Endometrial Clear Cell Carcinoma: Understanding Your Pathology Report

Section Editor: Kianoosh Keyhanian MD FRCPC
September 3, 2026

Endometrial clear cell carcinoma is an uncommon cancer that starts in the endometrium, the inner lining of the uterus. It makes up only a small share of endometrial cancers. It is considered high-grade, meaning it carries a higher risk of spreading beyond the uterus than low-grade endometrial cancers.

The name comes from the cells’ appearance. Many of them have cytoplasm, the material filling the cell around its center, that looks clear or empty under the microscope. Not every tumor with this diagnosis shows that appearance, and not every tumor showing it is a clear cell carcinoma.

This cancer behaves differently from the more common endometrioid carcinoma and is generally treated as high risk. Many cases are found at an early stage, and the outlook depends far more on the stage than on the diagnosis alone.

What causes endometrial clear cell carcinoma?

The cause is not fully understood, and this cancer significantly differs from the common type. Endometrioid carcinoma is driven by long-term exposure to estrogen without enough progesterone to balance it, and it usually develops out of a recognizable precancerous condition. Clear cell carcinoma is not clearly linked to estrogen, and it usually appears without a precursor.

It occurs most often in older adults, typically well after menopause. At the molecular level, no single genetic change defines it. Different tumors show different patterns, and some overlap biologically with serous carcinoma, some with endometrioid carcinoma, some with both, and some with neither.

What are the symptoms?

Abnormal vaginal bleeding — The most common symptom, particularly bleeding after menopause. Assess any bleeding after menopause promptly.
Unusual vaginal discharge — May be watery or blood-tinged.
Pelvic discomfort, pressure, or pain — Less common than bleeding.
An abnormal Pap test — Occasionally the first abnormal finding, particularly when the disease is advanced.

People with this diagnosis have an increased risk of blood clots in the veins. Assess swelling, pain, or redness in a leg, or sudden breathlessness or chest pain, urgently.

How is the diagnosis made?

The process usually begins with an endometrial biopsy, in which a small sample of the lining is removed and examined under the microscope by a pathologist.

If cancer is found, surgery generally follows to remove the uterus, and often the ovaries, fallopian tubes, and lymph nodes. Pathologists examine that tissue to determine how deeply the tumor has grown, whether it has spread, and which biomarkers are present.

This is one of the harder diagnoses in endometrial pathology to make with confidence. Several other tumors and even some normal changes can contain cells with clear cytoplasm, and pathologists do not always agree on the classification. A pathologist who specializes in gynecologic pathology often reviews cases, and the diagnosis is sometimes revised on review. Asking whether that review has happened is reasonable.

What does endometrial clear cell carcinoma look like under the microscope?

Endometrial clear cell carcinoma usually shows a mixture of growth patterns rather than one uniform appearance.

Tubulocystic growth — The tumor forms a mixture of small glands and cyst-like spaces.
Papillary growth — The tumor forms short, rounded, finger-like projections.
Solid growth — The tumor cells grow in sheets.

The cells themselves vary in shape. They may be angular, cube-shaped, flattened, or described as hobnail, meaning the nucleus bulges into the space inside a gland like a stud on a boot. The cytoplasm may be clear or pink.

One point often surprises people. Clear cytoplasm and hobnail cells are characteristic but not required. The diagnosis rests on the overall pattern and appearance of the tumor rather than on any single feature.

Nuclear size and shape vary from area to area, but at least some parts of the tumor usually show moderate to marked atypia. Squamous differentiation, which is common in endometrioid carcinoma, is not a feature here.

Immunohistochemistry

Immunohistochemistry is a laboratory test that uses antibodies to detect specific proteins inside cells. It matters here more than in most endometrial cancers, because clear cell carcinoma overlaps in appearance with several other diagnoses.

