HPV Independent Squamous Cell Carcinoma of the Cervix: Understanding Your Diagnosis

by Jason Wasserman MD PhD FRCPC
March 13, 2026

HPV-independent squamous cell carcinoma is a type of cervical cancer that develops from squamous cells, the flat cells that cover the outer surface of the cervix.

Unlike most cervical cancers, this tumor is not caused by infection with human papillomavirus (HPV). Instead, the cancer develops through other molecular changes that allow squamous cells to grow uncontrolled.

HPV-independent squamous cell carcinoma is uncommon, accounting for about 5–7% of all squamous cell carcinomas of the cervix. Compared with HPV-associated cervical cancers, these tumors are usually diagnosed in older patients, typically around 60 years of age.

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

The symptoms of HPV-independent squamous cell carcinoma are similar to those seen in HPV-associated cervical cancer.

The most common symptom is abnormal vaginal bleeding, such as bleeding after sexual intercourse, between menstrual periods, or after menopause. Some patients may also notice increased vaginal discharge or pelvic pain.

Because these tumors are often diagnosed at a later stage, symptoms such as pelvic pain or abdominal discomfort may be more noticeable at the time of diagnosis.

What causes HPV-independent squamous cell carcinoma?

The exact cause of HPV-independent squamous cell carcinoma of the cervix is not fully understood.

Unlike most cervical cancers, these tumors develop without infection by high-risk HPV types. Instead, the cancer appears to arise from other genetic changes within cervical cells.

Several molecular alterations have been described in these tumors, including mutations affecting genes such as TP53, KRAS, ARID1A, and PTEN, which are involved in regulating cell growth and DNA repair.

How is this diagnosis made?

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

Abnormal findings on a Pap test may warrant further evaluation with colposcopy, which allows the cervix to be examined closely and small tissue samples to be obtained.

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 examines 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-independent squamous cell carcinoma forms irregular nests, sheets, and cords of squamous cells that invade the supporting tissue of the cervix.

The tumor cells often show nuclear pleomorphism, meaning the nuclei vary in size and shape, and many cells are actively dividing. The surrounding tissue frequently shows a fibrous reaction called desmoplasia.

These tumors are often keratinizing squamous cell carcinomas, meaning the tumor cells produce keratin and may form round collections called keratin pearls. However, other squamous growth patterns can also occur.

Unlike HPV-associated tumors, there are no reliable microscopic features that clearly distinguish HPV-independent squamous cell carcinoma. The diagnosis relies on testing that confirms the absence of HPV.

Immunohistochemistry

Immunohistochemistry is a laboratory test that uses antibodies to detect specific proteins inside tumor cells.

HPV-independent squamous cell carcinomas typically show negative p16 staining, which helps distinguish them from HPV-associated tumors. In HPV-associated cancers, p16 staining is usually strong and diffuse.

Other 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 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.

HPV-independent squamous cell carcinomas do not show HPV signals on in situ hybridization testing, confirming that the tumor developed without HPV infection.

Biomarkers

Biomarker testing examines proteins or other molecular features in tumor cells to help guide treatment decisions. These tests are usually performed on tumor tissue using immunohistochemistry or other laboratory methods. Not all biomarkers are tested in every case, but the results can provide important information about treatment options.

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 measures PD-L1 expression in tumor cells and nearby immune cells.

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 describes how far the cancer extends along the surface of the cervix. Depth of invasion describes how far the tumor has grown from the surface into the supporting tissue of the cervix.

These measurements are important because tumors that invade more deeply are more likely to spread to lymph nodes or nearby organs.

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 vagina, uterus, parametrium, pelvic wall, bladder, or rectum. The parametrium is the fibrous tissue that surrounds the cervix.

The presence of tumor cells in these structures increases the cancer stage and may affect treatment decisions.

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 planning.

Perineural invasion

Perineural invasion means that tumor cells are growing along or around nerves in the cervix. This finding may increase the risk of the cancer returning in nearby tissues and may influence treatment decisions.

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, which increases the risk that some tumor cells remain.

Margins are evaluated in cone biopsies and hysterectomy specimens.

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?