Your pathology report for HPV-associated squamous cell carcinoma of the oropharynx

by Jason Wasserman MD PhD FRCPC
November 10, 2025

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, base of tongue (the back one-third of the tongue), soft palate, and the back wall of the throat.

This cancer starts from squamous cells, which are the flat cells that line the surface of the oropharynx. The term “HPV-associated” means the cancer is caused by high-risk human papillomavirus (HPV) infection, most often HPV type 16. HPV causes genetic changes in the squamous cells that allow them to grow in an uncontrolled way.

HPV-associated squamous cell carcinoma behaves differently from non-HPV-related cancers of the head and neck. It tends to affect younger patients, often without a history of heavy tobacco or alcohol use, and it usually has a better prognosis.

What are the symptoms of HPV-associated squamous cell carcinoma?

The symptoms of HPV-associated squamous cell carcinoma vary depending on the size and location of the tumor. Many people first notice a painless lump in the neck, which represents cancer that has spread to a lymph node.

Other symptoms may include:

• A sore throat that does not go away.

• Pain or difficulty swallowing (dysphagia).

• 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.

In some cases, the primary tumour in the oropharynx is very small or difficult to see, and the enlarged lymph node in the neck may be the only visible sign of cancer.

What causes HPV-associated squamous cell carcinoma?

This type of cancer is caused by persistent infection with high-risk types of human papillomavirus (HPV). HPV is a common virus transmitted through intimate contact, including oral contact. In most people, the infection clears on its own. However, in some individuals, the virus remains active for years, leading to genetic changes in squamous cells that eventually cause cancer.

Unlike traditional head and neck cancers linked to tobacco and alcohol, HPV-associated squamous cell carcinoma is primarily caused by the virus itself. Because HPV causes genetic rather than chemical damage, these cancers usually arise without preceding precancerous changes such as keratinizing squamous dysplasia.

How is this diagnosis made?

The diagnosis of HPV-associated squamous cell carcinoma is made after a biopsy is examined by a pathologist. In many cases, the first sign of this cancer is an enlarged lymph node in the neck, and the diagnosis is confirmed after that lymph node is biopsied.

Clinical examination

Your doctor will perform a detailed examination of the mouth and throat using a mirror or a flexible camera called a nasopharyngoscope. They will check for any masses or ulcers on the tonsils, base of tongue, or soft palate and feel the neck for enlarged lymph nodes.

Imaging

Imaging studies such as CT scans, MRI, or PET-CT help identify the size and location of the tumour, whether there are enlarged lymph nodes, and whether the disease has spread elsewhere in the body.

Biopsy

A biopsy may be performed from the oropharynx or from an enlarged lymph node in the neck. A fine needle aspiration (FNA) is often done first to sample the lymph node. If the FNA confirms squamous cell carcinoma, additional tissue from the oropharynx may be collected to determine the tumour’s site of origin and test for high-risk HPV.

Microscopic examination

Under the microscope, the pathologist looks for invasive squamous cell carcinoma, which means abnormal squamous cells have broken through the epithelium (surface lining) into the tissue underneath.

If only a lymph node biopsy is available, the pathologist may describe sheets or clusters of abnormal squamous cells and confirm that the tumour cells have the typical appearance of HPV-associated carcinoma, which often looks non-keratinizing (less keratin and more uniform cells). In this situation, the oropharynx is strongly suspected as the primary site, especially when testing shows high-risk HPV.

After the tumour or affected lymph nodes are surgically removed, the pathologist examines the entire specimen. The resection report includes the tumour’s size, exact location, extension into nearby structures, whether surgical margins are clear, and whether cancer has spread to lymph nodes.

Tests for high-risk HPV

Testing for high-risk HPV is essential to confirm that the cancer is HPV-associated. There are several ways to detect HPV in tumour tissue:

• p16 immunohistochemistry (IHC) – This test detects a protein called p16, which is overproduced in cells infected with high-risk HPV. Strong, diffuse staining of tumour cells for p16 is considered a reliable indicator of HPV-associated squamous cell carcinoma.

• In situ hybridization (ISH) or polymerase chain reaction (PCR) – These tests look for HPV DNA or RNA directly within the tumour cells. They are sometimes used when the p16 test gives uncertain results.

A diagnosis of HPV-associated squamous cell carcinoma requires both evidence of squamous cell carcinoma under the microscope and positive results for a high-risk HPV test such as p16 IHC.

Do pathologists grade HPV-associated squamous cell carcinoma of the oropharynx?

Unlike many other cancers, HPV-associated squamous cell carcinoma of the oropharynx is not assigned a histologic grade. This is because nearly all of these tumours share similar microscopic features and behave in a more uniform way than non-HPV-related squamous cell carcinomas. Instead of grading, the diagnosis focuses on confirming HPV association and describing the tumour’s size, extent, margins, and lymph node status.

Tumour extension

Tumour extension describes how far the cancer has spread from its original site within the oropharynx.

HPV-associated squamous cell carcinoma usually starts in the epithelial surface of the tonsils, base of tongue, or soft palate, where HPV infects the cells lining small crypts (pits) in the tissue. As the tumour grows, it can extend into nearby tissues such as the lateral or posterior pharyngeal wall, or parapharyngeal space.

