High serum alkaline phosphatase cooperating with MMP-9 predicts metastasis and poor prognosis in patients with primary osteosarcoma in Southern China

Abstract

Background: Osteosarcoma is a malignant tumor with high ability to form invasion and metastasis. Identifying prognostic factor in osteosarcoma is helpful to select those patients for more aggressive management. Our study evaluated serum alkaline phosphatase (ALP) cooperating with matrix metalloproteinase-9 (MMP-9) as an important prognostic predictor for local recurrence and distant metastasis of osteosarcoma.

Methods: 177 cases were included from the osteosarcoma patients treated at 1st Affiliated Hospital of Sun Yat-sen University (1999-2008). Pre-chemotherapy serum ALP (pre-ALP) were studied and correlated with tumor recurrence, lung metastasis and patient survival. MMP-9 protein in tumor tissues was detected by immunohistochemistry and correlated with pre-ALP level.

Results: Pre-ALP were partitioned into normal, high, and very high groups, in each group the incidence of metastases was 12.2%, 21.2% and 34.6%, respectively (p = 0.007). In the three groups the mean disease-free survival (DFS) was 57 ± 3.15, 28 ± 3.57 and 14 ± 3.35 months, respectively (p < 0.001); overall survival (OS) was 92 ± 26.89, 39 ± 8.61 and 17 ± 5.07 months, respectively (p < 0.001). By multivariate analysis, elevated serum pre-ALP were associated with shorter DFS (p = 0.018) and OS (p = 0.031). If elevated ALP levels decreased after clinical treatment, the incidence of lung metastasis rate decreased (p = 0.028); DFS and OS were both prolonged (p < 0.001). Pre-ALP was also positively correlated with MMP-9 expression (p = 0.015) in tumor tissue.

Conclusions: Pre-ALP was an independent prognostic factor for the survival of osteosarcoma patients in south China, and correlated with MMP-9 expression and lung metastasis. ALP can also serve as a prognostic marker for treatment, and merit large-scale validation studies.

Figure 1

The chemotherapeutic agents and the treatment protocol of 177 osteosarcoma patients.

Figure 2

Immunohistochemical analyses of MMP-9 staining (a: negatives, × 200; b: weak staining, x200; c: moderate staining, × 200; d: strong staining, × 200). As can be seen, MMP-9 shows strongest staining in very high pre-ALP group of primary osteosarcoma tissues (e).

Figure 3

Influence of serum ALP levels on Disease-free survival (DFS) and Overall survival (OS) Kaplan-Meier curves shows that the patients with high pre-ALP levels have poorer DFS(a) and OS (b); with pre-ALP decreased after clinical treatment have better DFS (c) and OS (d); all of them have significant difference(p < 0.05).

Figure 4

Overall survival curves were stratified by pre-ALP levels according to surgery style, Post-chemotherapy, metastasis and local recurrence after surgery. Kaplan-Meier curves shows that the patients with high pre-ALP levels have poorer OS independent of surgery type (a, b), Post-chemotherapy (c, d), metastasis (e, f) and local recurrence after surgery (g, h).