Lymphoepithelial Carcinoma: Causes, Symptoms, and Treatment

Lymphoepithelial carcinoma is a rare cancer defined by clusters of poorly differentiated epithelial cells surrounded by a dense infiltrate of immune cells, primarily lymphocytes. It arises most often in the nasopharynx but can appear in the salivary glands, lungs, larynx, skin, thymus, esophagus, and liver, among other sites. The Epstein-Barr virus (EBV) is strongly linked to many cases, though the strength of that link depends heavily on where in the body the tumor grows and on the patient’s ethnic background. Despite its aggressive-looking pathology, lymphoepithelial carcinoma tends to carry a better prognosis than other undifferentiated cancers at similar sites, and treatment options have expanded in recent years with the addition of immunotherapy.

What Lymphoepithelial Carcinoma Actually Is

The name captures the tumor’s defining feature: cancerous epithelial cells (the “carcinoma” part) growing in tight sheets or cords, interspersed with large numbers of lymphocytes (the “lympho” part). Under a microscope, pathologists describe two classic growth patterns. In one, the cancer cells blend almost seamlessly into a dense immune-cell background. In the other, distinct nests and sheets of tumor cells are separated by bands of lymphocytes.¹ The tumor cells themselves tend to have large, open-looking nuclei with prominent nucleoli and poorly defined borders, giving the tissue a “syncytial” appearance where individual cells seem to blur together.

The cancer was first characterized in the nasopharynx, where it is strongly associated with EBV. When tumors with identical microscopic appearance were discovered elsewhere in the body, they were designated “lymphoepithelioma-like carcinomas” to acknowledge the histologic resemblance.² In clinical practice, many oncologists and pathologists use the terms interchangeably regardless of the tumor’s location.

The Epstein-Barr Virus Connection

EBV infects the vast majority of humans at some point in life, usually without consequence. In a small number of people, the virus shifts its gene expression in epithelial cells in a way that drives those cells to multiply uncontrollably, setting the stage for cancers including nasopharyngeal carcinoma, certain gastric cancers, and lymphoepithelial carcinoma.³ In nasopharyngeal and salivary gland tumors, the association is robust: in one large series of parotid gland cases, roughly 95% of tumors tested positive for EBV.⁴ A smaller Taiwanese study found EBV in all nine salivary gland lymphoepithelial carcinomas examined.⁵

The picture becomes murkier once you move away from the nasopharynx. In the larynx, current evidence suggests EBV plays a limited role, and the cause of laryngeal lymphoepithelial carcinoma remains unsettled.⁶ Pulmonary lymphoepithelial carcinoma, by contrast, does show a close EBV association in most reported cases.⁷ EBV status matters clinically because it helps distinguish lymphoepithelial carcinoma from look-alike undifferentiated cancers and may influence treatment decisions, particularly when immunotherapy is being considered.

Who Gets It and Where

Lymphoepithelial carcinoma is rare overall, but it clusters in certain populations and anatomic sites. The nasopharynx accounts for the majority of cases globally. A large demographic study found that about 58% of lymphoepithelial carcinomas originated in the nasopharynx, and that people of Asian descent made up a disproportionately large share of both nasopharyngeal and pulmonary cases.⁸ Salivary gland lymphoepithelial carcinoma shows a strikingly high incidence among Inuit (Eskimo) populations, a pattern noted as far back as the 1980s.⁹

Beyond the nasopharynx and salivary glands, lymphoepithelial carcinoma has been documented in the lungs, larynx, thymus, esophagus, stomach, skin, urinary bladder, and liver. Many of these extra-nasopharyngeal sites produce only a handful of published cases, making it difficult to draw firm conclusions about risk factors specific to each location. What runs across nearly all sites is the dense lymphocytic infiltrate and, in most Asian patients, a strong EBV signal. Among non-Asian patients, EBV positivity is more variable: one multicenter study of salivary gland lymphoepithelial carcinoma found that all four Asian patients tested positive for EBV-encoded RNA, compared with four of twelve non-Asian patients.¹⁰

Symptoms by Site

Because lymphoepithelial carcinoma can grow in so many different organs, symptoms vary widely. There is no single “classic” presentation the way there might be for a more common cancer. Instead, the symptoms follow from whichever organ is involved.

Nasopharynx: Nasal obstruction, nosebleeds, hearing changes, and painless cervical lymph node enlargement are typical early complaints.
Salivary glands: The most common sign is a painless, slowly growing lump near the ear (parotid) or under the jaw (submandibular). Facial nerve paralysis occurs in about 20% of parotid cases, and enlarged cervical lymph nodes are present at diagnosis in roughly 15–30% of patients.¹ ⁴
Larynx: Hoarseness, difficulty swallowing, and shortness of breath, sometimes developing over months. One reported case involved an elderly man with a year-long history of progressive voice change and breathing difficulty caused by a mass spanning the entire larynx.¹¹
Lung: Cough, chest pain, and shortness of breath, often indistinguishable from other lung cancers until biopsy reveals the characteristic lymphoid-rich histology.
Skin: A firm, skin-colored or reddish nodule, usually on the head or neck, that may be mistaken for other skin tumors.

