The low response rate of adenoid cystic cancer to tyrosine kinase inhibitors and EGFR inhibitors indicates that no single molecule is dominant in tumor invasion and spread of this cancer [19–21, 24]. The class III receptor tyrosine kinase and c-kit is important for normal hematopoiesis, melanin production and reproductive cell production. Imatinib mesylate (Gleevec™), a tyrosine kinase inhibitor, is very effective in treating chronic myeloid leukemia and show good efficacy for the treatment of advanced gastrointestinal tumors with positive c-kit expression . The expression of c-kit in salivary adenoid cystic cancer has been variably reported as 78% to 100%. The high c-kit expression in adenoid cystic cancer suggests that this cancer may respond to treatment with imatinib mesylate, although studies with imatinib have not shown consistent results [12, 25]. The relationship between c-kit expression and prognosis has been controversial, although the expression of c-kit was stronger in the tubular or cribriform type than in the solid type [21, 26]. The discrepancy might have been caused by differences in staining techniques and the lack of a standard method for evaluating staining intensity. In the present investigation, 94% of the tumors expressed c-kit, but no significant relationship with other clinical variables or prognosis was identified.
EGF is found in the primary duct and terminal buds, and its distribution and density decrease with aging . EGFR is present in salivary gland tumors, with expression reported in 0% to 85% of adenoid cystic cancers . In the present study, 56% of the tumors were positive for EGFR. The overexpression of EGFR is reportedly related to a poor prognosis in salivary gland cancer , which is different from our results. VEGF promotes vascular proliferation in tumors from peripheral tissue and enhances vessel permeability with a selective effect on vascular endothelial cells. VEGF expression is found in various tumors, such as those of esophageal cancer, small cell lung cancer, thyroid cancer, breast cancer, and cervical cancer , as well as head and neck cancer. VEGF expression is associated with cervical lymph node metastasis, higher cancer stage, perineural invasion, recurrence, and low survival [18, 28]. Higher VEGF expression was found in solid tumors compared with tubular or cribriform types, and the survival rate decreased with higher VEGF expression . In the present study, there was no relationship between high VEGF expression and lymph node metastasis, recurrence, or survival, contrary to our expectations. This was possibly, attributable to the subjective assessment of the differences in immunostaining and the semiquantitative analysis. A few investigations on treatments targeting VEGF in salivary gland cancer have shown partial remission, suggesting the targeting of VEGF for the management of adenoid cystic cancer . Negative results regarding the prognostic usefulness of molecular markers in the present study might have been due to the threshold criteria used for positive EGFR, c-kit, and VEGF on immunoreactivity . The availability of normal tissue as a negative control would have helped in scoring positive immunochemical staining.
Histological differentiation in adenoid cystic cancer is variable and reflects its malignant potential . Indeterminate cases comprised 44% of all cases in the present study, and most of these were mixed type with no predominant type. This result was attributable to a lack of detailed pathologic reports on subtypes, which is a limitation of the present retrospective study. In addition, tumor size and involved sites were not recorded definitively enough to be analyzed. Lymph node metastasis alone was significantly associated with the prognosis. Previous studies have reported that perineural invasion had strong relationships to distant metastasis and the survival rate [32, 33]. These relationships were not significant in the present investigation because of the small number of cases. In earlier studies, cervical lymph node metastasis was present in 20% of adenoid cystic cancers and was related to a high recurrence rate and low survival rate [34, 35]. A similar pattern of metastasis was observed in the present study. Distant metastasis was observed in 10 cases, with the lung being the most frequently involved single site (n = 9). Multiple sites (lung, bone, and brain) were involved in one case.
Recurrence of adenoid cystic cancer has been found usually within 56 months. Death occurred within three years after the detection of distant metastasis in 54%, whereas survival in excess of 10 years was recorded in 10% of the patients [36, 37]. Considering that late recurrence is characteristic of adenoid cystic cancer, the analysis of recurrence during a short follow-up period is another limitation of the present study.
Lymph node metastasis is a key step in the development of metastasis and is a determining factor of prognosis. Traditionally, it has been thought that tumors spread to lymph nodes by direct extension in an orderly, defined manner based on mechanical considerations and transverse lymphatics . However, lymph node metastasis cannot explain local recurrence, distant metastasis, or poor treatment outcomes. Based on clinical and laboratory research, Fisher has proposed that biological, rather than anatomical, factors may be responsible for the appearance of metastasis in certain nodes and the lack of metastasis in others, suggesting that cancer is not a local disease, but a systemic disease . Oligometastasis implies a critical interaction between systemically disseminated cancer cells and the host; this concept leads to the notion that confined distant metastasis could be completely cured by local therapy in some cases . Based on these ideas, we believe that lymph node metastasis is both a key step and coincident finding. Thus, an analysis of markers specific for lymph node metastasis may be useful for stratifying prognosis.
Anticancer radiation therapy for head and neck cancer can reduce local recurrence, but not distant metastasis [23, 41]. The molecular markers used in the present study are related to the prognosis of other head and neck malignancies, including salivary gland tumors. Although we did not identify the prognostic significance of these molecular markers, immunohistochemical staining revealed high expression levels of c-kit, EGFR and VEGF in the present study. These findings indicate a need for further research on these markers in adenoid cystic cancer.