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

by Jason Wasserman MD PhD FRCPC
April 10, 2026

Keratinizing squamous cell carcinoma is the least common of the three main types of nasopharyngeal carcinoma, cancer arising in the nasopharynx. The nasopharynx is the area at the back of the nasal cavity above the soft palate. The term “keratinizing” describes the appearance of the cancer cells under the microscope: they produce keratin, a tough structural protein that gives squamous cells their characteristic pink color when stained. These cells may form rounded structures called keratin pearls, which are visible as pink whorls within the tumor.

Keratinizing squamous cell carcinoma of the nasopharynx is important to distinguish from the other two nasopharyngeal carcinoma types because it differs in its causes, behavior, and prognosis. Unlike the more common nonkeratinizing type — which is almost always caused by Epstein–Barr virus (EBV) and responds very well to treatment — the keratinizing type is usually not EBV-associated and carries a less favorable prognosis, behaving more similarly to tobacco- and alcohol-related squamous cell carcinomas of the oral cavity and oropharynx.

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

What causes keratinizing squamous cell carcinoma of the nasopharynx?

Unlike nonkeratinizing nasopharyngeal carcinoma — which is caused by EBV — keratinizing squamous cell carcinoma of the nasopharynx is typically driven by the same environmental and lifestyle factors that cause other head and neck squamous cell carcinomas. Tobacco use and heavy alcohol consumption are the most important risk factors. Long-term or heavy use of either substantially increases the risk, and the combination of both is particularly harmful. Other contributing factors include occupational exposure to certain chemicals or dusts, previous radiation to the head and neck region, and chronic immune suppression.

EBV does not play a significant role in the keratinizing type. EBER testing (the test for EBV activity in tumor cells) is typically negative or only weakly positive, which helps the pathologist distinguish this type from the nonkeratinizing and basaloid forms. This distinction is important because it affects both prognosis and the monitoring approach after treatment.

Keratinizing squamous cell carcinoma of the nasopharynx should not be confused with keratinizing squamous cell carcinoma of the nasal cavity and sinuses, which arises in a different anatomic site and has different staging and treatment considerations.

What are the symptoms?

Symptoms of keratinizing squamous cell carcinoma of the nasopharynx overlap considerably with those of other nasopharyngeal carcinoma types. They depend on the tumor’s size and whether it has spread to lymph nodes or adjacent structures. Common symptoms include:

• A lump in the neck from an enlarged lymph node.
• Nasal blockage or stuffiness, typically on one side.
• Nosebleeds or blood-tinged mucus.
• Ear fullness, ringing, or hearing loss on one side.
• Headache or facial pain.
• Double vision or other changes in eye movement, if cranial nerves are involved.
• Difficulty swallowing in advanced cases.

Because keratinizing nasopharyngeal carcinoma does not typically cause a dense lymphocytic infiltrate around the tumor (unlike the EBV-associated types), it may present as a firmer, more clearly defined mass in the nasopharynx rather than the soft, lymphocyte-rich lesion typical of nonkeratinizing disease.

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 lymph node is the presenting sign, a fine needle aspiration (FNA) of the node may be performed first, followed by a nasopharyngeal biopsy to confirm the primary site.

Under the microscope, the pathologist identifies the keratinizing pattern: abnormal squamous cells with abundant pink cytoplasm, visible cell-to-cell connections (intercellular bridges), and keratin production, which may appear as pink whorled structures called keratin pearls. This appearance is distinctly different from the blue-purple, non-keratin-producing cells of the nonkeratinizing type. Immunohistochemistry confirms the cells are epithelial in origin, and EBER in situ hybridization testing confirms the absence of EBV association. Once the diagnosis is established, imaging — CT, MRI, and often PET-CT — is used to determine the extent of the tumor and identify lymph node involvement.

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

Squamous cells normally mature through a process called keratinization, during which they accumulate keratin — a tough, fibrous protein — and take on a pink color when examined under the microscope. Cancers whose cells retain this process are called keratinizing; they appear pink and may form the characteristic round, layered structures called keratin pearls.

