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

by Jason Wasserman MD PhD FRCPC
May 15, 2026

HPV-associated squamous cell carcinoma is the most common type of cervical cancer. It develops from squamous cells, the flat cells that line the outer surface of the cervix, following persistent infection with high-risk types of human papillomavirus (HPV). Most cases develop slowly over many years from a precancerous condition called high-grade squamous intraepithelial lesion (HSIL).

This article will help you understand the findings in your pathology report, what each term means, and why it matters for your care. If you have been diagnosed with a different type of cervical cancer, our article on HPV-associated adenocarcinoma of the cervix may be helpful.

What causes HPV-associated squamous cell carcinoma?

HPV is a very common virus that spreads through sexual contact. Most HPV infections clear on their own within one to two years. When infection with a high-risk HPV type (most often HPV16 or HPV18) persists in the cervix, the virus produces proteins that interfere with the systems that normally control cell growth and division. Over time, this allows abnormal cells to accumulate genetic damage and progress from precancerous changes (HSIL) to invasive cancer.

Additional factors that increase the risk of progression include cigarette smoking, a weakened immune system, and the absence of regular cervical cancer screening. Vaccination against high-risk HPV types substantially reduces the risk of developing this cancer.

What are the symptoms?

Many people with early-stage cervical cancer have no symptoms, and the cancer is detected only through screening. When symptoms are present, they commonly include abnormal vaginal bleeding (such as bleeding after intercourse, between menstrual periods, or after menopause), increased vaginal discharge that may be watery, bloody, or have an unusual odor, and pelvic pain or discomfort during sexual intercourse. As the tumor grows larger, it may also cause pain in the lower back or pelvis.

How is the diagnosis made?

The diagnosis usually follows an abnormal result on a Pap test or a positive HPV test, which prompts a closer examination of the cervix called colposcopy. During colposcopy, the doctor identifies suspicious areas and takes small tissue samples called biopsies. The tissue may also be obtained through a cone biopsy or loop electrosurgical excision procedure (LEEP), which removes a larger cone-shaped portion of the cervix and allows the pathologist to assess both the depth of any invasion and whether the edges of the specimen are clear of disease.

Under the microscope, HPV-associated squamous cell carcinoma consists of irregular nests, sheets, and cords of squamous cells that have broken through the surface layer of the cervix and grown into the supporting tissue beneath, a process called invasion. The tumor cells often vary widely in size and shape, a feature called pleomorphism, and many are actively dividing. The surrounding tissue frequently shows a fibrous reaction called desmoplasia. The most common growth patterns are non-keratinizing and basaloid, while less common patterns include keratinizing, warty, papillary, and lymphoepithelioma-like.

To confirm the diagnosis, the pathologist often performs special tests called immunohistochemistry (IHC). HPV-associated cervical cancers typically show strong, diffuse staining for p16, a protein that becomes overexpressed when high-risk HPV disrupts normal cell-cycle control. In some cases, in situ hybridization (ISH) is also performed to detect HPV DNA or RNA directly within the tumor cells, providing further confirmation that the cancer is HPV-driven. Once the diagnosis is confirmed, imaging studies (typically CT, MRI, or PET-CT) are used to determine how far the cancer has spread.

Histologic grade

Histologic grade describes how closely the tumor cells resemble normal squamous cells under the microscope. Pathologists assign one of three grades:

Well differentiated (grade 1) — The tumor cells still resemble normal squamous cells, often producing keratin. These tumors tend to grow more slowly.
Moderately differentiated (grade 2) — The cells show more abnormality and are less organized, but squamous features are still recognizable.
Poorly differentiated (grade 3) — The cells look very different from normal squamous cells and grow in a disorganized pattern. These tumors tend to behave more aggressively.

Grade is one of several factors considered alongside stage, tumor size, and depth of invasion when planning treatment and estimating prognosis. In the current FIGO staging system for cervical cancer, grade is not used to assign a stage, but it still provides useful prognostic information and may appear in your pathology report.

Tumor size and depth of invasion

After the diagnosis is established, the pathologist measures two key features that determine the tumor stage: how large the tumor is and how deeply it has grown into the tissue of the cervix.

Tumor size is measured along the surface of the cervix in centimeters. Larger tumors are more likely to have spread to lymph nodes or nearby structures and are more likely to be assigned a higher stage.

Depth of invasion describes how far tumor cells have grown from the surface layer of the cervix into the underlying connective tissue, called the stroma. It is measured in millimeters from the base of the surface epithelium to the deepest point of invasion. Tumors that invade more deeply are more likely to reach lymphatic channels, blood vessels, and nearby structures, increasing the risk of spread. The combination of tumor size and depth of invasion determines the pathologic T stage (see the staging section below).

