Clear Cell Myoepithelial Carcinoma of Salivary Glands Showing EWSR1 Rearrangement

Abstract

This study examines the presence of the EWSR1 rearrangement in a variety of clear cell salivary gland carcinomas with myoepithelial differentiation. A total of 94 salivary gland carcinomas with a prominent clear cell component included 51 cases of clear cell myoepithelial carcinomas de novo (CCMC), 21 cases of CCMCs ex pleomorphic adenoma (CCMCexPA), 11 cases of epithelial-myoepithelial carcinoma (EMC), 6 cases of EMC with solid clear cell overgrowth, and 5 cases of hyalinizing clear cell carcinoma of minor salivary glands. In addition, 10 cases of myoepithelial carcinomas devoid of clear cell change and 12 cases of benign myoepithelioma were included as well. All the tumors in this spectrum were reviewed, reclassified, and tested by fluorescence in situ hybridization (FISH) for the EWSR1 rearrangement using the Probe Vysis EWSR1 Break Apart FISH Probe Kit. The EWSR1 rearrangement was detected in 20 of 51 (39%) cases of CCMC, in 5 of 21 (24%) cases of CCMCexPA, in 1 of 11 (9%) cases of EMC, and in 4 of 5 (80%) cases of hyalinizing clear cell carcinoma. The 25 EWSR1-rearranged CCMCs and CCMCexPAs shared similar histomorphology. They were arranged in nodules composed of compact nests of large polyhedral cells with abundant clear cytoplasm. Necrosis, areas of squamous metaplasia, and hyalinization were frequent features. Immunohistochemically, the tumors expressed p63 (96%), cytokeratin CK14 (96%), and S100 protein (88%). MIB1 index varied from 10% to 100%, with most cases in the 20% to 40% range. Clinical follow-up information was available in 21 cases (84%) and ranged from 3 months to 15 years (mean 5.2 y); 4 patients were lost to follow-up. Ten patients are alive with no evidence of recurrent or metastatic disease in the follow-up period from 3 months to 15 years (mean 5 y), 3 patients are alive with recurrent and metastatic disease, and 8 died of disseminated cancer 9 months to 16 years after diagnosis (mean 6 y). Lymph node metastasis appeared in 5 patients within 5 months to 4 years after diagnosis (mean 22 mo), distant metastases were noted in 7 patients with invasion of orbit (2 cases), and in 1 case each metastasis to the neck soft tissues, liver, lungs, mediastinum, and thoracic vertebra was noted. We describe for the first time EWSR1 gene rearrangement in a subset of myoepithelial carcinomas arising in minor and major salivary glands. The EWSR1-rearranged CCMC represents a distinctive aggressive variant composed predominantly of clear cells with frequent necrosis. Most EWSR1-rearranged CCMCs of salivary glands are characterized by poor clinical outcomes.

Thoracic Myoepithelial Tumors

“…Based on our series and previously reported cases fitting our inclusion criteria, thoracic MTs are tumors of adulthood, with an age range of 18-77 yrs (mean 52) in the combined data set. This is similar to myoepithelial carcinomas of the salivary gland, which have all been reported in adults with the exception of one in a 14 year-old male 6,7,28,30,31 . In contrast, approximately 10-20% of soft tissue MTs occur in the pediatric population, with several cases reported in children under 10 years of age 4,32,33 .…”

“…Similar to our series, most cases had a mixture of cytomorphologies with spindle cell being the most common (81%; 13/16 cases), and only one case was described as having marked cytologic atypia. Four reported cases had metastatic disease: one case with no evidence of disease (NED); one alive with disease (AWD); one case dead of disease (DOD); and one case dead of other causes (DOC; lung adenocarcinoma) 14,20,25,28 .…”

“…Our understanding of MTs in these sites has been strengthened by the identification of recurring rearrangements of EWSR1 or FUS in soft tissue MTs, and rearrangements with/or without amplification of PLAG1 or HMGA2 in salivary gland MTs 4-6,8 . In the thorax, MTs are rare, poorly characterized, and their precise incidence is unclear, with fewer than 25 case reports in the literature 4,9-26,28,52 . Due to their rarity, heterogeneous histomorphology, and often focal immunoreactivity, they remain a challenging diagnosis with ill-defined prognostic criteria and unclear molecular profile.…”

Myoepithelial Carcinoma and Epithelial-Myoepithelial Carcinoma

“…Whether low-grade and low-stage tumours can be treated with wide excision only needs to be further studied. The patients with newly established high-grade EWSR1 -positive clear cell keratinising myoepithelial carcinoma [ 58 ] and EMC with high-grade transformation [ 2 , 18 , 32 , 43 , 49 , 53 ] most likely need management as those with other high-grade salivary gland carcinomas.…”

“…The EWSR1 -rearranged MEC represent distinctive aggressive variant composed predominantly of clear cells with large comedonecroses in the central parts of tumour nests. The EWSR1 -rearranged clear cell myoepithelial carcinomas are characterised by poor clinical outcome [ 58 ]. Molecular and cytogenetic studies of EMC are limited.…”