Tissue and circulating immunoreactive protein for MMP-2 and TIMP-2 in head and neck squamous cell carcinoma--tissue immunoreactivity predicts aggressive clinical course

Mod Pathol. 2006 Feb;19(2):208-17. doi: 10.1038/modpathol.3800506.


Useful markers showing biological aggressiveness of head and neck squamous cell carcinoma (HNSCC) are needed to predict the outcome of the disease. MMP-2 is associated with aggressive behavior of several solid cancers. In this study, the clinical significance of tumor tissue and circulating immunoreactive proteins for MMP-2 and TIMP-2 was assessed in HNSCC. The study group consisted of 74 patients with HNSCC and 44 healthy controls. Expression of MMP-2 and TIMP-2 was examined in paraffin-embedded tumor sections by immunohistochemical methods using specific antibodies. The pretreatment serum levels of MMP-2, TIMP-2 and MMP-2:TIMP-2 complex were quantitatively measured by ELISA assay. The results were compared with the clinicopathological factors of the disease and the patients' outcome. Immunohistochemical overexpression of MMP-2 in tumor was found to be prognostic for shortened survival in HNSCC, the 5-year cumulative relapse-free survival being 42% in patients with high positivity for MMP-2 in tumor vs 61% in cases with a negative or only weakly MMP-2-positive tumor (P=0.045). Tissue MMP-2 positivity was also strongly connected with later lymph node or hematogenic relapses and associated to the cause-specific survival (P=0.055). Similarly, the 5-year cause-specific survival was significantly poorer in patients with extensive positive immunostaining for tumor TIMP-2 than in those with a TIMP-2-negative tumor (40 vs 64%, P=0.038). Patients with a TIMP-2-positive tumor also had an unfavorable 5-year relapse-free survival rate (43 vs 60%, respectively, P=0.071). Additionally, the overexpression of TIMP-2 was a powerful predictor of later lymph node or hematogenous metastases in HNSCC. Serum levels of MMP-2, TIMP-2 or MMP-2:TIMP-2 complex failed to associate with the clinical behavior of HNSCC in this material. The results of this study provide evidence that MMP-2 and TIMP-2 immunoreactive protein in tumor tissue of HNSCC patients, but not when assayed from preoperative serum samples, are prognostic in estimation of the aggressive clinical course of HNSCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Carcinoma, Squamous Cell / blood
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology*
  • Female
  • Head and Neck Neoplasms / blood
  • Head and Neck Neoplasms / metabolism
  • Head and Neck Neoplasms / pathology*
  • Humans
  • Immunohistochemistry
  • Lymphatic Metastasis
  • Male
  • Matrix Metalloproteinase 2 / analysis*
  • Middle Aged
  • Neoplasm Invasiveness
  • Predictive Value of Tests
  • Prognosis
  • Survival Analysis
  • Tissue Inhibitor of Metalloproteinase-2 / analysis*


  • Tissue Inhibitor of Metalloproteinase-2
  • Matrix Metalloproteinase 2