In the nasopharynx, the keratinizing pattern carries two important clinical implications. First, it signals that the cancer is almost certainly not EBV-associated — EBV-related nasopharyngeal carcinomas lose the keratinization program and appear nonkeratinizing instead. Second, keratinizing nasopharyngeal carcinoma behaves more like squamous cell carcinomas of other head and neck sites (such as the oral cavity), driven by tobacco and alcohol, which means it tends to have a less favorable response to treatment and a worse prognosis than EBV-associated disease. EBER testing confirms the absence of EBV in the tumor cells.

EBER and EBV testing

Testing for EBER (Epstein–Barr virus-encoded small RNA) by in situ hybridization is routinely performed on nasopharyngeal biopsies to determine EBV status. In keratinizing squamous cell carcinoma:

• EBER negative (typical) — No EBV RNA is detected in the tumor cells. This is the expected result for the keratinizing type and confirms that the cancer is EBV-independent. An EBER-negative result means that plasma EBV DNA monitoring is not useful for follow-up surveillance after treatment.
• EBER positive (rare) — If EBV RNA is detected in a keratinizing-appearing tumor, it may indicate an unusual EBV-associated tumor presenting with keratinizing features, or may prompt re-evaluation of the diagnosis. Your pathologist and oncologist will interpret this result in context.

Immunohistochemistry is also performed to confirm that the cells are epithelial (positive for pan-cytokeratin) and to exclude other tumors such as lymphoma. In some cases, p16 immunohistochemistry may be performed to check for HPV association, though HPV is an uncommon cause of nasopharyngeal cancer.

Histologic grade

Unlike nonkeratinizing squamous cell carcinoma of the nasopharynx — which is not graded — keratinizing squamous cell carcinoma is assigned a histologic grade. Grade describes how closely the tumor cells resemble normal squamous cells and how much keratin they produce, providing information about how aggressively the cancer may behave.

• Well differentiated — The cells closely resemble normal squamous cells and produce abundant keratin, including well-formed keratin pearls. These tumors tend to grow relatively slowly.
• Moderately differentiated — The cells show greater variation in size and shape and produce less keratin. Most keratinizing nasopharyngeal carcinomas fall into this category.
• Poorly differentiated — The cells look markedly abnormal and produce little keratin. These tumors tend to be more aggressive and may be harder to distinguish from the nonkeratinizing type.

A higher grade is generally associated with more aggressive behavior. Your pathology report will state the grade because it contributes to treatment planning alongside tumor stage and other pathologic features.

Tumor extension

Tumor extension describes how far the cancer has spread beyond the nasopharynx. As it grows, it may extend into the parapharyngeal space, the skull base, the sphenoid sinus, the cervical vertebrae, or the surrounding soft tissues of the neck. In advanced cases, it may involve cranial nerves, the orbit, or the intracranial compartment. Extension into adjacent structures raises the pathologic tumor stage (pT3 or pT4) and significantly influences radiation field planning and the extent of any surgical intervention.

Perineural invasion

Perineural invasion means cancer cells are growing along or around a nerve. The nasopharynx sits near major cranial nerves and the skull base, so perineural spread can carry tumor cells toward critical structures. Its presence is an adverse feature that may influence the radiation field used and is associated with a higher risk of local recurrence. Your report will state whether perineural invasion is present or absent.

Lymphovascular invasion

Lymphovascular invasion means cancer cells have entered lymphatic channels or blood vessels near the tumor. These vessels provide a route for cancer to spread to lymph nodes or distant organs such as the lungs, bones, or liver. Your report will state whether lymphovascular invasion is present or absent. When present, it is considered an adverse prognostic feature.

Surgical margins

Because surgery is rarely the initial treatment for nasopharyngeal carcinoma, 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 the tumor was completely surgically removed.
• Positive margin — Cancer cells at the cut edge. Suggests some tumor may remain; additional treatment is usually recommended.

Lymph nodes

Spread to lymph nodes in the neck is common in keratinizing squamous cell carcinoma of the nasopharynx. The nasopharynx drains primarily to the retropharyngeal lymph nodes and to the upper deep cervical nodes (levels II–V). A neck dissection may be performed for persistent or recurrent nodal disease after radiation.

