Prognostic significance of microvessel density, vascular cuffing and vascular endothelial growth factor expression in ovarian carcinoma: a special review for clear cell adenocarcinoma
Introduction
Angiogenesis is essential for tumor growth and metastasis. Folkman showed that tumor growth, after reaching the size of about 1–2 mm2, is strictly dependent on angiogenesis [1]. The evidence that angiogenesis, quantitated by microvessel counting, could be related to metastases and patient survival was shown in several tumors, including breast [2], lung [3], head and neck [4], prostate [5] and testis [6]. Furthermore, in a follow-up study, Weidner has found that microvessel density (MVD) in the area of most intense neovascularization in invasive breast carcinoma is an independent, highly significant, and accurate prognostic indicator in predicting overall and relapse-free survival in patients with early stage breast carcinoma [7]. We reported that MVD had an association with prognosis in endometrium [8] and uterine cervical adenocarcinomas [9].
We also demonstrated that epithelial-stromal vascular cuffing (VC), a bead-like arrangement of microvessels closely surrounding microscopic tumor nests, correlates with a significantly worse prognosis in squamous cell carcinoma of the uterine cervix.
Vascular endothelial growth factor (VEGF) is a multifunctional glycoprotein cytokine that potently stimulates angiogenesis in vivo [10]. Among several angiogenic factors, VEGF is thought to be one of the most important factors for tumor angiogenesis [11], [12]. VEGF has been observed in a variety of tumor cell lines and in many types of human solid tumors [13], [14], [15], [16], [17].
In ovarian carcinoma, however, the clinicopathologic role of angiogenesis is as yet unknown. While some authors presented a significant association of microvessel counts with prognosis in ovarian carcinoma, others did not.
This report presents MVD, VC and VEGF expression and their correlation with prognosis in epithelial ovarian carcinoma taking into account the stage and the histologic type.
Section snippets
Patients
One hundred and five consecutive patients with primary ovarian carcinoma were initially treated with surgery at the Department of Gynecology and Obstetrics of Kyushu University Hospital from 1980 to 1995. Patients with borderline epithelial ovarian carcinoma and primary peritoneal carcinoma were excluded. Initial surgery was composed of abdominal hysterectomy, bilateral salpingo-oophorectomy, paraaortic lymph node biopsy, omentectomy and appendectomy. Since 1986, dissection of the pelvic lymph
Results
Patient ages ranged from 25 to 77 years (median 52 years). The histologic types of tumors were as follows: 57 serous adenocarcinomas, 22 clear cell carcinomas, 17 mucinous adenocarcinomas, and nine endometrioid adenocarcinomas (Table 1).
The median MVD was 77 microvessels/high power field (range 21–244). Fig. 2a,d shows the relationship between MVD and progression-free survival. The MVD≧70 was associated with better progression-free survival in early stages (stages I–II) (log-rank, P=0.003). In
Discussion
In ovarian carcinoma, the clinicopathologic role of angiogenesis is as yet unknown. Some authors have found no significant relationship between MVD and survival [19], [20], [21]. Van Diest reported that MVD had no association with prognosis, stage, tumor grade and DNA ploidy in advanced ovarian carcinoma. Abulafia and Nakanishi similarly found that MVD was not correlated with patient survival.
On the other hand, others have found that high MVD correlated with a worse prognosis; however, MVD did
Acknowledgements
This work was supported in part by Grants-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science and Technolgy (Nos. 11671626, 12671612, 12671613).
References (38)
- et al.
Relation of neovascularization to metastasis of non-small cell lung cancer
Lancet
(1992) - et al.
Significance of vascular endothelial growth factor/vascular permeability factor for solid tumor growth, and its inhibition by the antibody
Biochem. Biophys. Res. Commun.
(1993) - et al.
Prognostic significance of epithelial-stromal vascular cuffing and microvessel density in squamous cell carcinoma of the uterine cervix
Gynecol. Oncol.
