Prognostic significance of intratumoural microvessel density (IMD) in resected pancreatic and ampullary cancers to standard histopathological variables and survival

doi:10.1053/ejso.2002.1307

European Journal of Surgical Oncology (EJSO)

Volume 28, Issue 6, September 2002, Pages 637-644

https://doi.org/10.1053/ejso.2002.1307 Get rights and content

Abstract

Aim: Angiogenesis is required for tumour growth. Its evaluation, by intratumoural microvessel density (IMD), has prognostic significance in many solid tumours. There is controversy regarding its use in pancreatic cancer and little is known about its role in ampullary tumours. The aim is to study IMD as a prognostic marker in resected ductal adenocarcinomas of head of pancreas and cancers of the ampullary region.

Methods: Forty-seven patients (23 pancreatic and 24 ampullary, mean age 62.0 years) surviving a potentially curative (R0/R1) resection were analysed. Paraffin-embedded sections of these tumours were immunohistochemically stained for CD-34 and IMD was determined (magnification ×200). This was correlated with histopathological data and survival using Cox's multivariate analysis.

Results: Mean survival for the pancreatic cancer group was 18.4 months (se=2.7) and 81.2 months (se=9.9) for the ampullary cancer group. In the pancreatic cancer group, IMD was found to have independent prognostic significance to survival on multivariate analysis (P=0.002, Hazard Ratio (HR) 13.60) along with microscopic resection margin involvement (P=0.003, HR 15.18). For ampullary cancers, IMD was higher in those with lymph node metastasis (P=0.02, Mann–Whitney U -test).

Conclusion: IMD in resected pancreatic cancers correlates with survival.

References (25)

TM Jaeger et al.
Tumor angiogenesis correlates with lymph node metastases in invasive bladder cancer
J Urol
(1995)
LM Ellis et al.
Vessel counts and vascular endothelial growth factor expression in pancreatic adenocarcinoma
Europ J Cancer
(1998)
PB Vermeulen et al.
Quantification of angiogenesis in solid human tumours: an international consensus on the methodology and criteria of evaluation
Europ J of Cancer
(1996)
J Folkman
What is the evidence that tumors are angiogenesis dependent?
J Natl Cancer Inst
(1990)
N Weidner et al.
(editorial). Tumor angiogenesis and metastasis – correlation in invasive breast carcinoma
N Engl J Med
(1991)
L Martin et al.
Is a histological section representative of whole tumour vascularity in breast cancer?
Br J Cancer
(1997)
G Fontanini et al.
Microvessel count predicts metastatic disease and survival in non-small cell lung cancer
J Pathol
(1995)
N Ikeda et al.
Prognostic significance of angiogenesis in human pancreatic cancer
Br J Cancer
(1999)
C Gebhardt et al.
Prognostic factors in the operative treatment of ductal pancreatic carcinoma
Arch Surg
(2000)
JH Klinkenbijl et al.
Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group
Ann Surg
(1999)

Sorensen et al.

Whipple's operation for carcinoma of the pancreatic head and the ampullary region. Short-and long-term results

Scand J Gastroenterol

(1998)

C Willett

G., Lewandrowski K, Warshaw A, Efird K, Compton C. Resection margins in carcinoma head of pancreas. Implications for radiation therapy

Ann Surg

(1993)

Cited by (42)

