The histological growth pattern of colorectal cancer liver metastases ...

Van den Eynden GG, Bird NC, Majeed AW, Van Laere S, Dirix LY, Vermeulen PB.

Clin Exp Metastasis. 2012 Aug;29(6):541-9.

Translational Cancer Research Unit, Augustinus Hospital, Oosterveldlaan 24, 2610, Wilrijk, Antwerp, Belgium. Gert.vandeneynden@gza.be

Abstract

Little is known about the biological characteristics that determine the prognosis of colorectal cancer (CRC) liver metastases. In previous work we reported three different histological patterns of the tumour-liver interface of CRC liver metastases, termed the pushing, replacement and desmoplastic growth pattern (GP). The purpose of this study was to confirm differences in angiogenic and hypoxic properties of CRC liver metastases with different GPs in a large data set and to study the value of the GP as a prognostic factor. In 205 patients undergoing a resection of CRC liver metastases, the GP of the metastasis was determined using haematoxylin-eosin and Gordon Sweet?s silver staining. The tumour cell proliferation fraction (TCP%), endothelial cell proliferation fraction (ECP%) and carbonic anhydrase 9 (CA9) expression were determined using immunohistochemistry. Standard clinicopathological data and overall survival were recorded. 27.8, 15.6, 34.6 and 17.6 % of liver metastases had a replacement, pushing, desmoplastic and mixed GP, respectively. Analyses of TCP%, ECP% and CA9 expression demonstrated that CRC liver metastases with a replacement GP are non-angiogenic, while the ones with a pushing GP are the most angiogenic with angiogenesis being, at least partially, hypoxia-driven. GP (pushing or not) was the only independent predictor of survival at 2 years. CRC liver metastases grow according to different GP patterns with different angiogenic properties. At 2 years of follow-up a GP with a pushing component was an independent predictor of poor survival, suggesting that the pushing GP is characterized by a more aggressive tumour biology. Further elucidation of the mechanisms and biological pathways involved in and responsible for the differences in GP between CRC liver metastases in different patients might lead to therapeutic agents and strategies taking advantage of this 2 year ?window of opportunity?.

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Additional Information:

Liver metastases of solid tumors are a heterogeneous disease that is difficult to manage with current treatment strategies. The underlying biology of this heterogeneity is poorly understood. However, differences in the interaction between tumor cells and several components of the liver microenvironment seem to play an important role.

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Earlier, we described 3 different histological growth patterns of liver metastases of solid tumours in general and of colorectal cancer in particular, based on the microscopical appearance and composition of the tumor-liver interface. It is a robust, easy-to-assess and reproducible histopathological parameter. These growth patterns are the obvious result of heterogeneity in tumor-stroma interactions and several lines of evidence have shown differences in hypoxia and vascularisation, inflammatory infiltrate and proteinase expression between different growth patterns (1-4). Our current paper describes the first evidence that the histological growth pattern of colorectal cancer liver metastases has prognostic value and as such also mirrors (part of) the clinical heterogeneity of the disease.

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On the one hand, our future research will now focus on the underlying biology of these growth patterns. Further insights in how heterogeneity of tumor-stroma interactions of liver metastases causes a different growth pattern, might lead to the discovery of new therapeutic targets. On the other hand, we will further investigate the role of the histological growth pattern in clinical disease management of patients with liver metastases: for this purpose the development of powerful imaging techniques to predict the growth pattern non-invasively is essential.

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References

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1.???? Vermeulen PB, Colpaert C, Salgado R, Royers R, Hellemans H, Van Den Heuvel E, et al. Liver metastases from colorectal adenocarcinomas grow in three patterns with different angiogenesis and desmoplasia. J. Pathol. 2001Oct.;195(3):336?42.

2.???? Stessels F, Van den Eynden G, Van der Auwera I, Salgado R, Van Den Heuvel E, Harris AL, et al. Breast adenocarcinoma liver metastases, in contrast to colorectal cancer liver metastases, display a non-angiogenic growth pattern that preserves the stroma and lacks hypoxia. Br. J. Cancer. 2004Apr.5;90(7):1429?36.

3.???? Illemann M, Bird N, Majeed A, Laerum OD, Lund LR, Dan? K, et al. Two distinct expression patterns of urokinase, urokinase receptor and plasminogen activator inhibitor-1 in colon cancer liver metastases. Int. J. Cancer. 2009Apr.15;124(8):1860?70.

4.???? Eefsen RL, Van den Eynden GG. Histopathological growth pattern, proteolysis and angiogenesis in chemonaive patients resected for multiple colorectal liver metastases. Journal Of Oncology. 2012;In press: 907971.

Source: http://globalmedicaldiscovery.com/key-scientific-articles/the-histological-growth-pattern-of-colorectal-cancer-liver-metastases-has-prognostic-value/

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