HPV Independent Squamous Cell Carcinoma of the Vagina: Understanding Your Pathology Report

Section Editor: Kianoosh Keyhanian MD FRCPC
May 22, 2026

HPV-independent squamous cell carcinoma of the vagina is a type of vaginal cancer that is not caused by infection with human papillomavirus (HPV). It develops when squamous cells in the lining of the vagina grow abnormally and form a tumor that can invade the surrounding tissue. Vaginal cancer is rare, and squamous cell carcinoma is its most common type.

Most squamous cell carcinomas of the vagina are caused by HPV, but a smaller number develop without any HPV infection. These HPV-independent cancers tend to occur in older patients, most often after menopause, with an average age at diagnosis of around 73 years. To make this diagnosis, the pathologist and treating doctors first confirm that the cancer is not caused by HPV and that it has not spread to the vagina from a nearby cancer of the cervix or vulva.

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-independent squamous cell carcinoma of the vagina?

Unlike the more common HPV-associated type, this cancer is not caused by HPV infection. The exact cause is not fully understood, and most cases occur without an identifiable trigger. Research suggests that several factors may contribute:

Long-standing inflammation or irritation — Chronic inflammation of the vaginal lining, including from long-term skin conditions or chronic irritation, is thought to play a role in some cases.
Genetic changes within the cells — HPV-independent squamous cell carcinomas often contain a change (mutation) in a gene called TP53, which normally helps protect cells from becoming cancer. This change is reflected in the abnormal p53 protein pattern often seen when the tissue is tested.
Older age — The risk increases with age, and most patients are postmenopausal.
Previous pelvic radiation therapy — Radiation to the pelvis given as treatment for another condition has been associated with an increased risk of vaginal cancer in some patients.

Because this cancer is not caused by HPV, it is not prevented by HPV vaccination, and it is not related to a sexually transmitted infection.

What are the symptoms?

The symptoms of HPV-independent squamous cell carcinoma of the vagina are similar to those of other vaginal cancers and depend on the size and location of the tumor. Common symptoms include:

Unusual vaginal bleeding — Bleeding after menopause, between menstrual periods, or after intercourse is the most common symptom.
Unusual vaginal discharge — The discharge may be watery, bloody, or have an unusual odor.
A lump or mass — Some patients notice a lump or a feeling that something is inside the vagina.
Pelvic pain — Discomfort or pain in the pelvis, which tends to occur with more advanced disease.
Pain or discomfort with urination — May occur when the tumor is located near the bladder or urethra.

Some early vaginal cancers cause no symptoms and are found during a routine examination. Any persistent vaginal symptom should be evaluated by a doctor.

How is the diagnosis made?

The diagnosis of HPV-independent squamous cell carcinoma of the vagina is made when a sample of tissue from the vagina is examined under the microscope by a pathologist. The sample is usually obtained through a biopsy taken during a physical examination. Imaging tests, such as MRI, CT, or PET-CT, are often performed to determine the size and extent of the tumor and to look for spread to lymph nodes or other organs.

An important part of making this diagnosis is confirming that the cancer is truly HPV-independent and that it has not spread into the vagina from a nearby cancer of the cervix or vulva. To do this, the pathologist performs additional tests called immunohistochemistry for two proteins:

p16 — Cells infected with high-risk HPV produce large amounts of p16, which shows up as strong, continuous “block-type” staining. HPV-independent tumors are typically negative for p16 or show only weak, patchy staining.
p53 — Many HPV-independent squamous cell carcinomas show an abnormal p53 staining pattern, which reflects an underlying change in the TP53 gene. An abnormal p53 result helps support the diagnosis of an HPV-independent cancer.

In some cases, HPV testing is also performed to confirm the absence of an HPV infection, because a small number of HPV-independent tumors can show weak p16 staining that could otherwise be confusing.

What does HPV-independent squamous cell carcinoma look like under the microscope?

Under the microscope, HPV-independent squamous cell carcinoma of the vagina is made up of abnormal squamous cells that have broken through the surface lining of the vagina and grown into the deeper tissue. Several features are commonly seen:

Keratinizing pattern — HPV-independent tumors most often show a keratinizing pattern, meaning the tumor cells produce keratin, a protein normally found in the skin. The cells may form round collections of keratin called keratin pearls.
Irregular, infiltrating growth — The tumor cells form irregular clusters, cords, and sheets that grow into the surrounding tissue.
Abnormal cell shapes — The tumor cells vary in size and shape, and their nuclei often look abnormal.
Frequent cell division — Dividing cells are commonly seen, a sign that the tumor is growing.

These microscopic features, together with the p16 and p53 results, help the pathologist confirm the diagnosis and separate this cancer from HPV-associated squamous cell carcinoma.