EGFR-Targeted Polymeric Mixed Micelles Carrying Gemcitabine for Treating Pancreatic Cancer
2016, Biomacromolecules
The objective of this study was to design GE11 peptide (YHWYGYTPQNVI) linked micelles of poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-gemcitabine-graft-dodecanol (PEG-b-PCC-g-GEM-g-DC) for enhanced stability and target specificity of gemcitabine (GEM) to EGFR-positive pancreatic cancer cells. GE11-PEG-PCD/mPEG-b-PCC-g-GEM-g-DC mixed micelles showed EGFR-dependent enhanced cellular uptake, and cytotoxicity as compared to scrambled peptide HW12-PEG-PCD/mPEG-b-PCC-g-GEM-g-DC mixed micelles and unmodified mPEG-b-PCC-g-GEM-g-DC micelles. Importantly, GE11-linked mixed micelles preferentially accumulated in orthotopic pancreatic tumor and tumor vasculature at 24 h post systemic administration. GE11-linked mixed micelles inhibited orthotopic pancreatic tumor growth compared to HW12-linked mixed micelles, unmodified mPEG-b-PCC-g-GEM-g-DC micelles, and free GEM formulations. Tumor growth inhibition was mediated by apoptosis of tumor cells and endothelial cells as determined by immunohistochemical staining. In summary, GE11-linked mixed micelles is a promising approach to treat EGFR overexpressing cancers.
The novel hypoxic cytotoxin, TX-2098 has antitumor effect in pancreatic cancer; possible mechanism through inhibiting VEGF and hypoxia inducible factor-1α targeted gene expression
2012, Experimental Cell Research
Citation Excerpt :
Indeed, hypoxia has been negatively correlated with various indicators of tumor aggression, as well as metastasis and poor prognosis, in a number of tumors [5–8]. Recently, it has been shown that angiogenesis is of prognostic value and may predict the extent of liver metastases in pancreatic carcinoma [9–11]. Moreover, some in vivo and in vitro reports suggest that the hypoxia contributes to growth in such tumors [12–14].
Tumor hypoxia has been considered to be a potential therapeutic target, because hypoxia is a common feature of solid tumors and is associated with their malignant phenotype. In the present study, we investigated the antitumor effect of a novel hypoxic cytotoxin, 3-[2-hydroxyethyl(methyl)amino]-2-quinoxalinecarbonitrile 1,4-dioxide (TX-2098) in inhibiting the expression of hypoxia inducible factor-1α (HIF-1α), and consequently vascular endothelial cell growth factor (VEGF) expression in pancreatic cancer. The antitumor effects of TX-2098 under hypoxia were tested against various human pancreatic cancer cell lines using WST-8 assay. VEGF protein induced pancreatic cancer was determined on cell-free supernatant by ELISA. Moreover, nude mice bearing subcutaneously (s.c.) or orthotopically implanted human SUIT-2 were treated with TX-2098. Tumor volume, survival and expression of HIF-1 and associated molecules were evaluated in treatment versus control groups. In vitro, TX-2098 inhibited the proliferation of various pancreatic cancer cell lines. In s.c model, tumors from nude mice injected with pancreatic cancer cells and treated with TX-2098 showed significant reductions in volume (P < 0.01 versus control). Quantitative real-time reverse transcription-PCR analysis revealed that TX-2098 significantly inhibited mRNA expression of the HIF-1 associated molecules, VEGF, glucose transporter 1 and Aldolase A (P < 0.01 versus control). These treatments also prolong the survival in orthotopic models. These results suggest that the effect of TX-2098 in pancreatic cancer might be correlated with the expression of VEGF and HIF-1 targeted molecules.
Angiogenesis: A prognostic determinant in pancreatic cancer?
2011, European Journal of Cancer
Citation Excerpt :
However, not all studies identified a negative relation with outcome,29–37 a study on colorectal cancer38 and one on node negative breast cancer39 even suggested a beneficial effect of a higher microvessel density on prognosis. Quantification of tumour microvessels has also been performed in some relatively small sized studies on pancreatic cancer, however again results are conflicting.40–48 Not all tumours need angiogenesis to grow, invade and metastasise.
Angiogenesis has been associated with disease progression in many solid tumours, however the statement that tumours need angiogenesis to grow, invade and metastasise seems no longer applicable to all tumours or to all tumour subtypes. Prognostic studies in pancreatic cancer are conflicting. In fact, pancreatic cancer has been suggested an example of a tumour in which angiogenesis is less essential for tumour progression.
The aim of the present study was therefore to measure angiogenesis in two anatomically closely related however prognostically different types of pancreatic cancer, pancreatic head and periampullary cancer, and investigate its relation with outcome.
Vessels were stained by CD31 on original paraffin embedded tissue from 206 patients with microscopic radical resection (R0) of pancreatic head (n = 98) or periampullary cancer (n = 108). Angiogenesis was quantified by microvessel density (MVD) and measured by computerised image analysis of three randomly selected fields and investigated for associations with recurrence free survival (RFS), cancer specific survival (CSS), overall survival (OS) and conventional prognostic factors.
MVD was heterogeneous both between and within tumours. A higher MVD was observed in periampullary cancers compared with pancreatic head cancers (p < .01). Furthermore, MVD was associated with lymph node involvement in pancreatic head (p = .014), but not in periampullary cancer (p = .55). Interestingly, MVD was not associated with RFS, CSS or with OS.
In conclusion, angiogenesis is higher in periampullary cancer and although associated with nodal involvement in pancreatic head cancer, pancreatic cancer prognosis seems indeed angiogenesis independent.
Novel therapeutic approaches in the treatment of advanced pancreatic carcinoma
2007, Cancer Treatment Reviews
Citation Excerpt :
Angiogenesis is a critical step in the development, progression and metastasis formation of malignant tumors, thus, control of new vessel formation could be another approach to the management of pancreatic carcinoma. High intratumoral or peripheral microvessel density was found to be an independent factor to survival that is associated with poor prognosis and/or occurrence of liver metastases.53,54 Similarly, high expression of VEGF is also a predictor of early recurrence after surgery and associated with shorter survival.55,56
Pancreatic cancer is still a malignant disease of grim prognosis despite all therapeutic efforts. Because clinical symptoms in the early stage are usually absent or aspecific, it is frequently discovered at advanced or metastatic stage, only around 15–20% of tumors are resectable. In the majority of patients only the chemotherapy offers a prolongation of life, but even the first-line chemotherapeutic agent, the gemcitabine has a modest survival benefit, and objective tumor response is rarely achieved. Combination of various cytostatics did not produce a significant improvement either. For that reason, continuous search for other agents is mandatory. Nowadays, in the era of molecular-targeted oncotherapeutic approaches, pancreatic cancer is also a subject such trials: epidermal growth factor receptor blockade, inhibition of angiogenesis, modulation of tumor response through the extracellular matrix, inhibition of cyclooxygenase-2, farnesyl transferase inhibitors, signal transduction inhibitors, ablation of the hormonal influence and some other aspects have all been studies, but to date, no breakthrough in the treatment of pancreatic carcinoma is proven. In several Phase II–III studies these compounds given alone displayed marginal effects, but when combined with the standard cytostatics, some beneficial effects were observed, however, some of them displayed a severe (sometimes fatal) toxicity. To date, the role of the molecular targeted therapy in pancreatic carcinoma is promising, but the results are not convincingly superior to the standard chemotherapeutic treatments. Pancreatic adenocarcinoma remains a great challenge for the oncologists, and continuous search for better molecules and/or combinations is inevitable.
Continuous administration of the three thrombospondin-1 type 1 repeats recombinant protein improves the potency of therapy in an orthotopic human pancreatic cancer model
2007, Cancer Letters
Citation Excerpt :
The pharmacological control of angiogenesis might provide a novel regimen to the management of pancreatic cancer, because the growth and persistence of solid tumors depends on angiogenesis. In patients with pancreatic cancer, intratumoral microvessel density has been identified as an independent prognostic factor for survival on multivariate analysis [2,3]. In preclinical studies, natural angiogenic inhibitors, such as endostatin, angiostatin, and thrombospondin-1, have shown promising anti-tumor effects in various pancreatic cancer models [4–7].
Thrombospondin-1 is one of most important natural angiogenic inhibitors. The three thrombospondin-1 type 1 repeats (3TSR), an anti-angiogenic domain of thrombospondin-1, is a promising novel agent for anti-angiogenic treatment. In the present study, we showed 3TSR was biologically stable at least for 7 days in mini-osmotic pumps in vivo, and continuous administration of 3TSR decreased the dosage and improved the potency of therapy in an orthotopic pancreatic cancer model. By using different dosage and delivery routes, we proved that the anti-tumor efficacy of 3TSR was correlated with its anti-angiogenic efficacy. 3TSR treatment also decreased tumor vessel patency and blood flow. The results indicate the advantage of continuous administration of angiogenic inhibitors and provide rationale for using such delivery methods for cancer treatment.
Transcriptional anti-angiogenesis therapy of human pancreatic cancer
2006, Cytokine and Growth Factor Reviews
Pancreatic cancer angiogenesis has been attributed to genetic and epigenetic alterations (e.g., oncogene activation and suppressor inactivation) and a chaotic tumor microenvironment (e.g., hypoxia, acidosis, free radical stress and imbalanced growth factor production). Those diverse “upstream signal” factors appear to converge their signaling pathways on limited sets of nuclear transcription factors (e.g., Sp1, Stat3 and NF-κB). Aberrant activities of these factors confer a tremendous survival and growth advantage to existing and/or emerging malignant cells through alteration of the expression and functions of their diverse “downstream effector” factors (e.g., VEGF and IL-8). Therefore, targeting a single transcription factor can affect the malignant phenotype more profoundly than just targeting any single upstream signal and/or downstream effector factor.

