Middle ear lymphoepithelioma-like carcinoma with cerebellopontine angle invasion misdiagnosed as meningioma: A case report and literature review

Introduction

Lymphoepithelioma-like carcinoma (LELC) is a rare and histologically distinct malignant epithelial neoplasm. Histopathologically, it is characterized by poorly differentiated carcinoma cells embedded within a prominent lymphocytic stroma, demonstrating morphological similarities to undifferentiated nasopharyngeal carcinoma variants. Tumor pathogenesis is strongly associated with Epstein-Barr virus (EBV) infection, particularly in specific anatomical sites and geographical populations.^1,2 Although extranasopharyngeal LELC manifestations have been documented in multiple organ systems, its primary origin in the middle ear with subsequent invasion into the cerebellopontine angle (CPA) is exceedingly rare. This anatomical and growth-pattern rarity has resulted in insufficient characterization of the clinical and neuroradiological features of LELC originated in the middle ear. We conducted a detailed clinicoradiological analysis of a histologically confirmed, EBV-associated LELC in an older male patient, considered to have originated in the middle ear and invaded the CPA, to improve the identification of this unusual tumor presentation.

Case presentation

A man in his early 80s was admitted to Guangdong Sanjiu Brain Hospital (Guangzhou, China) in January 2020, with a 2-year history of left-sided hearing loss, a 3-month history of left facial asymmetry characterized by skewness of the mouth and eyelid insufficiency, and a 10-day history of nausea and vomiting. Additionally, he had a long-standing history of otitis media. Detailed personal and family medical histories were unavailable. Upon physical examination, left eyelid insufficiency was observed, along with deviation of the left corner of the mouth to the right and lateral deviation of the tongue to the left. The patient presented with left-sided hearing loss and yellowish-white secretions in the left external auditory canal. Laboratory investigations revealed normal levels of seven tumor markers: (a) neuron-specific enolase, 9.93 ng/mL (reference range: 0–16.3 ng/mL); (b) alpha-fetoprotein, 2.66 ng/mL (reference range: 0.89–8.78 ng/mL); (c) carcinoembryonic antigen, 1.62 ng/mL (reference range: 0–5 ng/mL); (d) human chorionic gonadotropin, <1.20 IU/L (reference range: 0–5 IU/L); (e) squamous cell carcinoma antigen, 1.20 ng/mL (reference range: 0–1.5 ng/mL); (f) carbohydrate antigen 19-9, 6.46 U/mL (reference range: 0–37.0 U/mL); and (g) total prostate-specific antigen, 1.19 ng/mL (reference range: 0–4.0 ng/mL). The patient did not undergo testing for EBV serological markers (viral capsid antigen (VCA) immunoglobulin A (IgA) (VCA-IgA) and early antigen (EA)–IgA (EA-IgA)) or plasma EBV–deoxyribonucleic acid (EBV DNA) load. Noncontrast computed tomography (CT) revealed a hyperdense mass located in the left CPA, without calcification, associated with left chronic otitis media and mastoiditis, which were accompanied by partial bone destruction and sclerotic changes (Figure 1(a) to (c)). Magnetic resonance imaging (MRI) revealed that the lesion exhibited hypointensity on T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), and T2 fluid-attenuated inversion recovery (FLAIR) sequences. Contrast-enhanced imaging revealed homogeneous enhancement of the tumor, with no evidence of necrosis, cystic degeneration, or hemorrhage. The tumor extended along the left internal auditory canal (IAC), involving the middle and inner ear, and was associated with adjacent meningeal thickening and enhancement (Figure 1(d) to (h)). Multiplanar brain MRI and CT revealed no tumor in the nasopharynx or eustachian tube; however, nasopharyngoscopy was not performed. Based on these imaging findings, a diagnosis of meningioma was established. Following preoperative discussion, the patient underwent surgical resection of the CPA tumor via a left retrosigmoid approach. Intraoperatively, the tumor exhibited a grayish-white, firm appearance with moderate vascularity and was closely adherent to the adjacent meninges, trigeminal nerve, facial nerve, auditory nerve, and brainstem. These cranial nerves were preserved during resection; however, intraoperative neurophysiological monitoring was not performed. Microscopically, the tumor displayed irregular nested architecture with abundant lymphocytic infiltration and dense fibrous stroma surrounding the nests. The tumor cells exhibited ovoid nuclei with marked atypia, prominent nucleoli, and readily identifiable mitotic figures (Figure 2(a) to (c)). Immunohistochemical staining demonstrated that the tumor cells were positive for cytokeratin (CK), epidermal growth factor receptor (EGFR), CK5/6, and epithelial membrane antigen (EMA), whereas they were negative for progesterone receptor (PR), somatostatin receptor 2 (SSTR-2), cluster of differentiation 34 (CD34), signal transducer and activator of transcription (STAT-6), and S-100. The Ki-67 index was 50%. In situ hybridization revealed positivity for EBV-encoded ribonucleic acid (RNA) (EBER) (Figure 2(d) to (g)). The final pathological diagnosis confirmed LELC. Postoperatively, the patient’s clinical symptoms improved; however, left eyelid closure remained incomplete. Postoperative MRI confirmed gross total resection of the CPA component, with small residual lesions in the distal left IAC, petrous bone, and middle ear. Rehabilitation assessment revealed that the patient was alert, with a Holden Functional Ambulation Classification ³ score of 0 (nonfunctional ambulation) and a modified Barthel Index ⁴ score of 49 out of 100, indicating moderate dependence for activities of daily living. Following comprehensive discussion with the patient and family, and considering the patient’s advanced age, suboptimal postoperative functional recovery, financial limitations, and the family’s preference for conservative management, the patient received supportive care without adjuvant chemotherapy or radiotherapy. At the 13-month follow-up, the patient was reported to be receiving only supportive care locally, with progressive clinical deterioration. No follow-up brain MRI was performed to assess residual lesions. The patient ultimately survived for 23 months postoperatively (Supplementary Figure 1). The reporting of this study conforms to the Case Report (CARE) guidelines. ⁵ We have deidentified all patient details. Written informed consent for treatment was received from the patient.

