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PROX1 lymphatic density correlates with adverse clinicopathological factors, lymph node metastases and survival in neuroblastomas

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Abstract

Increased lymphatic density correlates with lymph node metastases and survival in some epithelial cancers. The transcription factor, Prospero-related homeobox-gene 1, PROX1, plays an important role in the differentiation and proliferation of the lymphatic and nervous systems. We studied the clinicopathological significance of PROX1 expression in neuroblastomas (NBs) as the majority of patients have lymphatic and/or haematogenous metastases at diagnosis. PROX1-immunostained lymphatic vessels were present in 40/69 (58%) of NBs and 1/6 benign ganglioneuromas (GNs). Lymphatic density (LD) counts were significantly increased in NBs from patients with unfavourable clinical and pathological factors, and with distant lymph node metastases (LNM). Lymphatic invasion (LI) by tumoral emboli was present in 27/40 (68%) of NBs. A significantly higher proportion of LI was seen in undifferentiated/poorly-differentiated, (UD/PD) compared with differentiated NBs. LI was increased in NBs from patients with advanced-stage and high-risk group. Nuclear-PROX1 expression in tumoral cells was present in 35/69 (51%) NBs but was absent in all GNs. PROX1 expression was significantly higher in UD/PD compared with differentiated NBs. It was also higher in NBs with all adverse clinicopathological and biological variables. LI, PROX1 cellular expression and high LD correlated with a shorter overall survival and event-free survival (EFS). Multivariable Cox regression analysis showed that the effect of LD on both OS and EFS was independent of mitosis-karyorrhexis index and MYCN amplification. Increased LD, LI and cellular expression correlated with adverse factors in NBs. Increased LD correlated with LNM suggesting that PROX1 contributes to neuroblastoma progression and lymphatic spread.

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Acknowledgments

The authors thank Above and Beyond Charities of the University Hospitals Bristol Foundation Trust and Ince and Company for their financial support. The authors are grateful to Mr. P.B. Savage for providing laboratory facilities, and to Josiah Dungwa, Alison Headford, Emile Sowa Avugrah and Mike Luckett for technical support.

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Authors and Affiliations

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

    Pramila Ramani & Aimie Norton

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

    Pramila Ramani & Michelle S. Somerville

  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. Aimie Norton
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Correspondence to Pramila Ramani.

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Ramani, P., Norton, A., Somerville, M.S. et al. PROX1 lymphatic density correlates with adverse clinicopathological factors, lymph node metastases and survival in neuroblastomas. J Neurooncol 108, 375–383 (2012). https://doi.org/10.1007/s11060-012-0838-z

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  • DOI: https://doi.org/10.1007/s11060-012-0838-z

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