Topoisomerase IIα (TopoIIα) Expression in Hodgkin’s Lymphoma (HL): Correlations with Conventional and Biological Markers and Prognostic Significance under Treatment with ABVD or Equivalent Regimens with or without Radiotherapy (RT).
Authors: Vassilakopoulos Theodoros P. , Doussis-Anagnostopoulou Ipatia A. , Karandrea Despina , Korkolopoulou Penelope , Angelopoulou Maria K. , Siakantaris Marina P. , Kokoris Styliani I. , Dimitriadou Evangelia M. , Dimopoulou Maria N. , Kalpadaki Christina , Kyrtsonis Maria-Christina , Thymara Irini , Kavantzas Nikolaos , Panayiotidis Panayiotis , Patsouris Efstratios , Kittas Christos , Pangalis Gerassimos A. 
Published: April 2020

Abstract
TopoIIα is a proliferation marker, as well as a target for cytotoxic agents used in HL, such as doxorubicine, epirubicine, etoposide, and mitoxantrone. High topoIIα expression has been associated with adverse prognosis in some neoplasms, but in the single study of 42 patients with HL, it was a favorable feature. We aimed to evaluate the immunohistochemical expression of topoIIα in patients with HL and investigate its potential association with clinical and biologic features and prognosis in lymph node biopsy sections of 235 patients with HL treated with ABVD or equivalents ± RT. Immunohistochemistry was performed with the streptavidin-biotin-peroxidase method, using the monoclonal antibody KiS1 (DAKO, Denmark,) and DAB as substrate. The proliferation marker Ki-67 was evaluated in 74 patients [MIB1 (YLEM)]. The median age of the patients was 30 years (15–82), 49% were males, 23%, 49%, 17% and 12% had stage I,II,III and IV (47% advanced stages, i.e.IB/IIB/III/IV), 36% B-symptoms, 15% ≥5 involved sites, 38% anemia, 16% leukocytes ≥15x109/l, 7% severe lymphocytopenia, 37% albumin &lt;4 g/dl, and 32% elevated LDH. TopoIIα expression was also evaluated with repect to biological markers, including serum levels of interleukin-10 (sIL-10) and soluble CD30 (sCD30) (n=87), and morphometric parameters reflecting angiogenesis in lymph node sections, such as microvascular density (MVD), total vascular area (TVA), and shape factor (SF) (n=224). The mean±SD percentage of topoIIα+ Hodgkin-Reed-Sternberg (HRS) cells was 63±19% (5%–98%), being 80±17% (17%–99%) for Ki-67+. TopoIIα and Ki-67 were loosely correlated (Spearman’s rho 0.265, p=0.02). Among conventional factors, topoIIα expression correlated with gender only (higher in males, p=0.04), while there was no correlation with sIL-10, sCD30, MVD, TVA or SF. The percentage of topoIIα+ HRS cells was &lt;30% in 15 patients (6%), 30–74% in 149 (63%) and ≥75% in 71 (30%) patients respectively. The 10-year failure free survival (FFS) for these 3 groups was 100%, 85±3% και 67±7% (p=0.002). In multivariate analysis independent adverse prognostic factors for FFS were high topoIIa expression (either as a continuous covariate or at a cutoff of 75%, p=0.002), followed by advanced stage and involvement of ≥5 sites. TopoIIα expression remained an independent prognostic factor when adjusted for the value of the International Prognostic Score (IPS). TopoIIα expression appears to be a ’’primary’’ prognostic variable in HL, because it did not correlate with established conventional and biological markers. Under standard anthracycline-based treatment, high topoIIα expression provided independent prognostic information, which may reflect its role in cell proliferation. Patients with high topoIIα expression might benefit from first-line chemotherapy regimens including another topoIIα inhibitor in addition to doxorubicine, such as etoposide in BEACOPP-escalated.