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Clinicopathological and prognostic significance of blood microvessel density in endometrial cancer: a meta-analysis and subgroup analysis

  • Gynecologic Oncology
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Objective

The study aimed to systematically review the association between angiogenesis and clinicopathological characteristics and its prognostic value in patients with endometrial cancer.

Methods

Eligible studies were searched in PubMed, Embase, China National Knowledge Infrastructure, and Wanfang database. Studies that assessed blood microvessel density (BMVD) and correlated with clinicopathological features and/or overall survival (OS) were included. Geometric mean values and hazard ratio with 95% confidence interval were pooled to examine the risk or hazard association. Subgroup analyses were conducted based on populations, BMVD criteria, BMVD markers, and type of survival analysis.

Results

A total of 29 studies of 2517 patients were included. BMVD was associated with depth of myometrial invasion (MI) [standard mean difference (SMD) 1.24; 95% CI 0.53–1.95; P = 0.0006], lymphovascular space invasion (LVSI) (SMD 0.75; 95% CI 0.3–1.21; P = 0.001), and lymph node metastasis (LNM) (SMD 0.99; 95% CI 0.46–1.52; P = 0.0003). BMVD was also significantly associated with poor OS (HR 2.65; 95% CI 1.86–3.77; P < 0.00001). The association remained significant in the subgroups Asian population, BMVD criteria using Weidner method, BMVD marker CD34 for MI, LVSI, and LNM, CD105 for MI, and factor VIII for MI and LNM, respectively. For OS, either Asian or non-Asian population, BMVD criteria using Weidner or non-Weidner method, BMVD marker CD31, or factor VIII antibody and analysis using univariate or multivariate were all significantly associated.

Conclusions

BMVD was associated with deeper MI, positive LVSI, positive LNM, and poor OS in patients with endometrial cancer. Therefore, angiogenesis is a useful measure for poor clinicopathological outcomes and prognosis in patients with endometrial cancer.

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References

  1. Papa A, Zaccarelli E, Caruso D, Vici P, Benedetti Panici P, Tomao F (2016) Targeting angiogenesis in endometrial cancer—new agents for tailored treatments. Expert Opin Investig Drugs 25:31–49

    Article  CAS  PubMed  Google Scholar 

  2. Weidner N, Semple JP, Welch WR, Folkman J (1991) Tumor angiogenesis and metastasis—correlation in invasive breast carcinoma. N Engl J Med 324:1–8

    Article  CAS  PubMed  Google Scholar 

  3. Uzzan B, Nicolas P, Cucherat M, Perret GY (2004) Microvessel density as a prognostic factor in women with breast cancer: a systematic review of the literature and meta-analysis. Cancer Res 64:2941–2955

    Article  CAS  PubMed  Google Scholar 

  4. Des Guetz G, Uzzan B, Nicolas P, Cucherat M, Morere JF, Benamouzig R et al (2006) Microvessel density and VEGF expression are prognostic factors in colorectal cancer. Meta-analysis of the literature. Br J Cancer 94:1823–1832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Huang J, Ma X, Chen X, Liu X, Zhang B, Minmin L et al (2014) Microvessel density as a prognostic factor in bladder cancer: a systematic review of literature and meta-analysis. Cancer Biomark 14:505–514

    Article  PubMed  Google Scholar 

  6. Amant F, Moerman P, Neven P, Timmerman D, Van Limbergen E, Vergote I (2005) Endometrial cancer. Lancet 366:491–505

    Article  PubMed  Google Scholar 

  7. Caplakova V, Babusikova E, Blahovcova E, Balharek T, Zelieskova M, Hatok J (2016) DNA methylation machinery in the endometrium and endometrial cancer. Anticancer Res 36:4407–4420

    Article  CAS  PubMed  Google Scholar 

  8. Espinosa I, Jose Carnicer M, Catasus L, Canet B, D’Angelo E, Zannoni GF et al (2010) Myometrial invasion and lymph node metastasis in endometrioid carcinomas: tumor-associated macrophages, microvessel density, and HIF1A have a crucial role. Am J Surg Pathol 34:1708–1714

    PubMed  Google Scholar 

  9. Jorge S, Hou JY, Tergas AI, Burke WM, Huang Y, Hu JC et al (2016) Magnitude of risk for nodal metastasis associated with lymphovascular space invasion for endometrial cancer. Gynecol Oncol 140:387–393

