Expression of HIF-1α in medullary thyroid cancer identifies a subgroup with poor prognosis
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Lutske Lodewijk1, Paul van Diest2, Petra van der Groep2, Natalie ter Hoeve2, Abbey Schepers4, Johannes Morreau5, Johannes Bonenkamp6, Adriana van Engen - van Grunsven7, Schelto Kruijff8, Bettien van Hemel9, Thera Links10, Els Nieveen van Dijkum11, Susanne van Eeden12, Gerlof Valk3, Inne Borel Rinkes1, Menno Vriens1
1University Medical Center Utrecht, Department of Surgery, 3584CX Utrecht, The Netherlands
2University Medical Center Utrecht, Department of Pathology, 3584CX Utrecht, The Netherlands
3University Medical Center Utrecht, Department of Endocrine Oncology, 3584CX Utrecht, The Netherlands
4Leiden University Medical Center, Department of Surgery, 2333ZA Leiden, The Netherlands
5Leiden University Medical Center, Department of Pathology, 2333ZA Leiden, The Netherlands
6Radboud University Medical Center, Department of Surgery, Nijmegen 6525GA, The Netherlands
7Radboud University Medical Center, Department of Pathology, Nijmegen 6525GA, The Netherlands
8University Medical Center Groningen, Department of Surgery, 9700 RB, Groningen, The Netherlands
9University Medical Center Groningen, Department of Pathology, 9700 RB, Groningen, The Netherlands
10University Medical Center Groningen, Department of Internal Medicine, 9700 RB, Groningen, The Netherlands
11Academic Medical Center Amsterdam, Department of Surgery, 1105 AZ, Amsterdam, The Netherlands
12Academic Medical Center Amsterdam, Department of Pathology, 1105 AZ, Amsterdam, The Netherlands
Menno Vriens, email: firstname.lastname@example.org
Keywords: medullary thyroid cancer, hypoxia inducible factor 1 alpha, immunohistochemistry, tissue microarray, oncology
Received: October 12, 2016 Accepted: January 24, 2017 Published: February 22, 2017
Background: Medullary thyroid cancer (MTC) comprises only 4% of all thyroid cancers and originates from the parafollicular C-cells. HIF-1α expression has been implied as an indicator of worse prognosis in various solid tumors. However, whether expression of HIF-1α is a prognosticator in MTC remained unclear. Our aim was to evaluate the prognostic value of HIF-1α in patients with MTC.
Methods: All patients with MTC who were operated on between 1988 and 2014 in five tertiary referral centers in The Netherlands were included. A tissue microarray was constructed in which 111 primary tumors could be analyzed for expression of HIF-1α, CAIX, Glut-1, VEGF and CD31 and correlated with clinicopathologic variables and survival.
Results: The mean age of patients was 46.3 years (SD 15.6), 59 (53.2%) were male. Of the 111 primary tumors, 49 (44.1%) were HIF-1α negative and 62 (55.9%) were HIF-1α positive. Positive HIF-1α expression was an independent negative indicator for progression free survival (PFS) in multivariate cox regression analysis (HR 3.1; 95% CI 1.3 – 7.3). Five-years survival decreased from 94.0% to 65.9% for the HIF-1α positive group (p=0.007). Even within the group of patients with TNM-stage IV disease, HIF-1α positivity was associated with a worse prognosis, shown by a decrease in 5-years survival of 88.0% to 49.3% (p=0.020).
Conclusion: Expression of HIF-1α is strongly correlated with adverse prognosis of MTC. This could open up new ways for targeted systemic therapy of MTC.
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