HNF1β, napsin A, and AMACR. Often positive, usually in most tumor cells when present. This combination is the most useful diagnostic evidence.
Estrogen receptor and progesterone receptor. Usually negative or positive in only scattered cells. This helps separate clear cell carcinoma from low-grade endometrioid carcinoma, which is typically strongly positive for both.
p53. Variable. Some tumors show an abnormal pattern, and some do not, which is itself a difference from serous carcinoma.
p16. Often positive throughout the tumor. This is not specific to clear cell carcinoma and is interpreted alongside the other results.

How is this different from other endometrial cancers?

Several diagnoses can contain cells with clear cytoplasm, and telling them apart is why additional stains are performed.

Endometrioid carcinoma with clear cells — Some endometrioid carcinomas contain areas of clear cells without being clear cell carcinomas. Hormone receptor results and the overall growth pattern usually settle this.
Secretory endometrioid carcinoma — An uncommon form of endometrioid carcinoma with clear cytoplasm, which behaves like an ordinary low-grade endometrioid carcinoma.
Serous carcinoma — Serous carcinoma can contain clear cells and shows widespread abnormal p53, whereas p53 in clear cell carcinoma is variable.
Arias-Stella reaction — A normal change in the lining during pregnancy that produces cells with clear cytoplasm and prominent nuclei. It is not cancer, and it is why pregnancy history matters when this appearance is seen.

Grade

The FIGO grading system used for endometrioid carcinoma is based largely on how much of the tumor grows in solid sheets. Clear cell carcinoma is considered high grade by definition, so it is not assigned grades 1, 2, or 3.

For this tumor, the stage and other high-risk features described below provide more useful information than a grade.

Biomarkers

Biomarkers are tests performed on tumor tissue to understand how a cancer is likely to behave and which treatments may work. Not every case is tested for every biomarker.

Mismatch repair proteins

Mismatch repair proteins fix small errors that occur when DNA is copied. The four tested are MLH1, PMS2, MSH2, and MSH6. Results are reported as retained, meaning normal, or lost, meaning abnormal.

Loss is seen in a proportion of clear cell carcinomas, although reported rates vary. A tumor missing one or more of these proteins is described as mismatch repair deficient. This identifies tumors that may respond to immunotherapy, and it raises the possibility of Lynch syndrome, which has implications for blood relatives.

Estrogen receptor and progesterone receptor

These proteins allow tumor cells to respond to estrogen and progesterone. Results are reported as positive or negative, sometimes with a percentage.

In clear cell carcinoma,, they are usually negative or positive onlyin scattered cells. This differs from low-grade endometrioid carcinoma, where they are typically strongly positive, and it means hormone-blocking treatment is generally not useful here.

p53

p53 is a protein that helps control cell growth and repair damaged DNA. An abnormal result, reported as aberrant, mutant-type, or abnormal expression, indicates that the TP53 gene is altered.

Results are variable in clear cell carcinoma, and a meaningful proportion of tumors are abnormal. Because an abnormal result also characterizes serous carcinoma, interpret it alongside the microscopic appearance and other stains. For tumors confined to the uterus, an abnormal result raises the stage under the current staging system.

POLE

POLE is a gene involved in copying DNA accurately. Tumors with a POLE mutation carry very large numbers of DNA changes yet behave far better than their appearance suggests.

POLE mutations are uncommon in clear cell carcinoma. When present, they carry a favorable outlook and lower the stage under the current staging system. Results are reported as mutated or wild-type.

Other genetic changes

These tumors show a range of other alterations, including changes in PIK3CA, KRAS, ARID1A, PTEN, PPP2R1A, PIK3R1, and SPOP. None of these defines the diagnosis, and none currently changes standard treatment.

They are identified through broader molecular profiling, which is generally reserved for advanced or recurrent disease, where the results may open up a clinical trial or a targeted treatment option.

