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

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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.

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Acknowledgments

The work was supported by Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration.

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Correspondence to Konrad Hoetzenecker.

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The authors declare no conflicts of interest.

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10585_2015_9763_MOESM1_ESM.jpg

Supplementary Fig. 1 Schematic description of the total study cohort (n = 71) and studied sub-groups (n = 56/n = 15). Supplementary material 1 (JPEG 415 kb)

10585_2015_9763_MOESM2_ESM.jpg

Supplementary Fig. 2 Pulmonary metastases (A) and corresponding primary CRC. (B) samples with evidence of LVI exhibited significantly higher values of LMVD. Supplementary material 2 (JPEG 236 kb)

10585_2015_9763_MOESM3_ESM.jpg

Supplementary Fig. 3 LMVD (A) and LVI (B) of primary CRC and paired pulmonary metastases dependent on the primary tumor site (colon vs rectum). Supplementary material 3 (JPEG 322 kb)

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Schweiger, T., Nikolowsky, C., Graeter, T. et al. Increased lymphangiogenesis in lung metastases from colorectal cancer is associated with early lymph node recurrence and decreased overall survival. Clin Exp Metastasis 33, 133–141 (2016). https://doi.org/10.1007/s10585-015-9763-9

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  • DOI: https://doi.org/10.1007/s10585-015-9763-9

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