HPV-associated Squamous Cell Carcinoma of the Oropharynx: Understanding Your Pathology Report

by Jason Wasserman MD PhD FRCPC
April 9, 2026

HPV-associated squamous cell carcinoma is a type of cancer that develops in the oropharynx — the part of the throat located behind the mouth. The oropharynx includes the tonsils, the base of tongue (the back one-third of the tongue), the soft palate, and the back wall of the throat. It is important not to confuse the oropharynx with the oral cavity (the mouth itself), which includes the lips, front two-thirds of the tongue, gums, and hard palate. Cancers of these two areas behave quite differently and are managed separately. For information about mouth cancers, see our article on squamous cell carcinoma of the oral cavity.

This cancer starts from squamous cells — the flat cells that line the surface of the oropharynx. The term “HPV-associated” means the cancer is caused by persistent infection with a high-risk strain of human papillomavirus (HPV), most often HPV type 16. HPV-associated squamous cell carcinoma behaves quite differently from tobacco- and alcohol-related head and neck cancers: it tends to affect younger patients, often without heavy tobacco or alcohol use, and it has a markedly better prognosis.

This article will help you understand the findings in your pathology report — what each term means and why it matters for your care.

What causes HPV-associated squamous cell carcinoma?

This cancer is caused by persistent infection with high-risk HPV, most commonly HPV type 16. HPV is a very common virus transmitted through intimate contact, including oral contact. In most people, the immune system clears the infection within one to two years. However, in some individuals the virus persists, integrating into the DNA of squamous cells in the oropharynx and triggering genetic changes that cause uncontrolled cell growth.

Because HPV causes genetic rather than chemical damage to cells, HPV-associated oropharyngeal cancers typically arise without preceding precancerous changes visible on examination, which is one reason they are often diagnosed at a later stage. The incidence of HPV-associated oropharyngeal cancer has risen substantially over recent decades and now accounts for the majority of oropharyngeal squamous cell carcinomas in many countries. The HPV vaccine, when given before first exposure, is highly effective at preventing HPV infection and thereby reducing the risk of these cancers.

What are the symptoms?

Many people 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 or difficult to see, and the enlarged lymph node is the only visible sign of cancer. Other symptoms may include:

• A sore throat that does not go away
• Pain or difficulty swallowing
• Ear pain that is not due to an ear infection
• A feeling of fullness or a lump in the throat
• Voice changes
• Unexplained weight loss or fatigue

How is the diagnosis made?

The diagnosis is made after a tissue sample is examined under the microscope by a pathologist. Because the primary tumor in the oropharynx is often small or located deep in the tonsillar tissue, the diagnosis is frequently first confirmed from a biopsy of an enlarged lymph node in the neck — either by fine needle aspiration (FNA) or by surgical removal of the node. Additional tissue from the tonsil or base of tongue may then be obtained to confirm the primary site.

Under the microscope, the pathologist looks for invasive squamous cell carcinoma — abnormal squamous cells that have broken through the epithelium (surface lining) and invaded the tissue beneath. HPV-associated oropharyngeal carcinoma typically has a distinctive non-keratinizing appearance — the cells are more uniform, form little or no keratin, and often grow in solid sheets or nests — which is quite different from the appearance of tobacco-related oral cavity cancers. Testing for high-risk HPV (described below) is required to confirm that the cancer is HPV-associated. Once cancer is confirmed, imaging studies — usually a contrast-enhanced CT or MRI of the head and neck — help define the tumor’s extent and identify involved lymph nodes. PET-CT may be used for more advanced disease.

How is HPV testing performed?

Confirming HPV association is an essential part of diagnosing and staging this cancer, because HPV status directly affects the staging system used and has major implications for prognosis. There are three main methods:

• p16 immunohistochemistry (IHC) — This is the most widely used test. 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. Strong, diffuse staining of at least 70% of the tumor cells (both the cytoplasm and nucleus) is considered a reliable surrogate for HPV association in oropharyngeal squamous cell carcinoma. A positive p16 result is reported as “p16 positive” or “strong and diffuse p16 expression.”
• In situ hybridization (ISH) — This test detects HPV DNA or RNA directly within the tumor cells using labeled probes. It is more specific than p16 alone and is sometimes used to confirm HPV association when p16 results are borderline or when the tumor is not in the oropharynx.
• Polymerase chain reaction (PCR) — A molecular test that amplifies and detects HPV DNA or RNA from tumor tissue. Like ISH, it can identify the specific HPV type (most commonly HPV-16).

A diagnosis of HPV-associated squamous cell carcinoma requires both invasive squamous cell carcinoma on microscopic examination and a positive HPV test. p16 IHC alone is generally sufficient for oropharyngeal tumors, but ISH or PCR may be added for confirmation in uncertain cases.

Is HPV-associated squamous cell carcinoma graded?

Unlike most other cancers, HPV-associated squamous cell carcinoma of the oropharynx is not assigned a histologic grade in standard pathology reporting. This is because nearly all HPV-associated oropharyngeal carcinomas share similar microscopic features — they are typically non-keratinizing, with relatively uniform cells — and behave more uniformly than non-HPV-related squamous cell carcinomas, where grade provides useful prognostic information. Your report may describe the tumor as “non-keratinizing” or note that grading is not applicable. This is expected and does not indicate a problem with the report.

Tumor extension

Tumor extension describes how far the cancer has grown from its original site within the oropharynx. HPV-associated squamous cell carcinoma usually starts in the surface lining of the tonsils or the base of tongue, where HPV infects cells lining the small crypts (pits) in the tissue. As the tumor grows, it can extend into the lateral or posterior pharyngeal wall, the parapharyngeal space, or soft tissue of the neck. Large tumors may grow beyond the oropharynx into the oral cavity, nasopharynx, or larynx, or invade the deep muscles of the tongue, the mandible (lower jaw), or surrounding structures. Tumor extension into these adjacent areas raises the stage to pT4 and influences both treatment planning 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 an increased risk that the cancer may return or spread beyond the main 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. These provide a route for cancer to 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 and may affect treatment planning.

