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

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. Electronic supplementary material The online version of this article (10.1007/s1045...

Enrichment of the tumour immune microenvironment in patients with desmoplastic colorectal liver metastasis

“…pushing, desmoplastic, and replacement type) was determined at the tumour-liver interface. Given recent findings by Galjart et al 32 , patients were classified as dHGP if only the desmoplastic type was observed in all the reviewed sections (i.e. 100% dHGP, Fig.…”

“…<100% dHGP; non-dHGP) pattern is observed, as multiple HGPs can appear in conjunction. 32 Especially in chemo-naive subjects (i.e. not treated with systemic chemotherapy within 6 months prior to resection of CRLM), patients with dHGP exhibit superior survival compared to their non-dHGP counterparts, with reported 5-year OS rates of nearly 80% in dHGP and as low as 40% in (any) non-dHGP.…”

“…not treated with systemic chemotherapy within 6 months prior to resection of CRLM), patients with dHGP exhibit superior survival compared to their non-dHGP counterparts, with reported 5-year OS rates of nearly 80% in dHGP and as low as 40% in (any) non-dHGP. 32 Upon histomorphological examination, dHGP is often characterised by a distinct immune infiltrate surrounding the desmoplastic stroma (Fig. 1c), although this has never been quantified, classified, or been compared to non-dHGP counterparts in light of the discovery of the any non-dHGP on/off phenomenon.…”

“…1c), although this has never been quantified, classified, or been compared to non-dHGP counterparts in light of the discovery of the any non-dHGP on/off phenomenon. 32 The aim of the current study was therefore to quantify, classify, and compare the TME of CRLM between patients with dHGP and non-dHGP. Given there is evidence to suggest that systemic therapy not only affects the immune infiltrate in the TME 26,33 but also influences the proportional distribution and possibly the prognostic value of the HGPs 32 , our study focussed on chemo-naive subjects only.…”

Identification of Predominant Histopathological Growth Patterns of Colorectal Liver Metastasis by Multi-Habitat and Multi-Sequence Based Radiomics Analysis

“…In the replacement HGP, the tumor cells forming the cell plate are continuous with the hepatocyte plate, with microvasculature of vessel co-option and without angiogenesis (3). The diversity of these biological microenvironments leads to different responses to treatment, especially to the anti-angiogeneic agent (5,6) and to different long-term prognosis (3,7,8). The replacement HGP is identified as a poor predictor of Bevacizumab treatment in patients with CRLMs (9).…”