A 42-year-old woman presented to the neurology clinic, 6 months after the diagnosis of cerebellar hemangioblastoma, with hearing difficulty in the right ear and right-sided facial nerve paralysis. Radiologic investigation showed an invasive tumor involving the right temporal bone. Surgical resection was performed, and the specimen received in the pathology laboratory consisted of multiple fragments of hemorrhagic soft tissue and bone measuring 2.4 × 2.0 × 2.0 cm in aggregate. Histologic sections showed a neoplasm composed of papillae lined by cuboidal cells with minimal nuclear pleomorphism extending into the bone (Figure, A). The nuclei of the lining cells were round to oval with bland and finely granular chromatin and no prominent nucleoli (Figure, B). The amount of cytoplasm was moderate in these cells and was palely eosinophilic with occasional fine vacuoles. Mitotic figures and necrosis were not identified. The stroma of the papillary fronds consisted of loose fibrous tissue with abundant, thin-walled, congested blood vessels. Scattered foci of hemorrhage and hemosiderin-laden macrophages were seen. A portion of the facial nerve submitted separately showed intraneural invasion. The neoplastic cells were strongly immunoreactive for epithelial membrane antigen (Figure, C) and cytokeratin 7 (CK7) (Figure, D). They were negative for CK20, carcinoembryonic antigen, and inhibin A.
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Pathologic Diagnosis: Endolymphatic Sac Tumor Associated With von Hippel-Lindau Disease
An endolymphatic sac tumor (ELST) is a rare epithelial neoplasm, so named because it is thought to arise from the epithelium of the endolymphatic sac, a part of the inner ear located in the petrous portion of the temporal bone.1 Endolymphatic sac tumors have been described in patients as young as 11 years and as old as 71 years.1,2 There is confusion in the literature regarding the nomenclature of these tumors and of similar tumors arising elsewhere in and around the temporal bone. Similar tumors may arise from neighboring areas, including the jugular bulb, the middle ear, and the mastoid portion of the temporal bone. These tumors have been given other names, including aggressive papillary middle ear tumors, low-grade adenocarcinomas of endolymphatic sac origin, and aggressive papillary tumors of the temporal bone and endolymphatic sac. Endolymphatic sac tumors do seem to be biologically unique because of their association with von Hippel-Lindau (VHL) disease, with up to 11% of VHL patients harboring ELSTs.3 VHL disease is an autosomal dominant disorder in which there is an inherited genetic abnormality of the VHL gene located on the short arm of chromosome 3 (3p26-p25). There is inactivation or deletion of the other copy of the VHL gene (second hit) in all the tumors associated with this disease, including cerebellar hemangioblastomas, spinal hemangioblastomas, retinal hemangioblastomas, clear cell renal cell carcinomas, pheochromocytomas, and pancreatic endocrine tumors. VHL gene mutations have been shown in ELSTs, both in the context of VHL disease and as sporadic tumors.4,5 Therefore, it appears that the ELST is a distinct biologic entity and should be diagnosed as such. This diagnosis should be supported by considering the location of the tumor, which can be deduced from its characteristic clinical, radiologic, and surgical features as well as the pathologic findings as discussed in the paragraphs that follow.
Radiologically, this tumor is seen in the posterior part of the petrous portion of the temporal bone, between the sigmoid sinus and the internal auditory canal.6 From here, the tumor can invade adjacent structures, including the cerebellopontine angle and the cranial nerves, accounting for the symptoms of sensorineural hearing loss, tinnitus, vertigo, ataxia, earache, headache, facial nerve palsy, and other cranial neuropathies. Morphologically, the ELST shows a papillary and glandular architecture. The papillary and glandular structures are lined by a single layer of flattened cuboidal-to-columnar cells that may or may not be ciliated. The lining cells have round-to-oval nuclei with fine granular chromatin and eosinophilic-to-clear cytoplasm. There is minimal cellular pleomorphism and rare mitotic activity. The stroma is richly vascular. In some tumors, there are cystic cavities filled with colloidlike material. In one case, the tumor cells were reactive for CAM 5.2, CK7, CK8, CK19, 34βE12, epithelial membrane antigen, vimentin, and vascular endothelial growth factor and were nonreactive for CK10/13, CK20, carcinoembryonic antigen, CA 19-9, glial fibrillary acidic protein, S100 protein, synaptophysin, chromogranin, and thyroglobulin.7 However, S100 protein–positive and glial fibrillary acidic protein–positive tumor cells have also been reported.8
The histopathologic differential diagnoses include metastatic carcinomas from the thyroid, lung, kidney, and breast; paraganglioma; choroid plexus papilloma; meningioma; and middle ear adenoma. The precise location of the tumor as defined radiologically and surgically and the use of immunohistochemical markers would help in differentiating ELSTs from these mimics. A personal or family history of VHL disease, or other tumors that occur with VHL disease, or of bilateral tumors (characteristic of ELSTs occurring in patients with VHL disease) would certainly help in making the diagnosis. However, metastatic renal clear cell carcinoma can still be a diagnostic consideration since it occurs in patients with VHL disease, and both ELSTs and clear cell carcinomas of the kidney may occur in the same patient.
Biologically, these tumors have an aggressive and locally infiltrative growth pattern, although metastases are not known to occur. Surgical resection is the treatment modality of choice. Preoperative embolization is performed for large tumors because of their propensity for hemorrhaging during surgery. Adjuvant radiotherapy may be attempted for the control of unresectable local recurrences. The destructive and infiltrative nature of these tumors may preclude a complete surgical resection. The hearing and other neurologic impairments that are present at the time of resection are permanent. However, if discovered early in the clinical course, hearing preservation surgery can be performed.9 Therefore, a high index of suspicion is clearly of importance, and it is especially important for clinicians to closely observe patients with a known personal or family history of VHL disease as well as patients with ELSTs who may develop contralateral ELSTs, as occurs in one third of such patients.
References
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