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Figure 1.

CT and MRI findings of the patient with LELC of the left CPA. (a to c) Plain CT scan (a) showed that the tumor had high density without calcification. The internal auditory canal was enlarged and the left mastoid process showed local destruction (b; short arrow) and osteosclerosis (c; long arrow) in the bone window. (d to h) The CPA lesion appeared hypointense on T1WI (d), T2WI (e), and T2 FLAIR (f), without evidence of necrosis, cystic degeneration, or hemorrhage. The pons and the left middle cerebellar peduncle were compressed and edematous. After contrast enhancement (g, h), the tumor showed homogeneous enhancement. The tumor was connected to the lesion of the middle and inner ear along the left internal auditory canal (short arrow), and the meninges were thickened and enhanced. CT: computed tomography; MRI: magnetic resonance imaging; LELC: lymphoepithelioma-like carcinoma; CPA: cerebellopontine angle; T1W1: T1-weighted imaging; T2W1: T2-weighted imaging; FLAIR: fluid-attenuated inversion recovery.

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Figure 2.

Histopathological images and EBV in situ hybridization. (a to c) Hematoxylin and eosin-stained sections showed irregular nests composed of tumor cells, with abundant fibrous stroma and numerous lymphocytes infiltrating around the nest. The tumor cells showed ill-defined cell borders, large nuclei, and prominent eosinophilic nucleoli. ((a): 50×, (b): 100×, (c): 400×). (d to f) Immunohistochemical staining demonstrated that the tumor cells were positive for CK (d), EGFR (e), and EMA (f). (g) In situ hybridization for EBV RNA showed positive diffuse nuclear staining. EBV: Epstein-Barr virus; CK: cytokeratin; EGFR: epidermal growth factor receptor; EMA: epithelial membrane antigen; RNA: ribonucleic acid.