Molecular subtypes

Large genomic studies group endometrial cancers into four molecular subtypes. Clear cell carcinoma is unusual in that it does not concentrate in any one of them, unlike serous carcinoma, which is nearly always p53 abnormal.

p53 abnormal — Where tumors with an abnormal p53 result fall. The least favorable group.
No specific molecular profile — A substantial share of clear cell carcinomas. Intermediate outlook.
Mismatch repair deficient — Tumors that have lost a mismatch repair protein—intermediate outlook, and often eligible for immunotherapy in advanced disease.
POLE ultramutated — A small number.—the most favorable group.

The subtype is more than a prognostic label. For tumors confined to the uterus, a POLE mutation lowers the stage and an abnormal p53 result raises it, as described in the staging section below.

What other findings will be described in the report?

Myometrial invasion

The myometrium is the thick muscular wall of the uterus. Myometrial invasion means the tumor has grown from the lining into that wall. The pathologist measures the depth and usually reports it as a percentage of the full thickness.

For this diagnosis, whether the tumor invades the muscle at all matters most because it changes the stage. This differs from the older staging system, in which the threshold was half the wall thickness. Deep invasion is also associated with a shorter time to recurrence.

Cervical stromal invasion

Cervical stromal invasion means the tumor has grown from the body of the uterus into the cervix’s supporting tissue. Involvement of only the surface lining of the cervix does not count. This finding may influence whether radiation therapy is recommended.

Involvement of other organs and tissues

The uterus sits against the ovaries, fallopian tubes, vagina, bladder, and rectum. The fallopian tubes, ovaries, and attached ligaments are together called the adnexa. The pathologist examines the removed tissue and reports whether tumor cells are present.

Involvement of the ovaries or fallopian tubes matters for this diagnosis. Published series have associated it with a shorter time to recurrence.

Lymphovascular invasion

Lymphovascular invasion means tumor cells have been seen inside small lymphatic channels or blood vessels. These pathways allow cells to reach lymph nodes or distant organs.

Your report will describe it as absent, focal, or substantial. That distinction matters, because substantial lymphovascular invasion changes the stage for some endometrial cancers and often leads to a recommendation for additional treatment.

Margins

A margin is the edge of the tissue removed during surgery. The pathologist examines the margins for tumor cells. Depending on the operation, these may include the cervical margin, the vaginal cuff margin, the tissue on either side of the uterus, and the peritoneal surface.

A positive margin means tumor cells reach the cut edge and some cancer may remain. A negative margin means no tumor cells were found at the edges. Positive margins may lead to a recommendation for radiation therapy.

Lymph nodes

Lymph nodes are small immune organs that filter fluid draining from tissues. Cancer cells can travel to them and form a metastasis.

Nodes from the pelvis, and sometimes from higher in the abdomen, are commonly removed for this diagnosis and examined individually. Your report will state how many were examined and how many contained cancer. When cancer is found, the size of the largest deposit determines the nodal stage.

Isolated tumor cells — A group measuring 0.2 mm or less. These are recorded as N0(i+) and are not counted as node-positive disease.
Micrometastasis — A deposit measuring more than 0.2 mm and up to 2 mm. This gives a nodal stage of N1mi or N2mi, depending on which nodes are involved.
Macrometastasis — A deposit measuring more than 2 mm. This gives a nodal stage of N1a or N2a and is associated with a less favorable outlook.

Pathologic stage

The pathologic stage uses the TNM system from the American Joint Committee on Cancer, which describes the tumor (T), the lymph nodes (N), and distant spread (M).

Tumor stage (pT):

T1 — The tumor involves only the body of the uterus.
T2 — The tumor has grown into the supporting tissue of the cervix.
T3 — The tumor has reached the outer surface of the uterus, or has spread to the fallopian tubes, ovaries, or vagina.
T4 — The tumor has grown into the lining of the bladder or the bowel.

Nodal stage (pN): N0 means no tumor cells in the nodes examined. N0(i+) means only isolated tumor cells. N1mi and N1a describe involvement of pelvic nodes. N2mi and N2a describe involvement of nodes higher in the abdomen. The “mi” categories are used for deposits of 2 mm or less. NX means no nodes were examined.

