HPV Associated Squamous Cell Carcinoma of the Cervix: Understanding Your Pathology Report

by Jason Wasserman MD PhD FRCPC
March 11, 2026

HPV-associated squamous cell carcinoma is the most common type of cervical cancer. It develops from squamous cells, which are the flat cells that cover the outer surface of the cervix.

This cancer is called HPV-associated because it is caused by infection with high-risk types of human papillomavirus (HPV). Persistent infection with these viruses can damage the DNA of cervical cells, allowing them to grow uncontrolled.

Most HPV-associated cervical cancers develop slowly over many years from a precancerous condition called high-grade squamous intraepithelial lesion (HSIL). Screening tests such as Pap tests and HPV tests can often detect these abnormal cells before cancer develops.

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

Many people with early-stage cervical cancer do not experience symptoms. In these cases, the cancer may only be detected through cervical screening.

When symptoms are present, they may include abnormal vaginal bleeding, such as bleeding after sex, between menstrual periods, or after menopause. Some patients notice increased vaginal discharge, which may be watery, bloody, or have an unusual odor. Pain during sexual intercourse or pelvic pain may also occur as the cancer grows.

What causes HPV-associated squamous cell carcinoma?

HPV-associated squamous cell carcinoma develops after long-term infection with high-risk types of HPV.

HPV is a very common virus that spreads through sexual contact. Most HPV infections clear on their own. When the infection persists, viral proteins can interfere with normal cell-cycle control, allowing abnormal cells to accumulate genetic damage over time.

Additional risk factors that may increase the likelihood of cervical cancer include smoking, a weakened immune system, and a lack of regular cervical cancer screening.

How is this diagnosis made?

The diagnosis of HPV-associated squamous cell carcinoma usually begins with cervical screening tests.

Abnormal findings on a Pap test or a positive HPV test may lead to further evaluation with colposcopy. This procedure allows the doctor to examine the cervix more closely and obtain small tissue samples.

The diagnosis is confirmed when a pathologist examines cervical tissue under the microscope. The tissue may be obtained through a biopsy, endocervical curettage, or a procedure such as a cone biopsy or loop electrosurgical excision procedure (LEEP).

If surgery is performed, the pathologist also evaluates the removed tissue to determine the size of the tumor, how deeply it has grown into the cervix, and whether it has spread to nearby structures.

Microscopic features

Under the microscope, HPV-associated squamous cell carcinoma forms irregular nests, sheets, and cords of squamous cells that grow into the supporting tissue of the cervix.

The tumor cells often vary in size and shape, a feature called pleomorphism, and many cells are actively dividing. Early invasion occurs when clusters of tumor cells break through the surface layer of the cervix and grow into the tissue beneath. The surrounding tissue frequently shows a fibrous response called desmoplasia.

Most tumors arise in the transformation zone, the area where squamous cells on the outer surface of the cervix meet glandular cells in the cervical canal. This region is especially vulnerable to persistent infection with high-risk HPV types.

Several growth patterns may be seen under the microscope. The most common patterns are non-keratinizing and basaloid squamous cell carcinoma. Other less common patterns include keratinizing, warty, papillary, and lymphoepithelioma-like squamous cell carcinoma.

Immunohistochemistry

Immunohistochemistry is a laboratory test that uses antibodies to detect specific proteins inside tumor cells. These tests help confirm the diagnosis and show that HPV infection is driving the cancer.

HPV-associated cervical cancers typically show strong, continuous staining for p16, a protein that becomes overexpressed when HPV disrupts normal cell-cycle control. Additional markers such as p40 or cytokeratins may be used to confirm that the tumor cells are of squamous origin.

In situ hybridization

In situ hybridization (ISH) is a laboratory test that detects HPV DNA or RNA directly within tumor cells.

This test uses specially designed probes that bind to HPV genetic material inside the cells. If HPV DNA or RNA is present, the probes produce a visible signal under the microscope.

ISH helps confirm that the cancer is caused by high-risk HPV infection and may be used when the diagnosis is uncertain.

Biomarkers

Biomarker testing examines proteins or genetic features in tumor cells that may help guide treatment decisions. These tests are usually performed on tumor tissue using immunohistochemistry or molecular methods. Not all biomarkers are tested in every case, but the results can provide important information about how the cancer may respond to specific treatments.

PD-L1

PD-L1 is a protein that helps cancer cells evade immune detection.

Testing for PD-L1 is performed using immunohistochemistry and is often reported using a combined positive score (CPS). This score reflects the proportion of tumor cells and nearby immune cells that express PD-L1.

Tumors that express PD-L1 may respond to immune checkpoint inhibitor therapy, which is sometimes used to treat advanced or recurrent cervical cancer.

Other features to look for in your pathology report

Tumor size and depth of invasion

Once the diagnosis is made, the pathologist measures the tumor to determine its size and how deeply it has grown into the cervix.

Tumor size is measured along the surface of the cervix, while depth of invasion describes how far the tumor has grown from the surface into the underlying supporting tissue. Depth of invasion is an important feature because tumors that invade more deeply are more likely to spread to lymph nodes or nearby organs.

These measurements help determine the stage of the cancer and guide treatment decisions.

Tumor spread

Pathologists examine the tumor to determine whether it has spread beyond the cervix.

