluţia metastatică al carcinomului mamar. Semnificaţia clinică a cca 5% cazuri cu transfer de fenotip necesită confirmare din partea altor grupuri de cercetare.Introduction. Overexpression of HER2 (human epidermal growth factor receptor 2) suppresses the apoptosis leading to a neoplastic progression.Purpose. Comparative analysis of HER2 receptor’s expression in mammary ductal invasive carcinoma versus correspondent axillary lymph node metastases. Materials and methods. Immunohistochemical assessment was done on formalin fixed paraffin embedded specimens (84 primary tumors NST type/lymph node metastases) using HER2 marker (clone HER2/polyclonal, Dako), counterstained with Harris haematoxylin (HHS32, SigmaAldrich). Histological grade of differentiation was performed by Scarff-Bloom-Richardson grading scale. Statistic analysis: Pearson’s correlation (r) and McNemar-test. Results. The number of cases according the grade of differentiation: G1 – 5, G2 – 45, G3 – 34. Within the primary tumor: HER2- – 66 cases/78,57%; HER2+ – 18 cases/21,43%. Within the lymph node metastases: HER2- – 68 cases/80,95%; HER2+ – 16 cases/19.05%. Statistics: r=0.87, p=0,00001. In 4 cases/4,76% HER2 state changed during the process of metastasizing - 1case/1,19% from HER2- into HER2+, 3 cases/3,57% from HER2+ into HER2-. All these cases had G2 grade of differentiation. There were found no statistically significant differences between the HER2 expression in both localizations (McNemar-test: χ²=0,2, p=0,65, kappa=0,85). The grade of differentiation did not correlate with the HER2 expression indifferent of its location. Conclusions. HER2 receptor is not stable during the mammary gland carcinogenesis. Clinical significance of 5% cases with phenotype transfer requires to be confirmed by other research groups

Главенствующая роль макрофагов в прогрессии опухолевого процесса

Catedra Histologie, Citologie şi Embriologie, USMF “Nicolae Testemiţanu”Clinical and experimental evidence have shown that macrophages (TAM) are the main component of the leukocyte infiltrate supporting tumor growth. Over the years the mechanisms that support the tumor growth have become increasingly clear and in several experimental tumor models, the activation of an inflammatory response mediated by macrophages has been shown to play an essential role for full neoplastic transformation and progression. TAMs are derived from peripheral blood monocytes recruited into the tumor. Upon being activated by cancer cells, TAMs can release a vast diversity of growth factors, proteolytic enzymes, cytokines and inflammatory mediators. Many of these agents are key factors in cancer progression. The presence of extensive TAM infiltration has been shown to correlate with poor prognosis in a variety of human carcinomas. TAMs promote cancer progression through several mechanisms including the growth of tumor cells, tumor angiogenesis and lymphangiogenesis, matrix remodeling, tumor cell migration and invasion. There are complex paracrine-signaling networks between TAMs and cancer cells to activate each other. This evidence strongly supports the idea that TAMs are one of the most important players in the inflammatory networks expressed in the tumor microenvironment, and it suggests these cells as possible targets of anticancer therapies.Результаты многочисленных клинических и экспериментальных исследований доказали что макрофаги являются самой многочисленной клеточной популяцией лейкоцитарного инфильтрата, поддерживающего опухолевый рост. Со временем, различные механизмы через которые реализуется эта поддержка, стали хорошо изучены. В экспериментальных опухолевых моделях было доказано, что воспалительная реакция, опосредованная макрофагами, играет огромную роль в полной неопластической трансформации и прогрессировании опухолевого процесса. Макрофаги являются производными клетками моноцитов крови. Под воздействием активации опухолевыми клетками, макрофаги способны синтезировать широкую гамму факторов роста, протеолитических ферментов, цитокинов и медиаторов воспаления. Многие из этих веществ свидетельствуют об опухолевой прогрессии. Было доказано, что высокая макрофагальная инфильтрация опухоли коррелирует с плохим прогнозом во многих человеческих опухолях. Макрофаги способствуют опухолевой прогрессии через несколько механизмов, таких как: рост опухоли, опухолевый ангиогенез и лимфангиогенез, моделирование межклеточного вещества, клеточная миграция и инвазия. Существует очень сложная и хорошо налаженная паракринная взаимосвязь по обоюдной активации между макрофагами и опухолевыми клетками. Эти данные указывают на то, что именно макрофаги являются важными участниками воспаления ассоциированного с опухолью, что делает из них потенциальную мишень в противораковой терапии

