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LYVE-1 upregulation and lymphatic invasion correlate with adverse prognostic factors and lymph node metastasis in neuroblastoma

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Abstract

Neuroblastoma (NB) accounts for 15% of all childhood cancer deaths. The majority of patients have widespread lymphatic and/or haematogenous metastases at diagnosis, but lymphangiogenesis has not been well documented. Sixty-seven NBs were immunostained for the lymphatic endothelial marker, LYVE-1, and the lymphatic density (LD) and lymphatic invasion (LI), were counted in LYVE-1-expressing lymphatics. LYVE-1-stained lymphatic vessels and LI were present in 26/67 (39%) and 14/67 (21%) of the NBs, respectively. Central LD (CLD) and LI were higher in NBs from stage 4 (p = 0.012, p = 0.004, respectively), high-risk group (p = 0.030, p = 0.002), NBs with high mitosis karyorrhexis index (MKI) (p = 0.011, p = 0.005), unfavourable histology group (p = 0.040, p = 0.017) and distant lymph node metastasis (LNM) (p < 0.001 for each). Marginal LD (MLD) was higher in patients with LNM (p < 0.001). CLD and MLD correlated with LI (p < 0.001 each). Total LYVE-1 protein levels, quantified by a sensitive enzyme-linked immunosorbent assay (n = 55), were also higher in NBs from patients with stage 4 disease (p = 0.046), high-risk group (p = 0.028), MYCN-amplified NBs (p = 0.034) and LNM (p = 0.038). Kaplan–Meier analysis showed that the presence of CLD was associated with both worse OS at 5 years (77% [95% CI: 62–87%] versus 60% [95% CI: 32–80%], p = 0.062) and EFS (74% [95% CI: 58–85%] versus 43% [95% CI: 15–69%], p = 0.070) and LI with OS (71% [95% CI: 57–81%] versus 56% [95% CI: 26–78%], p = 0.055). Significant upregulation of LYVE-1 and the presence of LI in patients with stage 4 and high-risk disease, MYCN-amplification and LNM suggests that LYVE-1 may have value as predictors of outcome.

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Abbreviations

NB:

Neuroblastoma

LYVE-1:

Lymphatic vessel endothelial hyaluronan receptor-1

LD:

Lymphatic density

CLD:

Central lymphatic density

MLD:

Marginal lymphatic density

LNM:

Lymph node metastasis

LI:

Lymphatic invasion

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Acknowledgments

The authors would like to thank Above and Beyond Charities of the University Hospitals Bristol Foundation Trust for their financial support and Ince & Co for their private donation. The authors are grateful to Mr. P.B. Savage for providing laboratory facilities.

Conflict of interest

The authors declare that there is no conflict of interest. No part of the article has been published or submitted elsewhere, and there are no financial relationships that may lead to conflict of interest. The manuscript has been read and approved by all authors.

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Authors and Affiliations

  1. Department of Histopathology, Bristol Royal Infirmary, Bristol, BS2 8HW, UK

    Pramila Ramani & Josiah V Dungwa

  2. School of Cellular and Molecular Medicine, School of Medical Sciences, University of Bristol, University Walk, Bristol, BS8 1TD, UK

    Pramila Ramani & Josiah V Dungwa

  3. School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, UK

    Margaret T. May

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  1. Pramila Ramani
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  2. Josiah V Dungwa
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Correspondence to Pramila Ramani.

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Supplementary File 1

Relationship between total protein and variables (DOC 43 kb)

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Ramani, P., Dungwa, J.V. & May, M.T. LYVE-1 upregulation and lymphatic invasion correlate with adverse prognostic factors and lymph node metastasis in neuroblastoma. Virchows Arch 460, 183–191 (2012). https://doi.org/10.1007/s00428-011-1190-y

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  • DOI: https://doi.org/10.1007/s00428-011-1190-y

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