Salivary gland carcinomas are rare tumors compared to head and neck squamous cell carcinomas (SCCs) (1). The major salivary glands include the paired parotid, submandibular and sublingual glands, while there is also a significant number of minor salivary glands widely distributed throughout the oral cavity. Salivary gland tumors may originate in either major or minor salivary glands. Tumors originating in the parotid glands account for approximately 70% of the cases and <30% of those tumors are malignant, whereas tumors originating in the submandibular glands account for approximately 10% of the cases, of which approximately half are malignant (2, 3). Tumors originating in the sublingual glands are very rare and the majority are malignant, whereas those originating in the minor salivary glands account for approximately 20% of all salivary gland tumors and the majority of those are also malignant (2, 3). According to the histological distribution described by Spiro (2), mucoepidermoid carcinoma, adenoid cystic carcinoma and adenocarcinoma are common malignant tumors. The initial World Health Organization (WHO) classification of salivary gland carcinomas included a small number of histological subtypes (4), which has increased over a prolonged period of time, emphasizing the need to update due to histological heterogeneity. The latest 2005 WHO classification of salivary gland carcinomas includes 24 different subtypes that present with distinct clinical characteristics and pathological behaviors (5). The rarity and heterogeneity of salivary gland carcinomas generate challenges in regard to histological diagnosis, treatment and outcome.

In the present study, we investigated prognostic factors in patients with salivary gland carcinomas who were diagnosed and treated at our institution and reviewed the available relevant literature.

Salivary gland carcinomas are relatively rare and exhibit marked heterogeneity (1). The diversity of their biological characteristics highlights the need for histological grading revisions and has resulted in the description of various tumor subtypes (5). The variety of histological subtypes may be attributed to the histogenetic origin of salivary gland carcinomas. Regezi and Batsakis (9) hypothesized that the presence of stem cell progenitors in the proximal and distal regions of the salivary duct system indicates the original location of related tumors, e.g., mucoepidermoid, adenoid cystic and acinic cell carcinomas arise from excretory duct cells, intercalated duct cells and acinar cells, respectively.

Of the 24 known types of malignant salivary gland tumors, the 2 most common are mucoepidermoid carcinoma and adenoid cystic carcinoma (2). The former is the most common, accounting for approximately 30% of all malignant salivary tumors, while the latter is the second most common, accounting for approximately 20% (2, 10). In the present study, mucoepidermoid carcinoma was the most common subtype, followed by adenoid cystic carcinoma, acinic cell carcinoma and malignant myoepithelioma in a descending order, which is in accordance with previously reported findings (2, 10). With regard to the location of salivary gland carcinomas, the majority of the tumors in the present cohort (72.5%) occurred in the minor salivary glands, with the most frequent site of origin being the palate.

As regards prognostic factors, clinical stage, particularly tumor size rather than histological grade, was reported to be the most significant factor for predicting the outcome of patients with salivary gland carcinomas (11). Intriguingly, the authors of that study reported a stage III/IV patient with a tumor sized >4 cm who had a poor outcome regardless of histological grade. On the other hand, patients classified as stage I/II, with tumors sized <4 cm, had a better prognosis despite histological grade (12). These results suggest that advanced both clinical stage and large tumor size are factors associated with poor outcome. In addition, other prognostic indicators such as age, surgical resection margin and lymph node metastasis have been reported (12–14).

In the present study, several clinicopathological factors, including histological grade, tumor size, lymph node metastasis and clinical stage, were identified as critical for disease-specific mortality. However, age and surgical resection margin were not identified as significant predictors. In particular, we found that lymph node metastasis and tumor size were independent prognostic factors indicating worse survival. Recent clinical studies reported that a high mortality rate was significantly correlated with lymph node positivity in patients with adenoid cystic and mucoepidermoid carcinomas (15, 16). Our results support a strong association between lymph node metastasis and poor survival.

A total of 9 patients in our study exhibited tumor recurrence (3 patients developed local recurrence, 1 patient had local recurrence as well as regional lymph node metastasis and 5 patients had distant metastasis). Of the 4 cases with local recurrence, 2 cases with high-grade mucoepidermoid carcinomas presented with local recurrence and 1 had an apparent positive resection margin. High-grade mucoepidermoid carcinomas recurred locally, despite histological evidence of a disease-free margin in the surgical specimen (17). These results indicate a significant correlation between local recurrence and the high-grade malignancy of mucoepidermoid carcinomas. In addition, adenoid cystic carcinoma was reported to be the most common type of salivary gland carcinoma associated with distant metastasis (18). In the present study, a high frequency of lung metastasis was found among patients with adenoid cystic carcinomas (3 of 11 cases), indicating the distinct metastatic capacity of this type of tumor. The univariate analysis identified histological grade, tumor size and clinical stage as the 3 critical factors for recurrence, while the multivariate analysis demonstrated that large tumor size was the most significant independent clinicopathological factor associated with tumor recurrence. These results suggest that not only a high grade of malignancy, but also a larger tumor size are significantly associated with tumor recurrence. Taken together, a large tumor size is significantly associated with poor outcome (i.e., high mortality rate and frequent recurrence), indicating the significance of complete removal of the lesion before it grows to a large-sized tumor.

Recent molecular biology studies have focused on the identification of the specific molecular characteristics of salivary gland carcinomas (19–23). The expression of the centromere protein and spindle assembly checkpoint gene were reported to be significantly correlated with Ki-67 labeling index and clinical stage in primary salivary gland carcinomas (19, 20). Furthermore, telomerase activity was found to be significantly higher in high-grade compared to low-grade mucoepidermoid carcinomas (21). With regard to histological type-specific gene expression, androgen receptor expression was found in carcinoma ex pleomorphic adenomas and salivary duct carcinomas (22). In addition, overexpression of epidermal growth factor receptor (EGFR) was identified in mucoepidermoid carcinomas by immunohistochemical analysis (23). Such gene expression may be a reliable marker of clinically advanced stage or tumors of high histological grade. Although surgery or surgery combined with postoperative radiation remain the standard treatment for this type of malignancy, a clinical trial for molecular-targeted chemotherapy using EGFR inhibitors for salivary gland cancer was recently conducted (24). Efforts focused on elucidating the molecular biological characteristics of the specific subtypes of salivary gland carcinomas may lead to improved therapeutic approaches, resulting in better patient outcomes.