High Expression of Galectin-1, VEGF and Increased Microvessel Density Are Associated with MELF Pattern in Stage I-III Endometrioid Endometrial Adenocarcinoma

다국어 초록 (Multilingual Abstract)

Background: In this study, we investigate the expression of markers of angiogenesis and microvessel density (MVD) in cases of microcystic, elongated and fragmented (MELF) pattern, with its prognostic role in the survival of endometrioid endometrial adenocarcinomas (EA) patients. Methods: In this study, 100 cases of EA, 49 cases with MELF pattern and 51 without, were immunohistochemically stained for galectin-1, vascular endothelial growth factor (VEGF), and MVD. Morphometry and statistical (univariate and multivariate) analyses were performed to assess overall survival (OS) and disease-free survival. Results: The expression of VEGF (p < .001) and galectin-1 (p < .001), as well as MVD area (p < .001) and number of vessels/mm2 (p < .050), were significantly higher in the +MELF pattern group compared to the –MELF group. A low negative correlation between MELF-pattern and the number of days of survival (p < .001, r = –0.47) was also found. A low positive correlation of MELF-pattern with galectin-1 expression (p < .001, r = 0.39), area of vessels/mm2 (p < .001, r = 0.36), outcome of EA (p < .001, r = 0.42) and VEGF expression (p < .001, r = 0.39) suggests potential pathological relevance of these factors in the prognosis of EA. A univariate survival analysis indicated a role for all parameters of survival. Multivariate Cox proportional hazard regression analysis revealed that only area of vessels/mm2 (hazard ratio [HR], 1.018; 95% confidence interval [CI], 1.002 to 1.033), galectin-1 (HR, 1.049; 95% CI, 1.025 to 1.074) and VEGF (HR, 1.049; 95% CI, 1.022 to 1.077) play key roles in OS. Conclusions: This study reports an increase in MVD, VEGF and galectin-1 expression in EA with MELF pattern and suggests that MELF pattern, along with the angiogenic profile, may be a prognostic factor in EA.

참고문헌 (Reference)

1 Melincovici CS, "Vascular endothelial growth factor(VEGF) : key factor in normal and pathological angiogenesis" 59 : 455-467, 2018

2 Goel HL, "VEGF targets the tumour cell" 13 : 871-882, 2013

3 Murray SK, "Unusual epithelial and stromal changes in myoinvasive endometrioid adenocarcinoma : a study of their frequency, associated diagnostic problems, and prognostic significance" 22 : 324-333, 2003

4 Zinovkin D, "Tumor-infiltrated lymphocytes, macrophages, and dendritic cells in endometrioid adenocarcinoma of corpus uteri as potential prognostic factors : an immunohistochemical study" 26 : 1207-1212, 2016

5 Zinovkin DA, "Tumor-associated T-lymphocytes and macrophages are decreased in endometrioid endometrial carcinoma with MELF-pattern stromal changes" 11 : 107-114, 2018

6 Jilaveanu LB, "Tumor microvessel density as a prognostic marker in high-risk renal cell carcinoma patients treated on ECOG-ACRIN E2805" 24 : 217-223, 2018

7 Joehlin-Price AS, "The microcystic, elongated, and fragmented(MELF)pattern of invasion : a single institution report of 464 consecutive FIGO grade 1 endometrial endometrioid adenocarcinomas" 41 : 49-55, 2017

8 Jeschke U, "The human endometrium expresses the glycoprotein mucin-1 and shows positive correlation for Thomsen-Friedenreich epitope expression and galectin-1 binding" 57 : 871-881, 2009

9 Dmitry Aleksandrovich Zinovkin, "The Potential Roles of MELF-Pattern, Microvessel Density, and VEGF Expression in Survival of Patients with Endometrioid Endometrial Carcinoma: A Morphometrical and Immunohistochemical Analysis of 100 Cases" The Korean Society of Pathologists and The Korean Society for Cytopathology 51 (51): 456-462, 2017

10 Li YL, "Relationship of VEGF/VEGFR with immune and cancer cells: staggering or forward?" 13 : 206-214, 2016

11 Miyata Y, "Reconsideration of the clinical and histopathological significance of angiogenesis in prostate cancer : Usefulness and limitations of microvessel density measurement" 22 : 806-815, 2015

12 Hu X, "Prognostic value of microvessel density in cervical cancer" 18 : 152-, 2018

13 Wu R, "Prognostic significance of galectin-1expression in patients with cancer : a meta-analysis" 18 : 108-, 2018

14 Reeves KW, "Obesity in relation to endometrial cancer risk and disease characteristics in the Women’s Health Initiative" 121 : 376-382, 2011

15 Banas T, "Non-endometrioid and high-grade endometrioid endometrial cancers show DNA fragmentation factor 40(DFF40)and B-cell lymphoma 2 protein(BCL2)underexpression, which predicts disease-free and overall survival, but not DNA fragmentation factor 45(DFF45)underexpression" 18 : 418-, 2018

16 Sandberg TP, "Molecular profiling of colorectal tumors stratified by the histological tumor-stroma ratio : increased expression of galectin-1in tumors with high stromal content" 9 : 31502-31515, 2018

17 Pelletier MP, "Microcystic, elongated, and fragmented pattern invasion is mainly associated with isolated tumor cell pattern metastases in International Federation of Gynecology and Obstetrics grade I endometrioid endometrial cancer" 62 : 33-39, 2017

18 Prodromidou A, "MELF pattern of myometrial invasion and role in possible endometrial cancer diagnostic pathway : a systematic review of the literature" 230 : 147-152, 2018

19 Stewart CJ, "MELF pattern invasion in endometrial carcinoma : association with low grade, myoinvasive endometrioid tumours, focal mucinous differentiation and vascular invasion" 41 : 454-459, 2009

20 Sanci M, "MELF pattern for predicting lymph node involvement and survival in grade I-II endometrioid-type endometrial cancer" 37 : 17-21, 2018

21 Kamili NA, "Key regulators of galectin-glycan interactions" 16 : 3111-3125, 2016

22 Mezheyeuski A, "Inter-and intra-tumoral relationships between vasculature characteristics, GLUT1 and budding in colorectal carcinoma" 30 : 1203-1211, 2015

23 Horn LC, "Histopathology of endometrial hyperplasia and endometrial carcinoma : an update" 11 : 297-311, 2007

24 Chen J, "High expressions of galectin-1 and VEGF are associated with poor prognosis in gastric cancer patients" 35 : 2513-2519, 2014

25 Zhu X, "Galectin-1 knockdown in carcinomaassociated fibroblasts inhibits migration and invasion of human MDA-MB-231 breast cancer cells by modulating MMP-9 expression" 48 : 462-467, 2016

26 SGO Clinical Practice Endometrial Cancer Working Group, "Endometrial cancer : a review and current management strategies : part II" 134 : 393-402, 2014

27 Albini A, "Contribution to tumor angiogenesis from innate immune cells within the tumor microenvironment : implications for immunotherapy" 9 : 527-, 2018

28 Wang JZ, "Clinicopathological and prognostic significance of blood microvessel density in endometrial cancer : a meta-analysis and subgroup analysis" 297 : 731-740, 2018

29 Kihara A, "Clinicopathologic association and prognostic value of microcystic, elongated, and fragmented(MELF)pattern in endometrial endometrioid carcinoma" 41 : 896-905, 2017

30 Tao L, "Cancer associated fibroblasts : an essential role in the tumor microenvironment" 14 : 2611-2620, 2017