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

by Jason Wasserman MD PhD FRCPC
April 10, 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 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 endocervical adenocarcinoma 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 HPV 16 or HPV 18 — persists in the cervix, the virus produces proteins that interfere with the normal systems that 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 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 sex, 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 can identify suspicious areas and take 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 is made up 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; less common patterns include keratinizing, warty, papillary, and lymphoepithelioma-like. The pathologist may also use special laboratory tests called immunohistochemistry (IHC) to confirm the diagnosis. 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, and/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 at 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 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:

• 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. Its presence 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 need for 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

Margins are the edges of the 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 the tumor was completely removed in that area.
• Positive margin — Cancer cells are present at the cut edge, raising concern that some tumor may remain in the body. Additional treatment or further surgery is usually recommended.

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, assessing 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 will describe 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 2 mm or less.
• 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 (pN1 or higher) 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 — it is part of the body’s mechanism for preventing an overactive immune response. In cervical cancer, tumor cells can exploit this mechanism to hide from immune attack. Immunotherapy drugs called 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 and indicates that the cancer may respond to immunotherapy. Pembrolizumab (Keytruda) is approved for use in combination with chemotherapy as first-line treatment for persistent, recurrent, or metastatic cervical cancer in patients with a CPS ≥1, and 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 checkpoint inhibitor immunotherapy — pembrolizumab has pan-tumor approval for dMMR/MSI-high cancers regardless of where they 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 usually recommended when MMR deficiency is identified, as it may have implications for other family members.

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

Pathologic stage (pTNM)

The pathologic stage describes how far the cancer has spread, based on what the pathologist finds when examining the surgical specimen. It uses the internationally recognized TNM staging system, which considers the primary tumor (T), lymph node involvement (N), and distant metastasis (M). Higher numbers indicate more advanced disease. Metastasis to distant organs is typically determined by imaging rather than by pathology.

You may also see reference to the FIGO staging system (from the International Federation of Gynecology and Obstetrics) in your clinical notes. FIGO staging is widely used by gynecologic oncologists for cervical cancer and assigns stages (I through IV) based on the same features of tumor size, invasion, and spread. The TNM and FIGO systems describe the same information in different formats; your care team will explain which system they are using.

Tumor stage (pT)

• pT1a1 — Microscopic invasion only; depth of invasion 3 mm or less.
• pT1a2 — Microscopic invasion only; depth of invasion more than 3 mm but 5 mm or less.
• pT1b1 — Clinically visible tumor or depth of invasion greater than 5 mm; tumor 2 cm or smaller.
• pT1b2 — Tumor more than 2 cm but 4 cm or smaller, confined to the cervix.
• pT1b3 — Tumor more than 4 cm, confined to the cervix.
• pT2a — Tumor extends beyond the cervix and uterus but has not reached the parametrium; the upper two-thirds of the vagina may be involved.
• pT2b — Tumor extends into the parametrium but has not reached the pelvic wall.
• pT3a — Tumor involves the lower third of the vagina but has not reached the pelvic wall.
• pT3b — Tumor extends to the pelvic wall, or the tumor is blocking a ureter and causing kidney damage (hydronephrosis).
• pT4 — Tumor has invaded the bladder or rectum, or has extended beyond the pelvis.

Nodal stage (pN)

• pN0 — No cancer found in any lymph nodes examined.
• pN0(i+) — Isolated tumor cells only (≤0.2 mm) — not counted as positive for staging.
• pN1 — Cancer found in one or more pelvic lymph nodes (micrometastasis or macrometastasis).
• pN2 — Cancer found in one or more para-aortic (abdominal) lymph nodes.
• pNX — Lymph nodes were not assessed.

What is the prognosis for HPV-associated squamous cell carcinoma of the cervix?

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

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 recommendation for concurrent 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 the need for 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 treat with 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 the diagnosis?

Treatment planning involves a team including a gynecologic oncologist, radiation oncologist, and medical oncologist. The approach depends on stage, tumor size, and whether specific high-risk features are present.

For early-stage disease (stages IA1 to IB2), treatment is typically surgery — either a cone biopsy or LEEP (for very early, microscopic tumors in patients who wish to preserve fertility) or a radical hysterectomy (surgical removal of the uterus, cervix, and surrounding parametrial tissue) combined with pelvic lymph node dissection. Radiation therapy may be recommended after surgery if high-risk features are present, such as positive lymph nodes, positive margins, or parametrial invasion — a combination known as adjuvant concurrent chemoradiation.

For locally advanced disease (stages IB3 through IVA), the standard treatment is concurrent chemoradiation — radiation therapy given together with chemotherapy (typically cisplatin), which sensitizes the cancer to radiation. This is delivered to the pelvis and may include brachytherapy (internal radiation placed directly near the cervix).

For advanced, recurrent, or metastatic disease, systemic treatment is the primary approach. This typically involves chemotherapy combined with bevacizumab (a drug that blocks tumor blood vessel growth) and pembrolizumab for tumors with a CPS ≥1. Clinical trials exploring new combinations of immunotherapy, targeted therapy, and antibody-drug conjugates are also available and actively enrolling.

After treatment, regular follow-up, including pelvic examinations, Pap tests, and imaging, is used to monitor for recurrence. Patients who had fertility-sparing surgery will have close surveillance of the remaining cervix.

Questions to ask your doctor

Your pathology report contains important information that will guide your care. The following questions may help you prepare for your next appointment.

• What stage is my cancer, and what does that mean for my treatment options and prognosis?
• What is the size of the tumor and the depth of invasion?
• Was lymphovascular invasion present in my specimen?
• Was perineural invasion present?
• Were the surgical margins clear? Was the tumor completely removed?
• Were any lymph nodes involved, and if so, how many and what size were the deposits?
• Did the cancer extend into the parametrium, vagina, or any other nearby structures?
• What was the histologic grade of my tumor?
• Was PD-L1 testing performed, and what was the CPS result? Does this 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?
• Is fertility preservation possible 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?