Serum matrix metalloproteinase-13 as a diagnostic biomarker for cutaneous squamous cell carcinoma

Abstract

Background: A significant proportion of newly diagnosed patients with cutaneous squamous cell carcinoma (cSCC) have metastasis and eventually die of the disease, necessitating the exploration of novel biomarkers for early detection of cSCC aggressiveness, risk assessment and monitoring. Matrix metalloproteinase-13 (MMP-13) has been implicated in cSCC pathogenesis. Serum MMP-13 levels have been shown to predict survival in patients with esophageal SCC, but their diagnostic value for cSCC has not been explored.

Methods: We conducted a case-control study to examine serum MMP-13 as a biomarker for cSCC. Patients with cSCC undergoing surgical resection and health controls undergoing plastic surgery were recruited. ELISA for measurement of serum MMP-13 and immunohistochemistry for detection of tissue MMP-13 were performed, and the results were compared between the case and the control group, and among different patient groups. ROC curve analysis was performed to determine the diagnostic value of serum MMP-13 levels.

Results: The ratio of male to female, and the age between the case (n = 77) and the control group (n = 50) were not significantly different. Patients had significantly higher serum MMP-13 levels than healthy controls. Subjects with stage 3 cSCC had markedly higher serum MMP-13 levels than those with stage 1 and stage 2 cSCC. Patients with invasive cSCC had remarkably higher serum MMP-13 than those with cSCC in situ. Post-surgery serum MMP-13 measurement was done in 12 patients, and a significant MMP-13 decrease was observed after removal of cSCC. Tumor tissues had a remarkably higher level of MMP-13 than control tissues. Serum MMP-13 predicted the presence of invasive cSCC with an AUC of 0.87 (95% CI [0.78 to 0.95]) for sensitivity and specificity of 81.7 and 82.4%, respectively for a cut-off value of 290 pg/mL. Serum MMP-13 predicted lymph node involvement with an AUC of 0.94 (95% CI [0.88 to 0.99]) for sensitivity and specificity of 93.8 and 88.5%, respectively for a cut-off value of 430 pg/mL.

Conclusion: Serum MMP-13 might serve as a valuable biomarker for early detection of cSCC invasiveness and monitoring of cSCC progression.

Keywords: Biomarker; Cutaneous squamous cell carcinoma; Matrix metalloproteinase-13; Metastasis.

Fig. 1

Comparison of serum MMP-13 levels between patients and healthy controls. As shown in this figure, patients with cSCC had significantly higher serum MMP-13 levels than healthy controls

Fig. 2

Comparison of serum MMP-13 levels among different groups of patients. Panel a shows the comparative results among patients with different stages of cSCC. Patients with invasive cSCC or lymph node metastasis had substantially higher serum MMP-13 levels than those with cSCC in situ (panel b) or without lymph node involvement (panel c), respectively

Fig. 3

Immunohistochemical analysis of MMP-13. IHC analysis of the normal tissue from a healthy subject showed several MMP-13 positive cells (light brown staining indicated by the red arrow in panel a). Panel b is an IHC microphotograph for the cSCC tissue, and brown staining can be seen in most of tumor cells

Fig. 4

ROC curve analysis results. ROC curve analysis revealed that serum MMP-13 levels had an AUC of 0.87 and 0.94 for prediction of the presence of invasive cSCC (panel a) and lymph node involvement (panel b), respectively