Epidermal growth factor receptor as a novel molecular target for aggressive papillary tumors in the middle ear and temporal bone

Abstract

Adenomatous tumors in the middle ear and temporal bone are rare but highly morbid because they are difficult to detect prior to the development of audiovestibular dysfunction. Complete resection is often disfiguring and difficult because of location and the late stage at diagnosis, so identification of molecular targets and effective therapies is needed. Here, we describe a new mouse model of aggressive papillary ear tumor that was serendipitously discovered during the generation of a mouse model for mutant EGFR-driven lung cancer. Although these mice did not develop lung tumors, 43% developed head tilt and circling behavior. Magnetic resonance imaging (MRI) scans showed bilateral ear tumors located in the tympanic cavity. These tumors expressed mutant EGFR as well as active downstream targets such as Akt, mTOR and ERK1/2. EGFR-directed therapies were highly effective in eradicating the tumors and correcting the vestibular defects, suggesting these tumors are addicted to EGFR. EGFR activation was also observed in human ear neoplasms, which provides clinical relevance for this mouse model and rationale to test EGFR-targeted therapies in these rare neoplasms.

Update From the 4th Edition of the World Health Organization Classification of Head and Neck Tumours: Tumours of the Ear

“…Pleomorphism is limited, with luminal secretions sometimes noted [36]. In spite of the uncertainty about the exact point of origin, this tumor is more aggressive than either middle ear adenoma or endolymphatic sac tumor, and may respond to targeted molecular therapy [29,37].…”

Papillary‐cystic neoplasms of the middle ear are distinct from endolymphatic sac tumours

“…No mutations were detected in KRAS , AKT1 , or EGFR , which are often mutated, respectively, in pancreatic IPMN 14,15 and oncocytic and inverted sinonasal papillomas, 16 salivary gland IPMN, 17 and papillary lesions of the ear in a murine model 18 . Also, no HRAS mutations were found 9 …”

An aggressive papillary tumor of middle ear: A case report

“…[9] Histopathologically, the structure of the tumor resembles a renal cell carcinoma, thyroid carcinoma, and papillary variant of choroid plexus tumor. [10] In 1989, Heffner [4] described the similarity between the histopathology of papillary tumors of the middle ear and endolymphatic sac tumors and co-incidence of VHL syndrome, and indicated that aggressive papillary tumors are originally adenocarcinomas of endolymphatic sac epithelium. In 1995, Pollak et al [11] reported that the endolymphatic sac was not involved and originated from the pneumatic cell mucosa around jugular bulbus.…”