    Article  PubMed  PubMed Central  Google Scholar 

  10. Mahdi H, Jernigan A, Nutter B, Michener C, Rose PG (2015) Lymph node metastasis and pattern of recurrence in clinically early stage endometrial cancer with positive lymphovascular space invasion. J Gynecol Oncol 26:208–213

    Article  PubMed  PubMed Central  Google Scholar 

  11. Stang A (2010) Critical evaluation of the Newcastle–Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 25:603–605

    Article  PubMed  Google Scholar 

  12. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR (2007) Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 8:16

    Article  PubMed  PubMed Central  Google Scholar 

  13. Ioannidis JP, Panagiotou OA (2011) Comparison of effect sizes associated with biomarkers reported in highly cited individual articles and in subsequent meta-analyses. JAMA 305:2200–2210

    Article  CAS  PubMed  Google Scholar 

  14. Ai X, Shu K, Xiong S (2009) The relationships between expression of COX-2, microvessel density and the prognosis of endometrial carcinoma. Acta Acad Med Jiangxi 49:32–34

    CAS  Google Scholar 

  15. Chen CA, Cheng WF, Lee CN, Wei LH, Chu JS, Hsieh FJ et al (2001) Cytosol vascular endothelial growth factor in endometrial carcinoma: correlation with disease-free survival. Gynecol Oncol 80:207–212

    Article  CAS  PubMed  Google Scholar 

  16. Chen S, Zhang Y, Gao L (2006) Clinical significance of CD105 and vascular endothelial growth factor expression in endometrial carcinima. J Hebei Med U 27:350–353

    CAS  Google Scholar 

  17. Erdem O, Taskiran C, Onan MA, Erdem M, Guner H, Ataoglu O (2006) CD105 expression is an independent predictor of survival in patients with endometrial cancer. Gynecol Oncol 103:1007–1011

    Article  CAS  PubMed  Google Scholar 

  18. Giatromanolaki A, Sivridis E, Brekken R, Thorpe PE, Anastasiadis P, Gatter KC et al (2001) The angiogenic “vascular endothelial growth factor/flk-1(KDR) receptor” pathway in patients with endometrial carcinoma: prognostic and therapeutic implications. Cancer 92:2569–2577

    Article  CAS  PubMed  Google Scholar 

  19. Guset G, Costi S, Lazar E, Dema A, Cornianu M, Vernic C et al (2010) Expression of vascular endothelial growth factor (VEGF) and assessment of microvascular density with CD34 as prognostic markers for endometrial carcinoma. Rom J Morphol Embryol 51:677–682

    CAS  PubMed  Google Scholar 

  20. Huang Y, Zheng X, Liu L, Jiang Z (2008) Expressions and its clinical significance of HIF-1α, VEGF, CD105-MVD in the endometrial cancer. J Pract Med 24:42–44

    Google Scholar 

  21. Jiang XF, Tang QL, Li HG, Shen XM, Luo X, Wang XY et al (2013) Tumor-associated macrophages correlate with progesterone receptor loss in endometrial endometrioid adenocarcinoma. J Obstet Gynaecol Res 39:855–863

    Article  PubMed  Google Scholar 

  22. Kaku T, Kamura T, Kinukawa N, Kobayashi H, Sakai K, Tsuruchi N et al (1997) Angiogenesis in endometrial carcinoma. Cancer 80:741–747

    Article  CAS  PubMed  Google Scholar 

  23. Kamat AA, Merritt WM, Coffey D, Lin YG, Patel PR, Broaddus R et al (2007) Clinical and biological significance of vascular endothelial growth factor in endometrial cancer. Clin Cancer Res 13:7487–7495

    Article  CAS  PubMed  Google Scholar 

  24. Kirschner CV, Alanis-Amezcua JM, Martin VG, Luna N, Morgan E, Yang JJ et al (1996) Angiogenesis factor in endometrial carcinoma: a new prognostic indicator? Am J Obstet Gynecol 174:1879–1882 (discussion 82–4)

    Article  CAS  PubMed  Google Scholar 

  25. Li F, Wang Y (2010) Relationships of survivin, VEGF, MVD in endometrial carcinoma tissues with prognosis of the patient. Chin J Women Child Health Res 21:320–324

    Google Scholar 

  26. Liang A, Shi H (2006) Expression of endostatin, VEGF and microvessel density in endometrial adenocarcinoma. J Med Forum 27:49–52

