Lymphoepithelial carcinoma (LEC) is a rare form of malignant tumor defined by a distinct microscopic appearance. It is characterized by poorly differentiated epithelial cancer cells intimately mixed with a dense, non-cancerous infiltrate of white blood cells, primarily lymphocytes, which gives the tumor its name. The tumor cells often exhibit an indistinct border and a syncytial growth pattern, which means the cells appear fused together. LEC is considered a subtype of squamous cell carcinoma, and while it can be aggressive, early diagnosis often leads to successful treatment.
Distinct Forms and Primary Locations
The presentation of lymphoepithelial carcinoma is broadly divided into two main categories based on its location: the classical nasopharyngeal type and the non-nasopharyngeal type. The prototypical form of LEC is non-keratinizing nasopharyngeal carcinoma (NPC), which accounts for the majority of cases and is highly prevalent in certain populations, particularly in Southeast Asia. This form is often referred to simply as “lymphoepithelioma” due to its historical association with the nasopharynx.
The non-nasopharyngeal LEC is much rarer and can arise in various other organs, making it a diagnostic challenge. These non-nasopharyngeal tumors, sometimes called lymphoepithelioma-like carcinomas (LELC), have been reported in sites such as the salivary glands, stomach, lungs, thymus, and skin. The salivary glands, particularly the parotid gland, are a relatively common site for non-nasopharyngeal LEC, especially in endemic regions.
While the appearance of the cancer cells mixed with the dense lymphocyte background is morphologically similar across all sites, the clinical behavior and underlying causes can vary significantly. Differentiating primary non-nasopharyngeal LEC from a metastasis originating in the nasopharynx requires careful clinical and imaging evaluation of the nasopharyngeal area.
The Role of Epstein-Barr Virus
The Epstein-Barr Virus (EBV), a common human herpesvirus, has a significant association with LEC. EBV is conclusively linked to nearly all cases of nasopharyngeal LEC and a subset of non-nasopharyngeal LECs, including those in the salivary glands, stomach, and lungs. The virus is thought to initiate the malignant transformation process within the epithelial cells.
The virus establishes a latent infection within the epithelial cells, expressing specific viral gene products that manipulate the host cell’s machinery. These products include EBV-encoded small RNAs (EBERs) and latent membrane proteins (LMP1, LMP2A). LMP1 acts like a persistently active growth signal, promoting uncontrolled cell proliferation and inhibiting programmed cell death.
This viral presence alters the cell’s epigenetic landscape, disrupting normal gene expression and activating oncogenic pathways like NF-κB. The constant presence of the virus in the tumor cells makes EBV a reliable marker for diagnosis and a potential target for treatment.
Identifying and Confirming the Diagnosis
The diagnostic process for lymphoepithelial carcinoma begins with a clinical examination and medical imaging, such as MRI or CT scans, to locate the tumor and assess the extent of local and regional spread. A PET scan may also be used for accurate staging and to check for distant metastases. However, the definitive diagnosis relies on obtaining a tissue sample through a biopsy.
A pathologist examines the tissue under a microscope, looking for the characteristic histological pattern that defines LEC. The epithelial cells typically stain positive for cytokeratin markers, confirming their epithelial origin, while the surrounding immune cells stain positive for lymphoid markers like CD45.
To confirm the diagnosis and its viral etiology, specialized molecular tests are performed to detect the presence of the Epstein-Barr Virus within the tumor cells. The most common and reliable method is in-situ hybridization (ISH) to detect EBER (Epstein-Barr virus-encoded RNA). A positive EBER result confirms the EBV-associated nature of the tumor, which is particularly relevant in the nasopharyngeal type, helping to distinguish it from other similar-looking cancers.
Current Treatment Approaches
The standard approach to treating lymphoepithelial carcinoma depends on the primary tumor location and the stage of the disease. For the most common form, nasopharyngeal LEC, radiation therapy is the primary treatment due to the tumor’s location, which makes surgical removal challenging. Radiation is often administered concurrently with chemotherapy, a regimen known as concurrent chemoradiation, which is effective for localized and locally advanced disease.
Chemotherapy regimens commonly involve platinum-based drugs, which enhance the tumor-killing effect of the radiation. In advanced cases or for tumors that have spread to distant sites, systemic chemotherapy alone is used. The high sensitivity of EBV-associated LEC to these treatments is a favorable factor in management.
For non-nasopharyngeal LECs, such as those in the salivary gland or lung, surgery is frequently the primary treatment, especially for early-stage tumors. Surgery aims to completely remove the cancerous tissue and is often followed by adjuvant radiation or chemoradiation to eliminate any remaining microscopic disease. Targeted therapies and immunotherapy have shown promise, particularly in advanced or recurrent cases, as LEC tumors often show high expression of the PD-L1 marker, suggesting responsiveness to immune checkpoint inhibitors.