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

by Jason Wasserman MD PhD FRCPC
April 10, 2026

Non-keratinizing squamous cell carcinoma (NKSCC) is a type of cancer that arises in the oropharynx — the part of the throat located behind the mouth — whose cells have a distinctive microscopic appearance. The term “non-keratinizing” describes what the pathologist sees under the microscope: the cancer cells produce little or no keratin, a tough protective protein that gives some squamous cells a pink color when stained. Instead, non-keratinizing cells appear blue-purple and tend to grow in solid sheets or nests.

In the oropharynx, this non-keratinizing pattern is almost always a sign that the cancer is driven by human papillomavirus (HPV). The vast majority of non-keratinizing oropharyngeal carcinomas test positive for p16 and high-risk HPV, confirming their HPV-associated nature. For this reason, NKSCC of the oropharynx and HPV-associated squamous cell carcinoma of the oropharynx are closely related diagnoses — the non-keratinizing pattern is the characteristic microscopic appearance of HPV-associated disease.

This article explains the findings in your pathology report. For detailed information about the causes, prognosis, and treatment of HPV-associated oropharyngeal cancer, see our companion article on HPV-associated squamous cell carcinoma of the oropharynx.

What causes non-keratinizing squamous cell carcinoma of the oropharynx?

Most non-keratinizing squamous cell carcinomas of the oropharynx are caused by persistent infection with high-risk HPV, most commonly HPV type 16. The virus infects squamous cells in the tonsillar crypts (small pits in the tonsil tissue) and base of tongue, causing genetic changes that drive uncontrolled cell growth over many years. Unlike head and neck cancers caused by tobacco and alcohol, HPV-associated oropharyngeal carcinoma typically arises without visible precancerous changes and can affect younger patients without a history of heavy tobacco or alcohol use.

A small minority of non-keratinizing oropharyngeal carcinomas are HPV-independent. In these cases, tobacco and alcohol are more likely contributing factors, and the prognosis is less favorable than for HPV-associated cases. HPV testing is required to distinguish these groups.

What are the symptoms?

Symptoms vary depending on the size and location of the tumor. Many patients first notice a painless lump in the neck, which represents cancer that has spread to a lymph node. In some cases, the primary tumor in the oropharynx is very small and the neck lump is the only sign. Other symptoms may include:

• A sore throat that does not go away.
• Pain or difficulty swallowing.
• Ear pain on one side.
• A sensation of fullness or a lump in the throat.
• Voice changes.
• Unexplained weight loss.

How is the diagnosis made?

The diagnosis is made after a tissue sample is examined under the microscope by a pathologist. Because many patients present with an enlarged lymph node in the neck before the throat tumor is detected, the first sample is often obtained by fine needle aspiration (FNA) or core biopsy of the lymph node. A biopsy of the oropharynx — the tonsil or base of tongue — is then performed to confirm the primary site.

Under the microscope, the pathologist identifies squamous cells arranged in solid sheets or nests, without the pink, keratin-rich appearance typical of other squamous cell carcinomas. This blue-purple, non-keratinizing pattern is strongly associated with HPV. Testing for p16 protein by immunohistochemistry is routinely performed to confirm HPV association (see below). Once the diagnosis is confirmed, imaging — typically contrast-enhanced CT or MRI of the head and neck, often supplemented by PET-CT — is used to determine the extent of the tumor and identify involved lymph nodes.

What does “non-keratinizing” mean?

Squamous cells normally produce a protein called keratin as they mature. Keratin makes cells tough and water-resistant. Cells that produce large amounts of keratin appear bright pink when stained and examined under the microscope; pathologists call them keratinizing. Cells that produce little or no keratin appear blue-purple and are called non-keratinizing.

In the oropharynx, the non-keratinizing pattern is important because it suggests the likely cause of the cancer. Non-keratinizing oropharyngeal squamous cell carcinomas are almost always HPV-associated, because HPV-infected cells lose their normal keratinization program. Keratinizing oropharyngeal carcinomas, by contrast, are more likely to be HPV-independent and driven by tobacco and alcohol. Your pathology report will describe the tumor as non-keratinizing (or may use terms like “basaloid” or “lymphoepithelioma-like” for specific variants), and this finding will prompt p16 and HPV testing to confirm the underlying cause.

p16 and HPV testing

Confirming whether the tumor is HPV-associated is one of the most important steps in evaluating non-keratinizing squamous cell carcinoma of the oropharynx, because HPV status determines which staging system is used and has a major effect on prognosis.

