title: Biological and Prognostic Significance of the Morphological Types and Vascular Patterns in Colorectal Liver Metastases (CRLM): Looking Beyond the Tumor Margin.
abstract: Patients with encapsulated colorectal liver metastases (CRLM) have a better prognosis than those without a capsule. The reason for the encapsulation is unknown. Hypoxia inducible factor-1α (HIF-1α) increases tumor angiogenesis and tumor tissue expression is associated with reduced survival. Our aim was to determine whether the good prognosis of encapsulated CRLM is associated with reduced HIF-1α expression by the cancer.The study selected only patients who had not undergone neoadjuvant chemotherapy prior to a potentially curative hepatectomy for CRLM. From 30 selected patients, serial sections were cut from a single randomly selected metastasis. Morphology was assessed following H&E staining. Tumor hypoxia, vascular endothelial growth factor (VEGF), proliferation, and microvascular density (MVD) were assessed by immunostaining for HIF-1α and carbonic anhydrase-9 (CA-9), VEGF, Ki67, and cluster of differentiation-31, respectively. MVD was calculated in the vascular hot spots. Pathology was reported without clinical outcome information. Actual long-term survival was recorded.Thirteen (43%) of the cancers were encapsulated CRLM containing glands which were large, complex, and cribriform. Thirteen (43%) were infiltrative CRLM and their glands were small, closely packed, and rounded with vessels in the interglandular fibrous tissue with no capsule; 3 (10%) had a mixed picture. Encapsulated CRLM had a higher expression of HIF-1α (58% vs 8%, P = 0.03), CA-9 (42% vs 0%, P = 0.04), and VEGF (92% vs 25%, P = 0.02). MVD was lower in the encapsulated CRLM group (37 mm vs 143 mm, P < 0.001). The median follow-up was 115 months. The encapsulated CRLM group had a better overall and 5-year survival (relative hazard: 0.58, P = 0.057 and hazard ratio: 0.52, P = 0.044).There are 2 main morphological appearances of CRLM which have very different long-term survival following liver resection surgery. The morphology is associated with differences in expression of HIF-1α, CA-9, VEGF, and angiogenesis.
authors.affiliation: From the Hepatopancreatobiliary and Liver Transplant Surgery Unit, University Department of Surgery, Royal Free London NHS Foundation Trust (MG) and University College London Medical School (PNS, BRD); Department of Cellular Pathology, Royal Free London NHS Foundation Trust (TVL, JW); Department of Oncology, UCL Cancer Institute (DH), London, UK; Nuffield Department of Clinical Laboratory Sciences, Tumor Pathology Group (HT) and Nuffield Division of Clinical Laboratory Sciences, Department of Medicine (KG), John Radcliffe Hospital, University of Oxford; and Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford University (ALH), Oxford, UK.
authors.forename: Pulathis N
authors.initials: PN
authors.lastname: Siriwardana
authors.forename: Tu Vinh
authors.initials: TV
authors.lastname: Luong
authors.forename: Jennifer
authors.initials: J
authors.lastname: Watkins
authors.forename: Helen
authors.initials: H
authors.lastname: Turley
authors.forename: Mohamed
authors.initials: M
authors.lastname: Ghazaley
authors.forename: Kevin
authors.initials: K
authors.lastname: Gatter
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.forename: Daniel
authors.initials: D
authors.lastname: Hochhauser
authors.forename: Brian R
authors.initials: BR
authors.lastname: Davidson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D018395:CA-19-9 Antigen / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000473:pathology*; D005260:Female; D006498:Hepatectomy; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000556:secondary* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000473:pathology*; D011379:Prognosis; D016019:Survival Analysis; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D018395:CA-19-9 Antigen; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A