Predictors of Outcome in Adenoid Cystic Carcinoma of Salivary Glands

Abstract

Adenoid cystic carcinoma (ACC) is the second most common salivary gland malignancy and it has a high rate of recurrences and a poor long term prognosis. Our aim was to assess the prognostic factors in ACC and study MYB-NFIB fusion and MYB protein expression in a large retrospective cohort of 135 patients with a median follow up of 6.3 years. The 5-year and 10-year local recurrence-free survival rate of 94% and 78%, 5-year and 10-year distant metastasis survival rate of 77% and 58%, and 5-year and 10-year recurrence free survival (RFS) of 66% and 44%. The following features were identified as adverse prognostic factors of RFS on univariate analysis: large tumor size, solid growth pattern, increased mitoses, positive margin, AJCC clinical staging, high grade transformation, vascular invasion, nuclear atypia, open chromatin, prominent nucleoli, and tumor necrosis. However, on multivariate analysis, only increased mitoses (≥5/10 high power fields), any solid growth pattern, and advanced AJCC TNM staging were independent adverse predictors for RFS. MYB immuno-expression and MYB-NFIB translocation were common findings in ACC, occurring in 72% and 59% of the tested ACCs, respectively. The sensitivity and specificity of MYB immunohistochemistry in detecting MYB-NFIB fusion was relatively low at 78% sensitivity and 50% specificity. The high prevalence of alterations leading to high expression of the MYB transcription factor family suggests that targeted approaches developed to suppress the expression of these oncogenic transcription factors and/or the transcriptional activity of these proteins would be a rational therapeutic approach to investigate in ACC.

MYB Translocation Status in Salivary Gland Epithelial-Myoepithelial Carcinoma

“…Genetic profiling has been shown to be a valid strategy for discerning the true nature of salivary gland tumors with divergent “hybrid” phenotypes. As one example, Jin et al used the presence of the EWR1-ATF1 fusion to support the diagnosis of hyalinzing clear cell carcinoma with high-grade transformation in a case that otherwise would have been regarded as a “hybrid clear cell-salivary duct carcinoma.”(33) Similarly, Bundele et al recently used the presence of MAML2 fusions to highlight mucoepidermoid carcinomas with acinar differentiation that would have otherwise been misclassified as “hybrid acinic cell-mucoepidermoid carcinoma.”(32) Using this same approach, we found that many of those EMCs that demonstrated AdCC-like areas including cribriform architecture and highly infiltrative growth harbored the AdCC-specific MYB fusion. Moreover, the fusion was distributed across all tumor components including the tightly biphasic areas.…”

“…Reliance on MYB immunostaining alone is not advised, as it suffers from suboptimal specificity (45% in this study, similar to other published reports). (18, 33)…”

Genetic hallmarks of recurrent/metastatic adenoid cystic carcinoma

“…Relapsed tumors are generally incurable because no systemic agents to date have been found to be effective. Therefore, overall prognosis has remained poor, with long-term overall survival (OS) rates of 23%-40% (2).…”

Detecting MYB and MYBL1 fusion genes in tracheobronchial adenoid cystic carcinoma by targeted RNA-sequencing

“…Adenoid cystic carcinoma is the second most common malignancy of salivary glands with a poor long-term prognosis (24). The identification of recurring t(6;9)/ MYB-NFIB and t(8;9)/ MYBL1-NFIB chromosomal rearrangements have significantly enhanced our knowledge of the pathogenesis of adenoid cystic carcinoma (19).…”