Expression of hormone receptors in breast carcinoma

Catedra de histologie, citologie şi embriologie, Laboratorul de morfologie, USMF „Nicolae Testemițanu”, Chișinău, Republica Moldova, Conferința stiințifică „Nicolae Anestiadi – nume etern al chirurgiei basarabene” consacrată centenarului de la nașterea profesorului Nicolae Anestiadi 26 august 2016Introducere. Receptorii hormonali au un rol crucial în homeostazia glandei mamare. Un rol controversat în progresia tumorală îi este atribuit androgenilor. Scopul. Studiul comparativ al expresiei receptorilor pentru estrogen (ER), progesteron (PR) şi androgeni (AR) în carcinomul mamar ductal invaziv. Material şi metode. Au fost studiate imunohistochimic 17 cazuri de carcinom mamar ductal invaziv, de tip NST (no specific type) cu markeri pentru ER (clona Er/6F11), PR (clona Pr16), AR (clona AR441). S-a cuantificat procentual expresia nucleară pozitivă la 1000 celule tumorale. Gradul histologic de diferențiere a fost evaluat conform sistemului de gradare Scarff-Bloom-Richardson. Analiza statistică: mediana, corelaţia după Pearson (r) şi ANOVA. Studiul a fost aprobat de către Comitetul de Etică a Cercetării (nr. 21/13/31.03.2014). Rezultate. Mediana pentru ER – 94, PR – 88,67, AR – 95. Diferenţe veridice a mediilor markerilor studiaţi nu s-au determinat. Corelaţii statistic semnificative s-au înregistrat între toţi markerii studiaţi, şi anume: ER cu PR r=0,67, p=0,001; ER cu AR r=0,8, p=0,0001; PR cu AR r=0,56, p=0,01. Unica corelaţie, inversă, de talie rezonabilă, statistic semnificativă a gradului de diferenţiere s-a determinat cu PR (r= -0,49, p=0,02). Concluzii. (1) Carcinomul mamar ductal invaziv de tip NST prezintă expresie cantitativă similară a receptorilor pentru estrogen, progesteron şi androgen. (2) Receptorii pentru androgen sunt o ţintă promiţătoare în tratamentul carcinomului mamar.Introduction. Hormone receptors play a crucial role in mammary gland homeostases. A contoversial role is attributed to the androgens in this process. Purpose. Comparative study of the expression of receptors for estrogens (ER), progesterone (PR) and androgen (AR) in breast ductal invasive carcinoma. Materials and methods. There have been immunohistochemicaly assessed 17 cases of breast ductal invasive carcinoma of NST (no specific type), using markers for ER (clone Er/6F11), PR (clone Pr16), AR (clone AR441). It has been counted the percentage of positive nuclear expression related to 1000 tumor cells. Histological grade of differentiation was performed in accordance with Scarff-Bloom-Richardson grading scale. Statistic analysis: the Median, Pearson’s correlation (r) and ANOVA. The study was approved by the Committee on Ethics of Research (nr. 21/13/31.03.2014). Results. The median for ER – 94, PR – 88,67, AR – 95. There have been found no significant differences in mean values of studied markers: ER cu PR r=0,67, p=0,001; ER cu AR r=0,8, p=0,0001; PR cu AR r=0,56, p=0,01. Single statistically significant inversed correlation was determined with PR (r= -0,49, p=0,02). Conclusions. (1) Breast ductal invasive carcinoma of NST type represents a similar quantitative expression of receptors for estrogens, progesterone and androgen. (2) Receptors for androgen are promissing targets in breast carcinoma therapy

