Non-Keratinizing Squamous Cell Carcinoma of the Nasopharynx: Understanding Your Pathology Report

By Jason Wasserman MD PhD FRCPC
April 10, 2026

Nonkeratinizing squamous cell carcinoma is the most common type of nasopharyngeal carcinoma, a cancer arising in the nasopharynx, the area at the back of the nasal cavity above the soft palate. The term “nonkeratinizing” describes the appearance of the cancer cells under the microscope: they produce little or no keratin (a tough protein that gives other squamous cell carcinomas their pink color) and instead appear blue-purple and grow in solid sheets or clusters, often surrounded by immune cells.

This microscopic pattern is important because nonkeratinizing squamous cell carcinoma of the nasopharynx is almost always caused by Epstein–Barr virus (EBV). EBV-associated nasopharyngeal carcinoma responds remarkably well to radiation and chemotherapy and carries a significantly more favorable prognosis than keratinizing nasopharyngeal carcinoma or other head and neck cancers. Understanding which type of nasopharyngeal carcinoma you have is therefore essential.

This article will help you understand the findings in your pathology report. For a broader overview of all types of nasopharyngeal carcinoma, see our article on nasopharyngeal carcinoma.

What causes nonkeratinizing squamous cell carcinoma of the nasopharynx?

Virtually all nonkeratinizing squamous cell carcinomas of the nasopharynx are caused by persistent infection with Epstein–Barr virus (EBV) — the same virus responsible for infectious mononucleosis (the “kissing disease”). EBV infects epithelial cells in the nasopharynx and, over time, causes genetic changes that allow the cells to grow uncontrollably. Most people infected with EBV never develop cancer — additional factors, including certain genetic variants (HLA types), geographic ancestry, a diet high in salt-preserved foods, and family history, all influence individual risk. This cancer is particularly common in East and Southeast Asia, North Africa, and among certain indigenous populations in North America.

Nonkeratinizing squamous cell carcinoma of the nasopharynx should not be confused with nonkeratinizing squamous cell carcinoma of the nasal cavity and sinuses, which is a different disease with different causes (often HPV rather than EBV) and different behavior. The anatomic site — nasopharynx vs. nasal cavity — is critical for diagnosis and treatment.

What are the symptoms?

Symptoms depend on the size of the tumor and whether it has spread. Some people have few or no symptoms early on. Common symptoms include:

• A painless lump in the neck, representing cancer spread to a lymph node — often the first sign, and sometimes the only sign.
• Nasal blockage or stuffiness, usually on one side.
• Nosebleeds or blood-tinged mucus.
• Ringing in the ears or hearing loss on one side.
• Ear fullness or recurrent middle ear infections in an adult.
• Headache or facial pain.
• Double vision or other eye changes, if cranial nerves near the skull base are involved.

How is the diagnosis made?

The diagnosis is made after a tissue sample is examined under the microscope by a pathologist. The sample is obtained by biopsy of the nasopharynx during nasopharyngoscopy — an examination in which a flexible camera is passed through the nose to visualize the nasopharynx. If an enlarged neck lymph node is the first sign of disease, a fine needle aspiration (FNA) of the lymph node may be done first, followed by a nasopharyngeal biopsy to confirm the primary site.

Under the microscope, the pathologist identifies the nonkeratinizing pattern: large, abnormal squamous cells growing in sheets and clusters without forming keratin, and frequently surrounded by a dense infiltrate of lymphocytes (immune cells). This mixture of cancer cells and lymphocytes creates the pattern sometimes called lymphoepithelioma — a name reflecting the dense immune response that characterizes this tumor. Immunohistochemistry confirms epithelial cell origin, and EBER in situ hybridization confirms EBV association (see below). Once cancer is confirmed, imaging — CT, MRI, and often PET-CT — determines the tumor’s extent, skull base involvement, and lymph node status.

What does “nonkeratinizing” mean and why does it matter?

In normal tissues, squamous cells mature through a process called keratinization — they produce and fill with keratin, a tough protective protein. When examined under the microscope, keratinizing cells appear pink and may form round structures called keratin pearls. Nonkeratinizing cells skip this process and appear blue-purple, with large nuclei and relatively little cytoplasm.

In the nasopharynx, the nonkeratinizing pattern matters for two reasons. First, it tells the pathologist that the cancer originated from the specialized epithelial cells lining the nasopharynx rather than from surface squamous cells. Second, and most importantly for patients, the nonkeratinizing pattern in the nasopharynx is a strong indicator of EBV association — and EBV-associated nasopharyngeal carcinomas respond dramatically better to radiation and chemotherapy than keratinizing (non-EBV) types. EBER testing confirms this association.