Metastatic stage (pM): M1 means the cancer has spread to a distant site. This can only be assigned when tissue from that site has been examined, so most reports list it as MX and use imaging instead.

FIGO stage

The International Federation of Gynecology and Obstetrics substantially revised the staging system in 2023, and the change matters for this diagnosis.

The current system divides endometrial cancers into two groups according to how they tend to behave. Clear cell carcinoma sits in the higher-risk group, alongside serous carcinoma, carcinosarcoma, undifferentiated carcinoma, and high-grade endometrioid carcinoma. Tumors in that group are staged differently from the rest.

Stage IC — The tumor is confined to the lining, with no growth into the muscular wall.
Stage IIC — The tumor has grown into the muscular wall to any depth. Under the previous system, this would have been stage IA or IB depending on the depth. Many patients are therefore assigned a higher stage now than they would have been before 2023.
Stage IIIA — The tumor involves the outer surface of the uterus, or the ovaries or fallopian tubes.
Stage IIIB — The tumor involves the vagina or the tissue on either side of the uterus.
Stage IIIC — The tumor has spread to lymph nodes. IIIC1 is pelvic nodes,s and IIIC2 is nodes higher in the abdomen.
Stage IVA — The tumor has grown into the lining of the bladder or bowel.
Stage IVB — The tumor has spread within the abdomen beyond the pelvis.
Stage IVC — The tumor has spread to distant organs such as the lungs or liver.

Molecular results can change the stage for tumors confined to the uterus. A POLE mutation lowers the stage to IAmPOLEmut. An abnormal p53 result raises it to IICmp53abn. Molecular results do not change stage III or stage IV disease.

Your report or your oncologist may use a stage that does not match what you have read elsewhere. The difference between the 2009 and 2023 systems likely explains the discrepancy, and it is worth asking which one was used.

What is the prognosis?

Stage is by far the strongest factor. Across all stages, reported five-year survival in a large multi-institutional series was around 58%. For tumors confined to the uterus, the figures are considerably better, with five-year survival reported above 85 out of 100 in surgically staged series.

Other findings associated with a shorter time to recurrence include advanced stage, involvement of the ovaries or fallopian tubes, deep growth into the muscular wall, and older age at diagnosis.

Published figures come from groups of patients and cannot tell you what will happen in your case. They do not account for your stage, your surgery, or the treatment you receive. Your own team is far better placed to discuss what the outlook means for you.

How is endometrial clear cell carcinoma treated?

Surgery — Removal of the uterus, cervix, fallopian tubes, and ovaries, with lymph node assessment. Complete surgical staging is standard.
Chemotherapy — Usually recommended for tumors that have spread beyond the uterus. Carboplatin and paclitaxel are the common regimen.
Radiation therapy — Used in some situations, including vaginal brachytherapy to reduce the risk of the cancer returning at the top of the vagina.
Treatment for early-stage disease — Less settled than you might expect. Several studies of surgically staged stage I and II disease have not shown a clear survival benefit from adjuvant treatment over careful observation. Practice varies between centers, and molecular results increasingly guide the decision.
Immunotherapy — An option for mismatch repair deficient tumors that are advanced or have returned.

Hormone-blocking treatment is generally not useful for this diagnosis, because these tumors are usually negative for estrogen and progesterone receptors.

Questions to ask your doctor

What stage is my cancer, and was the 2023 FIGO system used?
Did a pathologist who specializes in gynecologic pathology review my case?
Did the tumor grow into the muscle wall of the uterus?
Were the ovaries or fallopian tubes involved?
Was lymphovascular invasion present, and was it focal or substantial?
Were the margins negative?
Were lymph nodes examined, and did any contain cancer?
What did the p53 and mismatch repair testing show?
What molecular subtype is my tumor, and does it change my treatment?
Do you recommend chemotherapy or radiation, and what is the evidence in my situation?
Should I be tested for Lynch syndrome?
Should I be referred to a gynecologic oncology center?
What will follow-up involve, and how often?