Your pathology report will include the total number of lymph nodes examined, how many contain cancer, the size of the largest tumor deposit, and whether extranodal extension is present — meaning cancer cells have broken through the lymph node capsule into surrounding tissue. Extranodal extension is a high-risk feature associated with increased recurrence risk and is a standard indication for more aggressive adjuvant treatment. Unlike in EBV-associated nonkeratinizing disease, lymph node involvement in keratinizing nasopharyngeal carcinoma carries a more significant adverse prognostic weight, similar to other head and neck squamous cell carcinomas.

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, allowing the immune system to recognize and attack the cancer. PD-L1 testing may be performed for patients with recurrent or metastatic disease being considered for immunotherapy. Results are reported as a Combined Positive Score (CPS); a higher CPS is generally associated with a greater likelihood of benefit from immunotherapy.

Pathologic stage (pTNM)

Keratinizing squamous cell carcinoma of the nasopharynx is staged using the same AJCC TNM staging system for nasopharyngeal carcinoma used for all three types. The T stage reflects how far the tumor has grown into adjacent structures. Because this cancer is not EBV-associated, plasma EBV DNA levels do not reliably reflect disease burden and are not used for staging or follow-up monitoring.

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 keratinizing squamous cell carcinoma of the nasopharynx is considerably worse than for the nonkeratinizing (EBV-associated) type. This difference reflects the fundamental biology of the two diseases: EBV-associated tumors generate a rich immune response and are highly sensitive to radiation and chemotherapy, while keratinizing tumors behave more like conventional tobacco-related head and neck cancers, which are less radiosensitive and have higher recurrence rates.

Five-year survival rates for keratinizing nasopharyngeal carcinoma are substantially lower than for EBV-associated types and are closer to outcomes seen in squamous cell carcinoma of the oral cavity or oropharynx (HPV-independent) at comparable stages. The exact figures depend on stage at presentation and treatment intensity.

Factors associated with worse outcomes include higher tumor stage (pT3–T4), lymph node involvement — particularly with extranodal extension — positive or close surgical margins, perineural invasion, lymphovascular invasion, poorly differentiated grade, and continued tobacco use after treatment. Distant metastasis, most commonly to the lungs, bones, or liver, represents the most challenging clinical scenario.

Because this cancer is not EBV-associated, plasma EBV DNA monitoring is not used for follow-up surveillance after treatment, which removes one of the sensitive early-warning tools available for nonkeratinizing disease. Surveillance relies on regular endoscopic examination, cross-sectional imaging, and clinical assessment.

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.

The primary treatment for keratinizing squamous cell carcinoma of the nasopharynx, as for all nasopharyngeal carcinoma types, is radiation therapy to the nasopharynx and neck, usually combined with concurrent chemotherapy (platinum-based). Although this cancer is less radiosensitive than EBV-associated types, chemoradiation remains the standard of care for most patients. For locally advanced disease, induction chemotherapy may be given before the main radiation course. Surgery may be considered for residual or recurrent disease in the nasopharynx or neck after radiation.

For recurrent or metastatic disease, treatment options include platinum-based chemotherapy, immunotherapy with checkpoint inhibitors (for PD-L1-positive tumors), and clinical trial participation. Smoking cessation is strongly encouraged before, during, and after treatment — continued tobacco use worsens outcomes and increases the risk of second primary cancers in the head and neck or lungs.

After treatment, follow-up includes regular nasopharyngoscopy, neck examination, and periodic imaging. Because EBV DNA monitoring is not applicable to this tumor type, the surveillance schedule relies on clinical and radiologic assessment.

Questions to ask your doctor

• Is my tumor confirmed to be the keratinizing type of nasopharyngeal carcinoma?
• Was EBER testing performed, and is my tumor EBV-negative?
• What histologic grade was assigned — well, moderately, or poorly differentiated?
• What is my 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 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?
• Since my tumor is EBV-negative, how will the disease be monitored after treatment without EBV DNA testing?
• What treatment is recommended — chemoradiation, induction chemotherapy, or another approach?
• How will side effects such as dry mouth, hearing changes, and swallowing difficulties be managed?
• Are there clinical trials available for this type of nasopharyngeal carcinoma?
• How often will I need follow-up imaging and examinations?