EBER and EBV testing

Confirming EBV association is one of the most important steps in evaluating nonkeratinizing squamous cell carcinoma of the nasopharynx. The standard test is EBER in situ hybridization (ISH). EBER (Epstein–Barr virus-encoded small RNA) is a molecule produced in abundance by EBV-infected cells. The ISH test uses labeled probes that bind to EBER inside tumor cells, making infected cells visible under the microscope.

• EBER positive — EBV RNA is detected inside the cancer cells. Virtually all nonkeratinizing squamous cell carcinomas of the nasopharynx are EBER positive. This confirms EBV association, supports the diagnosis, and triggers EBV-specific follow-up monitoring.
• EBER negative — No EBV RNA detected. An EBER-negative result in a nasopharyngeal tumor is unusual and may prompt re-evaluation of the diagnosis or consideration of an alternative tumor type.

Immunohistochemistry is also performed to confirm the cells are epithelial (positive for pan-cytokeratin and high-molecular-weight keratins such as CK5) and to exclude lymphoma and other tumors that can look similar under the microscope.

Is nonkeratinizing squamous cell carcinoma graded?

Nonkeratinizing squamous cell carcinoma of the nasopharynx is not assigned a histologic grade. Because these tumors share a uniform nonkeratinizing appearance and behave in a consistent, predictable way, grading does not provide useful additional information. Your report may note that grading is not applicable, or may simply describe the tumor as nonkeratinizing without assigning a grade. This is expected and normal.

Tumor extension

Tumor extension describes how far the cancer has spread from its original site in the nasopharynx. As the tumor grows, it may extend into the parapharyngeal space (tissue beside the throat), the skull base, the sphenoid sinus, or the cervical vertebrae. In advanced cases, it can reach the cranial nerves, the orbit (eye socket), or the intracranial compartment (the space containing the brain). Extension into these critical structures raises the tumor stage and influences radiation field design and treatment planning.

Perineural invasion

Perineural invasion means cancer cells are growing along or around a nerve. Because major cranial nerves run near the nasopharynx and skull base, perineural spread can carry cancer toward the brain or cause nerve dysfunction (such as facial numbness or double vision). Perineural invasion is an adverse feature that may influence the radiation field used. Your report will state whether it is present or absent.

Lymphovascular invasion

Lymphovascular invasion means cancer cells have entered lymphatic channels or blood vessels near the tumor. These provide a route for spread to lymph nodes or distant organs. Your report will state whether lymphovascular invasion is present or absent.

Surgical margins

Because surgery is not the standard initial treatment for nonkeratinizing squamous cell carcinoma of the nasopharynx — radiation and chemotherapy are the primary approaches. Margins are typically assessed only when surgery is performed for residual or recurrent disease after radiation. When assessed:

• Negative margin — No cancer cells at the cut edge. Suggests complete surgical removal.
• Positive margin — Cancer cells are at the cut edge. Suggests some tumor may remain; additional treatment is usually recommended.

Lymph nodes

Spread to lymph nodes in the neck is very common in nonkeratinizing squamous cell carcinoma of the nasopharynx — the majority of patients have lymph node involvement at diagnosis, and bilateral neck disease (nodes on both sides) is frequent. The nasopharynx drains first to the retropharyngeal nodes and upper deep cervical nodes at levels II–V. A neck dissection may be performed for residual or recurrent nodal disease after initial treatment.

Your pathology report will include the total number of lymph nodes examined, how many contain cancer, the size of the largest deposit, and whether extranodal extension is present — meaning cancer cells have broken through the lymph node capsule into surrounding tissue. Because of the favorable overall biology of EBV-associated disease, bilateral lymph node involvement does not carry the same poor prognosis in nonkeratinizing nasopharyngeal carcinoma as it does in most other head and neck cancers.

PD-L1

PD-L1 is a protein that some cancer cells produce to avoid immune attack. Checkpoint inhibitor immunotherapy drugs — including pembrolizumab (Keytruda) — block this mechanism. PD-L1 testing is typically performed for patients with recurrent or metastatic nasopharyngeal carcinoma being considered for immunotherapy. Results are reported as a Combined Positive Score (CPS); a higher score is generally associated with a greater likelihood of benefit from immunotherapy.

