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

by Jason Wasserman MD PhD FRCPC
May 16, 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, it develops through other genetic and molecular changes that allow squamous cells to grow uncontrollably.

HPV-independent squamous cell carcinoma is uncommon, accounting for approximately 5 to 7% of all squamous cell carcinomas of the cervix. Compared with HPV-associated cervical squamous cell carcinoma, these tumors usually occur in older patients (typically around 60 years of age), are less likely to be detected by routine cervical screening, and tend to behave more aggressively at any given stage.

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?

The exact cause of HPV-independent squamous cell carcinoma is not fully understood. Unlike most cervical cancers, this tumor develops without infection by high-risk HPV types. Instead, it appears to arise from other genetic changes in cervical squamous cells. Several molecular alterations have been described, including mutations in genes that regulate cell growth and DNA repair, such as TP53 (the gene that codes for the p53 tumor suppressor protein), KRAS, ARID1A, and PTEN. TP53 mutations are particularly common in HPV-independent squamous cell carcinoma and are one of the molecular features that distinguish it from HPV-associated cervical cancers, which typically have a normal TP53.

Because the standard cervical screening tests (Pap and HPV testing) are designed to detect HPV-associated cervical cancers and their precursors, HPV-independent squamous cell carcinoma can be missed during routine screening. As a result, it is more likely than HPV-associated cervical cancer to be diagnosed only after symptoms develop, and it may be more advanced at the time of diagnosis.

What are the symptoms?

The symptoms of HPV-independent squamous cell carcinoma are similar to those of other cervical cancers. The most common symptom is abnormal vaginal bleeding, such as bleeding after sexual intercourse, between menstrual periods, or after menopause. Some patients also notice increased vaginal discharge or pelvic pain. Because these tumors are often diagnosed at a later stage, symptoms such as pelvic pain, lower back pain, or abdominal discomfort may be more prominent at the time of diagnosis than they typically are in HPV-associated cervical cancers.

How is the diagnosis made?

The diagnosis of HPV-independent squamous cell carcinoma usually begins when symptoms or an abnormal finding on examination prompt further evaluation. An abnormal result on a Pap test may also lead to colposcopy, which allows the cervix to be examined closely and small tissue samples to be obtained. Tissue is then examined under the microscope by a pathologist. The sample may be obtained through a biopsy during colposcopy, an endocervical curettage to sample tissue inside the cervical canal, a cone biopsy, or a loop electrosurgical excision procedure (LEEP). If surgery is performed to treat the cancer, the pathologist also examines the removed tissue to determine the size of the tumor, how deeply it has grown into the cervix, the status of the surgical margins, and whether any lymph nodes contain cancer.

To confirm the diagnosis and distinguish HPV-independent squamous cell carcinoma from HPV-associated cervical cancer and other cancers that may look similar under the microscope, the pathologist performs several special tests. A protein stain called p16, performed by immunohistochemistry, is typically negative or shows only patchy, weak staining in HPV-independent squamous cell carcinoma. This is one of the most important features that distinguishes it from HPV-associated cervical cancer, in which p16 staining is typically strong and continuous. Other stains, such as p40, p63, and squamous-type cytokeratins, are usually positive and confirm the squamous origin of the tumor. p53 staining may show an abnormal pattern (either complete loss or strong, diffuse overexpression), reflecting the underlying TP53 mutation that is common in this tumor type. In situ hybridization (ISH) for HPV is used in many cases to confirm that the tumor is HPV-independent. In HPV-independent squamous cell carcinoma, HPV ISH shows no signals, confirming that no HPV genetic material is present in the tumor cells.

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

Under the microscope, HPV-independent squamous cell carcinoma is composed of 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, meaning the tumor cells produce keratin and may form round, concentric collections called keratin pearls. Other squamous growth patterns, including non-keratinizing and basaloid forms, can also occur. Importantly, there are no reliable microscopic features that on their own distinguish HPV-independent squamous cell carcinoma from HPV-associated cervical cancer. The diagnosis depends on testing that confirms the absence of HPV (negative p16 staining and negative HPV in situ hybridization).