Expression of CK5 basal cytokeratin in primary breast carcinoma

Department of Histology, Cytology and Embryology, Laboratory of Morphology, Nicolae Testemitsanu State University of Medicine and Pharmacy, Chisinau, the Republic of MoldovaBackground: CK5 positive cells represent progenitors for glandular and myoepithelial lineages of mammary epithelium. During epithelial differentiation there is a gradual decrease of CK5 expression. In case of benign lesions the proliferating luminal cells show a high expression of CK5. Contrary, the majority of malignancies which are derived from differentiated glandular cells line do not reveal immunohistochemical staining with CK5 marker. The aim of this study was to compare the expression of basal cytokeratin CK5 vs hormone receptors, HER2, Ki67 and molecular subtype’s immunohistochemically defined in the primary breast carcinomas of NST type. Material and methods: We processed 108 invasive breast carcinomas of NST type. The specimens were formalin-fixed and paraffin-embedded as traditionally. Sections were immunostained (ER, PR, HER2, CK5 and Ki67) automatically with Leica Bond-Max autostainer. Results: Breast carcinoma of NST type was in majority of cases CK5 negative (94 cases/87%). The positive CK5 cases had a high grade of differentiation. CK5 negative tumors were usually hormone positive, but in 8 cases/6.5% a combined simultaneous CK5-ER (PR) positive expression was determined. From 22 HER2 positive cases, 16 were CK5 negative. CK5 value correlated statistically significant with all used markers, except grade of differentiation: a positive Pearson coefficient was determined in relation to HER2 and Ki67, and a negative one compared to hormone receptors and molecular subtype. Conclusions: We support CK5 potential value in molecular subtype’s differentiation. Breast carcinoma of NST type is usually CK5 negative and hormone positive. The presence of cases with simultaneous expression of CK5 and hormone receptors is an open field to debate the existence of other, transient molecular subtypes and we expect a further confirmation in larger study groups

Роль рецептора сосудистого эндотелиального фактора роста (VEGFR-3) в процессе канцерогенеза шейки матки