    Google Scholar 

  27. Merritt WM, Kamat AA, Hwang JY, Bottsford-Miller J, Lu C, Lin YG et al (2010) Clinical and biological impact of EphA2 overexpression and angiogenesis in endometrial cancer. Cancer Biol Ther 10:1306–1314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Niu Z, Ji X (2008) Relationship among intratumor microvessel density, clinicopathological features and cell proliferation in human endometrial adenocarcinoma. Acta Acad Medi Qingdao U 44:335–340

    Google Scholar 

  29. Obermair A, Tempfer C, Wasicky R, Kaider A, Hefler L, Kainz C (1999) Prognostic significance of tumor angiogenesis in endometrial cancer. Obstet Gynecol 93:367–371

    CAS  PubMed  Google Scholar 

  30. Ohno S, Ohno Y, Suzuki N, Soma G, Inoue M (2007) Cyclooxygenase-2 expression correlates with apoptosis and angiogenesis in endometrial cancer tissue. Anticancer Res 27:3765–3770

    PubMed  Google Scholar 

  31. Ozalp S, Yalcin OT, Acikalin M, Tanir HM, Oner U, Akkoyunlu A (2003) Microvessel density (MVD) as a prognosticator in endometrial carcinoma. Eur J Gynaecol Oncol 24:305–308

    CAS  PubMed  Google Scholar 

  32. Ozuysal S, Bilgin T, Ozan H, Kara HF, Ozturk H, Ercan I (2003) Angiogenesis in endometrial carcinoma: correlation with survival and clinicopathologic risk factors. Gynecol Obstet Investig 55:173–177

    Article  Google Scholar 

  33. Pansrikaew P, Cheewakriangkrai C, Taweevisit M, Khunamornpong S, Siriaunkgul S (2010) Correlation of mast cell density, tumor angiogenesis, and clinical outcomes in patients with endometrioid endometrial cancer. Asian Pac J Cancer Prev 11:623–626

    PubMed  Google Scholar 

  34. Salvesen HB, Iversen OE, Akslen LA (1999) Prognostic significance of angiogenesis and Ki-67, p53, and p21 expression: a population-based endometrial carcinoma study. J Clin Oncol 17:1382–1390

    Article  CAS  PubMed  Google Scholar 

  35. Salvesen HB, Das S, Akslen LA (2000) Loss of nuclear p16 protein expression is not associated with promoter methylation but defines a subgroup of aggressive endometrial carcinomas with poor prognosis. Clin Cancer Res 6:153–159

    CAS  PubMed  Google Scholar 

  36. Soeda S, Nakamura N, Ozeki T, Nishiyama H, Hojo H, Yamada H et al (2008) Tumor-associated macrophages correlate with vascular space invasion and myometrial invasion in endometrial carcinoma. Gynecol Oncol 109:122–128

    Article  CAS  PubMed  Google Scholar 

  37. Stefansson IM, Salvesen HB, Akslen LA (2006) Vascular proliferation is important for clinical progress of endometrial cancer. Cancer Res 66:3303–3309

    Article  CAS  PubMed  Google Scholar 

  38. Straume O, Chappuis PO, Salvesen HB, Halvorsen OJ, Haukaas SA, Goffin JR et al (2002) Prognostic importance of glomeruloid microvascular proliferation indicates an aggressive angiogenic phenotype in human cancers. Cancer Res 62:6808–6811

    CAS  PubMed  Google Scholar 

  39. Tan Y, Sha X, Zeng Y, Lin Z, Zhang B (2003) The relationships between microvessel density, expression of vascular endothelial growth factor and the prognosis of endometrial carcinoma. J Sun Yat-sen U (Med Sci) 24:475–478

    Google Scholar 

  40. Wagatsuma S, Konno R, Sato S, Yajima A (1998) Tumor angiogenesis, hepatocyte growth factor, and c-Met expression in endometrial carcinoma. Cancer 82:520–530

    Article  CAS  PubMed  Google Scholar 

  41. Watanabe M, Aoki Y, Kase H, Tanaka K (2003) Heparanase expression and angiogenesis in endometrial cancer. Gynecol Obstet Investig 56:77–82

    Article  CAS  Google Scholar 

  42. Zhang C, Dong J (2010) Relationship between the expression of HIF-1α, VEGF and microvessel density in endometrial carcinoma tissues. Chin J Cancer Prev Treat 17:1086–1089