Pathologic stage (pTNM)

The pathologic stage uses the AJCC TNM staging system for nasopharyngeal carcinoma. The T stage reflects how far the tumor has grown into adjacent structures; lymph node staging reflects the size, location, and bilaterality of involved nodes.

Tumor stage (pT)

• pT1 — Tumor confined to the nasopharynx, or with extension to the oropharynx and/or nasal cavity, without parapharyngeal involvement.
• pT2 — Tumor with extension into the parapharyngeal space or adjacent soft tissue (medial pterygoid, lateral pterygoid, or prevertebral muscles).
• pT3 — Tumor invades the bony skull base, cervical vertebrae, pterygoid structures, or paranasal sinuses.
• pT4 — Tumor with intracranial extension, involvement of cranial nerves, the hypopharynx, orbit, parotid gland, or extensive soft tissue infiltration beyond the lateral pterygoid muscle.

Nodal stage (pN)

• pN0 — No cancer in any lymph nodes examined.
• pN1 — Unilateral lymph nodes 60 mm or smaller, unilateral or bilateral retropharyngeal nodes, or bilateral nodes above the caudal border of the cricoid cartilage.
• pN2 — Bilateral lymph nodes 60 mm or smaller, below the caudal border of the cricoid cartilage.
• pN3 — Any lymph node larger than 60 mm, or involvement of the supraclavicular fossa.

What is the prognosis?

The prognosis for nonkeratinizing squamous cell carcinoma of the nasopharynx is significantly better than for keratinizing nasopharyngeal carcinoma and, stage-for-stage, better than most other head and neck cancers. This favorable biology — driven by EBV association and the rich lymphocytic immune environment of these tumors — makes nonkeratinizing nasopharyngeal carcinoma one of the most treatment-responsive solid tumors in oncology. Five-year survival rates for non-metastatic disease are typically 60–80% or higher with modern chemoradiation protocols, and long-term cure is achievable even in patients with locally advanced disease and bilateral neck lymph node involvement.

An important part of long-term follow-up for EBER-positive patients is monitoring of plasma EBV DNA levels. EBV DNA from tumor cells is detectable in the bloodstream, and rising or persistently detectable levels after treatment can signal residual or recurrent disease, sometimes before it is visible on imaging. This blood test is a standard part of surveillance after treatment completion.

Factors associated with a less favorable outcome within this disease include skull base invasion (pT3–T4), large or bilateral lymph node deposits, extranodal extension, perineural invasion, and distant metastasis. Distant spread — most commonly to the bone, liver, or lungs — represents the most challenging clinical scenario and is managed with systemic chemotherapy and immunotherapy.

What happens after the diagnosis?

After diagnosis, your healthcare team — typically an ENT surgeon, radiation oncologist, medical oncologist, and pathologist — reviews your pathology report, imaging, and overall health to create a treatment plan.

For most patients, the primary treatment is radiation therapy to the nasopharynx and neck, combined with concurrent chemotherapy (typically platinum-based). EBV-associated nonkeratinizing carcinoma is highly radiosensitive, which is why this approach is so effective and surgery is rarely needed initially. For advanced disease, induction chemotherapy before radiation may be recommended. Surgery may be considered for residual or recurrent disease in the nasopharynx or neck after radiation.

For recurrent or metastatic disease, options include platinum-based chemotherapy, immunotherapy (for PD-L1-positive tumors), and participation in clinical trials. Regular follow-up with imaging, nasopharyngoscopy, and plasma EBV DNA monitoring is standard after treatment. Managing the long-term effects of radiation — including dry mouth, difficulty swallowing, hearing changes, and dental problems — is an important part of ongoing care.

Questions to ask your doctor

• Is my tumor confirmed to be nonkeratinizing type, and was EBER testing performed to confirm EBV association?
• What is the pathologic stage — both tumor (pT) and nodal (pN)?
• Did the tumor extend into the skull base, cranial nerves, or other adjacent structures?
• Were lymph nodes involved, and on which side(s) of the neck? Was extranodal extension present?
• Was perineural invasion or lymphovascular invasion found?
• If surgery was performed, were the margins negative?
• Was PD-L1 testing done, and could I benefit from immunotherapy?
• Will my plasma EBV DNA levels be monitored, and how will this guide my follow-up?
• What treatment is recommended — radiation, chemoradiation, induction chemotherapy?
• How will side effects such as dry mouth, hearing changes, and difficulty swallowing be managed?
• Are there clinical trials available for my stage of nasopharyngeal carcinoma?
• How often will I need follow-up imaging, nasopharyngoscopy, and EBV blood tests?