In spite of the huge achievements made in the early detection of uterine cervix cancer, this disease remains one of the most widespread human malignancies throughout the world. Nowadays, there is a tendency of cervical cancer to affect the youth population. Early metastasizing is a critical point in evolution of this disease. Lymphatic vessels (LV) represents the primary route of cancer cells spreading towards the distant sites. That is why understanding of new lymphatics recruitment by the tumor, at molecular level, could be a potent support in solving of metastasizing. VEGFR-3 is a tyrosine-kinase receptor, specific for lymphatic endothelial cells, that being activated provides their proliferation, surviving and migration. It has been demonstrated that VEGF-R3 mediates invasion activity of tumor cells into surrounding stroma and vascular structures. The aim of this research was to study the importance of VEGFR-3 in cervical carcinogenesis. Material and methods: We studied biological material, taken by targeted biopsy and conization, from women with detectable cervical lesions. Detection VEGFR-3 was made using monoclonal antibody anti VEGF-R3 through Avidin-Biotin working system, LSAB technique. Lymphatic microvascular density was assessed by podoplanin labeling, using anti D2-40. A statistical analysis was made with SPSS 13.0. Results: We obtained VEGFR-3 expression in LV, blood vessels, tumor mass and stromal cells. The highest density of VEGFR-3 LV was in CIN III with gradually decreasing in invasive stages. In invasive carcinoma we obtained statistically significant correlation between tumor VEGFR-3 expression and vascular invasion. Conclusions: VEGFR-3 is not specific for lymphatic endothelium. It can not be used for alone lymphatic microvascular density assessing. It is actively involved in vascular invasion.Несмотря на огромный успех, достигнутый в выявление рака шейки матки (РШМ) на ранних стадиях развития, данное заболевание остается одной из самых часто встречающихся злокачественных новообразований во всем мире. На сегодняшний день наблюдается тенденция омоложения РШМ. Раннее метастазирование является ключевым моментом в эволюции заболевания. Лимфатические сосуды представляют собой первичный путь распространения опухолевых клеток. В связи с этим, понимание механизмов образования лимфатических сосудов на молекулярном уровне, может помочь решить эту проблему. VEGFR-3 является тирозин-киназным рецептором. Он находится на поверхности лимфатических эндотелиальных клеток, при активации которого происходит их пролиферация, миграция и выживание. Было доказано, что VEGFR-3 регулирует инвазию раковых клеток в строму и сосуды. Цель работы: изучить роль VEGFR-3 в канцерогенезе РШМ. Материал и методы: был изучен биологический материал, полученный посредством прицельных биопсий и конизаций у пациенток с макроскопически выявленным поражением шейки матки. Для определения VEGFR-3 была использована система Avidin-Biotin, техника LSAB , с применением первичного антитела анти VEGFR-3. Для определения лимфатических сосудов были использованы моноклональные антитела анти D2-40. Статистический анализ данных был произведен при помощи SPSS 13.0. Результаты: мы выявили экспрессию VEGFR-3 не только в лимфатических сосудах, а также в кровеносных сосудах, в опухолевой массе и клетках стромы. Наибольшая плотность лимфатических сосудов была определена на стадии CIN III (интраэпителиальная цервикальная неоплазия), с последующим прогрессивным уменьшением. На стадии инвазивного рака мы получили статистически значимую корреляцию между интенсивностью экспрессии VEGFR-3 опухолью и сосудистой инвазией, а также между интенсивностью экспрессии VEGFR-3 опухолью и внутрисосудистыми опухолевыми эмболами. Выводы: VEGFR-3 не является специфическим маркером для лимфатического эндотелия. Данный маркер не может использоваться самостоятельно для определения лимфатической микрососудистой плотности. VEGFR-3 активно вовлечен в процесс сосудистой инвазии

Корреляция плотности макрофагов с тяжестью неоплазии шейки матки

Despite all recent efforts, cancer of the uterine cervix still remains one of the most frequent malignancies among women. Lymphatic vessels represent the primary route of tumor cells dissemination in cervical cancer. It has been demonstrated that cervical neoplasia actively participates in the recruitment of new blood and lymphatic vessels. Macrophages are extremely versatile cells which have a significant contribution to tumor progression. The aim: 1) To establish the correlation between tumor-associated macrophages (TAM) and the grade of the uterine cervix neoplasia; 2) To evaluate the distribution of TAM within both intratumoral and peritumoral areas. Material and Methods: Ninety-six cases were studied. The specimens were fixed in buffered formalin and paraffin embedded. Step sections, 5μm thick, were performed for each case. Initial sections were stained with haematoxylin-eosin, for the pathological diagnosis and grading of the tumor. Lesions were classified as follows: squamous cell metaplasia (n = 12), CIN I (n = 8), CIN II (n = 6), CIN III (n = 24), microinvasive carcinoma (n = 16) and invasive squamous cell carcinoma (n = 26). Additional sections for each case were stained for CD68 antibody, in order to highlight the macrophages. Quantification of macrophage population has been made based on hot-spot technique. The arithmetic media of 3 (× 200) fields represented the final result. Results: We found a statistical correlation between peritumoral macrophages (PTM) and intratumoral macrophages in all stages of cervical neoplasia, macrophage density and tumor stage (p = 0.01). In 16 cases we found vascular invasion. Almost in all these cases (87.5%) intravascular tumor emboli were embedded with CD68 cells. Conclusions: based on these findings, we consider that macrophages are key regulators of cervical cancer progression. TAM targeted management could be an essential therapeutic strategy, not only in order to suppress the progression of cervical neoplasia, but also to inhibit macrophage-mediated vascular invasion.Рак шейки матки остается одной из самых часто встречающихся злокачественных заболеваний женского населения. Лимфатические сосуды являются первичным путем метастазирования при данном заболевании. Было доказано, что клетки цервикальной неоплазии активно участвуют в образовании новых лимфатических сосудов. Макрофаги – многофункциональные клетки, оказывающие большое влияние на прогрессирование опухоли. Цель: 1). Выявление корреляции между макрофагами и стадией прогрессии неоплазии шейки матки; 2). Определение особенностей распределения макрофагов внутри опухолевой массы и вокруг нее. Материал и методы. Было изучено 96 случаев. Материал фиксировали в формалине с последующим заключением в парафин. Для каждого случая производили срезы, толщиной в 5 мкм. Изначально, срезы окрашивали гематоксилин-эозином для определения гистопатологического диагноза. Были получены следующие группы поражений: плоскоклеточная метаплазия (n = 12), CIN I (n = 8), CIN II (n = 6), CIN III (n = 24), микрокарцинома (n = 16), инвазивный рак (n = 26). Для выявления макрофагов, произвoдили иммуногистохимическое исследование с использованием маркера CD68. Подсчет популяции макрофагов производили по методике hot-spot. Результаты. Мы получили статистически значимую корреляцию между внутритуморальными и перитуморальными макрофагами во всех стадиях прогрессии неоплазии шейки матки, между плотностью макрофагов и стадией опухоли (p = 0,01). В 16 случаях выявили сосудистые эмболы. Почти во всех случаях (87,5%) внутрисосудистые эмболы содержали в себе CD68 клетки. Выводы: Основываясь на полученных результатах, мы считаем, что макрофаги вовлечены в прогрессию рака шейки матки

