Lymph microvascularization as a prognostic indicator in neuroblastoma

// Irene Tadeo 1, 2, * , Esther Gamero-Sandemetrio 1, 2, * , Ana P. Berbegall 1, 2 , Marta Gironella 3, 4 , Felix Ritort 3, 4 , Adela Canete 5 , Gloria Bueno 6 , Samuel Navarro 1, 2 and Rosa Noguera 1, 2 1 Pathology Department, Medical School, University of Valencia-INCLIVA, Valencia, Spain 2 CIBERONC, Madrid, Spain 3 Condensed Matter Physics Department, University of Barcelona, Barcelona, Spain 4 CIBER-BBN, Madrid, Spain 5 Hospital U I P La Fe, Valencia, Spain 6 VISILAB, 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: rnoguera@uv.es Keywords: lymphatic vessels; extracellular matrix; digital pathology; tumor interstitial fluid pressure; neuroblastoma Received: March 07, 2018      Accepted: May 05, 2018      Published: May 25, 2018 ABSTRACT 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.