Biological and Prognostic Significance of the Morphological Types and Vascular Patterns in Colorectal Liver Metastases (CRLM): Looking Beyond the Tumor Margin.
Siriwardana PN., Luong TV., Watkins J., Turley H., Ghazaley M., Gatter K., Harris AL., Hochhauser D., Davidson BR.
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.