The tumor may extend into nearby structures such as the uterus, the upper or lower vagina, the parametrium (fibrous tissue surrounding the cervix), the pelvic wall, the bladder, or the rectum. Spread into these structures increases the stage of the cancer and may influence treatment planning.

Lymphovascular invasion

Lymphovascular invasion means that tumor cells are present inside small lymphatic channels or blood vessels in the cervix.

These vessels normally carry fluid or blood through the body. When tumor cells enter these channels, they may travel to nearby lymph nodes or other organs. The presence of lymphovascular invasion increases the risk of cancer spread and may influence treatment recommendations.

Perineural invasion

Perineural invasion means that tumor cells are growing along or around small nerves in the cervix.

This finding suggests that cancer cells may spread along nerve pathways, increasing the risk of local recurrence. When perineural invasion is present, doctors may recommend additional treatments such as radiation therapy.

Margins

Margins are the edges of the tissue removed during surgery.

A negative margin means that no cancer cells are present at the edge of the tissue, suggesting that the tumor was completely removed. A positive margin means that cancer cells extend to the edge of the tissue, which increases the risk that some tumor cells remain.

Margins are evaluated in cone biopsies and hysterectomy specimens. For small early-stage tumors, a clear margin on a cone biopsy may allow patients to avoid larger surgery.

Lymph nodes

Lymph nodes are small immune organs that help filter harmful substances from the body.

The cervix drains into lymph nodes in the pelvis and abdomen. During surgery for cervical cancer, lymph nodes from these areas may be removed and examined under the microscope.

If tumor cells are found in these lymph nodes, the cancer is considered to have spread beyond the cervix, and the stage of the cancer increases.

When tumor cells are present in lymph nodes, the pathology report may describe the size of the tumor deposits.

  • Isolated tumor cells measure 0.2 mm or less.
  • Micrometastases measure more than 0.2 mm but 2 mm or less.
  • Macrometastases measure more than 2 mm.

The pathology report may also describe the number of lymph nodes examined, the number containing tumor cells, and the location of involved nodes.

How is HPV associated cervical cancer staged?

Staging describes how far the cancer has spread within the cervix and beyond. It is the most important factor for predicting outcome and deciding on treatment. Two systems are commonly used for cervical cancer: TNM and FIGO.

  • The TNM system records tumor size and spread in the cervix (T), whether lymph nodes contain cancer (N), and whether the cancer has spread to distant organs (M).

  • The FIGO system focuses on how far the cancer has spread beyond the cervix into surrounding tissues, lymph nodes, or distant sites. Gynecologic oncologists widely use it to guide treatment planning.

TNM pathologic stage

  • The letter T describes how far the tumor has grown in and around the cervix.

    • T1a means the tumor is only visible under the microscope and measures no more than 5 millimeters in depth and 7 millimeters in width.

    • T1b means that the tumor is visible or measures deeper than five millimeters or wider than seven millimeters.

    • T2a means that the tumor has spread beyond the cervix and uterus but has not entered the parametrium.

    • T2b means that the tumor has grown into the parametrium.

    • T3a means that the tumor involves the lower part of the vagina.

    • T3b means that the tumor reaches the pelvic wall or blocks a ureter, which can harm the kidneys.

    • T4 means that the tumor has grown into the bladder or rectum or has extended beyond the pelvis.

  • The letter N describes lymph nodes.

    • NX means that no nodes were removed.

    • N0 means that no cancer was found in the nodes.

    • N0 with isolated tumor cells means that only tiny clusters smaller than zero point two millimeters were present.

    • N1 means that a larger cancer deposit was found in at least one node.

  • The letter M describes distant spread to organs such as the lungs or liver.

FIGO stage

  • Stage I means that the cancer is confined to the cervix.

    • Stage IA1 means that the depth of invasion is three millimeters or less.

    • Stage IA2 means the depth of invasion is between 3 and 5 millimeters.

    • Stage IB1 means that the tumor is two centimetres or smaller.

    • Stage IB2 means the tumor is more than 2 centimetres but no more than 4 centimetres.

    • Stage IB3 means that the tumor is larger than four centimetres.

  • Stage II means that the cancer has spread beyond the cervix but not to the pelvic wall or the lower third of the vagina.

    • Stage IIA1 means that the tumor involves the upper vagina and measures four centimetres or less.

    • Stage IIA2 means that the tumor in the upper vagina is larger than four centimetres.

    • Stage IIB means that the tumor extends into the parametrium.

  • Stage III means more extensive local spread.

    • Stage IIIA means that the cancer involves the lower third of the vagina.

    • Stage IIIB means that the cancer reaches the pelvic wall or blocks a ureter.

    • Stage IIIC1 means that cancer is present in pelvic lymph nodes.

    • Stage IIIC2 means that cancer is present in para-aortic lymph nodes.

  • Stage IV means spread to nearby organs or to distant sites.

    • Stage IVA means invasion of the bladder or rectum.

    • Stage IVB means distant metastasis to organs such as the lungs, liver, or bones.

Staging guides treatment and helps predict outcome.

Questions to ask your doctor

  • What stage is my cervical cancer?

  • How large is the tumor, and how deeply has it grown into the cervix?

  • Was lymphovascular invasion present?

  • Were the surgical margins clear?

  • Were lymph nodes involved?

  • Was PD-L1 testing performed, and what do the results mean for my treatment?

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