Lymph node metastases are a recurring theme across sites. Imaging of head and neck lymphoepithelial carcinomas found nodal metastases in 70% of patients at presentation, with about a third of those nodes showing internal necrosis.¹² That high rate of nodal involvement makes thorough imaging of the neck and chest an essential part of the initial workup.

How the Diagnosis Is Made

Diagnosing lymphoepithelial carcinoma usually requires a tissue biopsy and a pathologist with experience in the entity, because the tumor can look deceptively similar to more common cancers. In the lung, for instance, its microscopic appearance overlaps with conventional squamous cell carcinoma closely enough that misdiagnosis is a recognized pitfall.⁷

Immunohistochemistry helps confirm the diagnosis. The tumor cells stain positive for epithelial markers such as cytokeratins and p63, proving they are truly carcinoma cells rather than lymphoma cells infiltrating the tissue.¹³ In situ hybridization for EBV-encoded small RNAs (EBER) is then performed to check for the virus. A positive EBER result in the right histologic context is strong evidence for lymphoepithelial carcinoma and helps differentiate it from other undifferentiated tumors.¹⁴

What Imaging Shows

On CT and MRI, salivary gland lymphoepithelial carcinoma typically appears as a lobular, well-enhancing mass. In one large imaging series, about 90% of salivary gland tumors showed obvious contrast enhancement, and roughly 60% had homogeneous density.¹⁵ Around 45% of cases presented as multiple lesions rather than a single mass, often because of concurrent lymph node metastases within or around the gland.

Head and neck tumors outside the salivary glands tend to have ill-defined margins and restrict water diffusion on MRI, a finding that signals high cellularity. They also light up intensely on PET scans, which is useful for staging but not specific enough to clinch the diagnosis on its own.¹² In rare cases involving the liver, the tumor mimics other liver cancers on imaging: it enhances brightly in the arterial phase and washes out gradually, sometimes with a delayed central scar and a thin pseudocapsule.¹⁶

Treatment Approaches

Treatment for lymphoepithelial carcinoma depends on the site, stage, and whether the tumor is resectable. For localized disease in the salivary glands and head and neck, the traditional approach has been surgery followed by radiation. For advanced or metastatic pulmonary cases, platinum-based chemotherapy has been the backbone of first-line treatment, and immunotherapy is rapidly entering the picture.

Surgery and Radiation

In salivary gland lymphoepithelial carcinoma, surgical removal combined with postoperative radiation has long been considered standard. One study of parotid gland cases reported a five-year overall survival of about 86% with this approach.¹⁷ A more recent series treating salivary gland lymphoepithelial carcinoma with radical radiotherapy (with or without surgery) reported five-year progression-free survival near 85% and ten-year overall survival around 89%.¹⁸

These tumors tend to be highly radiosensitive, which has led researchers to ask whether radiation alone or chemoradiation could replace surgery in some patients. A study comparing upfront surgery with upfront chemoradiation in salivary gland cases found comparable five-year locoregional control and overall survival between the two approaches, suggesting that chemoradiation is a viable alternative when surgery carries high risk.¹⁹ A separate analysis of non-nasopharyngeal head and neck lymphoepithelial carcinoma likewise found no significant survival difference between surgery alone and radiation alone through the first five years, though surgery showed an advantage beyond that time point.²⁰

For skin lymphoepithelial carcinoma, wide surgical excision is the standard first step. Adjuvant radiation may be added when pathology reveals features like perineural invasion, where cancer cells are growing along nerves.²¹

Chemotherapy for Advanced Disease

When lymphoepithelial carcinoma of the lung is locally advanced or has spread, platinum-based doublet chemotherapy is the established first-line treatment. In a cohort of 127 patients receiving first-line chemotherapy, median progression-free survival was about eight months and median overall survival was roughly 37 months. Among the regimens tested, gemcitabine plus a platinum drug achieved the highest response rate (about 63%) and modestly longer progression-free survival compared with taxane-platinum or pemetrexed-platinum combinations.²² Smoking and advanced stage were both independently linked to worse overall survival in lung cases.

Immunotherapy and Emerging Options

Lymphoepithelial carcinoma’s dense lymphocytic infiltrate and frequent EBV positivity make it a logical candidate for immune checkpoint inhibitors, and early results are encouraging. Many pulmonary lymphoepithelial carcinomas express high levels of PD-L1, the protein that checkpoint drugs target.²³

In one cohort of chemotherapy-resistant pulmonary cases, patients with PD-L1 expression above 30% had dramatically higher response rates to anti-PD-1 therapy (about 82%) compared with those whose tumors expressed PD-L1 at 30% or below (10%). Progression-free survival in the high-expression group reached over 25 months, compared with roughly six months for the low-expression group.²³

Combining immunotherapy with chemotherapy from the outset is also being tested. A phase 2 trial evaluated the anti-PD-1 drug sintilimab combined with gemcitabine and carboplatin as a first-line treatment in 30 patients with advanced pulmonary lymphoepithelial carcinoma, followed by maintenance sintilimab.²⁴ Other case reports have described prolonged progression-free survival exceeding two years in individual patients receiving PD-1 inhibitors combined with targeted anti-angiogenic agents. These are still early-stage findings and small numbers, but they point toward a treatment landscape that is shifting quickly.

