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Low endoglin vascular density and Ki67 index in Gleason score 6 tumours may identify prostate cancer patients suitable for surveillance
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. (Prostatacancer gruppen)
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.
Department of Urology, Central Hospital Västerås, Västerås, Sweden.
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(English)Article in journal (Other academic) Submitted
Abstract [en]

Objectives: To explore if vascular density and tumour cell proliferation are related to the risk of prostate cancer death in patients managed by watchful waiting.

Methods: From a consecutive series of men diagnosed with prostate cancer at transurethral resection in 1975-1990, tissue micro-arrays (TMAs) were constructed. A majority of men had no metastases at diagnosis and was followed by watchful waiting (n=295). The TMAs were stained for Ki67, endoglin and factor VIII related antigen (vWf).

Results: In univariate Cox analyses, increased Ki67 index, endoglin vascular density (v.d.) and vWf v.d. were associated with shorter cancer specific survival. : Ki67 index and endoglin v.d. added independent prognostic information to clinical stage, estimated tumour size and Gleason score (GS) in multivariate Cox analysis. In GS 6 tumours high Ki67 index and high endoglin v.d. indentified patients with poor outcome. After 15 years of follow-up not a single man out of 34 men with low staining for both markers (35% of all GS 6 tumours) had died of prostate cancer, in contrast to 15 prostate cancer deaths among the remaining 63 men with GS 6 tumours (65 % cumulative risk of prostate cancer death). vWf v.d. in benign areas was a prognostic marker in GS 6 and GS 7 tumours.

Conclusions: Men with GS 6 tumours with both low Ki67 index and endoglin v.d. staining scores have a low risk of progression. Additional studies are needed to test if these two markers can be applied to core biopsies to select patients suitable for surveillance.

Keyword [sv]
Immunohistokemi, prognostiska markörer
National Category
Urology and Nephrology
Research subject
Pathology; Pathology
URN: urn:nbn:se:umu:diva-50719OAI: diva2:467774
Available from: 2011-12-19 Created: 2011-12-19 Last updated: 2011-12-20Bibliographically approved
In thesis
1. Prognostic markers in prostate cancer: studies of a watchful waiting cohort with long follow up
Open this publication in new window or tab >>Prognostic markers in prostate cancer: studies of a watchful waiting cohort with long follow up
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Prostate Cancer (PC) is a common and highly variable disease. Using current diagnostic methods, the prostate specific antigen (PSA) blood test and histological grading of prostate tissue needle biopsies, it is often difficult to evaluate whether the patient has a PC that requires active treatment or not. The absolute majority of all 10,000 cases of PCs diagnosed annually in Sweden have tumours graded as Gleason score (GS) 6-7 and a PSA value in blood below 10. Many of these are harmless and can be left without active treatment and hence spared problematic post-therapy side-effects, others are highly malignant and require early diagnosis and treatment. Better prognostic markers are needed and the aim of this study was to evaluate prognostic markers and to test if these markers could identify patients with indolent tumours.

Methods: We have studied tumour material from 419 men consecutively diagnosed with PC at transurethral resection (1975-1990). The majority of these patients (295) had no metastasis at diagnosis and was not given any curative treatment and only hormonal treatment upon symptoms from metastatic progression. Standard histological sections and tissue microarrays (TMA) from these tumours and surrounding normal prostate tissue were stained and evaluated for cell proliferation (Ki67), blood vessels (endoglin and von Willebrand factor, vWf) and the extracellular matrix component hyaluronan (HA). An orthotopic rat PC model was used to explore hyaluronan staining, hyaluronic acid synthase (HAS)-1 mRNA levels and the effect of local HA treatment on tumour growth.

Results: Tumour cell proliferation (Ki67) and the density of intra-tumoural endoglin stained blood vessels were independent prognostic markers (i.e. they added prognostic information to the conventional prognostic markers; clinical stage and GS). None of the GS 6 patients with low staining for both Ki67 and endoglin died of PC within 15 years of follow-up. High HA staining in the tumour epithelium and stroma was a negative prognostic marker of cancer specific survival but they were not independent of GS. High HA staining and high vascular density in the stroma of the surrounding morphologically normal prostate were prognostic for short cancer specific survival. Implantation of tumour cells in the normal rat prostate resulted in an increase in HA and HAS-1 mRNA levels in the prostate tissue surrounding prostate tumours. Concurrently intra-prostatic injection of HA also stimulated tumour growth.

Conclusions: By evaluating both tumour cell proliferation (Ki67) and vascular density, it is possible to identify patients with very low risk of cancer specific death in the absence of active treatment. Prostate tumours influence the surrounding non-malignant prostate tissue, for example they cause an increased angiogenesis and synthesis of hyaluronan. Such responses can possibly be used to diagnose PC and to evaluate PC aggressiveness.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2011. 59 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1472
Prostate cancer, Immunohistochemistry, Prognostic markers, biomarkers, Survival analysis, human, pathology, watchful waiting, tissue micro array, Endoglin, von willebrandt factor, ki67, ki-67, hyaluronan
National Category
Urology and Nephrology
Research subject
urn:nbn:se:umu:diva-50722 (URN)978-91-7459-347-1 (ISBN)
Public defence
2012-01-20, Bergasalen, Byggnad 27, Norrlands universitetssjukhus, Umeå, 13:00 (Swedish)
Available from: 2011-12-20 Created: 2011-12-19 Last updated: 2011-12-20Bibliographically approved

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