Clear Cell Carcinoma of the Cervix: Understanding Your Pathology Report

By Jason Wasserman MD PhD FRCPC
May 17, 2026

Clear cell carcinoma is a rare type of cervical cancer that develops from glandular cells in the cervix. It is called “clear cell” because the cancer cells often have pale or transparent-looking cytoplasm (the body of the cell that surrounds the nucleus) when viewed under the microscope. Clear cell carcinoma accounts for approximately 3 to 9% of all cervical adenocarcinomas. Unlike most cervical cancers, it is not caused by infection with human papillomavirus (HPV) and is classified as an HPV-independent cervical adenocarcinoma in the 2020 World Health Organization classification of female genital tumors. This article will help you understand the findings in your pathology report, what each term means, and why it matters for your care.

Clear cell carcinoma of the cervix has a distinctive pattern in who it affects. Two groups of patients are most commonly diagnosed: younger patients in their teens or 20s (historically linked to in utero exposure to a medication called diethylstilbestrol, or DES) and older patients in their 50s or beyond who have had no such exposure. Because DES has not been used since the early 1970s, current cases in younger patients without DES exposure are increasingly being recognized.

What causes clear cell carcinoma of the cervix?

Unlike most cervical cancers, clear cell carcinoma is not caused by HPV infection. The exact cause is not fully understood, and most cases occur without any identifiable risk factor. Two recognized situations are associated with clear cell carcinoma of the cervix:

In utero diethylstilbestrol (DES) exposure — DES is a synthetic form of estrogen that was prescribed to pregnant women between 1940 and the early 1970s to try to prevent miscarriage. Female children whose mothers took DES during pregnancy were later found to have an increased risk of clear cell carcinoma of the vagina and cervix, often at a young age. The median age at diagnosis for DES-related clear cell carcinoma has historically been about 19 years. DES has not been used in pregnancy for decades, and DES-related cases are now rare.
Sporadic (non-DES) cases — Most current cases of clear cell carcinoma of the cervix occur in patients without DES exposure. The median age at diagnosis for these sporadic cases is approximately 51 years, although clear cell carcinoma can also occur in adolescents and young adults without prior DES exposure. The cause of these sporadic cases is not yet known, but research suggests they may arise from a change in the cells lining the cervix called tubo-endometrial metaplasia.

In rare cases, clear cell carcinoma of the cervix has been described in patients with Lynch syndrome, an inherited condition that increases the risk of several types of cancer. If clear cell carcinoma is found alongside features suggesting an inherited cancer predisposition, the team may discuss referral for genetic counseling and testing.

What are the symptoms?

The symptoms of clear cell carcinoma of the cervix are similar to those of other cervical cancers but can sometimes be missed because of where the tumor develops. The most common symptom is abnormal vaginal bleeding, including bleeding after intercourse, between menstrual periods, or after menopause. Some patients notice an unusual vaginal discharge, which may be watery or blood-tinged. Pelvic pain is less common and tends to occur with more advanced disease.

Clear cell carcinoma often grows deep within the wall of the cervix rather than on the surface, which means it can be difficult to detect by visual examination alone and may not be picked up reliably by routine cervical cancer screening with a Pap test and HPV test. Younger patients are sometimes initially evaluated for what appears to be irregular bleeding from a non-cancerous cause, and the diagnosis may only be made when a tissue sample is taken.

How is the diagnosis made?

The diagnosis of clear cell carcinoma of the cervix usually begins when symptoms or an abnormal finding on examination lead to further evaluation. Tissue from the cervix is removed and examined under the microscope by a pathologist. The sample may be obtained through a biopsy taken during colposcopy, an endocervical curettage to sample tissue inside the cervical canal, a cone biopsy that removes a larger cone-shaped portion of the cervix, or a hysteroscopy in cases where the tumor extends into the body of the uterus. If surgery is performed to treat the cancer, the pathologist also examines the removed tissue to measure the size of the tumor, to determine how deeply it has grown into the cervix and surrounding structures, to assess the surgical margins, and to evaluate any lymph nodes that were removed.

