Adenoid cystic carcinoma of the lacrimal gland is frequently characterized by MYB rearrangement

Abstract

PurposeAdenoid cystic carcinoma (ACC) represents ~10-15% of salivary neoplasms and almost universally exhibits a lethal clinical course. ACC is also known to occur in the lacrimal gland. ACC is characterized by its heterogeneous morphology and may demonstrate tubular, cribriform, and/or solid architectural patterns. Unfortunately, these histopathological features are not specific to ACC and can be seen in other salivary gland-type neoplasms, introducing a diagnostic dilemma. The discovery of fusion transcripts has revolutionized the diagnosis, surveillance, and treatment of epithelial malignancies. In several anatomic subsites ACC is frequently characterized by a fusion transcript involving genes MYB and NFIB; more specifically, t(6;9)(q22-23;p23-24). This study explores the incidence of MYB rearrangement in cases of lacrimal gland ACC using fluorescent in situ hybridization.Materials and methodsRetrospective clinical and histopathological review of 12 cases of lacrimal gland ACC seen at Mayo Clinic over a 25-year period (1990-2015) was performed. Demographic and clinical data were obtained from medical records. Surgical pathology archival material including H&E slides and immunostains was re-examined. Formalin-fixed paraffin-embedded material was further evaluated using immunohistochemistry when appropriate. Fluorescent in situ hybridization (FISH) using a MYB break-apart probe was applied to all histologically confirmed cases of ACC and benign salivary gland parenchyma.ResultsThe median patient age was 53.6 years (range 12-64) and distributed equally by gender (six male and six female). Rearrangement of MYB was identified using FISH in seven cases (58%). Twenty-five sections of benign salivary gland parenchyma showed no evidence of MYB rearrangement. Primary surgical resection was most common treatment, and 78% of the patient received adjuvant radiation therapy. Median overall survival (OS) was 11 years. Rearrangement of MYB did not affect OS.ConclusionsIn summary, our results indicate that the MYB rearrangement defines a significant subset of lacrimal gland ACCs. Importantly, FISH for MYB rearrangement may be used as a diagnostic tool during pathological examination of lacrimal gland neoplasms. Our results showed no relationship between rearrangement status and clinical outcome. Lastly, the presence of t(6;9) in ACC may provide a platform for molecular-targeting strategies in the future.

The value of MYB as a prognostic marker for adenoid cystic carcinoma: Meta‐analysis

“…Targeting the transcriptional function of MYB itself is challenging but targeting molecules that are downstream of t(6;9) might be more promising, and some clinical trials are currently underway. The explicit targetable downstream effectors of MYB include cell proliferation proteins, cell cycle proteins, apoptosis‐related markers, and cellular adhesion molecules . NFIB , which modulates transcriptional activation or repression of specific gene promoters in a tissue‐specific manner and presents as an MYB fusion partner, is also regarded as a possible therapeutic target for tumor suppression .…”

“…The explicit targetable downstream effectors of MYB include cell proliferation proteins, cell cycle proteins, apoptosis-related markers, and cellular adhesion molecules. 35 NFIB, which modulates transcriptional activation or repression of specific gene promoters in a tissue-specific manner and presents as an MYB fusion partner, is also regarded as a possible therapeutic target for tumor suppression. 31,36 Given these reasons, MYB remains an important factor that requires further studies to verify its roles in ACC.…”

Molecular features of adenoid cystic carcinoma with an emphasis on microRNA expression

“…Also, we found isolated NFIB rearrangement (NFIB-X) in a larger proportion of breast ACC, which, to the best of our knowledge, has not previously been identified in breast ACC in which others have found the vast majority of cases to harbor MYB-NFIB fusions (Fig. 11) (28,33,207). In the salivary gland, NFIB-X fusions are rare and include several different partner genes, which for now remain unknown in breast ACC (20,21).…”

“…Salivary gland ACC is driven by the MYB-NFIB gene fusion in the majority of cases, which has also been demonstrated in breast and lacrimal gland ACC, although much fewer cases have been examined (28,29,33,34,161,207). Recently, the identification of the MYBL1-NFIB gene fusion was shown to account for a subset of salivary gland and breast ACC without MYB-NFIB or the expression of MYB protein, whereas MYBL1 is yet to be shown to be involved in lacrimal gland ACC (21,30).…”

“…Regardless of the site, ACC is characterized by recurrent fusion oncogenes and relatively few but diverse mutations (5,18,21,24,(27)(28)(29)(30)(31)(32). Lacrimal gland ACC shares the clinical characteristics of salivary gland ACC, with pronounced infiltrative growth and frequent recurrences in local as well as distant sites (29,33). In contrast, ACC in the breast is a rare, indolent type of breast cancer, with recurrences and distant spread being vanishingly rare events (34).…”