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12.01.2019 | Original Paper | Ausgabe 2/2019 Open Access

Angiogenesis 2/2019

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

Angiogenesis > Ausgabe 2/2019
Boris Galjart, Pieter M. H. Nierop, Eric P. van der Stok, Robert R. J. Coebergh van den Braak, Diederik J. Höppener, Sofie Daelemans, Luc Y. Dirix, Cornelis Verhoef, Peter B. Vermeulen, Dirk J. Grünhagen
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1007/​s10456-019-09661-5) contains supplementary material, which is available to authorised users.
Boris Galjart and Pieter M. H. Nierop have contributed equally to this work.

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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.


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.


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.


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.

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Supplementary table 1. Baseline characteristics compared for the presence of any non-dHGP (DOCX 17 KB)
Supplementary table 2. Baseline characteristics pre-treated patients dHGP vs non-dHGP (DOCX 17 KB)
Supplementary table 3. Baseline characteristics chemo-naive versus pre-treated patients (DOCX 19 KB)
Supplementary table 4. Uni- and multivariable logistic regression analysis for association with dHGP (DOCX 14 KB)
Supplementary table 5. (Rebuttal table 2.) Uni- and multivariable logistic regression analysis for association with dHGP in the neoadjuvantly treated group (DOCX 14 KB)
Supplementary table 6. Overall Survival Cox regression analysis all neoadjuvantly treated patients +/- Bevacizumab (DOCX 14 KB)
Supplementary table 7. Progression-Free Survival Cox regression all neoadjuvantly treated patients +/- Bevacizumab (DOCX 14 KB)
Supplementary table 8. Baseline characteristics chemo-naive patients 50% cut-off (DOCX 18 KB)
Supplementary table 9. Uni- and multivariable Cox regression analysis OS of chemo-naive patients &#x003E;50% cut-off (DOCX 15 KB)
Supplementary table 10. Uni- and multivariable logistic regression analysis for association with dHGP &#x003E;50% cut-off (DOCX 14 KB)
Supplementary table 11. Baseline characteristics pre-treated patients &#x003E;50% cut-off (DOCX 18 KB)
Supplementary table 12. Uni- and multivariable Cox regression analysis for OS of pre-treated patients &#x003E;50% cut-off (DOCX 15 KB)
Supplementary figure 1. A flowchart of the patient inclusion (TIF 15495 KB)
Supplementary figure 2A-B. OS using the &#x003E;50% cut-off. 2A: OS chemo-naive patients. 2B: OS pre-treated patients (TIF 1177 KB)
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