Histologic grade

Histologic grade describes how closely the tumor cells resemble normal squamous cells under the microscope. Pathologists divide HPV-independent squamous cell carcinoma of the vagina into three grades:

Well differentiated (grade 1) — The tumor cells look very similar to normal squamous cells. These tumors tend to grow more slowly.
Moderately differentiated (grade 2) — The tumor cells clearly differ from normal squamous cells but are still recognizable as squamous in origin.
Poorly differentiated (grade 3) — The tumor cells look very abnormal and bear little resemblance to normal squamous cells. They can look so abnormal that immunohistochemistry may be needed to confirm the diagnosis. These tumors tend to grow more quickly and are more likely to spread.

Tumor size and depth of invasion

After the tumor is removed, the pathologist measures it in three dimensions and reports the largest dimension, usually in centimeters. Tumor size is one of the features used to determine the stage. Tumors larger than 4 cm are associated with a higher risk of spread and recurrence. The pathologist also describes how deeply the tumor has grown into the wall of the vagina and whether it has extended into the surrounding tissue. Larger and more deeply invasive tumors are more likely to spread to lymph nodes and nearby organs.

Lymphovascular invasion

Lymphovascular invasion means that tumor cells are seen inside small lymphatic channels or blood vessels in or around the tumor. These vessels normally carry fluid or blood through the body. When tumor cells gain access to them, they can travel to nearby lymph nodes or distant organs. The presence of lymphovascular invasion indicates a higher risk of spread and may influence treatment decisions.

Perineural invasion

Perineural invasion means that tumor cells are growing along or around small nerves in or near the tumor. This pattern of growth allows the cancer to extend along nerves beyond the visible edge of the tumor and is associated with a higher risk of local recurrence after treatment.

Surgical margins

A margin is the cut edge of tissue removed during surgery. When the tumor is removed surgically, the pathologist examines all of the margins under the microscope to determine whether any tumor cells are present at the cut edges.

Negative margin — No tumor cells are present at the cut edge of the tissue. Most reports also describe how far the closest tumor cells are from the margin.
Positive margin — Tumor cells extend to the cut edge of the tissue. This means some tumor cells may still remain, increasing the risk that the tumor will return in the same area.

Margins are reported only when surgery is performed to remove the tumor. Many vaginal cancers are treated primarily with radiation therapy rather than surgery, in which case margins are not part of the report.

Lymph nodes

Lymph nodes are small immune organs that filter fluid as it returns from the body’s tissues. The part of the vagina where the tumor develops determines which lymph nodes are most likely to be involved: tumors in the upper two-thirds of the vagina tend to drain to lymph nodes in the pelvis, while tumors in the lower one-third tend to drain to lymph nodes in the groin (the inguinal lymph nodes).

When lymph nodes are removed during surgery, the pathologist examines them under the microscope and reports the number of lymph nodes examined, the number that contain tumor cells, and the size of the largest tumor deposit. The report may also note whether tumor cells have broken through the outer wall of a lymph node into the surrounding tissue, a finding called extranodal extension. The presence of tumor cells in lymph nodes is one of the most important factors in determining the stage and predicting outcome.

Biomarker and molecular testing

Biomarker testing is most relevant in advanced, recurrent, or metastatic squamous cell carcinoma of the vagina, where the results help determine eligibility for specific systemic therapies. Not every biomarker is tested in every case.

PD-L1

PD-L1 is a protein that some tumor cells use to suppress the immune system’s ability to recognize and destroy them. Testing for PD-L1 is performed by immunohistochemistry on a tumor sample and is commonly reported using the Combined Positive Score (CPS), which reflects PD-L1 expression on both tumor cells and nearby immune cells. A PD-L1 result does not by itself dictate treatment; instead, it informs the discussion the medical oncology team has with the patient about whether immune checkpoint inhibitor therapy is an appropriate option for advanced or recurrent disease.

Mismatch repair (MMR) testing

Mismatch repair proteins (MMR) are part of the cell’s system for correcting small errors that occur in DNA during cell division. When one or more of these proteins is absent from tumor cells, the result is called mismatch repair-deficient (dMMR), also known as microsatellite instability-high (MSI-high). MMR deficiency is uncommon in vaginal squamous cell carcinoma, but when present, it identifies patients who may benefit from immune checkpoint inhibitor therapy regardless of where the cancer started.

Pathologic stage

Staging describes how far the cancer has spread. Stage is the most important factor in predicting outcome and in shaping treatment decisions. Vaginal cancer is staged using two related systems: the AJCC TNM system (currently AJCC 8th edition) and the FIGO system (currently the FIGO 2018 revision). The two systems are aligned. FIGO stages vaginal cancer based on physical examination and imaging, because most vaginal cancers are treated with radiation rather than surgery. The AJCC TNM system also incorporates pathologic information from the resected tissue when surgery is performed.

The TNM system describes the size and extent of the tumor in the vagina (T), whether nearby lymph nodes contain cancer (N), and whether the cancer has spread to distant organs (M).

Tumor stage (T)

T1 — Tumor confined to the vagina.
- T1a — Tumor 2 cm or less in greatest dimension.
- T1b — Tumor greater than 2 cm in greatest dimension.
T2 — Tumor invades the tissue around the vagina (paravaginal tissue) but has not reached the pelvic wall.
- T2a — Tumor 2 cm or less in greatest dimension.
- T2b — Tumor greater than 2 cm in greatest dimension.
T3 — Tumor extends to the pelvic wall, involves the lower one-third of the vagina, or blocks the flow of urine from a kidney (causing the kidney to swell or stop working).
T4 — Tumor invades the lining of the bladder or rectum, or extends beyond the pelvis.