Because clear cell carcinoma can look similar to several other cancers under the microscope, including HPV-associated cervical adenocarcinoma, HPV-independent gastric-type adenocarcinoma, and endometrial cancer that has extended into the cervix, the pathologist performs several special tests to confirm the diagnosis. These tests, called immunohistochemistry, use antibodies to detect specific proteins inside the tumor cells. Clear cell carcinoma of the cervix typically shows the following pattern:

Positive markers — Napsin A, HNF1-beta, PAX8, and broad-spectrum cytokeratins (CK7, AE1/AE3, CAM 5.2). Napsin A and HNF1-beta are particularly characteristic of clear cell carcinoma and help separate it from other cervical cancers.
Negative or near-negative markers — Estrogen receptor (ER), progesterone receptor (PR), vimentin, p63, and p40. The negativity for p63 and p40 helps distinguish clear cell carcinoma from squamous cell carcinoma.
p16 — Typically negative or shows only patchy, weak staining, in contrast to HPV-associated cervical cancers, which usually show strong, continuous “block-type” p16 staining.
p53 — Typically shows a wild-type (normal) pattern in most cases, which helps distinguish clear cell carcinoma from HPV-independent gastric-type adenocarcinoma, which often shows an abnormal p53 pattern.
HPV testing — In situ hybridization for HPV genetic material is negative, confirming that the cancer is not HPV-driven.

What does clear cell carcinoma of the cervix look like under the microscope?

Under the microscope, clear cell carcinoma of the cervix is made up of cancer cells with several recognizable features:

Clear cells — The most characteristic cells have pale or transparent-looking cytoplasm, which gives the tumor its name. The clear appearance is caused by stored glycogen, a form of sugar that washes out during tissue processing, leaving the cell looking empty under the microscope.
Hobnail cells — Some cells have a distinctive shape in which the nucleus bulges outward into the open space inside a gland, resembling the shape of a hobnail (a short, stubby nail). Hobnail cells are a hallmark feature of clear cell carcinoma.
Eosinophilic or oxyphilic cells — Some tumors contain cells with bright pink cytoplasm rather than clear cytoplasm. These cells may be mixed with clear cells or, rarely, constitute the entire tumor.
Variable growth patterns — Clear cell carcinoma can grow in several patterns, including tubulocystic (small tubes and cysts), papillary (finger-like projections), and solid (sheets of cells). Most tumors show a mixture of these patterns.
Deep, infiltrative growth — These tumors often grow in an “endophytic” pattern, meaning they extend deep into the wall of the cervix rather than outward into the canal. This deep growth pattern contributes to the difficulty of detecting clear cell carcinoma on routine examination and screening.
Lower mitotic activity — The number of dividing cells (mitotic figures) is usually lower in clear cell carcinoma than in HPV-associated cervical cancers, which can sometimes lead to confusion with a benign lesion if the tumor is not carefully examined.

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. Clear cell carcinoma often shows deep invasion at the time of diagnosis because of its tendency to grow in an endophytic pattern.

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, and the team may 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.

Clear cell carcinoma of the cervix has a meaningful risk of spreading to lymph nodes, which is one of the strongest predictors of outcome. 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 is most relevant in advanced, recurrent, or metastatic clear cell carcinoma, 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 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 persistent, recurrent, or metastatic disease. A PD-L1 result on the pathology report does not, by itself, dictate treatment; instead, it informs the discussion the medical oncology team has with the patient about whether immunotherapy is an appropriate option. Because clear cell carcinoma may be less responsive to conventional chemotherapy than other cervical cancers, PD-L1-guided immunotherapy is a particularly important consideration in advanced 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 clear cell carcinoma of the cervix, but when present, it identifies patients who may benefit from pembrolizumab, which is approved across tumor types for cancers that are dMMR or MSI-high regardless of where the cancer started. MMR deficiency may also indicate Lynch syndrome, an inherited condition that increases the risk of multiple cancer types, and referral for genetic counseling may be discussed if dMMR is found.