Эпителиально-мезенхимальный переход в неопластических поражениях шейки матки

Catedra Histologie, Citologie şi Embriologie, USMF„Nicolae Testemiţami”, Laboratorul Morfologie, USMF „Nicolae Testemiţami", Chişinău, Republica MoldovaIn this work studied tissue taken using biopsy and cervical conization in patients with abnormal epithelial organ sites identified macroscopically. The lesions were classified as follows: C1N1 (n=17), CIN2 (n=ll), CIN3 (n=7), microinvasive carcinoma (n = 10) and invasive carcinoma (n — 49). As a control (n = 5) were studied conization of the cervix intact (normal) histological. Immunohistochemical study was applied to the identification of epithelial cells and cells of mesenchymal origin. Epithelial cells were identified using polyclonal antibodies AE1/AE3 clone АЕ1/ AE3, mesenchymal cells origin, respectively using anti-vimentin antibodies clone V9. In patients with microinvasive carcinoma and invasive carcinoma of the cervix in the area of infestation was found vimenti-expres si on and lack of expression on tumor cells AE1/AE3.В настоящей работе были изучены ткани взятые при помощи прицельных биопсий и конизаций шейки матки у пациенток с патологическими участками эпителия органа, выявленных макроскопически. Поражения были классифицированы следующим образом: CIN1 (п=17), C1N2 (п=11), CIN3 (п=7), микроинвазивная карцинома (п=10) и инвазивная карцинома (п=49). В качестве контроля (п=5) были изучены конизации шейки матки с неизмененной (нормальной) гистологической картиной. Было применено иммуногистохимическое исследование с идентификацией эпителиальных клеток и клеток мезенхимального происхождения. Эпитепиалъные клетки были выявлены при помощи поликлональных антител АЕ1/АЕЗ клон АЕ1/АЕЗ, клетки мезенхимального происхождения — соответственно при помощи антител анти-виментина клон V9. У пациенток с микроинвазивной карциномой и инвазивной карциномой шейки матки в зоне инвазии была выявлена экспрессия виментина и отсутствие экспрессии АЕ1/АЕЗ опухолевых клеток

BCL2 expression depending on the proliferative activity of breast ductal invasive carcinoma