Tumor size and depth of invasion

Once invasive cancer is confirmed, the pathologist measures the tumor to determine its size and how deeply it has grown into the cervix. Tumor size describes the largest dimension of the cancer along the surface of the cervix and is usually reported in centimeters. Depth of invasion describes how far the tumor has grown from the surface lining into the supporting tissue (the stroma) of the cervix and is usually reported in millimeters. Both measurements are important because larger tumors and those that invade more deeply are more likely to spread to lymph nodes and nearby organs. These measurements also determine the tumor stage and influence which surgical and other treatment options the gynecologic team discusses with the patient.

Lymphovascular invasion

Lymphovascular invasion means that tumor cells are seen inside small lymphatic channels or blood vessels in the cervix. These vessels normally carry fluid or blood through the body, and tumor cells that gain access to them can travel to nearby lymph nodes or distant organs. The presence of lymphovascular invasion is associated with a higher risk of lymph node spread and recurrence, and it may influence the team’s discussion about whether to add radiation or chemoradiation after surgery.

Perineural invasion

Perineural invasion means that tumor cells are growing along or around nerves in the cervix. This pattern of growth allows the cancer to extend along nerves into surrounding tissue and is associated with a higher risk of local recurrence after treatment. Its presence may influence the team’s discussion about adding radiation therapy after surgery.

Surgical margins

A margin is the cut edge of tissue removed during a surgical procedure such as a cone biopsy or hysterectomy. After surgery, the pathologist examines the margins under the microscope to determine whether any cancer cells are present at the cut edges.

Negative margin — No cancer cells are present at the cut edge of the tissue. This suggests that the entire tumor was removed and is the most reassuring result.
Close margin — Cancer cells are within a few millimeters of the cut edge but not reaching it. A close margin may prompt the team to consider additional treatment, depending on the rest of the pathology findings.
Positive margin — Cancer cells extend to the cut edge of the tissue. This means some cancer cells may still remain in the cervix or surrounding tissue and increases the risk of recurrence. Positive margins may lead the team to discuss further surgery or postoperative radiation.

Lymph nodes

Lymph nodes are small immune organs that filter fluid as it returns from the body’s tissues to the bloodstream. The cervix drains into lymph nodes in the pelvis, and from there to lymph nodes higher in the abdomen along the aorta (the para-aortic nodes). During surgery for cervical cancer, lymph nodes from these areas may be removed and examined under the microscope.

If tumor cells are found inside a lymph node, the cancer is considered to have spread beyond the cervix, and the pathologic stage is increased. The pathology report describes the number of lymph nodes examined, the number that contain tumor cells, the location of the involved nodes, and the size of the tumor deposit in each node:

Isolated tumor cells — Tiny clusters measuring 0.2 mm or less.
Micrometastases — Tumor deposits larger than 0.2 mm but no larger than 2 mm.
Macrometastases — Tumor deposits larger than 2 mm.

The pathology report may also note whether cancer has broken through the outer wall of a lymph node into the surrounding tissue, a finding called extranodal extension, which is associated with a higher risk of recurrence.

Biomarker and molecular testing

Biomarker testing examines proteins or other molecular features in the tumor to guide treatment decisions. Not every biomarker is tested in every case. Testing is typically performed when the cancer is advanced, recurrent, or metastatic, and the results help determine eligibility for specific therapies.

PD-L1

PD-L1 is a protein that some tumor cells use to evade immune system detection. Testing for PD-L1 is performed by immunohistochemistry on a tumor sample and is reported as the Combined Positive Score (CPS), which reflects PD-L1 expression on tumor cells and on nearby immune cells. For cervical cancer, a CPS of 1 or higher is the threshold that indicates eligibility for immune checkpoint inhibitor therapy with pembrolizumab in advanced, recurrent, or metastatic disease. A PD-L1 result on the pathology report does not by itself dictate treatment; instead, it informs the discussion that the medical oncology team has with the patient about whether immunotherapy is an appropriate option.

Mismatch repair (MMR) testing

Mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) 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 cervical squamous cell carcinoma, but when present, it identifies patients who may benefit from pembrolizumab, which is approved for tumors that are dMMR or MSI-high regardless of where the cancer started. MMR deficiency may also indicate an inherited cancer syndrome (Lynch syndrome), and referral for genetic counseling may be discussed.

Pathologic stage

Staging describes how far the cancer has spread within the cervix and beyond. Stage is the single most important factor in predicting outcome and in shaping the decisions made by the gynecologic and medical oncology teams about further treatment. Cervical cancer is staged using two related systems: the AJCC pTNM system (currently AJCC 8th edition) and the FIGO system (currently the FIGO 2018 revision). The two systems are aligned and use the same anatomic categories, but FIGO is more commonly used by gynecologic oncologists for treatment planning.