Large tumours may grow beyond the oropharynx into the oral cavity, nasopharynx, or larynx, or they may invade the deep muscles of the tongue, the mandible (lower jaw), or surrounding soft tissue of the neck. When the tumour grows beyond the oropharynx, it is assigned a higher stage (T4). These findings influence both treatment and prognosis.

Perineural invasion

Perineural invasion (PNI) means cancer cells are growing along or around a nerve. Nerves are small structures that carry sensation and movement signals. When tumour cells spread along nerves, there is an increased risk that the cancer may return or extend beyond the main tumour site. Pathologists report this finding because it can influence the decision to use radiation therapy after surgery.

Lymphovascular invasion

Lymphovascular invasion (LVI) means that cancer cells are found inside lymphatic channels or blood vessels near the tumour. These channels provide a route for cancer to spread to lymph nodes or distant organs. If lymphovascular invasion is seen, it is considered an adverse feature and may affect treatment planning.

Margins

Margins are the edges of tissue removed during surgery. After the specimen is received, the pathologist inks the outer surfaces and examines the tissue under the microscope to see how close the tumour comes to the edge.

A negative margin means no cancer cells are seen at the edge, suggesting the tumour was completely removed. A positive margin means cancer cells are found at the edge, suggesting that some tumour may remain. A close margin means the cancer comes within a few millimetres of the edge. Positive or close margins may lead to recommendations for additional surgery or radiation therapy.

Lymph nodes

Lymph nodes are small immune organs that filter fluid and trap abnormal cells, including cancer cells. The oropharynx drains into lymph nodes on both sides of the neck, particularly levels II through IV.

Because HPV-associated squamous cell carcinoma often spreads to lymph nodes early, a neck dissection is usually performed as part of the surgery. During this procedure, lymph nodes are removed and sent to the pathology laboratory for examination.

The pathologist examines each lymph node to determine if it contains cancer, records the number of positive and negative nodes, measures the size of the largest tumour deposit, and notes whether there is extranodal extension, which means cancer cells have broken through the capsule of the lymph node into surrounding tissue.

Lymph node involvement is common in HPV-associated squamous cell carcinoma but does not necessarily mean a poor prognosis. The number of affected lymph nodes helps determine the nodal stage (pN category).

PD-L1

PD-L1 is a protein that allows cancer cells to hide from the immune system. Testing for PD-L1 may be performed when the cancer is unresectable (cannot be removed surgically), has returned, or has spread to other parts of the body.

The PD-L1 test result is reported as a Combined Positive Score (CPS), which measures PD-L1 expression on both tumour and immune cells. A higher CPS score may indicate that the tumour is more likely to respond to immunotherapy drugs such as pembrolizumab.

Pathologic stage

Tumour stage (pT) for HPV-associated squamous cell carcinoma

HPV-associated squamous cell carcinoma of the oropharynx is given a tumour stage between 1 and 4. The tumour stage is based on the size of the tumour and whether the tumour has grown to include parts of the mouth or throat outside of the oropharynx.

T1 – The tumour is 2 cm or smaller.
T2 – The tumour is greater than 2 cm but not larger than 4 cm.
T3 – The tumour is larger than 4 cm but only located within the oropharynx.
T4 – The tumour has spread into tissues outside the oropharynx, such as the deep muscles of the tongue, the larynx, or the bone of the lower jaw (the mandible).

Nodal stage (pN) for HPV-associated squamous cell carcinoma

HPV-associated squamous cell carcinoma is given a nodal stage between 0 and 2 based on the number of lymph nodes that contain cancer cells.

N0 – No cancer cells are found in any lymph nodes examined.
N1 – Cancer cells are found in 1 to 4 lymph nodes examined.
N2 – Cancer cells are found in more than 4 lymph nodes examined.

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, radiation oncologist, medical oncologist, and pathologist.

Treatment options depend on the stage and extent of the cancer. For many patients, the main treatments are surgery, radiation therapy, or a combination of both. Some early-stage tumours can be treated with transoral robotic or laser surgery, while others may require radiation therapy as the primary treatment.

For more advanced tumours, or when lymph nodes are involved, combined chemoradiation therapy may be recommended. In recurrent or metastatic disease, systemic therapies such as chemotherapy, targeted therapy, or immunotherapy (based on PD-L1 results) may be used.

HPV-associated squamous cell carcinoma generally has a better prognosis than non-HPV-related cancers. After treatment, regular follow-up visits, imaging studies, and ongoing dental and swallowing rehabilitation are important for long-term recovery. Avoiding tobacco and alcohol and maintaining good oral hygiene can further reduce the risk of recurrence.

Questions for your doctor

• Where in the oropharynx did my cancer start, and how large is it?

• Was the diagnosis confirmed by HPV testing?

• Were surgical margins clear, and did the tumour show perineural or lymphovascular invasion?

• How many lymph nodes contained cancer, and was extranodal extension seen?

• What is my pathologic stage (pT and pN categories)?

• What treatments do you recommend, and what are their side effects?

• Could I benefit from immunotherapy based on PD-L1 testing?

• How will my swallowing, speech, and nutrition be managed during and after treatment?

• How often should I have follow-up examinations and imaging studies?