Surgical margins

Margins are the edges of tissue removed during surgery. The pathologist examines the cut surfaces to determine how close the tumor comes to the edge of the specimen.

• Negative margin — No cancer cells at the edge. This suggests the tumor was completely removed.
• Close margin — Cancer cells are within a few millimeters of the edge but do not reach it. May influence whether additional radiation is recommended.
• Positive margin — Cancer cells are present at the cut edge. This suggests some tumor may remain and typically prompts additional surgery or radiation therapy.

Lymph nodes

Lymph nodes are small immune organs that filter lymphatic fluid and can trap cancer cells. The oropharynx drains into lymph nodes on both sides of the neck, particularly at levels II through IV. Because HPV-associated squamous cell carcinoma spreads to lymph nodes early and frequently, a neck dissection is typically performed as part of treatment, and the removed nodes are examined by the pathologist.

Your report will include the total number of lymph nodes examined, the number that 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 the lymph node into the surrounding tissue.

Lymph node involvement is very common in HPV-associated squamous cell carcinoma — it is present in the majority of patients at diagnosis — but because of the tumor’s overall favorable biology, finding cancer in multiple lymph nodes does not carry the same poor prognosis it would in tobacco-related cancers. The number of affected lymph nodes is used to determine the nodal stage (pN category) using a specific staging system for HPV+ disease.

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) — work by blocking 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. The result is reported as a Combined Positive Score (CPS), which measures the proportion of tumor cells and surrounding immune cells that express PD-L1. A CPS of 1 or higher indicates that immunotherapy may provide benefit, and higher scores are generally associated with a greater likelihood of response. Your oncologist will use the CPS result together with other clinical factors to decide whether immunotherapy is appropriate.

Pathologic stage (pTNM)

HPV-associated squamous cell carcinoma of the oropharynx is staged using a dedicated staging system for HPV-positive oropharyngeal cancer that is separate from the system used for non-HPV-related oropharyngeal or oral cavity cancers. This is because HPV-positive disease behaves much more favorably, and the same tumor and nodal features carry a better prognosis. The staging uses the AJCC TNM system.

Tumor stage (pT)

• pT1 — Tumor 20 mm or smaller in greatest dimension.
• 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 (jaw bone).

Nodal stage (pN)

The nodal staging system for HPV-positive oropharyngeal cancer differs from oral cavity SCC. It is based primarily on the number of involved lymph nodes and whether extranodal extension is present, not on the size of the nodes:

• pN0 — No cancer in any lymph nodes examined.
• pN1 — Cancer found in 1 to 4 lymph nodes on the same side as the tumor, with no extranodal extension.
• pN2 — Cancer found 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, regardless of the number of nodes.

What is the prognosis for HPV-associated squamous cell carcinoma?

The prognosis for HPV-associated squamous cell carcinoma of the oropharynx is significantly better than for non-HPV-related head and neck cancers of comparable stage. This favorable biology is one of the most important features of this diagnosis and is the reason a dedicated, less aggressive staging system exists for HPV-positive disease.

Five-year survival rates for HPV-positive oropharyngeal SCC are substantially higher than for HPV-negative disease at equivalent stages — often cited above 80% for non-metastatic disease in clinical trial populations. Many patients achieve long-term disease-free survival with treatment, even when multiple lymph nodes are involved. Because of this favorable prognosis, there is active clinical research into whether treatment intensity (particularly the dose of radiation and the extent of surgery) can be safely reduced for some patients without compromising outcomes — an approach called de-escalation therapy.

Factors associated with a less favorable outlook within HPV-positive disease include extranodal extension in lymph nodes, positive or close surgical margins, perineural invasion, and tumor extension beyond the oropharynx (pT4 disease). Tobacco use also worsens prognosis even in HPV-positive patients — smoking appears to reduce the immune response that makes HPV-associated cancers more treatment-sensitive. Patients who have never smoked or who smoked little tend to do best.

What happens after the diagnosis?

After diagnosis, your healthcare team reviews your pathology report, imaging studies, and overall health to create a treatment plan. The team usually includes a head and neck surgeon, a radiation oncologist, a medical oncologist, and a pathologist.

For many patients, the main treatments are surgery, radiation therapy, or a combination of both. Early-stage tumors may be treated with transoral robotic surgery (TORS) or transoral laser microsurgery, which removes the tumor through the mouth without an external incision, or with radiation therapy as the primary treatment. For more advanced tumors or when lymph nodes are involved, combined chemoradiation (chemotherapy given alongside radiation to make the cancer cells more sensitive) may be recommended. In recurrent or metastatic disease, systemic therapies such as chemotherapy, targeted therapy (cetuximab), or immunotherapy (based on PD-L1 results) may be used.

After treatment, regular follow-up visits, imaging studies, and support for swallowing, speech, and dental health are important parts of long-term recovery. Avoiding tobacco and alcohol supports the best possible outcome.

Questions to ask your doctor

• Where in my oropharynx did the cancer start — the tonsil, base of tongue, or elsewhere?
• Was the diagnosis confirmed by HPV testing (p16 staining or another test), and what were the results?
• What is the tumor size (pT stage), and has it grown into any 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 additional treatment needed to address 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 a candidate for de-escalation therapy — a reduced-intensity treatment approach?
• What treatments do you recommend, and what are the likely side effects on swallowing, speech, and saliva production?
• How will my swallowing, nutrition, and dental health be monitored during and after treatment?
• How often will I need follow-up examinations and imaging?