Minor salivary gland adenoid cystic carcinoma : diagnostic and prognostic factors and treatment outcome

Salivary gland cancer (SGC) comprises less than 5% of head and neck malignancies. Adenoid cystic carcinoma (ACC) is denoted as the second most common SGC worldwide. In Finland, ACC is the most common histological subtype according to a nationwide study. ACC is a slow-growing neoplasm and has a tendency for perineural invasion. ACC shows three distinct histological growth patterns: cribriform, tubular, and solid. Surgery is the pivotal treatment modality, but treatment is modified according to tumor site, biological aggressiveness, and stage of the disease, which is determined according to the Union for International Cancer Control (UICC) Tumor-Node-Metastasis (TNM) classification. Postoperative radiotherapy is recommended for all patients, but chemotherapy is used mainly for inoperable, recurrent, or metastatic disease. Recurrencies affect approximately 50% of patients. Especially local and distant recurrent tumors are fairly common, with distant metastasis being more frequent and lungs the most common site. ACC has a good 5-year disease-specific survival (76-88%), but the 10-year survival (34-67%) is clearly worse. Prognostic factors affecting survival are tumor site, TNM classification, histology, surgical margin status, and distant metastasis. In this thesis, the goal was to collect all patient data and tumor samples of the minor salivary gland ACC patients diagnosed between years 1974 and 2012 in the Helsinki University Hospital area. Patient and tumor characteristics, treatment, outcome, and their associations were studied. To evaluate the viral role in ACC samples, the presence of three polyomaviruses were assessed genotyping of 24 human papillomaviruses (HPV) was performed. Furthermore, by immunohistochemistry matrix metalloproteinase (MMP)-7, -8, -9, -15, and -25 and antizyme inhibitor (AZIN) 1 and 2 in ACC were studied. The most common tumor site was the palate. Of patients, 94% were treated with curative intent. Moreover, 53% of patients suffered from recurrent ACC of which 36% were local, 12% regional, and 52% distant. Almost all distant metastases appeared within 10 years. The 5- and 10-year overall survival and disease-specific survival were 70% and 79%, and 42% and 52%, respectively. Stage I ACC patients had better survival than patients with higher stages (II-IV). Of interest, John Cunningham polyomavirus (JCPyV) DNA was found in 10% of the tumor samples. In the immunohistochemical studies on MMPs, abundant MMP-7 and -25 were associated with better survival. High tumorous MMP-9 associated with advanced stage and high MMP-15 immunoexpression with poorer survival. Intriguingly, abundant MMP-9 immunoexpression in inflammatory cells in the vicinity of ACC and in luminal material of pseudocysts of ACC associated with better survival and fewer local recurrent tumors. Immunoexpression of AZIN2 was abundant in well-differentiated tumor tissue (cribriform and tubular), but in the solid pattern the expression was negative or mild. AZIN2 immunoexpression associated with better survival. To conclude, these results show that especially stage II ACC should be considered as advanced disease and patients would benefit from more aggressive treatment. Follow-up time should be prolonged for at least ten years. JCPyV could participate in the pathogenesis of a small proportion of ACC. MMPs could participate in ACC carcinogenesis by tissue modulation, activating different signaling pathways, and by immunomodulation. MMP-7, -9, -15, and -25 are related to prognostic factors. High AZIN2 immunoexpression in well-differentiated ACC could be related to a functioning vesicle transport system of tumor cells that no longer exists in poorly differentiated ACC tissue. AZIN2 could be a prognostic factor for better survival of ACC patients.