Discussion

LELC is a rare malignancy, with an estimated incidence of 0.91 cases per 100,000 person-years. The median age at diagnosis is 54 years and incidence rates increase with age, peaking between 75 and 79 years. ⁶ Although LELC is primarily located in the nasopharynx, it has also been identified in various other organs, including the lungs, digestive system (esophagus, stomach, and liver), urogenital system (bladder, kidney, ureter, and uterus), breast, skin, and parotid and salivary glands.^6,7 However, the middle ear is an exceptionally rare location for LELC. A systematic literature search of PubMed, Scopus, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), and Wanfang databases was conducted up to 3 February 2026 using the keywords “middle ear,” “cerebellopontine angle,” “lymphoepithelioma-like carcinoma,” and “lymphoepithelial carcinoma.” This search identified four Chinese-language articles (10 cases) (Supplementary 2) and four English-language articles (6 cases).^8–11 Among these 16 reported cases of middle ear LELC, the patients’ ages ranged from 26 to 66 years (median, approximately 46 years), with a male-to-female ratio of 1:1. Geographically, the majority of patients (15/16, 93.8%) were from southern China, particularly the Guangdong Province, whereas the remaining patient was from the Philippines. This demographic and geographic distribution is consistent with the broader epidemiological pattern observed for LELC at other anatomical sites. ² Imaging data were available for eight cases. In five of these eight cases, the tumor was confined to the middle ear and mastoid region; in the remaining three cases, the tumor extended into the middle cranial fossa. One additional case reported a right CPA mass on MRI 2 years after middle ear cholesteatoma surgery; however, no imaging was provided. Accordingly, primary middle ear LELC with secondary invasion into the CPA represents a particularly rare growth pattern.

LELC is associated with EBV and other viruses. Most EBV-related extranasopharyngeal LELCs arise in foregut-derived organs, particularly the lung, whereas the middle ear is a rare site.^6,12,13 Among the 16 reported primary middle ear LELCs, 15 (94%) were positive for EBV. Our patient resided in Guangdong, an EBV-endemic region, and also tested positive for EBER, thereby suggesting a pathogenic role of EBV. Given the histological and virological similarities with nasopharyngeal carcinoma (NPC), EBV likely reaches the middle ear via eustachian tube reflux or recruitment of EBV-positive B cells, with subsequent epithelial infection established through cell-to-cell contact.^14,15 Viral oncogenes such as latent membrane protein 1 (LMP1) subsequently drive local inflammation; together with early host genetic alterations, this establishes a microenvironment permissive for type II EBV latency. ¹⁵ Once established, LMP1 constitutively activates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and other pathways, amplifying chemokine and cytokine release to facilitate immune evasion.^15–17 This persistent virus-driven inflammation synergizes with latent viral gene expression, promoting genomic instability, oncogenic pathway activation, and acquisition of stem-like properties. Ultimately, these processes lead to monoclonal malignant transformation and the formation of LELC with its characteristic lymphoid-rich stroma. In addition to EBV infection, consumption of Cantonese-style salted fish is a well-established risk factor for nasopharyngeal carcinoma and other EBV-associated malignancies in southern China and is classified as a Group 1 carcinogen by the International Agency for Research on Cancer (IARC). In the present case, detailed dietary information could not be retrieved from the medical records. This lack of data limits further exploration of the potential interaction between environmental factors and viral infection in the development of middle ear LELC, representing a limitation of the present study.

Based on the clinical and imaging findings, the differential diagnosis in this case included vestibular schwannoma, meningioma, lymphoma, and metastatic tumor.^18,19 Vestibular schwannoma, the most common CPA tumor, typically presents with hearing loss. On imaging, it characteristically appears hypo- to iso-dense on CT and hyperintense on T2WI, often with cystic changes. Although the “ice cream on cone” sign is characteristic, the “dural tail” sign is absent. In contrast, the tumor in this case demonstrated hyperdensity on CT and homogeneous hypointensity on T1WI, T2WI, and T2 FLAIR, which diverges from the typical imaging features of vestibular schwannoma. Meningioma shared some imaging similarities with this case, including homogeneous enhancement and the presence of a “dural tail” sign. However, the “ice cream on cone” sign and growth along the IAC are not characteristic of meningioma. Lymphoma, an aggressive malignancy characterized by rapid growth and prominent bone destruction, was considered inconsistent with the clinical manifestations and imaging findings in this patient. The absence of a prior malignancy history further reduced the likelihood of metastatic tumor. Therefore, meningioma was regarded as the most probable preoperative diagnosis. The misdiagnosis likely resulted from insufficient analysis of the relationship between CPA tumor and middle ear lesion, combined with a lack of familiarity with LELC, particularly cases arising from the middle ear with an uncommon growth pattern. In the present case, only CT and conventional MRI were performed, without advanced sequences such as diffusion weighted imaging, susceptibility-weighted imaging, or arterial spin labeling. This limited the availability of more meaningful imaging data that could have aided in the diagnosis and differentiation of this rare tumor. Among these 16 cases, early diagnosis of middle ear LELC was challenging, as it was frequently misdiagnosed as chronic otitis media or cholesteatoma. The present case further illustrates that long-standing chronic otitis media can obscure early tumor detection. For patients with chronic otitis media, regular high-resolution CT follow-up may facilitate early tumor identification. When a tumor is detected, MRI plays a critical role in preoperative characterization, assessment of tumor extent, and guidance of surgical planning.

