title: Breast adenocarcinoma liver metastases, in contrast to colorectal cancer liver metastases, display a non-angiogenic growth pattern that preserves the stroma and lacks hypoxia.
abstract: Although angiogenesis is a prerequisite for the growth of most human solid tumours, alternative mechanisms of vascularisation can be adopted. We have previously described a non-angiogenic growth pattern in liver metastases of colorectal adenocarcinomas (CRC) in which tumour cells replace hepatocytes at the tumour-liver interface, preserving the liver architecture and co-opting the sinusoidal blood vessels. The aim of this study was to determine whether this replacement pattern occurs during liver metastasis of breast adenocarcinomas (BC) and whether the lack of an angiogenic switch in such metastases is due to the absence of hypoxia and subsequent vascular fibrinogen leakage. The growth pattern of 45 BC liver metastases and 28 CRC liver metastases (73 consecutive patients) was assessed on haematoxylin- and eosin-stained tissue sections. The majority of the BC liver metastases had a replacement growth pattern (96%), in contrast to only 32% of the CRC metastases (P<0.0001). The median carbonic anhydrase 9 (CA9) expression (M75 antibody), as a marker of hypoxia, (intensity x % of stained tumour cells) was 0 in the BC metastases and 53 in the CRC metastases (P<0.0001). There was CA9 expression at the tumour-liver interface in only 16% of the BC liver metastases vs 54% of the CRC metastases (P=0.002). There was fibrin (T2G1 antibody) at the tumour-liver interface in only 21% of the BC metastases vs 56% of the CRC metastases (P=0.04). The median macrophage count (Chalkley morphometry; KP-1 anti-CD68 antibody) at the interface was 4.3 and 7.5, respectively (P<0.0001). Carbonic anhydrase 9 score and macrophage count were positively correlated (r=0.42; P=0.002) in all metastases. Glandular differentiation was less in the BC liver metastases: 80% had less than 10% gland formation vs only 7% of the CRC metastases (P<0.0001). The liver is a densely vascularised organ and can host metastases that exploit this environment by replacing the hepatocytes and co-opting the vasculature. Our findings confirm that a non-angiogenic pattern of liver metastasis indeed occurs in BC, that this pattern of replacement growth is even more prevalent than in CRC, and that the process induces neither hypoxia nor vascular leakage.
authors.affiliation: Department of Pathology, University Hospital, University of Antwerp, Edegem, Belgium.
authors.forename: F
authors.initials: F
authors.lastname: Stessels
authors.forename: G
authors.initials: G
authors.lastname: Van den Eynden
authors.forename: I
authors.initials: I
authors.lastname: Van der Auwera
authors.forename: R
authors.initials: R
authors.lastname: Salgado
authors.forename: E
authors.initials: E
authors.lastname: Van den Heuvel
authors.forename: A L
authors.initials: AL
authors.lastname: Harris
authors.forename: D G
authors.initials: DG
authors.lastname: Jackson
authors.forename: C G
authors.initials: CG
authors.lastname: Colpaert
authors.forename: E A
authors.initials: EA
authors.lastname: van Marck
authors.forename: L Y
authors.initials: LY
authors.lastname: Dirix
authors.forename: P B
authors.initials: PB
authors.lastname: Vermeulen
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002256:Carbonic Anhydrases / Q000032:analysis; D015687:Cell Hypoxia; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D005337:Fibrin / Q000032:analysis; D006023:Glycoproteins / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary*; D008264:Macrophages / Q000473:pathology; D009389:Neovascularization, Pathologic; D033921:Vesicular Transport Proteins; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D002256:Carbonic Anhydrases; D005337:Fibrin; D006023:Glycoproteins; D033921:Vesicular Transport Proteins; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C119248:LYVE1 protein, human