Expression of renal cell markers and detection of 3p loss links endolymphatic sac tumor to renal cell carcinoma and warrants careful evaluation to avoid diagnostic pitfalls

Rachel Jester,Jason Mull,Craig M Horbinski,Maria Garnovskaya,Razvan Lapadat,Malak Abedalthagafi,William Moore,Ryan Kegl,Sunil Patel,Tuan Tran,Daynna J Wolff,Joseph N Rozier,Fausto J Rodriguez,Mary Richardson,Adriana Olar,Iya Znoyko

doi:10.1186/s40478-018-0607-0

Abstract

Endolymphatic sac tumor (ELST) is a rare neoplasm arising in the temporal petrous region thought to originate from endolymphatic sac epithelium. It may arise sporadically or in association with Von-Hippel-Lindau syndrome (VHL). The ELST prevalence in VHL ranges from 3 to 16% and may be the initial presentation of the disease. Onset is usually in the 3rd to 5th decade with hearing loss and an indolent course. ELSTs present as locally destructive lesions with characteristic computed tomography imaging features. Histologically, they show papillary, cystic or glandular architectures. Immunohistochemically, they express keratin, EMA, and variably S100 and GFAP. Currently it is recommended that, given its rarity, ELST needs to be differentiated from other entities with similar morphologic patterns, particularly other VHL-associated neoplasms such as metastatic clear cell renal cell carcinoma (ccRCC). Nineteen ELST cases were studied. Immunohistochemistry (18/19) and single nucleotide polymorphism microarray testing was performed (12/19). Comparison with the immunophenotype and copy number profile in RCC is discussed. Patients presented with characteristic bone destructive lesions in the petrous temporal bones. Pathology of tumors showed characteristic ELST morphology with immunoexpression of CK7, GFAP, S100, PAX-8, PAX-2, CA-9 in the tumor cells. Immunostaines for RCC, CD10, CK20, chromogranin A, synaptophysin, TTF-1, thyroglobulin, and transthyretin were negative in the tumor cells. Molecular testing showed loss of 3p and 9q in 66% (8/12) and 58% (7/12) cases, respectively. Immunoreactivity for renal markers in ELST is an important diagnostic caveat and has not been previously reported. In fact, renal markers are currently recommended in order to rule out metastatic RCC although PAX gene complex and CA-9 have been implicated in the development of the inner ear. Importantly copy number assessment of ELST has not been previously reported. Loss of 3p (including the VHL locus) in ELST suggests similar mechanistic origins as ccRCC.

Highlights

Von-Hippel Lindau (VHL) is an autosomal dominant hereditary cancer predisposition syndrome characterized by abberations in the VHL tumor supressor gene at chromosome location 3p25.3
Patients with VHL are at increased risk of developing a variety of neoplasasms such as central nervous system (CNS) hemangioblastomas, clear cell renal cell carcinomas, pheochromocytomas and extra-adrenal paragangliomas, pancreatic neuroendocrine tumors and adenomas, and endolymphatic sac tumors (ELST) of the inner ear [7, 32]
Four μm sections were prepared for immunohistochemical evaluation with the following antibodies: CK7 (OV-TL 12/30, 1:500, citrate, Cell Marque, Rocklin, California, USA), CK20 (Ks20.8, 1:500, EDTA, Cell Marque, Rocklin, CA, USA), paired box (PAX)-8 (MRQ-50, 1:3000, EDTA, Cell Marque, Rocklin, CA, USA), Renal cell carcinoma (RCC) (PN-15, 1:500, protease, Cell Marque, Rocklin, CA, USA), CD10 (56C6, 1:1000, EDTA, Cell Marque, Rocklin, CA, USA), carbonic anhydrase 9 (CA-9) (MRQ-54, 1:2000, EDTA, Cell Marque, Rocklin, CA, USA), glialfibrillary acidic protein (GFAP) (EP672Y, 1:200, EDTA, Cell Marque, Rocklin, CA, USA), thyroglobulin (2H11+6E1, 1:5000, EDTA, Cell Marque, Rocklin, CA, USA), S100 (4C4.9, 1:4000, EDTA, Cell Marque, Rocklin, CA, USA), chromogranin A (LK2H10, 1:6000, citrate, Cell Marque, Rocklin, CA, USA), synaptophysin (MRQ-40, 1:5000, citrate, Cell Marque, Rocklin, CA, USA), PAX-2

Summary

Introduction

Von-Hippel Lindau (VHL) is an autosomal dominant hereditary cancer predisposition syndrome characterized by abberations in the VHL tumor supressor gene at chromosome location 3p25.3. ELST are very rare tumors of neuroectodermal origin, thought to arise from the rugose, intraosseous portion of the endolymphatic sac. The endolymphatic sac represents an extension of the membranous labyrinth that follows the endolymphatic duct. It has both intraosseous and extraosseous components and ends in a blind pouch in the dura mater lining the posterior surface of the temporal bone. The endolymphatic sac is composed of a single layer of flat to cuboidal to low and tall columnar cells resting on a basement membrane with folds and papillae formation in the inferomedial aspect of the intraosseous portion [1, 3, 18]. The histologic appearance of ELST ranges from a follicular growth pattern with colloid-filled cystic spaces to a papillary arrangement with solid and hypercellular areas, and occasionally an epithelioid clear cell pattern. Tumors are cytokeratin positive and immunoexpress epithelial membrane antigen (EMA), vimentin, neuron specific enolase (NSE), glialfibrillary acidic protein (GFAP), and variable S100, vascular endothelial growth factor (VEGF), and synaptophysin [14, 39]

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