Tumor extension

As squamous cell carcinoma grows larger, it may spread beyond the cervix into surrounding structures. This is called tumor extension. The pathologist examines the specimen to determine whether the cancer has spread into nearby tissues:

The parametrium — the fibrous tissue that surrounds and supports the cervix on both sides. Parametrial invasion significantly increases the stage and is an important factor in treatment planning.
The vagina — the upper or lower vagina may become involved as the tumor grows downward.
The uterine body — the tumor may extend upward into the body of the uterus.
The pelvic wall — in advanced cases, the tumor may extend to the pelvic wall, potentially compressing the ureters (the tubes that carry urine from the kidneys to the bladder).
The bladder or rectum — the most advanced local spread, indicating stage IVA disease.

Lymphovascular invasion

Lymphovascular invasion means that tumor cells have entered the small lymphatic channels or blood vessels within the cervical tissue. These channels serve as pathways for cancer cells to travel to nearby lymph nodes or more distant organs. The presence of lymphovascular invasion is associated with a higher risk of lymph node involvement and distant spread, and it may influence decisions about the extent of surgery and the use of additional treatment such as radiation therapy. Your pathology report will state whether lymphovascular invasion is present or absent.

Perineural invasion

Perineural invasion means that tumor cells are growing along or around small nerves within the cervix. Nerves run through the cervical tissue, and tumor cells that reach them can use nerve pathways to spread into surrounding tissues beyond the visible tumor mass. Perineural invasion is associated with a higher risk of local recurrence after treatment. Your pathology report will state whether perineural invasion is present or absent.

Surgical margins

A margin is the edge of tissue removed during surgery or a cone biopsy. The pathologist examines these surfaces to determine whether cancer cells are present at the cut edges of the specimen.

Negative margin — No cancer cells are present at the cut edge. This suggests that the tumor was completely removed in that area.
Positive margin — Cancer cells are present at the cut edge. This raises concern that some tumor may remain in the body, and the team typically discusses additional treatment or further surgery.

For cone biopsies and LEEP specimens, several specific margins are assessed:

Endocervical margin — the inner edge of the specimen, toward the uterus. A positive endocervical margin raises concern that the disease extends higher into the cervical canal.
Ectocervical margin — the outer edge of the specimen, toward the vagina.
Deep (stromal) margin — the deepest surface of the specimen, indicating whether invasion reaches the edge of the tissue removed.

For a hysterectomy specimen, the pathologist additionally evaluates the vaginal cuff margin (the top of the vagina where it was cut) and, when present, the parametrial margin (the soft tissue surrounding the cervix). Clear margins on a cone biopsy may allow some patients with very early-stage disease to avoid a hysterectomy.

Lymph nodes

Lymph nodes are small immune organs that filter the fluid draining from the cervix and surrounding tissues. During surgery for cervical cancer, the lymph nodes in the pelvis (and sometimes those along the major blood vessels of the abdomen) are removed and examined under the microscope. Your report will state the total number of lymph nodes examined and how many, if any, contain cancer cells.

When cancer is found in a lymph node, the report describes the size of the tumor deposit using standard categories:

Isolated tumor cells — Clusters measuring 0.2 mm or less. These are generally not considered true metastases and are noted separately. Their clinical significance is uncertain.
Micrometastasis — Deposits measuring more than 0.2 mm but no larger than 2 mm.
Macrometastasis — Deposits measuring more than 2 mm. This is the standard definition of a positive lymph node for staging purposes.

The report may also describe 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. Lymph node involvement significantly increases the cancer stage and is one of the strongest predictors of outcome.

Biomarker and molecular testing

Biomarker testing in HPV-associated squamous cell carcinoma of the cervix is most relevant in advanced, recurrent, or metastatic disease, where the results help determine which systemic treatments are most likely to be effective.

PD-L1

PD-L1 is a protein that some cancer cells and immune cells produce to suppress immune activity. Normally, PD-L1 signals immune cells to stand down, helping prevent an overactive immune response. Some cancer cells exploit this mechanism to hide from immune attack. Immunotherapy drugs called immune checkpoint inhibitors block PD-L1 or its receptor, removing this shield and allowing the immune system to recognize and destroy cancer cells.

PD-L1 testing is performed by immunohistochemistry on the tumor tissue. Results are reported as a Combined Positive Score (CPS), which counts the number of tumor cells and nearby immune cells expressing PD-L1, then reports this as a proportion of the total tumor cells. A CPS of 1 or higher is considered positive. In cervical cancer, a CPS of 1 or higher identifies patients eligible for treatment with pembrolizumab (Keytruda) in combination with chemotherapy for persistent, recurrent, or metastatic disease, and for pembrolizumab as a single agent in some later-line settings. PD-L1 testing is typically performed when the cancer has returned after initial treatment or has spread beyond the pelvis.

Mismatch repair (MMR) protein 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). When all four proteins are present, the result is mismatch repair proficient (pMMR).

MMR deficiency is uncommon in HPV-associated cervical squamous cell carcinoma, but when present, it has two important implications. First, dMMR tumors may respond particularly well to immune checkpoint inhibitor therapy. Pembrolizumab is approved for any solid tumor that is dMMR or MSI-high, regardless of where the cancer started. Second, MMR deficiency may indicate an inherited condition called Lynch syndrome, which significantly increases the lifetime risk of colorectal, endometrial, and other cancers. Referral for genetic counseling is typically recommended when MMR deficiency is identified, as it may affect other family members.