The unexpected pathology prompted further investigation into the tumor’s precise origin, which is essential to understanding this rare entity. Although the dominant CPA mass with IAC widening may suggest an “inside-out” pattern, integration of clinical history, imaging reassessment, and literature review strongly supports a middle ear primary with secondary CPA invasion via the IAC. The patient’s long-standing chronic otitis media provides a plausible basis for middle ear mucosal malignancy. Radiologically, the tumor maintained clear continuity with the middle ear through the IAC, favoring an “outside-in” route. No nasopharyngeal or eustachian tube involvement was observed on preoperative imaging, excluding a primary nasopharyngeal tumor spreading via the eustachian tube. One domestically reported CPA LELC developed following cholesteatoma surgery, without evidence supporting a CPA origin. In contrast, although rare, middle ear is a documented primary site for LELC, and reported cases, including ours, were EBV-positive. Therefore, we consider it more reasonable to classify this case as primary middle ear EBV-associated LELC with secondary CPA invasion.

The primary treatment option for middle ear LELC is surgical resection. In this case, a left retrosigmoid approach was considered for tumor resection rather than the more commonly used transmastoid or combined approaches. This decision was based on several considerations. First, the main tumor bulk was located in the CPA, with compression of the adjacent cranial nerves, the brainstem, and the middle cerebellar peduncle, producing corresponding clinical symptoms. The retrosigmoid approach provided optimal exposure for maximal tumor resection and symptom relief. Second, this approach minimized the risk of infection associated with chronic otitis media. Third, it reduced surgical trauma in this older patient and preserved neurological function. Although the retrosigmoid approach precludes complete resection due to the inaccessibility of the lateral IAC, deep petrous apex, and middle ear, the resultant residual tumor can be managed with adjuvant chemoradiotherapy. The combined modality represents the safest individualized treatment for this older patient with concomitant chronic otitis media. Nevertheless, the patient received only supportive care, without adjuvant therapy postoperatively or during follow-up.

A review of 16 reported middle ear LELC cases revealed that 13 patients (81%) underwent surgery combined with postoperative radiotherapy or chemoradiotherapy. During follow-up periods ranging from 13 months to 6 years, 12 of these 13 patients (92%) achieved disease-free survival, with only one case of local recurrence. In contrast, patients receiving radiotherapy alone or incomplete comprehensive treatment demonstrated poorer outcomes, including disease progression or death (Supplementary 2). ⁸ Serum EBV DNA, a biomarker of tumor burden, has been used for treatment response assessment and recurrence monitoring in middle ear LELC.^11,20 In the present case, the patient survived only 23 months postoperatively. When clinical deterioration occurred at 13 months, no follow-up MRI or serum EBV DNA monitoring was performed to assess residual disease. The absence of both adjuvant therapy and follow-up surveillance likely contributed to the unfavorable outcome. ⁹

Conclusion

To the best of our knowledge, this is the first detailed description of the clinical and imaging features of middle ear EBV-associated LELC with secondary CPA invasion. Overlapping imaging characteristics and limited awareness of this unusual growth pattern led to preoperative misdiagnosis. For atypical CPA tumors, particularly in patients with a history of chronic otitis media, careful imaging analysis and pathological evaluation are essential for improving diagnostic accuracy. Although surgical resection remains the primary treatment, the choice of surgical approach should be individualized rather than pursuing gross total resection indiscriminately. Although middle ear LELC generally carries a favorable prognosis, the absence of adjuvant therapy and follow-up monitoring may contribute to a poor outcome. Despite certain limitations, this case report provides novel insights into the intracranial extension pattern of this rare tumor and underscores the importance of maintaining clinical vigilance in patients from EBV-endemic regions with chronic otitis media as well as the potential role of proactive multidisciplinary management in improving patient outcomes.

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