Vascular Endothelial Growth Factor (VEGF) Expression by Neoplastic Hodgkin-Reed-Sternberg Cells Is An Independent Adverse Prognostic Factor for Relapse in Hodgkin Lymphoma.
Authors: Gutierrez Antonio , Mestre Francisco , Ramos Rafael , Martinez-Serra Jordi , Bautista Antonia , Fuster José , Lopez-Marti Pilar , Casasus Marta , Nicolau Cristina , Rifa Julio , Besalduch Joan , Garcia Juan Fernando , Rodriguez Jose 
Published: October 2019

Abstract
Abstract 1561
Poster Board I-584
Vascular endothelial growth factor (VEGF) is a key regulator of tumor angiogenesis as well as a growth and metastatic inducer in several malignancies. Numerous studies have demonstrated up-regulation of this protein at both mRNA and protein level in various tumours and a correlation with advanced stage and prognosis has been demonstrated in several solid tumors and hematologic malignancies such as multiple myeloma or non-Hodgkin lymphomas. There is evidence that also the neoplastic Hodgkin-Reed-Stenberg cells express VEGF and their receptors and that VEGF expression both in macrophages and the extracellular matrix might facilitate tumour progression, contributing to the pathophysiology of this malignancy. We aim to investigate the prognostic value of VEGF expression in a large uniformly treated population with Hodgkin lymphoma.
In this immunohistochemical study we retrospectively included 252 patients of the Hodgkin Lymphoma Spanish Network uniformly treated with ABVD (3-6 cycles, in function of clinical factors) with or without radiotherapy. Tissue sections were stained with monoclonal antibodies to VEGF-A and the expression was scored and validated by a pathology review. VEGF expression was scored as negative (no RS staining), middle or strong positive staining. Overall survival (OS) and progression-free survival (PFS) were measured from the diagnosis and were estimated according to the Kaplan-Meier method. Comparisons among those variables of interest were performed by the log-rank test. Multivariate analysis with the variables that proved to be significant in univariate analysis was performed according to the Cox proportional hazard regression model. Most recognized clinical variables (age, sex, presence of bulky disease, B symptoms, AA stage, international prognostic score for Hodgkin lymphoma (IPS) and ECOG performance status (PS) were investigated for their prognostic importance along with VEGF expression.
Median age was 33 years (10-84). Prognostic factors were as follows: 41% Ann Arbor stage III-IV, 40% B-symptoms, 9% ECOG PS >1 and 26% IPS > 2. One hundred and thirty patients (52%) of cases received ABVD plus radiotherapy. Median follow-up was 59 months (8-199). Relapses were significantly higher in patients with positive VEGF staining in a stain-dependent manner (no stain: 10%; middle stain: 44% and strong stain: 65%) (p<0.001). VEGF positive patients also had a significant worst 5-year PFS (no stain: 81%; middle: 63% and strong: 28%; p < 0.001) (figure) with only 5-year OS impact in patients with strong staining (no stain: 87%; middle: 84%; strong: 61%) suggesting that most middle VEGF stain patients respond to salvage treatment. Univariate PFS and OS analysis also found as adverse prognostic factors: age > 60 years, III-IV AA stage, ECOG PS > 1, B-symptoms, IPS > 2 and non receiving radiotherapy). By multivariate analysis only the IPS (HR 2.19) and VEGF middle (HR 3.2) or strong (HR 7.24) expression were independently associated with the outcome.

Conclusion
Middle and strong VEGF staining on neoplastic Hodgkin-Reed-Stenberg cells is associated with a greater risk for relapse and a worst PFS. However in this series this fact only affected OS in the strong staining cases. This could imply that these VEGF-positive cases may need a more intensive induction therapy and justify the development of trials including anti-VEGF or antiangiogenic drugs as part of therapeutic regimens in this malignancy.

Disclosures
No relevant conflicts of interest to declare.