For more information about these and other biomarker tests, visit our Biomarkers and Molecular Testing section.

Pathologic stage

Staging describes how far the cancer has spread. Stage is the single most important factor in predicting outcome and in shaping the treatment decisions made by the gynecologic and medical oncology teams. Cervical cancer is staged using two related systems: the AJCC pTNM system (currently the AJCC 8th edition) and the FIGO system (currently the FIGO 2018 revision, which remains in effect). 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 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?

The prognosis depends on several factors, with the pathologic stage at diagnosis being the most important. Early-stage cancers confined to the cervix have the most favorable outcomes. Five-year survival rates are approximately 90 to 95% for stage I disease, 70 to 80% for stage II, 40 to 60% for stage III, and less than 20% for stage IV. These are population-level estimates, and individual outcomes vary by tumor characteristics and treatment response.

Additional pathologic features that influence prognosis include:

Lymph node involvement — The strongest pathologic predictor of recurrence and survival. Even a single positive pelvic lymph node significantly worsens the outlook and typically drives the discussion about adding chemoradiation after surgery.
Parametrial invasion — Indicates locally advanced disease (stage IIB or higher) and is associated with a higher risk of local recurrence.
Positive surgical margins — Associated with a higher risk of local recurrence and may prompt the team to discuss additional treatment.
Lymphovascular invasion — Increases the risk of lymph node involvement and distant spread, even in otherwise early-stage tumors. Its presence often influences the decision to add radiation after surgery.
Tumor size and depth of invasion — Larger, more deeply invasive tumors carry a higher risk of nodal spread and recurrence.
Histologic grade — Poorly differentiated tumors tend to behave more aggressively than well-differentiated ones, though grade is a less dominant factor than stage.
PD-L1 status — In advanced disease, a positive CPS result predicts that the cancer is more likely to respond to pembrolizumab-based immunotherapy, which has meaningfully improved survival in the recurrent and metastatic setting.

What happens after this diagnosis?

Treatment planning involves a multidisciplinary team that includes a gynecologic oncologist, radiation oncologist, and medical oncologist. The approach the team discusses with the patient depends on stage, tumor size, the presence of specific high-risk features, the patient’s age and overall health, and whether fertility preservation is a priority.

Options the team may consider include:

Cone biopsy or LEEP — For very early, microscopic tumors (typically stage IA1) in patients who wish to preserve fertility, complete excision with a cone biopsy or LEEP may be sufficient on its own.
Radical hysterectomy with pelvic lymph node assessment — For early-stage disease (typically stage IA2 to IB2), radical hysterectomy (surgical removal of the uterus, cervix, and surrounding parametrial tissue) combined with sentinel lymph node biopsy or pelvic lymph node dissection is a commonly considered approach. The pathology findings from this specimen guide whether additional treatment is needed afterward.
Concurrent chemoradiation after surgery — When the pathology report shows high-risk features such as positive lymph nodes, positive surgical margins, or parametrial invasion, the team often discusses adding chemoradiation after surgery to reduce the risk of recurrence.
Concurrent chemoradiation as primary treatment — For locally advanced disease (stages IB3 through IVA), the standard approach is concurrent chemoradiation rather than primary surgery. This involves radiation therapy delivered together with chemotherapy (typically cisplatin), which sensitizes the cancer to radiation. Treatment usually includes brachytherapy (internal radiation placed directly near the cervix) as well.
Systemic therapy for advanced or recurrent disease — For stage IVB or recurrent disease, the medical oncology team discusses systemic options that may include chemotherapy combined with bevacizumab (a drug that blocks tumor blood vessel growth), and pembrolizumab-based immunotherapy when PD-L1 testing shows a CPS of 1 or higher. Clinical trials of new combinations, including additional immunotherapies, targeted therapies, and antibody-drug conjugates, may also be available.

After treatment, regular follow-up is essential. Surveillance typically includes pelvic examinations, Pap testing, and imaging at intervals determined by the original stage and pathology findings. Patients who had fertility-sparing surgery have close ongoing surveillance of the remaining cervix.

Questions to ask your doctor

What stage is my cancer using both the TNM and FIGO systems?
What is the size of the tumor and the depth of invasion in my pathology specimen?
Was lymphovascular invasion present?
Was perineural invasion present?
Were the surgical margins clear? Was the tumor completely removed?
How many lymph nodes were examined, and how many were involved?
Did the cancer extend into the parametrium, vagina, or other nearby structures?
What was the histologic grade of my tumor?
Was PD-L1 testing performed, and what was the CPS result? How does it affect my treatment options?
Was mismatch repair (MMR) testing performed? If my tumor is MMR-deficient, should I be referred for genetic counseling to assess for Lynch syndrome?
What treatment options would you discuss with me based on my pathology findings?
Is fertility preservation an option for me given my stage and tumor features?
What follow-up tests and appointments will I need, and how often?
Are there any clinical trials available for my stage and tumor profile?