(1999) - et al.
Prognostic value of microvessel quantitation in cisplatin treated FIGO 3 and 4 ovarian cancer patients
Pathol. Res. Pract.
(1995) - et al.
Angiogenesis in primary and metastatic epithelial ovarian carcinoma
Am. J. Obstet. Gynecol.
(1997) - et al.
Prognostic significance of tumor angiogenesis in epithelial ovarian cancer
Cancer Lett.
(1999) - et al.
Prevalence of ovarian endometriosis in epithelial ovarian cancer
Int. J. Gynecol. Oncol.
(1997) - et al.
Vascular endothelial growth factor expression as a prognostic index in serous ovarian cystoadenocarcinomas: relationship with MIB1 immunostaining
Gynecol. Oncol.
(1999) - et al.
Vascular density and the response of breast carcinomas to mastectomy and adjuvant chemotherapy
Eur. J. Cancer
(1993) What is the evidence that tumors are angiogenesis dependent?
J. Natl. Cancer Inst.
(1990)
Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma
N. Engl. J. Med.
Intratumoral microvessel density and p53 protein: correlation with metastasis in head-and-neck squamous cell carcinoma
Int. J. Cancer
Tumour angiogenesis in prostatic carcinoma with and without bone metastasis: a morphometric study
J. Pathol.
Neovascularization in clinical stage A testicular germ cell tumor: prediction of metastatic disease
Cancer Res.
Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma
J. Natl. Cancer Inst.
Angiogenesis in endometrial carcinoma
Cancer
Angiogenesis in adenocarcinoma of the uterine cervix
Cancer
Regulation of VEGF/VPF expression in tumor cells: consequences for tumor growth and metastasis
Cancer Metastasis Rev.
Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumor growth in vivo
Nature
Cited by (58)
Enhanced anti-tumor efficacy and safety with metronomic intraperitoneal chemotherapy for metastatic ovarian cancer using biodegradable nanotextile implants
2019, Journal of Controlled ReleaseCitation Excerpt :For the control groups, a gradual and substantial increase in VEGF in ascitic fluid was noted over 35 days, indicating the development of an angiogenic vasculature, resulting in the accumulation of malignant ascites [50]. VEGF over-expression in ascitic fluid is therefore a strong predictive marker for poor prognosis and rapid recurrence of late-stage OC [39,51]. For the PTX-treated groups, high VEGF levels at day 16 in contrast to that of control groups, can be attributed to the enhanced VEGF mRNA up-regulation mediated by the bolus dose effect of IP PTX-solution and the initial burst PTX-release from nanotextiles [52,53].
MiR-718 represses VEGF and inhibits ovarian cancer cell progression
2014, FEBS LettersCitation Excerpt :The crucial role of VEGF in ovarian cancer has been well elaborated in earlier studies from the previous century. Upregulated levels of VEGF have been reported in ovarian carcinoma compared with benign tumors or healthy patients [7,20,21]. VEGF repression has been shown to inhibit cell proliferation, migration, and tumor growth in ovarian cancer [8,18,23].
Maspin overexpression correlates with increased expression of vascular endothelial growth factors A, C, and D in human ovarian carcinoma
2008, Pathology Research and PracticeQuantification of angiogenesis by the Chalkley method and its prognostic significance in epithelial ovarian cancer
2007, European Journal of CancerCitation Excerpt :In addition, a lack of standardised immunohistochemical techniques hampers the comparison of studies. For example, antibodies to CD34,4–6,8–10 CD31,7,11,12 von Willebrand factor (Factor VIII)13,14 and Ulex15 have been used to detect vascular structures in prognostic ovarian carcinoma studies. CD34 is a cell surface protein that is selectively expressed by human hematopoietic progenitor cells and vascular endothelial cells,16,17 and it has been shown to mark tumour vessels also in the solid cancers of ovary.18