Researchers have documented a rare case of Epstein-Barr virus-positive nonkeratinizing squamous cell carcinoma centered in the right medial periorbital area of a 67-year-old Asian male presenting with diplopia and periocular edema. The findings highlight unusual extra-nasopharyngeal presentations of lymphoepithelioma-like carcinoma.
Rare Orbital Presentation of Epstein-Barr Virus-Associated Carcinoma
Epstein-Barr virus-positive nonkeratinizing squamous cell carcinoma—historically known as lymphoepithelioma or lymphoepithelioma-like carcinoma—most frequently develops in the nasopharynx. However, medical literature notes that these high-grade tumors can occasionally arise in extra-nasopharyngeal locations such as the lung, major salivary glands, larynx, temporal bone, and middle ear. Orbital involvement remains exceptionally rare, with the majority of prior instances localized to the ocular adnexa or lacrimal glands.
Medical documentation describes the condition as a high-grade carcinoma characterized by distinctive morphologic features, including nests of pleomorphic epithelial cells with nucleomegaly and prominent nucleoli, arranged either in small clusters or in large syncytial nests, associated with a dense lymphoplasmacytic infiltration. Recognizing this distinct histology is critical for pathologists because the prominent lymphocytic component closely mimics other orbital conditions, including orbital lymphoma and inflammatory pseudotumors.
Clinical Presentation and Diagnostic Findings
The documented patient, a 67-year-old Asian male, developed right-sided diplopia and periocular edema. Tumors involving the orbit may be primary or secondary, and their histological types differ based on precise anatomical localization and the patient’s age. Lymphoepithelioma-like carcinomas of the hepatobiliary system represent a rare histological variant characterised by undifferentiated epithelial tumour cells set within a dense lymphoid stroma. Two principal subtypes are recognised: lymphoepithelioma-like hepatocellular carcinoma arising from hepatocytes, and lymphoepithelioma-like intrahepatic cholangiocarcinoma originating from bile duct epithelium. Although most lymphoepithelioma-like intrahepatic cholangiocarcinoma cases are associated with Epstein-Barr virus in endemic regions, lymphoepithelioma-like hepatocellular carcinoma often lacks the virus but may coexist with hepatitis B virus infection. Histopathological hallmarks include syncytial tumour nests, prominent CD8-positive T-cell infiltration and variable expression of immune checkpoints such as PD-L1. Radiological appearance is non-specific, so definitive diagnosis rests on tissue sampling and immunohistochemistry.
Biopsy Results and Viral Association
Clinically, these tumours tend to present as solitary masses with relatively indolent behaviour compared with conventional hepatobiliary carcinomas. Surgical resection remains the mainstay of therapy, and emerging evidence suggests that immune-based strategies may further improve outcomes by harnessing the underlying immune-rich microenvironment. Ongoing research into tumour–immune interactions promises both deeper biological insight and novel translational approaches for this uncommon cancer variant. A multicentre retrospective study of dynamic contrast-enhanced MRI in primary intrahepatic lymphoepithelioma-like cholangiocarcinoma delineated key imaging patterns: peripheral rim enhancement, central T2 hypointensity and occasional T2-hyperintense foci. Epstein-Barr virus-positive tumours exhibited lower Ki-67 proliferation indices and distinct CA19-9 profiles, reinforcing the need for histological confirmation despite typical cholangiocarcinoma mimics.
Broader Medical Context of Epstein-Barr Virus and Carcinomas
Other investigations explore viral co-infections in distinct clinical contexts, such as adult-onset recurrent respiratory papillomatosis caused by human papillomavirus. Because adult-onset recurrent respiratory papillomatosis prevalence is much lower than human papillomavirus prevalence, human papillomavirus infection is necessary, but not sufficient, to cause the condition, and other factors likely contribute to its pathogenesis. A prospective case-control study conducted from January 2018 to November 2019 at a tertiary referral centre investigated whether co-infection with herpetic viruses may contribute to the pathogenesis of adult-onset recurrent respiratory papillomatosis, evaluating 18 consecutive patients with the condition and 18 adults with healthy laryngeal mucosa as a control group undergoing surgery. Cytomegalovirus, Epstein-Barr virus, herpes simplex viruses 1 and 2, human herpesvirus 6, varicella zoster virus, and human papillomavirus including genotyping were detected in biopsies of papilloma or healthy mucosa using real-time polymerase chain reaction and reverse line blot, while dysplasia and Ki67 levels were determined in papilloma specimens. The results showed that Epstein-Barr virus was present in 6 (33.3%) of adult-onset recurrent respiratory papillomatosis patients and no control patients with a P value of .019, with presence not dependent on tobacco exposure or human papillomavirus genotype or concentration. Epstein-Barr virus presence was strongly related to increased cell proliferation and the number of previous surgeries, but not dysplasia. Human herpesvirus 6 was found in 3 adult-onset recurrent respiratory papillomatosis biopsies with one false positive, and no other herpetic virus was found, leading researchers to conclude that unlike other herpetic viruses, Epstein-Barr virus seems to interact with human papillomavirus, enhancing cell proliferation and contributing to the pathogenesis and progression of adult-onset recurrent respiratory papillomatosis.
Implications for Differential Diagnosis
The rarity of periorbital lymphoepithelioma-like carcinoma underscores the challenges clinicians and pathologists face when evaluating uncommon head and neck masses. Because clinical symptoms like diplopia and periorbital edema overlap with common inflammatory or vascular disorders, detailed imaging and tissue-based immunohistochemical evaluation remain mandatory to secure an accurate diagnosis. Readers seeking personal health guidance should consult qualified medical professionals regarding symptoms, diagnosis, and management options.
