Increased lymphangiogenesis in lung metastases from colorectal cancer is associated with early lymph node recurrence and decreased overall survival

Abstract

Pulmonary metastasectomy (PM) is an accepted treatment modality in colorectal cancer (CRC) patients with pulmonary tumor spread. Positive intrathoracic lymph nodes at the time of PM are associated with a poor prognosis and 5-year survival rates of <20 %. Increased lymphangiogenesis in pulmonary metastases might represent an initial step for a subsequent lymphangiogenic spreading. We aimed to evaluate the presence of lymphangiogenesis in clinically lymph node negative patients undergoing PM and its impact on outcome parameters. 71 patients who underwent PM for CRC metastases were included in this dual-center study. Tissue specimens of pulmonary metastases and available corresponding primary tumors were assessed by immunohistochemistry for lymphatic microvessel density (LMVD) and lymphovascular invasion (LVI). Results were correlated with clinical outcome parameters. LMVD was 13.9 ± 8.1 and 13.3 ± 8.5 microvessels/field (mean ± SD) in metastases and corresponding primary CRC; LVI was evident in 46.5 and 58.6 % of metastases and corresponding primary CRC, respectively. Samples with high LMVD had a higher likelihood of LVI. LVI was associated with early tumor recurrence in intrathoracic lymph nodes and a decreased overall survival (p < 0.001 and p = 0.029). Herein, we present first evidence in a well-defined patient collective that increased lymphangiogenesis is already present in a subtype of pulmonary metastases of patients staged as N0 at the time of PM. This lymphangiogenic phenotype has a strong impact on patients' prognosis. Our findings may have impact on the post-surgical therapeutic management of CRC patients with pulmonary spreading.

Impact of cyclooxygenase-2 and prostaglandin-E2 expression on clinical outcome after pulmonary metastasectomy

“…Neither COX-2 nor PGE were independent prognostic factors. However, the KRAS mutational status and the presence of lymphatic vessel invasion were associated with an impaired prognosis, as previously published (17,18).…”

Microvessel density as a prognostic factor in esophageal squamous cell cancer patients

“…[39–41] As to other malignances such as lung adenocarcinoma, LMVD was reported to cause worse prognosis, [42,43] so was the same with colorectal cancer. [44,45] To conclude, although the role of MVD in ESCC has been identified in this study, the prognostic role of MVD in other pathological types and the role of LMVD remains unclear, and they should be revalued when abundant clinical evidence has emerged by then.…”

KRAS exon 2 codon 13 mutation is associated with a better prognosis than codon 12 mutation following lung metastasectomy in colorectal cancer

“…More specifically, exon 2 codon 12 mutations, in particular, G12D and G12V mutations, seem to be able to induce a more robust link with GTP molecules leading to higher resistance to GTPase activity compared to codon 13 mutations, in particular, G13D [23, 24]. On the other hand, it seems that KRAS codon 12 mutations, but not codon 13 mutations, are associated with a strong upregulation of vascular endothelial growth factor (VEGF) [24, 25], which is implicated in the promotion of lymphangiogenesis [26], which seems to be related to recurrence and decreased OS after lung metastasectomy in CRC [26]. These two observations suggest a higher aggressiveness of codon 12 mutations over codon 13 mutations.…”