Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 May;22(2):355-368.
doi: 10.1007/s10456-019-09661-5. Epub 2019 Jan 12.

Angiogenic desmoplastic histopathological growth pattern as a prognostic marker of good outcome in patients with colorectal liver metastases

Boris Galjart  1 , Pieter M H Nierop  1 , Eric P van der Stok  1 , Robert R J Coebergh van den Braak  2 , Diederik J Höppener  1 , Sofie Daelemans  3   4 , Luc Y Dirix  5 , Cornelis Verhoef  1 , Peter B Vermeulen  4   5 , Dirk J Grünhagen  6
Affiliations

Angiogenic desmoplastic histopathological growth pattern as a prognostic marker of good outcome in patients with colorectal liver metastases

Boris Galjart et al. Angiogenesis. 2019 May.

Abstract

Background: In patients with resectable colorectal liver metastases (CRLM), distinct histopathological growth patterns (HGPs) develop at the interface between the tumour and surrounding tissue. The desmoplastic (d) HGP is characterised by angiogenesis and a peripheral fibrotic rim, whereas non-angiogenic HGPs co-opt endogenous sinusoidal hepatic vasculature. Evidence from previous studies has suggested that patients with dHGP in their CRLM have improved prognosis as compared to patients with non-desmoplastic HGPs. However, these studies were relatively small and applied arbitrary cut-off values for the determination of the predominant HGP. We have now investigated the prognostic effect of dHGP in a large cohort of patients with CRLM resected either with or without neoadjuvant chemotherapy.

Methods: All consecutive patients undergoing a first partial hepatectomy for CRLM between 2000 and 2015 at a tertiary referral centre were considered for inclusion. HGPs were assessed in archival H&E stained slides according to recently published international consensus guidelines. The dHGP was defined as desmoplastic growth being present in 100% of the interface between the tumour and surrounding liver.

Results: In total, HGPs in CRLMs from 732 patients were assessed. In the chemo-naive patient cohort (n = 367), the dHGP was present in 19% (n = 68) and the non-dHGP was present in 81% (n = 299) of patients. This dHGP subgroup was independently associated with good overall survival (OS) (HR: 0.39, p < 0.001) and progression-free survival (PFS) (HR: 0.54, p = 0.001). All patients with any CRLM with a non-dHGP had significantly reduced OS compared to those patients with 100% dHGP, regardless of the proportion of non-dHGP (all p values ≤ 0.001). In the neoadjuvantly treated patient cohort (n = 365), more patients were found to express dHGP (n = 109, 30%) (adjusted odds ratio: 2.71, p < 0.001). On univariable analysis, dHGP was associated with better OS (HR 0.66, p = 0.009) and PFS (HR 0.67, p = 0.002). However, after correction for confounding by means of multivariable analysis no significant association of dHGP with OS (HR 0.92, p = 0.623) or PFS (HR 0.76, p = 0.065) was seen.

Conclusions: The current study demonstrates that the angiogenic dHGP in CRLM resected from chemo-naive patients acts as a strong, positive prognostic marker, unmatched by any other prognosticator. This observation warrants the evaluation of the clinical utility of HGPs in prospective clinical trials.

Keywords: Colorectal cancer; Histopathological growth pattern; Liver metastases; Prognostic factor; Vessel co-option.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Figures

Fig. 1
Fig. 1
a–f Collated HE tissue sections. a, b dHGP low and high magnification; c, d rHGP low and high magnification; e, f pHGP low and high magnification. T: tumour; D: desmoplastic stroma; L: liver parenchyma
Fig. 2
Fig. 2
a Distribution of HGPs. Ranking based on percentage dHGP. a Distribution of HGPs in the chemo-naive cohort. b Distribution of HGPs in the pre-treated cohort. c, d Total proportion rHGP (c) and dHGP (d) in chemo-naive patients compared to pre-treated patients (percentages do not always add up to 100% due to rounding)
Fig. 3
Fig. 3
a OS chemo-naive patients; b Cut-off analysis with OS for percentage dHGP amongst chemo-naive patients; c pre-treated patients
Fig. 4
Fig. 4
a PFS of chemo-naive patients. b PFS of pre-treated patients
Fig. 5
Fig. 5
a–d Graphical display of the changes in HGPs between first and second surgery for CRLM found per group: a −/−; b +/−; c −/+; d +/+
See this image and copyright information in PMC

References

    1. Vermeulen PB, Colpaert C, Salgado R, Royers R, Hellemans H, Van Den Heuvel E, Goovaerts G, Dirix LY, Van Marck E. Liver metastases from colorectal adenocarcinomas grow in three patterns with different angiogenesis and desmoplasia. J Pathol. 2001;195(3):336–342. doi: 10.1002/path.966. - DOI - PubMed
    1. van Dam PJ, van der Stok EP, Teuwen LA, Van den Eynden GG, Illemann M, Frentzas S, Majeed AW, Eefsen RL, van den CoeberghBraak RRJ, Lazaris A, Fernandez MC, Galjart B, Laerum OD, Rayes R, Grunhagen DJ, Van de Paer M, Sucaet Y, Mudhar HS, Schvimer M, Nystrom H, Kockx M, Bird NC, Vidal-Vanaclocha F, Metrakos P, Simoneau E, Verhoef C, Dirix LY, Van Laere S, Gao ZH, Brodt P, Reynolds AR, Vermeulen PB. International consensus guidelines for scoring the histopathological growth patterns of liver metastasis. Br J Cancer. 2017;117(10):1427–1441. doi: 10.1038/bjc.2017.334. - DOI - PMC - PubMed
    1. Stessels F, Van den Eynden G, Van der Auwera I, Salgado R, Van den Heuvel E, Harris AL, Jackson DG, Colpaert CG, van Marck EA, Dirix LY, Vermeulen PB. 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. 2004;90(7):1429–1436. doi: 10.1038/sj.bjc.6601727. - DOI - PMC - PubMed
    1. Frentzas S, Simoneau E, Bridgeman VL, Vermeulen PB, Foo S, Kostaras E, Nathan MR, Wotherspoon A, Gao ZH, Shi Y, Van den Eynden G, Daley F, Peckitt C, Tan X, Salman A, Lazaris A, Gazinska P, Berg TJ, Eltahir Z, Ritsma L, van Rheenen J, Khashper A, Brown G, Nystrom H, Sund M, Van Laere S, Loyer E, Dirix L, Cunningham D, Metrakos P, Reynolds AR. Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases. Nat Med. 2016;22(11):1294–1302. doi: 10.1038/nm.4197. - DOI - PMC - PubMed
    1. Brunner SM, Kesselring R, Rubner C, Martin M, Jeiter T, Boerner T, Ruemmele P, Schlitt HJ, Fichtner-Feigl S. Prognosis according to histochemical analysis of liver metastases removed at liver resection. Br J Surg. 2014;101(13):1681–1691. doi: 10.1002/bjs.9627. - DOI - PubMed

MeSH terms

Substances