Expression of hypoxia-inducible factor 1 alpha in papillary thyroid carcinoma is associated with desmoplastic stromal reaction and lymph node metastasis

Papillary thyroid carcinoma (PTC) is the most common thyroid cancer, and it early metastasizes into regional lymph nodes. We evaluated immunohistochemically the expression of the hypoxia marker hypoxia-inducible factor 1 alpha (HIF-1 alpha) as well as extracellular matrix protein tenascin C as a marker of stroma remodelling in a cohort of 160 PTCs. Expression of HIF-1 alpha was seen focally accentuated in 100 of the 160 tumours (62.5 %) including 16 cases with equivocal staining (faint staining or only single-cell staining) and 84 cases with unequivocal staining. HIF-1 alpha expression correlated with the degree of desmoplastic stromal reaction as well as with the expression of tenascin C (p < 0.001, Kruskal-Wallis test, respectively). Moreover, expression of HIF-1 alpha was significantly associated with the presence of lymph node metastases (p < 0.001, Mann-Whitney test) as well as signs of invasion, namely, peritumoural and extrathyroidal invasion as well as angioinvasion (p = 0.024, p < 0.001, p = 0.017, Mann-Whitney test, respectively). Additionally, PTC with unequivocal HIF-1 alpha nuclear staining was a larger tumour than PTC with negative (-) or equivocal HIF-1 alpha expression (p < 0.001, Kruskal-Wallis test). Interestingly, the expression of HIF-1 alpha was not significantly associated with BRAF V600E status (p > 0.05, Mann-Whitney test). Our data show that the expression of HIF-1 alpha is associated with stroma remodelling processes within the tumour and, thus, may play an important role in an invasive behaviour of these tumours independent of BRAF mutation status.