Exp Clin Endocrinol Diabetes 2015; 123 - P03_06
DOI: 10.1055/s-0035-1547633

Evaluation of hENT1 expression in adrenocortical tumors: Correlation with clinical outcome and response to gemcitabine chemotherapy

E Henning 1, S Steinhauer 1, S Sbiera 2, V Wild 3, B Allolio 4, A Rosenwald 3, M Fassnacht 5, C Ronchi 1
  • 1Universitätsklinikum Würzburg
  • 2Department of Medicine I; University Hospital Würzburg
  • 3University of Würzburg
  • 4Medizinische Klinik und Poliklinik I; Endokrinologie und Diabetologie; Universitätsklinikum Würzburg
  • 5Universitätsklinikum Würzburg; Medizinische Klinik I; Schwerpunkt Endokrinologie

Background: the human equilibrative plasma membrane nucleoside transporter type 1 (hENT1) mediates cellular entry of cytotoxic nucleosides, such as gemcitabine (GEM), and its deficiency confers resistance to efficacy of these drugs.

Aim: to evaluate the mRNA and protein expression of hENT1 in normal and neoplastic adrenocortical glands and to correlate it with clinical outcome and response to GEM-therapy.

Material and methods: 71 fresh frozen adrenocortical tissues (21 normal adrenal, NA, 20 adenomas, ACAs and 30 carcinomas, ACCs) were evaluated by quantitative real-time RT-PCR, while 317 adrenocortical tissues (17 NA, 22 ACAs and 276 ACCs) were evaluated by immunohistochemistry. Among ACCs, 48 patients with tumor samples deriving from first surgery were treated with GEM and were considered responders in case of stable disease ≥6 months (n = 8).

Results: hENT1 mRNA expression was higher in ACA and NA than in ACCs (P = 0.0033), without correlations with histo-pathological parameters. High hENT1 levels were associated with a trend to longer progression free survival (PFS) in ACCs (P = 0.14, HR = 1.87). The hENT1 immunostaining in the cytoplasma was high (H-score 2 – 3) in more tumors than in NA, being positive in 99% ACCs, 99% ACAs and 76% NA (P < 0.005). Similarly to mRNA expression, the hENT1 staining in the cell membrane (hENT1 m) was positive in more ACAs (68%) and NA (53%) than in ACCs (32%, P < 0.005), being even more rare in metastasis tissues (n = 20, 10% pos). Moreover, ACCs with positive hENT1 m had a lower ki67 proliferation index than the negatives (P = 0.057) and a longer PFS (median 16 vs. 8 months, P = 0.010, HR = 1.53, 95%CI = 1.1 – 2.1). In this series, no significant relationship was observed between both cytoplasmatic and membranous staining and response to therapy with GEM.

Conclusions: hENT1 mRNA expression and membranous protein expression seem to be associated with more differentiated phenotype and better clinical outcome in ACCs and might represent a new prognostic factor. However, hENT1 seems not to play a major role on the response to GEM-therapy in ACCs.