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.
  - 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 outlook for clear cell carcinoma of the cervix depends most strongly on the stage at diagnosis. Outcomes are generally similar to other cervical cancers when matched for stage, but several features of clear cell carcinoma make stage-by-stage comparisons complicated. The tumor often grows deep within the cervix and may not be detected until it has reached a meaningful size, and it can be less responsive to conventional chemotherapy than HPV-associated cervical cancers. Reported five-year overall survival rates for clear cell carcinoma of the cervix include approximately 80 to 90% for stage I to IIA disease and approximately 40 to 65% for stage IIB to IV disease, although these numbers vary across studies and patient populations.

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

Stage at diagnosis — The single most important prognostic factor. Outcomes are substantially better for early-stage (FIGO I to IIA) disease than for advanced disease.
Lymph node involvement — Has a particularly strong impact on prognosis. Negative pelvic lymph nodes are associated with the most favorable outcomes; positive nodes are associated with a meaningfully higher risk of 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.
Lymphovascular invasion — Increases the risk of lymph node spread and recurrence.
Tumor size and depth of invasion — Larger and deeper tumors carry a higher risk of recurrence and worse outcomes.
Tumor extension — Clear cell carcinoma is more likely than other cervical cancers to extend upward into the body of the uterus or to spread to the ovaries, and these patterns of extension worsen the prognosis.
Perineural invasion — When present, is associated with a higher risk of local recurrence.
DES exposure status — Historically, DES-related cases in young patients have been distinguished from sporadic cases. Stage-matched comparisons suggest the two groups have broadly similar prognosis, though long-term outcomes continue to be studied.

Recurrences, when they occur, most often happen within the first 2 to 3 years after treatment. Common sites of distant spread include the lungs, liver, and bones.

What happens after this diagnosis?

Once clear cell carcinoma of the cervix is diagnosed, the gynecologic oncology team will discuss the treatment options with the patient. The choice depends on the stage, the size and location of the tumor, the patient’s age and wish to preserve fertility, overall health, and the specific findings on the pathology report. Because clear cell carcinoma is rare, treatment generally follows the same principles as for other cervical cancers, with particular attention to features such as lymph node involvement and tumor extension that are more common in this tumor type.

Options that the team may consider include:

Radical hysterectomy with pelvic lymph node assessment — For early-stage disease (typically FIGO IA2 through IIA), radical hysterectomy (surgical 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. Because clear cell carcinoma has an increased risk of ovarian spread compared with other cervical cancers, the team may also discuss bilateral salpingo-oophorectomy (removal of the fallopian tubes and ovaries) at the time of surgery.
Fertility-sparing surgery — For carefully selected younger patients with small early-stage tumors, fertility-preserving options such as cone biopsy or radical trachelectomy (removal of the cervix while leaving the uterus in place) may be discussed. Reported outcomes in selected patients have been favorable in small case series, but the rarity of the tumor means decisions are made on an individual basis.
Chemoradiation therapy — For locally advanced disease (typically FIGO IB3 and higher), the team often discusses concurrent chemotherapy and radiation. 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. Conventional chemotherapy regimens (typically platinum-based, sometimes with bevacizumab) are commonly considered, although clear cell carcinoma may be less responsive to chemotherapy than other cervical cancers. Eligibility for immunotherapy (pembrolizumab) depends on the PD-L1 result, with a CPS of 1 or higher generally required, or on the MMR status. Enrollment in clinical trials may be discussed because clear cell carcinoma is rare and standard treatment data are limited.
Genetic counseling — Because clear cell carcinoma of the cervix has been described in patients with Lynch syndrome, referral for genetic counseling may be discussed when there are clinical or family history features that suggest an inherited cancer predisposition, or when MMR testing identifies mismatch repair deficiency.

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, the 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?
Did the cancer extend into the body of the uterus, the parametrium, or any other nearby structure?
Was p16 staining performed, and did it confirm that my cancer is HPV-independent?
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?
Should I be referred for genetic counseling, particularly given the rare association with Lynch syndrome?
What treatment options would you discuss with me based on my pathology findings?
I want to preserve my fertility — is fertility-sparing surgery a safe option for my situation?
How does my outlook compare with other types of cervical cancer at the same stage?
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?