title: Expression of HIF-1α in medullary thyroid cancer identifies a subgroup with poor prognosis.
abstract: 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).
  
  
  CONCLUSIONS
  Expression of HIF-1α is strongly correlated with adverse prognosis of MTC. This could open up new ways for targeted systemic therapy of MTC.
authors.affiliation: University Medical Center Utrecht, Department of Surgery, 3584CX Utrecht, The Netherlands.
authors.forename: Lutske
authors.initials: L
authors.lastname: Lodewijk
authors.affiliation: University Medical Center Utrecht, Department of Pathology, 3584CX Utrecht, The Netherlands.
authors.forename: Paul
authors.initials: P
authors.lastname: van Diest
authors.affiliation: University Medical Center Utrecht, Department of Pathology, 3584CX Utrecht, The Netherlands.
authors.forename: Petra
authors.initials: P
authors.lastname: van der Groep
authors.affiliation: University Medical Center Utrecht, Department of Pathology, 3584CX Utrecht, The Netherlands.
authors.forename: Natalie
authors.initials: N
authors.lastname: Ter Hoeve
authors.affiliation: Leiden University Medical Center, Department of Surgery, 2333ZA Leiden, The Netherlands.
authors.forename: Abbey
authors.initials: A
authors.lastname: Schepers
authors.affiliation: Leiden University Medical Center, Department of Pathology, 2333ZA Leiden, The Netherlands.
authors.forename: Johannes
authors.initials: J
authors.lastname: Morreau
authors.affiliation: Radboud University Medical Center, Department of Surgery, Nijmegen 6525GA, The Netherlands.
authors.forename: Johannes
authors.initials: J
authors.lastname: Bonenkamp
authors.affiliation: Radboud University Medical Center, Department of Pathology, Nijmegen 6525GA, The Netherlands.
authors.forename: Adriana
authors.initials: A
authors.lastname: van Engen-van Grunsven
authors.affiliation: University Medical Center Groningen, Department of Surgery, 9700 RB, Groningen, The Netherlands.
authors.forename: Schelto
authors.initials: S
authors.lastname: Kruijff
authors.affiliation: University Medical Center Groningen, Department of Pathology, 9700 RB, Groningen, The Netherlands.
authors.forename: Bettien
authors.initials: B
authors.lastname: van Hemel
authors.affiliation: University Medical Center Groningen, Department of Internal Medicine, 9700 RB, Groningen, The Netherlands.
authors.forename: Thera
authors.initials: T
authors.lastname: Links
authors.affiliation: Academic Medical Center Amsterdam, Department of Surgery, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: Els
authors.initials: E
authors.lastname: Nieveen van Dijkum
authors.affiliation: Academic Medical Center Amsterdam, Department of Pathology, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: Susanne
authors.initials: S
authors.lastname: van Eeden
authors.affiliation: University Medical Center Utrecht, Department of Endocrine Oncology, 3584CX Utrecht, The Netherlands.
authors.forename: Gerlof
authors.initials: G
authors.lastname: Valk
authors.affiliation: University Medical Center Utrecht, Department of Surgery, 3584CX Utrecht, The Netherlands.
authors.forename: Inne
authors.initials: I
authors.lastname: Borel Rinkes
authors.affiliation: University Medical Center Utrecht, Department of Surgery, 3584CX Utrecht, The Netherlands.
authors.forename: Menno
authors.initials: M
authors.lastname: Vriens
mesh_terms: D000328:Adult; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D000071231:Carbonic Anhydrase IX / Q000235:genetics / Q000378:metabolism*; D018278:Carcinoma, Neuroendocrine / Q000175:diagnosis* / Q000401:mortality; D005260:Female; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009367:Neoplasm Staging; D009426:Netherlands; D011237:Predictive Value of Tests; D011379:Prognosis; D016019:Survival Analysis; D013964:Thyroid Neoplasms / Q000175:diagnosis* / Q000401:mortality; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D051272:Glucose Transporter Type 1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C495677:SLC2A1 protein, human; D042461:Vascular Endothelial Growth Factor A; D000071231:Carbonic Anhydrase IX
keywords: hypoxia inducible factor 1 alpha; immunohistochemistry; medullary thyroid cancer; oncology; tissue microarray