• p16 immunohistochemistry — p16 is a protein that becomes markedly overproduced in cells infected by high-risk HPV. The test uses a special antibody stain applied to the tumor tissue. A positive result — defined as strong, diffuse staining in at least 70% of tumor cells — is a reliable surrogate marker for HPV association. Most non-keratinizing oropharyngeal carcinomas are strongly p16-positive. Your report will state whether p16 staining is positive or negative.
• HPV in situ hybridization (ISH) or PCR — These tests directly detect HPV DNA or RNA in the tumor cells and may be used to confirm the p16 result, particularly in ambiguous cases or when the tumor is not from the oropharynx.

A p16-positive result in a non-keratinizing oropharyngeal carcinoma confirms HPV association and triggers the use of the dedicated HPV-positive staging system (described below), which reflects the substantially better prognosis of this cancer compared to HPV-negative disease.

Is non-keratinizing squamous cell carcinoma graded?

Non-keratinizing squamous cell carcinoma of the oropharynx is not assigned a histologic grade. Because these tumors share a uniform non-keratinizing microscopic appearance and behave in a more consistent way than non-HPV-related squamous cell carcinomas, grading does not provide useful additional information. Your report may note that grading is not applicable or may simply describe the tumor as non-keratinizing without a grade. This is expected and does not represent a problem with the report.

Tumor extension

Tumor extension describes how far the cancer has grown from its original site in the oropharynx. Non-keratinizing squamous cell carcinoma typically starts in the tonsillar crypts or base of tongue. As the tumor grows, it may extend into the lateral or posterior pharyngeal wall, the parapharyngeal space, or surrounding soft tissue. Large tumors may invade the oral cavity, the larynx, the deep muscles of the tongue, or the mandible (jaw bone). Extension into these adjacent structures raises the pathologic tumor stage (pT4) and influences both treatment and prognosis.

Perineural invasion

Perineural invasion means cancer cells are growing along or around a nerve. When tumor cells travel along nerve pathways, there is a higher risk that the cancer may recur locally or extend beyond the primary tumor site. Your report will state whether perineural invasion is present or absent. Its presence may influence the recommendation for radiation therapy after surgery.

Lymphovascular invasion

Lymphovascular invasion means cancer cells have entered lymphatic channels or blood vessels near the tumor, providing a potential route for spread to lymph nodes or distant organs. Your report will state whether lymphovascular invasion is present or absent. When found, it is considered an adverse feature that may affect treatment recommendations.

Surgical margins

A margin is the edge of tissue removed during surgery. The pathologist examines the cut surfaces to determine how close the tumor comes to each edge.

• Negative margin — No cancer cells at the cut edge. This suggests the tumor was completely removed.
• Close margin — Cancer cells are within a few millimeters of the edge. May prompt additional radiation therapy.
• Positive margin — Cancer cells are present at the cut edge, suggesting some tumor may remain. Further treatment — re-excision or radiation — is usually recommended.

Lymph nodes

Lymph nodes are small immune organs in the neck that can trap cancer cells. Non-keratinizing squamous cell carcinoma spreads to neck lymph nodes early and frequently — lymph node involvement is present in the majority of patients at diagnosis and is often the first sign of the disease. A neck dissection is typically performed to remove and examine these nodes.

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 outer capsule of a lymph node into surrounding tissue. Importantly, lymph node involvement in p16-positive, HPV-associated non-keratinizing carcinoma does not carry the same poor prognostic significance as it does in HPV-negative head and neck cancers. Even patients with several involved lymph nodes can achieve excellent long-term outcomes with treatment.

PD-L1

PD-L1 is a protein that some cancer cells produce to shield themselves from immune attack. Immunotherapy drugs called checkpoint inhibitors — particularly pembrolizumab (Keytruda) and nivolumab (Opdivo) — block this mechanism, allowing the immune system to recognize and attack the cancer. PD-L1 testing is typically performed when the cancer is unresectable, has returned after treatment, or has spread to distant sites. Results are reported as a Combined Positive Score (CPS), with a CPS of 1 or higher indicating potential benefit from immunotherapy.