    CAS  Google Scholar 

  43. Puro DG, Kohmoto R, Fujita Y, Gardner TW, Padovani-Claudio DA (2016) Bioelectric impact of pathological angiogenesis on vascular function. Proc Natl Acad Sci USA 113:9934–9939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Folkman J (1990) What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 82:4–6

    Article  CAS  PubMed  Google Scholar 

  45. Baluk P, Morikawa S, Haskell A, Mancuso M, McDonald DM (2003) Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors. Am J Pathol 163:1801–1815

    Article  PubMed  PubMed Central  Google Scholar 

  46. Jacquemier JD, Penault-Llorca FM, Bertucci F, Sun ZZ, Houvenaeghel GF, Geneix JA et al (1998) Angiogenesis as a prognostic marker in breast carcinoma with conventional adjuvant chemotherapy: a multiparametric and immunohistochemical analysis. J Pathol 184:130–135

    Article  CAS  PubMed  Google Scholar 

  47. Bamberger ES, Perrett CW (2002) Angiogenesis in epithelian ovarian cancer. Mol Pathol 55:348–359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Karkkainen MJ, Makinen T, Alitalo K (2002) Lymphatic endothelium: a new frontier of metastasis research. Nat Cell Biol 4:E2–E5

    Article  CAS  PubMed  Google Scholar 

  49. Birau A, Ceausu RA, Cimpean AM, Gaje P, Raica M, Olariu T (2012) Assessement of angiogenesis reveals blood vessel heterogeneity in lung carcinoma. Oncol Lett 4:1183–1186

    Article  PubMed  PubMed Central  Google Scholar 

  50. Czekierdowski A, Czekierdowska S, Czuba B, Cnota W, Sodowski K, Kotarski J et al (2008) Microvessel density assessment in benign and malignant endometrial changes. J Physiol Pharmacol 59(Suppl 4):45–51

    PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Hong Kong Obstetrical & Gynaecological Trust Fund 2016–2017.

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Authors and Affiliations

  1. Department of Obstetrics and Gynaecology, Block E, 1/F, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong

    Jian Zhang Wang, Yu Jing Xiong, Gene Chi Wai Man, Xiao Yan Chen, Joseph Kwong & Chi Chiu Wang

  2. Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Shatin, Hong Kong

    Gene Chi Wai Man

  3. Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong

    Chi Chiu Wang

  4. School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong

    Chi Chiu Wang

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Contributions

JZW: project development, data collection, data analysis, and manuscript writing. YJX: data collection and data analysis. GCWM: data collection and data analysis. XYC: data analysis. JK: project development. CCW: project development, data analysis, and manuscript editing.

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Correspondence to Chi Chiu Wang.

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All authors declare that there is no conflict of interest. All authors have had full control of all primary data and agree to allow the Journal to review their data if requested.

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This article does not contain any studies with human participants performed by any of the authors.

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404_2018_4648_MOESM1_ESM.pptx

Fig. S1. Subgroup analysis of the association between BMVD and myometrial invasion, lymphovascular space invasion, lymph node metastasis, and overall survival in endometrial cancer of Asian and non-Asian patients. Fig. S2. Subgroup analysis of the association between BMVD and myometrial invasion, lymphovascular space invasion, lymph node metastasis, and overall survival in patients with endometrial cancer which used Weidner or non-Weidner method for BMVD detection. Fig. S3. Subgroup analysis of the association between BMVD and myometrial invasion, lymphovascular space invasion, lymph node metastasis, and overall survival according to the markers used for BMVD detection in endometrial cancer. Fig. S4. Subgroup analysis of the association between BMVD and overall survival according to HR from univariate or multivariate survival analyses. Fig. S5. a) Quantile–quantile plot of included cut-off values indicated that the value (36.5, Ai 2009) was an outlier, so it was excluded. b) Subgroup analysis of BMVD association with overall survival in patients with endometrial cancer whose cut-off value for high BMVD was in normal distribution. c) Subgroup analysis of CD34 antibody with cut-off value in normal distribution (PPTX 438 kb)

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Wang, J.Z., Xiong, Y.J., Man, G.C.W. et al. Clinicopathological and prognostic significance of blood microvessel density in endometrial cancer: a meta-analysis and subgroup analysis. Arch Gynecol Obstet 297, 731–740 (2018). https://doi.org/10.1007/s00404-018-4648-1

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