The TNM system describes the size and extent of the tumor in the cervix (T), whether nearby lymph nodes contain cancer (N), and whether the cancer has spread to distant organs (M). The metastasis category (M) is generally determined by imaging studies rather than by examination of the surgical specimen.

Tumor stage (pT)

pT1 — Tumor confined to the cervix.
- pT1a — Invasive cancer that can be identified only under the microscope, with depth of invasion of 5 mm or less. (FIGO 2018 removed the prior 7 mm horizontal width criterion, so pT1a is now defined by depth alone.)
  - pT1a1 — Depth of invasion 3 mm or less.
  - pT1a2 — Depth of invasion greater than 3 mm but no more than 5 mm.
- pT1b — Invasive cancer with depth of invasion greater than 5 mm, still confined to the cervix.
  - pT1b1 — Tumor 2 cm or less in greatest dimension.
  - pT1b2 — Tumor greater than 2 cm but no more than 4 cm.
  - pT1b3 — Tumor greater than 4 cm.
pT2 — Tumor extends beyond the cervix but has not reached the pelvic wall or the lower third of the vagina.
- pT2a — Tumor involves the upper two-thirds of the vagina but not the parametrium. Subdivided into pT2a1 (4 cm or less) and pT2a2 (greater than 4 cm).
- pT2b — Tumor has invaded the parametrium.
pT3 — Tumor involves the lower third of the vagina, reaches the pelvic wall, or blocks a ureter (which can damage the kidney).
- pT3a — Tumor involves the lower third of the vagina without extension to the pelvic wall.
- pT3b — Tumor extends to the pelvic wall, blocks a ureter, or both.
pT4 — Tumor has grown into the lining of the bladder or rectum, or has extended beyond the pelvis.

Nodal stage (pN)

pNX — Regional lymph nodes were not examined.
pN0 — No cancer found in the examined regional lymph nodes.
pN0(i+) — Only isolated tumor cells (clusters 0.2 mm or smaller) are present in regional lymph nodes.
pN1 — Larger tumor deposits are present in regional lymph nodes.
- pN1a — Metastasis to pelvic lymph nodes only.
- pN1b — Metastasis to para-aortic lymph nodes, with or without pelvic lymph node involvement.

Metastatic stage (pM)

The metastasis category is determined by imaging studies and clinical evaluation rather than by examination of the surgical specimen. pM0 means no distant spread has been identified. pM1 means cancer has spread to distant organs such as the lungs, liver, or bones.

FIGO stage

The FIGO stage is reported alongside the TNM stage. It reflects the combined pathologic and imaging findings and is the system most commonly used to guide treatment planning:

Stage I — Cancer confined to the cervix. Subdivided into IA1, IA2, IB1, IB2, and IB3 using the same depth and size cut-offs as the AJCC pT1 categories above.
Stage II — Cancer has spread beyond the cervix but has not reached the pelvic wall or the lower third of the vagina. Subdivided into IIA1 (upper vagina, 4 cm or less), IIA2 (upper vagina, greater than 4 cm), and IIB (parametrial invasion).
Stage III — More extensive spread.
- Stage IIIA — Cancer involves the lower third of the vagina.
- Stage IIIB — Cancer reaches the pelvic wall or blocks a ureter.
- Stage IIIC1 — Cancer is present in pelvic lymph nodes (regardless of tumor size).
- Stage IIIC2 — Cancer is present in para-aortic lymph nodes (regardless of tumor size).
Stage IV — Cancer has spread to nearby organs or distant sites.
- Stage IVA — Cancer invades the lining of the bladder or rectum.
- Stage IVB — Cancer has spread to distant organs such as the lungs, liver, or bones.

What is the prognosis?

HPV-independent squamous cell carcinoma generally has a less favorable outlook than HPV-associated cervical squamous cell carcinoma. Several factors contribute to this difference. The tumor is often diagnosed at a later stage because it is not reliably detected by HPV-based screening. It tends to grow in an infiltrative pattern. And tumors with abnormal p53 patterns (reflecting underlying TP53 mutations) generally behave more aggressively than tumors without such patterns.

