Research Papers:

Lymph microvascularization as a prognostic indicator in neuroblastoma

Irene Tadeo, Esther Gamero-Sandemetrio, Ana P. Berbegall, Marta Gironella, Félix Ritort, Adela Cañete, Gloria Bueno, Samuel Navarro and Rosa Noguera _

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Oncotarget. 2018; 9:26157-26170. https://doi.org/10.18632/oncotarget.25457

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Irene Tadeo1,2,*, Esther Gamero-Sandemetrio1,2,*, Ana P. Berbegall1,2, Marta Gironella3,4, Félix Ritort3,4, Adela Cañete5, Gloria Bueno6, Samuel Navarro1,2 and Rosa Noguera1,2

1Pathology Department, Medical School, University of Valencia-INCLIVA, Valencia, Spain

2CIBERONC, Madrid, Spain

3Condensed Matter Physics Department, University of Barcelona, Barcelona, Spain

4CIBER-BBN, Madrid, Spain

5Hospital U I P La Fe, Valencia, Spain

6VISILAB, E.T.S.I. Industriales, University of Castilla-La Mancha, Ciudad Real, Spain

*These authors contributed equally to this work

Correspondence to:

Rosa Noguera, email: [email protected]

Keywords: lymphatic vessels; extracellular matrix; digital pathology; tumor interstitial fluid pressure; neuroblastoma

Received: March 07, 2018     Accepted: May 05, 2018     Published: May 25, 2018


Neuroblastoma is the most common extra-cranial solid pediatric cancer and causes approximately 15% of all childhood deaths from cancer. Although lymphatic vasculature is a prerequisite for the maintenance of tissue fluid balance and immunity in the body, little is known about the relationship between lymphatic vascularization and prognosis in neuroblastoma. We used our previously-published custom-designed tool to close open-outline vessels and measure the density, size and shape of all lymphatic vessels and microvascular segments in 332 primary neuroblastoma contained in tissue microarrays. The results were correlated with clinical and biological features of known prognostic value and with risk of progression to establish histological lymphatic vascular patterns associated with unfavorable histology. A high proportion of irregular intermediate lymphatic capillaries and irregular small collector vessels were present in tumors from patients with metastatic stage, undifferentiating neuroblasts and/or classified in the high risk. In addition, a higher lymphatic microvascularization density was found to be predictive of overall survival. Our findings show the crucial role of lymphatic vascularization in metastatic development and maintenance of tumor tissue homeostasis. These patterns may therefore help to indicate more accurate pre-treatment risk stratification and could provide candidate targets for novel therapies.

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