High-grade transformation/dedifferentiation of an adenoid cystic carcinoma of the minor salivary gland to myoepithelial carcinoma.

High-grade transformation (HGT)/dedifferentiation is an unusual phenomenon in salivary gland carcinomas. Here we report a case of adenoid cystic carcinoma (ACC) with HGT/dedifferentiation to myoepithelial carcinoma, occurring in the epipharynx of a 42-year-old woman. The surgically resected tumor was a pedunculated mass, 31 × 25 mm in size, which had two histologically distinct carcinomatous areas, including a high-grade sarcomatoid area composed of pleomorphic spindle cells and an area consisting of low-grade typical ACC. These two components gradually changed from the low-grade to the high-grade component. MIB-1 index in the low-grade and high-grade component was 15% and 50%, respectively. An immunohistochemical profile of the high-grade component showed immunoreactivity for α-SMA, p63, calponin and focal S100, as well as for several cytokeratin markers, which were compatible with the features of myoepithelial carcinoma. In contrast, the immunohistochemical profile of the low-grade component coincided with that of typical ACC. This HGT/dedifferentiation to myoepithelial carcinoma is extremely rare. The pathogenesis of HGT/dedifferentiation in salivary gland carcinomas still remains largely unknown, regardless of the presence or absence of myoepithelial differentiation. Further studies are required due to the more aggressive biological behavior and poorer prognosis associated with ACC with HGT/dedifferentiation, compared with conventional ACC.

Activation of pro-MMP-2 mediated by MT1-MMP in human salivary gland carcinomas: possible regulation of pro-MMP-2 activation by TIMP-2.

Matrix metalloproteinases (MMPs), a family of extracellular matrix-degrading enzymes, are considered to play important roles in cancer invasion and metastasis. The present study examined the production levels of eight different MMPs (MMP-1, 2, 3, 7, 8, 9 and 13, and MT1-MMP) and two tissue inhibitors of metalloproteinases (TIMP-1 and 2) in homogenates of human salivary gland carcinomas [mucoepidermoid carcinomas (MECs), adenoid cystic carcinomas (ACCs), and adenocarcinomas (ADEs)] and non-neoplastic control salivary glands using sandwich enzyme immunoassay systems. The levels of MMP-1, MMP-2, MMP-13, MT1-MMP, and TIMP-1 were significantly higher in the carcinoma samples than in the controls (p < 0.05). Gelatin zymography demonstrated that the activation ratio of the MMP-2 zymogen (pro-MMP-2) was significantly higher in the carcinomas than in the controls (p < 0.05). In addition, the activation ratio in MECs was significantly higher than that in ACCs or ADEs (p < 0.01) and also correlated with histological grade and lymph node metastasis in MECs (p < 0.05), whereas the ratio showed no such correlation in ACCs or ADEs. Although the production levels of pro-MMP-2 and MT1-MMP were similar among these carcinoma groups, TIMP-2 levels were significantly higher in ACCs and ADEs than in MECs (p < 0.01). In carcinoma samples, the pro-MMP-2 activation ratio correlated directly with the MT1-MMP/TIMP-2 ratio (r = 0.736, n = 23; p < 0.01). Immunohistochemistry and in situ zymography demonstrated localization of MMP-2, MT1-MMP, and TIMP-2 to carcinoma cells, but only in MECs did carcinoma cell nests exhibit gelatinolytic activity, which was inhibited by 1,10-phenanthroline. These results suggest that enhanced activation of pro-MMP-2 mediated by MT1-MMP is implicated in the invasion and metastasis of MECs and that TIMP-2 may regulate pro-MMP-2 activation in salivary gland carcinomas.