Current Treatment of Endolymphatic Sac Tumor of the Temporal Bone

Like other parts of the membranous labyrinth, the endolymphatic sac is derived from the ectodermal otocyst and is located on the posteromedial aspect of the temporal bone [1, 2]. The proximal segment of the endolymphatic sac is contiguous with the endolymphatic duct [3]. The posterior segment of the endolymphatic sac is in the dura of the posterior cranial fossa. While the main functions of the sac relate to monitoring the volume and pressure of endolymph, as well as eliminating waste products therein via heterophagy, an endocrine/paracrine function has recently been considered [4, 5]. Different kinds of failure in the endolymphatic sac homeostasis have been implicated in the development of Ménière’s disease [6].

In 1988, Gaffey et al. described a locally destructive tumor of the temporal bone in the region of the endolymphatic sac [7]. The authors reviewed 9 similar cases identified retrospectively in the English literature and suggested the term “aggressive papillary middle ear tumor” for an entity distinct from middle ear adenoma [7]. The following year, Heffner reported 20 similar cases, referring to them as low-grade adenocarcinoma of probable endolymphatic sac origin [8]. The terminology has been reviewed by Mills et al., but eventually the WHO endorsed the widely popular term ‘endolymphatic sac tumor’ (ELST) [9]. It should be, however, noted that a definite origin from the endolymphatic sac remains to be established.

ELSTs are rare, with fewer than 300 cases reported in the literature [10‐13]. The aim of this article is to review the presentation, diagnosis, treatment, and outcomes for this entity. This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

Patients with ELST often present with the gradual onset of sensorineural hearing loss and tinnitus [14‐22]. This may slowly progress to include earache, vertigo, ataxia, facial nerve paresis, and otorrhea (Table 1) [14]. Most patients present in their 30s or 40s with a wide age range [23, 24]. Husseini et al. analyzed 107 patients who were treated by the Gruppo Otologico (Piacenza, Italy) or reported in the literature (only papers including 3 or more patients were considered) and observed the following presenting symptoms: hearing loss, 94%; tinnitus, 55%; vertigo, 47%; facial palsy, 33%; lower cranial nerve deficits, 5%; and facial paresthesias, 5% [11]. Thus, particularly in patients with clinical manifestations simulating Ménière’s disease, the endolymphatic sac region must be carefully examined in order not to miss an ELST [25].

ELSTs may be sporadic or associated with von Hippel–Lindau (VHL) disease which is attributable to inactivation of a tumor suppressor gene on the short arm of chromosome 3, and inherited as an autosomal dominant trait with variable expression [1, 14, 15, 20, 26‐37]. VHL predisposes patients to multiple hemangioblastomas of the retina or central nervous system as well as tumors and cysts in various organs, including renal cell carcinoma, pheochromocytoma, paraganglioma, ELST, epididymal cystadenoma, and pancreatic serous cystadenoma or neuroendocrine tumors [1]. The incidence of ELSTs in patients with VHL may be as high as 24% [1], but this is not universally accepted. Bausch et al. reported on 1789 patients with VHL who were evaluated in all university and large city hospitals with otolaryngology units in Germany, France, and The Netherlands, as well as selected centers in Spain and Italy [27]. Among the 93 ELST registrants, 52 (56%) presented with the characteristic clinical features of VHL disease. Although the remaining 41 registrants (44%) presented with apparently sporadic ELST, 16 (39%) among these were found to harbor a VHL germline mutation. Thus, 25 patients had truly sporadic ELSTs and 68 had VHL-associated ELSTs, so that the incidence of ELSTs in VHL was 3.6% in the entire series. When the two groups were compared, patients with sporadic ELST tended to be older, with a mean age of 40 years (range 12–78) versus 30 years (range 6–62), less likely to be bilateral (0 vs. 9%), and more likely to be male (60 vs. 38%). ELST was observed at initial presentation of VHL in 32% of the patients. The fact that ELST can be the first manifestation of VHL disease underscores the importance of early diagnosis of VHL-associated ELSTs, preferably with VHL germline mutation analysis in all apparently sporadic ELST cases [27]. Conversely, all patients with VHL should receive regular clinical screening for ELST. This is important in order to perform a complete tumor resection preserving hearing function, which is crucial in these patients, who often suffer from vision loss and gait disturbances associated with VHL.

As ELST progresses, it may extend medially into the cerebellopontine angle, superiorly to the middle cranial fossa, laterally into the middle ear, and anteromedially to the cavernous sinus [1]. The likelihood of regional lymph node metastases is remote [1]. The probability of distant metastases is also very low, although drop metastases in the spinal canal have been reported [26].