Prognosis Compared With Other Undifferentiated Cancers

One of the more counterintuitive aspects of lymphoepithelial carcinoma is that, despite looking aggressive under the microscope, it often behaves better than other poorly differentiated cancers in the same organ. A study comparing salivary gland lymphoepithelial carcinoma with large cell undifferentiated carcinoma of the same glands found a stark difference: five-year survival was about 86% for lymphoepithelial carcinoma versus a two-year survival of only 36% for large cell undifferentiated carcinoma. Patients with the undifferentiated tumors also presented with more advanced disease, with 75% at stage IV compared with just 13% of lymphoepithelial carcinoma patients.¹⁷

A similar pattern holds in the lung: a study of 32 cases found that pulmonary lymphoepithelial carcinoma carried a significantly better prognosis than non-lymphoepithelial undifferentiated lung cancers, with the survival advantage particularly evident in stage II and stage III-IV disease.²⁵ The dense immune infiltrate itself may partly explain the relatively favorable outcomes; those lymphocytes are not passive bystanders but appear to mount a meaningful anti-tumor response.

For parotid gland lymphoepithelial carcinoma specifically, five-year overall survival exceeded 97% and ten-year survival was about 91% in a large series of 146 patients, though older age was a significant negative prognostic factor.⁴ These are encouraging numbers for a cancer that often has lymph node involvement at the time of diagnosis.

Lymphoepithelial Carcinoma in Children

While overwhelmingly an adult disease, lymphoepithelial carcinoma does occasionally appear in children and adolescents, most often in the thymus. A case series described four boys aged 9 to 13 with thymic lymphoepithelial carcinoma presenting as large masses in the front of the chest. Three of the four had positive EBV markers in their blood. Three patients with earlier-stage disease survived after surgery, while one with stage IV disease died nine months after the operation.²⁶

Pediatric lymphoepithelial carcinoma may respond well to combined immunotherapy and chemotherapy. In a genomic and clinical study of pediatric cases, patients who received anti-PD-1 therapy plus chemotherapy achieved 100% one-year overall survival and roughly 88% two-year overall survival.²⁷ Genomic profiling of pediatric tumors is beginning to reveal molecular features that could guide targeted treatment, though this work is in its early stages given the rarity of the disease in this age group.

Why Getting the Pathology Right Matters

Because lymphoepithelial carcinoma responds well to radiation, often responds to immunotherapy, and carries a meaningfully better prognosis than many of its mimics, correct diagnosis is not merely academic. Misidentifying the tumor as conventional squamous cell carcinoma or large cell undifferentiated carcinoma could lead to a more aggressive surgical plan when radiation alone might suffice, or to chemotherapy regimens that miss the opportunity to add a checkpoint inhibitor. It could also lead to a grimmer prognosis conversation than the evidence supports.

The diagnostic checklist is straightforward in concept: tissue biopsy showing the classic morphology, immunohistochemistry confirming epithelial markers, and EBV testing by in situ hybridization. In practice, the challenge is that the tumor is rare enough that not every pathologist has seen one. When an undifferentiated carcinoma shows up at an unusual site with a heavy lymphocytic infiltrate, requesting EBV testing and cytokeratin stains can make the difference between an accurate diagnosis and a consequential miss. For patients, the practical takeaway is that pathology review at a center experienced with head and neck or thoracic tumors can be worth pursuing if the initial diagnosis is an undifferentiated carcinoma.

The PD-L1 Question and Patient Selection for Immunotherapy

Not every lymphoepithelial carcinoma will respond to immune checkpoint therapy, and PD-L1 expression appears to be the most useful biomarker for sorting out who is most likely to benefit. High PD-L1 expression tracks strongly with response rates and longer progression-free survival on anti-PD-1 drugs.²³ For that reason, PD-L1 staining is becoming a routine part of the pathology workup in advanced lymphoepithelial carcinoma, even though it is not yet a universally standardized decision point in treatment guidelines.

EBV status may also play an indirect role. EBV-positive tumors tend to have a more inflamed microenvironment, which could prime the immune system to respond when checkpoint inhibitors remove the brakes. Some researchers suspect this is part of why lymphoepithelial carcinoma has a relatively favorable prognosis in general: the virus attracts immune attention, and the immune system partially controls the tumor even without treatment. Checkpoint inhibitors may amplify that existing immune response rather than starting one from scratch, which could explain the high response rates seen in some series. The data supporting this hypothesis is still circumstantial, but it aligns with what has been observed in other EBV-associated cancers like nasopharyngeal carcinoma.

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