Pathologic stage (pTNM)

Because non-keratinizing squamous cell carcinoma of the oropharynx is almost always HPV-associated (p16-positive), it is staged using the dedicated HPV-positive oropharyngeal staging system, which is based primarily on the number of involved lymph nodes rather than their size. This is a more favorable system than the traditional size-based nodal staging used for HPV-negative oropharyngeal and oral cavity cancers, reflecting the better overall outcomes of HPV-associated disease.

If p16 testing is negative, the traditional non-HPV nodal staging system (size- and extranodal extension-based) applies instead. Your report will specify the p16 result, which determines which staging system your doctors will use.

Tumor stage (pT)

• pT1 — Tumor 20 mm or smaller.
• pT2 — Tumor larger than 20 mm but 40 mm or smaller.
• pT3 — Tumor larger than 40 mm, or extension to the lingual surface of the epiglottis.
• pT4 — Tumor invades adjacent structures such as the larynx, deep muscles of the tongue, medial pterygoid muscle, hard palate, or mandible.

Nodal stage (pN) — HPV-positive staging

• pN0 — No cancer in any lymph nodes examined.
• pN1 — Cancer in 1 to 4 lymph nodes, with no extranodal extension.
• pN2 — Cancer in 5 or more lymph nodes, or in any lymph node on the opposite side of the neck, with no extranodal extension.
• pN3 — Extranodal extension present in any involved lymph node.

What is the prognosis?

The prognosis for p16-positive (HPV-associated) non-keratinizing squamous cell carcinoma of the oropharynx is significantly better than for HPV-negative head and neck cancers of comparable stage. Five-year survival rates for HPV-associated oropharyngeal cancer are commonly reported above 80% for non-metastatic disease, and many patients achieve long-term cure even when multiple lymph nodes are involved. This favorable outlook is why a dedicated, less aggressive staging system exists for HPV-positive oropharyngeal cancer.

In the small minority of non-keratinizing oropharyngeal carcinomas that are p16-negative (HPV-independent), the prognosis is considerably worse, and these cases are staged and managed more similarly to keratinizing (HPV-negative) oropharyngeal cancer.

Factors that can affect outcomes within HPV-associated disease include extranodal extension, positive or close surgical margins, perineural invasion, tumor extension into adjacent structures (pT4), and tobacco use, which worsens prognosis even in HPV-positive patients. For more details on prognosis and treatment, see our article on HPV-associated squamous cell carcinoma of the oropharynx.

What happens after the diagnosis?

After diagnosis, your healthcare team — typically a head and neck surgeon, radiation oncologist, medical oncologist, and pathologist — reviews your pathology report and imaging to develop a treatment plan. Treatment is guided by the p16/HPV status, tumor stage, and overall health.

For p16-positive (HPV-associated) disease, treatment options include surgery (often transoral robotic surgery for smaller tumors), radiation therapy as the primary treatment, or combined chemoradiation for more advanced cases. Because outcomes are favorable, clinical trials exploring de-escalation of treatment intensity — reducing radiation dose or chemotherapy — are ongoing, and some patients may be eligible. For p16-negative cases, treatment is generally more intensive, following the approach for HPV-independent oropharyngeal cancer.

Regular follow-up visits, imaging, and rehabilitation for swallowing, speech, and dental health are important parts of long-term recovery after treatment.

Questions to ask your doctor

• Was my tumor p16-positive or p16-negative, and what does that mean for my prognosis?
• Was additional HPV testing (ISH or PCR) performed to confirm HPV association?
• Where in my oropharynx did the cancer start — the tonsil, base of tongue, or elsewhere?
• What is the tumor size (pT stage), and has it grown into adjacent structures?
• How many lymph nodes contained cancer, and was extranodal extension present?
• What is my pathologic stage (pT and pN)?
• Were surgical margins negative, or is further treatment needed for a close or positive margin?
• Was perineural invasion or lymphovascular invasion found?
• Was PD-L1 testing performed, and what was the CPS score?
• Am I eligible for a de-escalation treatment trial?
• What treatment do you recommend, and how will side effects on swallowing, speech, and saliva production be managed?
• How often will I need follow-up visits and imaging?