Expression of HIF-1 alpha in medullary thyroid cancer identifies a subgroup with poor prognosis

Lodewijk, L., van Diest, P., van der Groep, P., ter Hoeve, N., Schepers, A., Morreau, J., Bonenkamp, J., van Engen-van Grunsven, A., Kruijff, S., van Hemel, B., Links, T., van Dijkum, E. N., van Eeden, S., Valk, G., Rinkes, I. B. & Vriens, M., 2017, In : Oncotarget. 8, 17, p. 28650-28659 10 p.

Research output: Contribution to journalArticleAcademicpeer-review

  • Lutske Lodewijk
  • Paul van Diest
  • Petra van der Groep
  • Natalie ter Hoeve
  • Abbey Schepers
  • Johannes Morreau
  • Johannes Bonenkamp
  • Adriana van Engen-van Grunsven
  • Schelto Kruijff
  • Bettien van Hemel
  • Thera Links
  • Els Nieveen van Dijkum
  • Susanne van Eeden
  • Gerlof Valk
  • Inne Borel Rinkes
  • Menno Vriens

Background: Medullary thyroid cancer (MTC) comprises only 4% of all thyroid cancers and originates from the parafollicular C-cells. HIF-1 alpha expression has been implied as an indicator of worse prognosis in various solid tumors. However, whether expression of HIF-1 alpha is a prognosticator in MTC remained unclear. Our aim was to evaluate the prognostic value of HIF-1 alpha 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-1 alpha, 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-1 alpha negative and 62 (55.9%) were HIF-1 alpha positive. Positive HIF-1 alpha 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-1 alpha positive group (p= 0.007). Even within the group of patients with TNM-stage IV disease, HIF-1 alpha 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-1 alpha is strongly correlated with adverse prognosis of MTC. This could open up new ways for targeted systemic therapy of MTC.

Original languageEnglish
Pages (from-to)28650-28659
Number of pages10
Issue number17
Publication statusPublished - 2017


  • medullary thyroid cancer, hypoxia inducible factor 1 alpha, immunohistochemistry, tissue microarray, oncology, HYPOXIA-INDUCIBLE FACTOR-1, ANTIGEN DOUBLING-TIMES, TISSUE MICROARRAYS, CARCINOMA, MUTATIONS, PROTEIN, RET, CALCITONIN, SURVIVAL, MARKER

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