Oddziaływanie kwaśnego białka włókienkowego gleju i białka S100 w gruczolakach przysadki mózgowej: dwóch czy więcej graczy?

Introduction: S100 protein and GFAP expression in pituitary adenomas tumour cells is not well known; few correlations with other prognostic or therapeutic factors have previously been reported in pituitary adenomas. We aim to elucidate their involvement in the pathogenesis of pituitary adenomas and to establish the correlation of their expression with different growth factors and growth factor receptors known to have a prognostic and/or therapeutic role. Material and methods: Sixty-one cases of pituitary adenomas were immunohistochemically assessed for the expression of GFAP and S100 protein in both tumour cells and FS cells, in close relationship with hormone profile, and correlated with vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expression, previously studied by our team. Results: GFAP and S100 protein were expressed both in tumour cells and FS cells. Differences between morphology, distribution, and density of GFAP+ FS cells and S100+ FS cells were observed according to the hormone profile of pituitary adenomas. GFAP and S100 protein expression in tumour cells was significantly related to hormone profile of pituitary adenomas and also with VEGF and EGFR expression. Conclusions: GFAP and S100 protein expressions in tumour cells from pituitary adenomas are influenced by hormone profile. Our re­sults support the presence of two molecular subtypes of FS cells GFAP+/VEGF+/S100 respectively and another one that is GFAP-/S100+/EGFR+ simultaneously with the classical variant GFAP+/S100+. It is possible that S100+/EGFR+ pituitary adenomas represent a group of pituitary adenomas with an aggressive behaviour and a high ability of invasion and recurrence.Wstęp: Ekspresja białka S100 i kwaśnego białka włókienkowego gleju (GFAP, glial fibrillary acid protein) w gruczolakach przysadki mózgowej nie została dobrze poznana. Dostępne są nieliczne publikacje dotyczące korelacji tych cząsteczek z innymi czynnikami prognostycznymi lub terapeutycznymi w gruczolakach przysadki. Celem niniejszej pracy jest wyjaśnienie udziału tych białek w patogenezie gruczolaków przysadki i ustalenie korelacji między ich ekspresją a różnymi czynnikami wzrostu lub receptorami czynników wzrostu o znanej wartości prognostycznej i/lub terapeutycznej. Materiał i metody: Sześćdziesiąt sześć przypadków gruczolaka przysadki zbadano metodami immunohistochemicznymi w celu oceny ekspresji białek GFAP i S100 zarówno w komórkach guza, jak i w komórkach pęcherzykowo-gwiaździstych (FS, folliculo-stellate cells) oraz przeanalizowania uzyskanych wyników w ścisłej zależności z profilami hormonalnymi gruczolaków i w korelacji z ekspresją czynnika wzrostu śródbłonka naczyniowego (VEGF, vascular endothelial growth factor) i receptora naskórkowego czynnika wzrostu (EGFR, epidermal growth factor receptor), ocenianych w badaniu przeprowadzonym wcześniej przez nasz zespół. Wyniki: Ekspresję białek GFAP i S100 stwierdzono zarówno w komórkach guza, jak i w komórkach FS. Zaobserwowano różnice pod względem morfologii, rozkładu i gęstości komórek FS z dodatnią ekspresją białek GFAP i S100 (GFAP+FS i S100+FS) odpowiadające profilowi hormonalnemu gruczolaków przysadki. Ekspresja białek GFAP i S100 w komórkach guza była istotnie związana z profilem hormonalnym gruczolaków przysadki, a także z ekspresją VEGF i EGFR. Wnioski: Ekspresja białek GFAP i S100 w komórkach gruczolaka przysadki zależy od profilu hormonalnego guza. Uzyskane w badaniu wyniki potwierdzają obecność dwóch podtypów molekularnych komórek FS GFAP+/VEGF+/S100 oraz jednego typu GFAP–/S100+/EGFR+ występujących jednocześnie z klasycznym wariantem GFAP+/S100+. Możliwe, że gruczolaki przysadki z ekspresją S100+/EGFR+ należą do grupy tych nowotworów cechujących się agresywnością i dużą zdolnością do naciekania i nawrotów

Endocrine Gland-Derived Vascular Endothelial Growth Factor/Prokineticin-1 in Cancer Development and Tumor Angiogenesis

A lot of data suggests endocrine gland-derived vascular endothelial growth factor (EG-VEGF) to be restricted to endocrine glands and to some endocrine-dependent organs. Many evidences show that EG-VEGF stimulates angiogenesis and cell proliferation, although it is not a member of the VEGF family. At the time, a lot of data regarding the role of this growth factor in normal development are available. However, controversial results have been published in the case of pathological conditions and particularly in malignant tumors. Thus, our present paper has been focused on the role of EG-VEGF in normal tissues and various malignant tumors and their angiogenic processes

VEGF, VEGF165b and EG-VEGF expression is specifically related with hormone profile in pituitary adenomas