Radiographic evaluation with high-resolution computed tomography (CT) using a thin-slice bone algorithm may reveal bone destruction of the posterior aspect of the petrous ridge (Fig. 1) [38‐41]. Magnetic resonance imaging (MRI) usually reveals a heterogeneous mass which is hyperintense on contrast enhanced T1 and T2 sequences due to hypervascularity [38, 42]. The heterogeneous appearance may be due to blood products, cysts, cholesterol crystals, calcifications, and flow voids due to vessels [38]. Digital subtraction angiography is helpful for displaying the tumor’s vascular structure and supply, which is often complex and may help to map pre-surgical landmarks and to differentiate ELST from other lesions [43]. Increased activity on the Ga 68-DOTATATE positron emission tomography (PET/CT), used to search for VHL-associated neuroendocrine tumors, has also been reported in ELST, indicating cell-surface expression of somatostatin receptors by this tumor [26].

ELSTs are a low-grade adenocarcinoma [8, 9]. They may be very vascular and biopsy may be complicated by bleeding, which may be severe [32]. In addition, the origin of the tumor in the region of the inner ear makes it inaccessible for a biopsy unless this is intra-operative. Macroscopically, the tumor is red/brown and fibrous.

Histologically, various growth patterns of papillary, solid, follicular or cystic architecture are seen. Papillary or luminal arrangements usually show a single layer of tumor cells (Fig. 2a, b). The tumor cells may be flattened, cuboidal or columnar with bland central or excentrically-located nuclei and pale eosinophilic or clear cytoplasm (Fig. 2b, c). Cellular pleomorphism, mitoses and necrosis are not seen. Small glands and follicular structures containing deeply eosinophilic colloid-like and periodic acid–Schiff-positive material combined with papillary arrangements simulate thyroid tumors. However, the nuclear features characteristic of papillary thyroid carcinoma are not a feature of ELST. The vascularity of the papillary arrangements bears a resemblance to choroid plexus papillomas.

Immunohistochemically, ELST stains for pan-cytokeratins as well as cytokeratins CK5, CK7 and CK19, but CK20 is negative (Fig. 2d). There is variable expression of epithelial membrane antigen, Ber EP4, glial fibrillar acid protein, and S-100 protein. There is no expression of thyroglobulin or transcription termination factor 1. The proliferation rate as assessed by the Ki67 immunostain is low.

The ultrastructure of ELST has been briefly addressed by Heffner [8]. Electron microscopic examination shows a single epithelial layer overlying the basal lamina. The cells show short interdigitating cytoplasmic processes joined by desmosomes. Apical microvilli are present with moderate amounts of intracytoplasmic organelles. Occasional electron-dense neurosecretory-type granules are identified that are 200–350 μm in diameter.

The differential diagnosis includes middle ear adenoma, middle ear adenocarcinoma, jugulotympanic paraganglioma, choroid plexus papilloma, non-specific ceruminal gland adenocarcinoma, and metastatic adenocarcinoma (particularly thyroid and renal primaries) which typically show greater nuclear irregularities [14, 38, 44‐46]. Diaz et al. reported on 134 temporal bone lesions evaluated at the University of California-Davis between 1994 and 2005: paragangliomas, 78%; jugular foremen schwannomas, 4%; hemangiomas 4%; 7th nerve schwannomas, 4%; endolymphatic sac lesions, 4%; metastases, 3%; middle ear adenoma, 1%; and chondrosarcoma, 1% [43]. Of the endolymphatic sac lesions, 3 were ELSTs and 2 were pseudotumors. Thus, 3 of 134 lesions (2%) were ESLTs [43].

There are no universally accepted staging recommendations. Bambakidis et al. suggested the following system: stage I, tumor confined to the temporal bone and middle ear cavity; stage II, extension to the posterior fossa; stage III, extension to the middle cranial fossa; and stage IV, extension to the clivus and/or sphenoid wing [13].

The later system by Schipper et al. distinguishes type-A, locally confined, tumors without temporal bone erosion or infiltration of the dura; type-B tumors showing evidence of infiltration of the osseous labyrinth and sensorineural hearing loss; and type-C tumors further invading the sigmoid sinus and jugular bulb [47].

These systems are revisited below in conjunction with treatment.

The majority of patients reported in the literature were treated surgically (Fig. 3). Experience with stereotactic radiosurgery (SRS) and with fractionated radiotherapy (RT) is limited [3, 8, 48, 49]. Generally, low-grade adenocarcinomas are unlikely to be radiosensitive and complete resection with negative margins is likely to be the treatment of choice.

Evaluation of outcomes is hampered by the rarity of ELST, the limited number of patients included in reports, variable treatment, and short follow-up. Patel et al. reported on a patient treated with RT for presumed temporal bone paraganglioma who, 13 years later, was found to have an ELST, highlighting the necessity for long follow-up to assess the efficacy of treatment [60]. That said, the following are some institutional experiences and a recent literature review.