Stage at diagnosis is the most important factor in predicting outcome at any cancer type, but five-year survival rates for HPV-independent cervical squamous cell carcinoma are lower than for HPV-associated cervical squamous cell carcinoma at each comparable stage. Several additional pathologic features influence the chance of recurrence:

Stage at diagnosis — The single most important prognostic factor. Earlier stages have better outcomes, but outcomes are less favorable than for HPV-associated tumors at any given stage.
Lymph node involvement — The number and location of involved lymph nodes, whether pelvic or para-aortic, all influence prognosis.
Lymphovascular invasion — Increases the risk of lymph node spread and recurrence.
Surgical margin status — Negative margins are associated with a lower risk of local recurrence. Positive margins increase the chance that residual disease is present.
Tumor size and depth of invasion — Larger and deeper tumors are associated with a higher risk of recurrence and worse outcomes.
Perineural invasion — When present, is associated with a higher risk of local recurrence.
p53 staining pattern — An abnormal p53 staining pattern (loss of expression or strong overexpression), which reflects an underlying TP53 mutation, is associated with more aggressive behavior in some studies.
Biomarker results — A PD-L1 CPS of 1 or higher identifies patients who may benefit from immune checkpoint inhibitor therapy in advanced disease.

What happens after this diagnosis?

Once HPV-independent squamous cell carcinoma is diagnosed, the gynecologic oncology team will discuss the treatment options with the patient. The choice depends on the stage, the size of the tumor, the patient’s age and overall health, and the specific findings on the pathology report. Treatment paradigms are largely the same as for HPV-associated cervical squamous cell carcinoma, but because HPV-independent tumors tend to behave more aggressively, the team often pays particular attention to features such as lymph node involvement, margin status, and biomarker results when planning treatment.

Options the team may consider include:

Cone biopsy or simple hysterectomy — For the earliest invasive cancers (typically stage IA1) without high-risk features, complete excision with a cone biopsy may be sufficient. Simple hysterectomy is another option for patients who have completed their families. Fertility-preserving surgery is less commonly an option for HPV-independent squamous cell carcinoma than for HPV-associated tumors because of the more aggressive behavior of this cancer.
Radical hysterectomy with pelvic lymph node assessment — For patients with stage IA2 to stage IIA cancer, radical hysterectomy (removal of the uterus, cervix, parametrium, and upper vagina) combined with sentinel lymph node biopsy or pelvic lymph node dissection is a commonly considered approach. The pathology report from this specimen provides definitive staging and the information needed to decide whether additional treatment is needed.
Chemoradiation therapy — For locally advanced cancer (typically stage IB3 and higher), the team often discusses concurrent chemotherapy and radiation rather than primary surgery. Chemoradiation may also be added after surgery when the pathology report shows high-risk features such as positive margins, parametrial invasion, or lymph node involvement.
Systemic therapy for advanced or recurrent disease — For stage IVB or recurrent disease, the medical oncology team discusses systemic options including chemotherapy and immune checkpoint inhibitor therapy. Eligibility for immunotherapy (pembrolizumab) depends on the PD-L1 result, with a CPS of 1 or higher generally required. MMR or MSI testing may also be performed to determine eligibility for pan-tumor immunotherapy approvals. Enrollment in clinical trials of new combinations may be discussed because HPV-independent cervical cancers are less well-studied than their HPV-associated counterparts.

After treatment, regular follow-up is essential. Surveillance typically includes physical and pelvic examinations every three to six months for the first two to three years, then less frequently. Imaging and additional tests are added based on the original stage, pathology findings, and the patient’s overall risk of recurrence.

Questions to ask your doctor

What is the stage of my cervical cancer using both the TNM and FIGO systems?
How large is the tumor, and how deeply has it grown into the cervix?
Was p16 testing performed, and did it confirm that my cancer is HPV-independent?
Was p53 testing performed, and what did the result show?
Was lymphovascular invasion present in my pathology specimen?
Was perineural invasion present?
Were the surgical margins negative, close, or positive?
How many lymph nodes were examined, and were any involved by cancer?
Was PD-L1 testing performed, and what does the result mean for my treatment options?
Was MMR or MSI testing performed, and what did it show?
How does my prognosis compare with someone who has HPV-associated cervical cancer at the same stage?
What treatment options would you discuss with me based on my pathology findings?
Are there clinical trials available that might be appropriate for my situation?
What follow-up schedule will I have after treatment, and what symptoms should prompt me to contact you between appointments?