Vascular endothelial growth factor (VEGF), its inhibitory splice variant, VEGF165b and Endocrine Gland derived VEGF (EG-VEGF) have a controversial role in pituitary gland. We aim to study VEGF, VEGF165b and EG-VEGF expression in pituitary adenomas. A significant correlation was found between growth hormone (GH) and VEGF secretion (P=0.024). For prolactinomas, VEGF and prolactin expression, had a P-value of 0.02 for Kendall coefficient and a P-value of 0.043 for the Spearman coefficient. VEGF-mRNA amplification was detected in both tumor cells and folliculostellate cells. VEGF165b was positive in 16.66% of pituitary adenomas. EG-VEGF was significantly correlated with prolactin (P=0.025) and luteinizing hormone (P=0.028). Our data strongly support VEGF, VEGF165b and EG-VEGF as important players of pituitary adenomas tumorigenesis. Particular hormonal milieu heterogeneity, special vascular network with an unusual reactivity to tumor growth correlated with variability of VEGF, VEGF165b and EG-VEGF secretion may stratify pituitary adenomas in several molecular groups with a direct impact on therapy and prognosis

High Ki-67 expression is associated with prolactin secreting pituitary adenomas

Pituitary adenomas represent the third most common primary intracranial tumor in neurosurgical practice. To understand the biological behaviour of the pituitary adenomas previous studies have determined the tumor proliferation rate using monoclonal antibodies targeted against the Ki-67 antigen. The aim of this study was to correlate the Ki-67 index with hormonal profiles of pituitary adenomas. The study included 50 pituitary adenomas. For histopathologic evaluation, the sections were stained with routine hematoxylin and eosin method. Additional paraffin sections from each tumor were immunostained using primary antibodies against the following pituitary hormones: somatotropin (STH), prolactin (PRL), adrenocorticotrophic hormone (ACTH), thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH). To detect the expression of Ki-67 we used a mouse anti-human monoclonal antibody (clone K2). The percentage of Ki-67 positive nuclei (Ki-67 labeling index) was assessed by counting approximately 1000 nuclei of the tumor cells at ×400 magnification. Out of the 50 tumor samples, 31 (62%) pituitary adenomas showed proliferative activity, and the proliferation rate was variable in this group. The overall mean Ki-67 labeling index was 1.59 ± 1.47, ranging from 0.3% to 6.6%. In 5 cases, the Ki-67 index was >3%, all of them being prolactinomas. The Ki-67 index was higher in PRL-secreting adenomas (mean ± SD was 3.37 ± 1.80, range 0.9 - 6.6%). Our study provides the evidence that a higher Ki-67 value is associated with pituitary adenomas that secrete PRL (prolactinomas and mixed STH/PRL-secreting adenomas)

HETEROGENEITY OF C ERB B FAMILY MEMBERS EXPRESSION IS RELATED TO CELL MORPHOLOGY AND IMMUNOPROFILE IN PITUITARY ADENOMAS

Purpose. Epidermal growth factor receptor (EGFR, HER1) and human epidermal receptor 2 (HER2) assessement in pituitary adenomas related to hormone profile. Design and methods. For 60 retrospective cases of pituitary adenomas, we established the histopathologic diagnosis by using morphological stains, followed by case selection for immunoprofile and EGFR and HER 2 assessement. Results. More than one third of the studied pituitary adenomas (33,33%) were positive for HER2, with membranar pattern in basophilic cells and with predominantly cytoplasmic, granular pattern for acidophils cells. HER2 immuno-expression characterized PRL secreting adenomas (p=0.005) and associations between FSH-LH (p< 0.001) TSH-FSH (p=0,024) and TSH-LH (p=0.028). In situ hybridization confirmed HER2 gene amplification in 33,34% out of all positive cases for HER2 by immunohistochemistry. EGFR positivity was found significantly for GH-prolactin (p=0.000) and prolactin-ACTH (p=0.045) co-expressing pituitary adenomas, peritumoral macrophages and folliculostellate cells. Conclusions. Differential HER2 and EGFR expression related to hormone profile heterogeneity can define different subclasses of pituitary adenomas and could explain clinical, prognostic and therapeutic heterogeneity which are observed in clinical practice. Our results support re-classification of pituitary adenomas based on molecular approach which should include markers with well certified prognostic and therapeutic impact

Geographic-Related Differences of Pituitary Adenomas Hormone Profile: Analysis of Two Groups Coming from Southeastern and Eastern Europe

We compared the immunoprofile of pituitary adenomas from Romania and Moldova. One hundred and eighty cases coming from Romania (94 cases, group 1) and Moldova (86 cases, group 2) were assessed by immunohistochemistry regarding all six basic hormones expressed in pituitary adenomas. Specific differences and similarities were found and stated for both groups. In group 1, 70% of cases were pituitary adenomas positive for one hormone, 13% were plurihormonal, while 17% were negative. In group 2, 50,3% of the cases expressed only one hormone and 12,5% were negative for all hormones. The highest difference was observed for plurihormonal adenomas, found in about 37,2% of cases for group 2 (2.86 times higher for group 2 compared with group 1). A higher incidence of GH-secreting adenomas characterized group “1,” while group “2” had the highest percent of LH-secreting adenomas, 55% of cases being positive. Triple association was noticed in 4.25% of cases of group 1 and in 8,13% out of total cases, from group 2. Four-hormone association was found only in group 2, noticed in 15,56% of the cases. The present paper highlights strong evidences of a particular and different immunoprofile of pituitary adenomas coming from Romania and Moldova