Nevoux et al. reported on 6 sporadic and 8 VHL-related ELSTs treated at two tertiary care centers [29]. Two patients with small tumors were observed; they died at 6 years of metastatic renal carcinoma (1 patient) and gastric cancer (1 patient). The remaining patients were treated surgically. Four of 6 sporadic tumors and 5 of 6 VHL tumors were locally controlled—hence, the overall local control rate was 9 of 12 (75%). Follow-up ranged from 0.5 to 10 years (median 4 years); 1 patient had no follow-up.

Rodrigues et al. reported on 7 patients treated surgically at St. Vincent’s Hospital (Sydney): 1 was alive with disease at 63 months; 1 patient died of intercurrent disease at 120 months; and 5 patients were alive and disease-free at 6, 10, 41, 98, and 144 months [61].

Carlson et al. reported on 13 patients with unilateral (12) or bilateral (1) ELSTs treated at the Mayo Clinic between 1988 and 2010 [58]. Sporadic tumors were seen in 8 patients and associated with VHL in 5 patients. Twelve patients were previously untreated and 11 were treated surgically; 10 were controlled and 1 developed a local recurrence successfully salvaged with a second operation. Follow-up ranged from 5 to 121 months (median 76 months); 6 patients were followed for more than 5 years. A single infirm patient was subjected to SRS with a marginal dose of 15 Gy and remained locally controlled at 94 months. Two patients were operated for a local recurrence after surgery elsewhere; one patient was locally controlled at 2 years, and 1 patient experienced additional recurrence which was locally controlled 11 months after SRS.

Kim et al. [50] reported on 31 patients, including 4 with bilateral ELSTs, who underwent resection of 33 ELSTs at the NIH (Bethesda). Complete tumor resection was achieved in 30 ears (91%). The tumor remained stable in 1 patient (follow-up 78 months) but progressed in the other (follow-up 105 months). Two of these patients underwent focused irradiation. There was only 1 case of recurrence after initial complete gross resection (46 months postresection) which was successfully resected.

Friedman et al. reported on 18 patients treated at the House Ear Institute (Los Angeles) between 1971 and 2011 and followed from 1 to 261 months (mean 67 months) [18]. Fifteen of 18 patients (83%) treated surgically remained locally controlled, including 1 patient who also received RT to 70 Gy. One patient was operated on 3 times plus 48 Gy and was alive with disease at 261 months, 1 patient was operated on 4 times plus 54 Gy and died with disease at 18 months, and 1 patient who underwent surgery alone was alive with disease at 88 months. Six patients who were locally controlled had follow-up of less than 1 year, including 3 who were lost to follow-up. Excluding these 6 patients, the local control of the remaining 12 patients with 1 or more years of follow-up was 9/12 (75%).

Heffner reported a clinicopathologic study of 20 patients from the Armed Forces Institute of Pathology [8]. One patient with inadequate data was excluded. Seven patients underwent a subtotal resection and 1 of 7 died postoperatively. Four patients underwent postoperative RT to 47.15, 47.15, and 50.29 Gy. The RT dose was not specified for 1 patient. Five patients developed a local recurrence from 1 to 6 years following surgery (mean 2.4 years). Two patients subsequently underwent a gross total resection and were disease-free at 2 and 8 years, respectively. Twelve patients initially underwent a gross total resection and 11 of 12 patients (92%) remained disease-free from 2 to 12 years after surgery. The remaining patient developed a questionable local recurrence at 2 years.

Kunzel et al. reported on 1 patient with a sporadic 3.5-cm ELST who underwent resection with an R1 margin followed by postoperative RT to 60 Gy [16]. The patient remained disease-free at 10 years [11].

Balasubramaniam et al. reported on a patient who had a local recurrence after surgery who was treated with SRS to a marginal dose of 15 Gy and remained disease-free at 2.5 years [48].

On the other hand, Hou et al. reported on 11 patients with ELST; 9 of 11 underwent a complete resection and all were disease-free after a follow-up period of 14 months to 10 years [51].

Husseini conducted a literature search that encompassed 16 publications with 3 or more patients, including a total of 107 patients of whom 106 patients underwent surgery [11]. Subtotal resection was performed in 11%, 19% underwent preoperative embolization, and 22% received postoperative RT or SRS. Follow-up ranged from 1 month to 21 years. Five percent of patients were dead with disease within 2 years and 10% were alive with disease. Tumor recurred in 10% of patients within 8 months to 13 years after treatment.

ELST is a rare, slow growing, but locally destructive, temporal bone low-grade adenocarcinoma that may be sporadic or associated with VHL. The likelihood of regional and distant metastases is low. If uncontrolled, ELST may cause death by local disease progression. Wide excision with negative margins is the treatment of choice. Patients with positive margins, incompletely resected gross disease or inoperable tumors should be considered for RT or SRS.