Catedra de histologie, citologie şi embriologie, Laboratorul de morfologie, USMF „Nicolae Testemițanu”, Chișinău, Republica Moldova, Conferința stiințifică „Nicolae Anestiadi – nume etern al chirurgiei basarabene” consacrată centenarului de la nașterea profesorului Nicolae Anestiadi 26 august 2016Introducere. BCL2 (B-cell lymphoma 2) este un marker cu rol controversat în carcinomul mamar. Scop. Studiul expresiei BCL2 în funcţie de indicele de proliferare Ki67. Material şi metode. Expresia markerilor BCL2 (clona bcl-2/100/D5) şi Ki67 (clona K2) a fost studiată pe 87 cazuri de carcinom mamar invaziv, tip NST (no specific type). Lotul a fost divizat în 3 grupe în funcţie de Ki67: (1) general, (2) cu rată joasă de proliferare – până la 14% (34 cazuri), (3) cu rată înaltă - mai mult de 14% (53 cazuri). Gradul de diferenţiere a fost evaluat după sistemul Scarff-Bloom-Richardson. Analiza statistică: corelaţie după Pearson (r). Studiul a fost aprobat de către Comitetul de Etică a Cercetării (nr.21/13/31.03.2014). Rezultate. Cazurile au fost repartizate după gradul de diferenţiere, precum: G1 – 5 cazuri/5,7% , G2 – 46 cazuri/52,9%, G3 – 36 cazuri/41,4%. În cohorta generală indicele de proliferare Ki67 corelează pozitiv cu gradul de diferenţiere (r=0,23, p=0,02) şi invers cu valoarea expresiei BCL2 (r= -0,29, p=0,003). Aceiaşi corelaţie negativă cu BCL2 s-a determinat şi în grupul cu rată înaltă de proliferare. În grupul cu rata joasă, Ki67 a corelat pozitiv cu BCL2 (r=0,31, p=0,04). Concluzii. Expresia markerului BCL2 este în funcţie de indicele de proliferare Ki67. Creşterea activităţii proliferative duce la diminuarea expresiei BCL2 de către celulele tumorale.Introduction. BCL2 (B-cell lymphoma 2) is a marker with a controversial role in breast carcinoma. Purpose. BCL2 expression in function of Ki67 index of proliferation. Materials and methods. Expression of BCL2 (clone bcl-2/100/D5) and Ki67 (clone K2) was investigated on 87 breast ductal invasive carcinomas of NST (no specific type) type. The study group was divided in 3 subgroups based on Ki67 activity: (1) general, (2) with low rate of proliferation – up to 14% (34 cases), (3) with high rate of proliferation – more than 14% (53 cases). Histological grade of differentiation was performed by Scarff-Bloom- Richardson grading scale. Statistic analysis: Pearson’s correlation (r). The study was approved by the Committee on Ethics of Research (nr.21/13/31.03.2014). Results. The cases have been distributed according to the grade of differentiation as follows: G1 – 5 cases/5,7% , G2 – 46 cases/52,9%, G3 – 36 cases/41,4%. In general subgroup, Ki67 index of proliferation correlated with the grade of differentiation (r=0,23, p=0,02) and had inverse correlation with expression of BCL2 (r= -0,29,p=0,003). The same negative correlation of BCL2 was determined in the group of high rate proliferation. In the group with high rate proliferation, Ki67 correlated with BCL2 (r=0,31, p=0,04). Conclusions. Expression of BCL2 in invasive ductal breast carcinoma, depends on index of nuclear proliferation. Intensification of proliferative activity leads to decreasing of BCL2 expression by the tumor cells