View all citing articles on Scopus

^f1: Part of this work was presented at the International Hepato-Pancreatic Biliary Association meeting, 26 May 2000, Australia. Correspondence to: Brian R. Davidson, Professor of Surgery, Royal Free & University College Medical School, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK. Tel: 4402078302757; Fax: 4402078302688.

View full text

Regular ArticlePrognostic significance of intratumoural microvessel density (IMD) in resected pancreatic and ampullary cancers to standard histopathological variables and survival

Abstract

J Urol

Europ J Cancer

Europ J of Cancer

What is the evidence that tumors are angiogenesis dependent?

J Natl Cancer Inst

(editorial). Tumor angiogenesis and metastasis – correlation in invasive breast carcinoma

N Engl J Med

Is a histological section representative of whole tumour vascularity in breast cancer?

Br J Cancer

Microvessel count predicts metastatic disease and survival in non-small cell lung cancer

J Pathol

Prognostic significance of angiogenesis in human pancreatic cancer

Br J Cancer

Prognostic factors in the operative treatment of ductal pancreatic carcinoma

Arch Surg

Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group

Ann Surg

Whipple's operation for carcinoma of the pancreatic head and the ampullary region. Short-and long-term results

Scand J Gastroenterol

G., Lewandrowski K, Warshaw A, Efird K, Compton C. Resection margins in carcinoma head of pancreas. Implications for radiation therapy

Ann Surg

Regular Article
Prognostic significance of intratumoural microvessel density (IMD) in resected pancreatic and ampullary cancers to standard histopathological variables and survival