Nodal stage (N)

NX — Regional lymph nodes cannot be assessed.
N0 — No cancer found in the regional lymph nodes.
N1 — Cancer has spread to regional lymph nodes in the pelvis or the groin.

Metastatic stage (M)

The metastasis category is determined by imaging studies and clinical evaluation. M0 means no distant spread has been identified. M1 means cancer has spread to distant organs such as the lungs, liver, or bones.

FIGO stage

The FIGO 2018 stage is reported alongside the TNM stage and is most commonly used for treatment planning:

Stage I — Cancer confined to the vaginal wall. Stage IA is 2 cm or less; stage IB is greater than 2 cm.
Stage II — Cancer involves the tissue around the vagina but has not reached the pelvic wall. Stage IIA is 2 cm or less; stage IIB is greater than 2 cm.
Stage III — Cancer extends to the pelvic wall, involves the lower one-third of the vagina, blocks the flow of urine from a kidney, or has spread to lymph nodes in the pelvis or groin.
Stage IV — More extensive spread.
- Stage IVA — Cancer invades the lining of the bladder or rectum, or extends beyond the pelvis.
- Stage IVB — Cancer has spread to distant organs such as the lungs, liver, or bones.

What is the prognosis?

The prognosis for HPV-independent squamous cell carcinoma of the vagina depends most strongly on the stage at diagnosis. Earlier stages have substantially better outcomes than advanced stages. On average, HPV-independent vaginal cancers tend to have a somewhat less favorable outlook than HPV-associated vaginal cancers at a similar stage. One reason is that HPV-independent cancers often occur in older patients and are sometimes found at a later stage. It is important to keep in mind that prognosis describes averages across many patients and cannot predict what will happen for any one person.

Several features in the pathology report influence the chance of recurrence:

Stage at diagnosis — The single most important prognostic factor.
Tumor size — Tumors larger than 4 cm are associated with a higher risk of recurrence.
Lymph node involvement — The presence of tumor cells in lymph nodes is associated with a meaningfully higher risk of recurrence.
Surgical margin status — When surgery is performed, negative margins are associated with a lower risk of local recurrence.
Lymphovascular invasion — Increases the risk of spread and recurrence.
Histologic grade — Poorly differentiated tumors tend to behave more aggressively.

What happens after this diagnosis?

Once HPV-independent squamous cell carcinoma of the vagina is diagnosed, the gynecologic oncology and radiation oncology teams will discuss treatment options with the patient. Decisions depend on the stage, the size and location of the tumor, the patient’s age and overall health, and the specific findings on the pathology report. Because the vagina lies close to the bladder and rectum, treatment is planned carefully to control the cancer while limiting harm to these nearby organs.

Options that the team may consider include:

Radiation therapy — Radiation is the most common treatment for vaginal cancer. It often combines external beam radiation (directed at the pelvis from outside the body) with brachytherapy (radiation placed inside the vagina). Radiation can be used for tumors of many sizes and stages.
Concurrent chemoradiation — For many tumors, particularly larger or more advanced ones, the team may discuss combining chemotherapy with radiation. Chemotherapy makes radiation more effective.
Surgery — Surgery may be considered for selected early-stage tumors, particularly small tumors in the upper vagina. The type of surgery depends on the size and location of the tumor.
Systemic therapy for advanced or recurrent disease — For metastatic or recurrent disease, the medical oncology team discusses systemic options, including chemotherapy and, when applicable, immune checkpoint inhibitor therapy guided by PD-L1 or MMR/MSI testing. Clinical trial enrollment may also be discussed because vaginal cancer is uncommon and standard treatment data for advanced disease are limited.

After treatment, regular follow-up is essential. Surveillance typically includes physical and pelvic examinations on a defined schedule, with imaging and additional tests added based on the original stage and the patient’s overall risk of recurrence.

Questions to ask your doctor

What is the stage of my cancer using both the TNM and FIGO systems?
What was the size of the tumor, and how deeply had it grown?
Was p16 and p53 testing performed, and what did the results show?
How did the team confirm that my cancer is HPV-independent?
What was the histologic grade of my tumor?
Was lymphovascular invasion or perineural invasion present?
If I had surgery, were the margins negative or positive?
Were any lymph nodes examined, and if so, were any involved?
Was PD-L1 or MMR testing performed, and what do the results mean for my treatment options?
What treatment options would you discuss with me based on my pathology findings?
Will my treatment involve radiation, chemotherapy, surgery, or a combination?
How will treatment affect nearby organs such as my bladder and rectum?
What follow-up schedule will I have, and what symptoms should prompt me to contact you?
What is my chance of recurrence, and what can be done to reduce that risk?
Are there clinical trials available that might be appropriate for my situation?