Supporting molecular factors of mammary gland development

Caredra histologie, citologie și embriologie, Labortorul Morfologie, Universitatea de Stat de Medicină și Farmacie „Nicolae Testemițanu”, Chişinău, Republica Moldova, Conferința Ştiinţifică Internaţională ”Probleme actuale ale morfologiei” dedicată celor 70 de ani de la fondarea Universității de Stat de Medicină și Farmacie „Nicolae Testemiţanu”, Chişinău, 15-16 octombrie 2015Abstract Background: The first distinctive feature in the development of mammary glands is the apparition of milk lines that is followed by the formation of 5 pairs of the placodes, which outgrowths to form mammary buds. Later, the buds give rise tubular branched structures. These structures represent the primordial of lactiferous ducts, which from 18th day of embryonic development stop to differentiate until the puberty. The major events that occur during the breast development are strongly connected to cyclic hormonal modifications in pregnancy, lactation and menopause. At the puberty occurs the branching of ductal excretory system – a process controlled by a broad spectrum of molecular factors. These are the hormones, growth factors, matrix active substances, metaloproteinases (MMP), and the components of immune system. The aim was to highlight the molecular factors involved in the control of mammary gland development at different embryonic and post-natal stages. Conclusions: Molecular factors, involved in mammary development have diverse pathways and origin. Sophisticated interactions of these factors determine step-like development and permanent rearrangement of the gland. Any disturbance within these signaling pathways may lead to appearance of different pathologies: from morphological abnormalities to malignancies. As a result, understanding of these mechanisms represents a theoretical basis necessary to elaborate a new strategy of diagnosis and therapeutic management of breast carcinoma

Invasive breast carcinoma – the EGFR receptor evolution during metastatic process

Catedra de histologie, citologie și embriologie, Laboratorul de morfologie Universitatea de Stat de Medicină și Farmacie “Nicolae Testemițanu”, Chișinău, Republica Moldova, Conferința Ştiinţifică Internaţională ”Probleme actuale ale morfologiei” dedicată celor 70 de ani de la fondarea Universității de Stat de Medicină și Farmacie „Nicolae Testemiţanu”, Chişinău, 15-16 octombrie 2015Abstract Background: Mammary carcinoma possesses multiple morphological expressions, classified into subtypes based on histological grade and receptors expression. In spite of various screening and prevention programs implementation its incidence is still on the top among malignant diseases. The aim: assessment of EGFR expression based on tumor’s histological type and grade of differentiation and determining of this factor stability within the metastatic process. Material and methods: there were examined primary tumors and ipsilateral axillary lymph node metastasis, collected from 85 patients with mammary ductal invasive carcinoma of NOS (not otherwise specified) type and 18 patients with lobular invasive carcinoma, using conventional histological and immunohistochemical (IHC) techniques. With the help of IHC has been determined the expression of receptor for Epidermal Growth Factor (EGFR). Results: in ductal invasive carcinoma we obtained weak but statistically significant correlation between histological grade and age of patients (rs =0,23, p<0,03). Comparing the values of EGFR expression in both locations, we obtained in 6 cases (15.8%) the expression’s score transfer. All these transfers have been characterized by the loosing of positive pattern in lymph node microenvironment and were found in both age groups: “before 49 years” and “after 49 years”. In lobular invasive carcinoma also have been obtained statistically significant correlation between EGFR score of expression and patients age (rs =0,45, p<0,031). The age correlated with the grade of differentiation, as well (rs =0,57, p<0,007). Comparing the values of EGFR in both locations, we determined that the scores of EGFR are statistically different (t=2,12, with an p<0,05). However the correlation test highlighted strong positive association between EGFR values in primary tumor and metastasis. Conclusions: ductal invasive mammary carcinoma of NOS type could in an equal manner EGFR positive or negative. Histological grade of these tumors positively correlates with the patients’ age. EGFR is unstable during the metastasizing, the cases of score’s transfer being exclusively characterized by the loosing of this receptor within the lymph node microenvironment. Unstable cases have a low grade of histological differentiation. The tumors with high grade of differentiation represent negative EGFR pattern. In lobular invasive carcinoma, the most of the tumors are EGFR negative, not only in the primary tumor, but also in the lymph node metastases. In this type of tumors, the values of EGFR expression depend on location, however the EGFR’ score in metastasis is directly dependent on its value in the primary tumo