Endometrial Clear Cell Carcinoma: Understanding Your Pathology Report

by Jason Wasserman MD PhD FRCPC
March 4, 2026

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Endometrial clear cell carcinoma is a rare type of cancer that starts in the endometrium, the inner lining of the uterus. It is considered a high-grade tumour, meaning it has a higher chance of spreading beyond the uterus compared to low-grade endometrial cancers.

Endometrial clear cell carcinoma behaves differently from the more common endometrial endometrioid carcinoma and is often treated more aggressively. However, many cases are diagnosed at an early stage, and prognosis depends strongly on the stage of the tumour and whether it has spread beyond the uterus.

What are the symptoms of endometrial clear cell carcinoma?

The most common symptom is abnormal vaginal bleeding, especially bleeding after menopause. Some people also notice unusual vaginal discharge, which may be watery or blood-tinged. Other symptoms may include pelvic discomfort, pelvic pressure, or pain.

In some cases, a screening test of the cervix (cervical cytology) may be abnormal, especially in advanced-stage disease. People diagnosed with endometrial clear cell carcinoma may also have an increased risk of blood clots in the veins.

Because bleeding after menopause is not normal, it should always be evaluated.

What causes endometrial clear cell carcinoma?

The exact cause of endometrial clear cell carcinoma is not fully understood.

Unlike the more common endometrial endometrioid carcinoma, clear cell carcinoma is not clearly linked to long-term exposure to estrogen. It most often occurs in older adults and usually develops without an obvious precancerous condition.

At the molecular level, clear cell carcinoma lacks a single defining genetic alteration. Instead, different tumours can show a range of genetic changes, and some cases overlap biologically with serous carcinoma, endometrioid carcinoma, neither, or both.

How is this diagnosis made?

The diagnosis of endometrial clear cell carcinoma usually begins with an endometrial biopsy, in which a small sample of tissue is removed from the lining of the uterus and examined under the microscope by a pathologist.

If cancer is identified, surgery is often performed to remove the uterus and often the ovaries, fallopian tubes, and lymph nodes. The removed tissue is carefully examined to determine tumor spread, depth of invasion, lymph node involvement, and other important features.

Microscopic features

When examined under a microscope, endometrial clear cell carcinoma commonly shows a mixture of growth patterns. The most typical patterns are tubulocystic, papillary, and solid.

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

The tumour cells can have a variety of shapes. They may be polygonal, cuboidal, flat, or “hobnail.” Hobnail cells have nuclei that bulge into the space inside a gland, giving the cells a distinctive shape. The cytoplasm (the body of the cell) may be clear or pink. Importantly, obvious, clear cytoplasm or hobnail cells are not required for the diagnosis; the diagnosis is based on the overall pattern and appearance of the tumour.

Nuclear pleomorphism (variation in nuclear size and shape) is variable, but at least some areas usually show moderate to severe atypia. Squamous differentiation is not a typical feature of clear cell carcinoma.

Immunohistochemistry

Immunohistochemistry is a laboratory test that uses antibodies to detect specific proteins inside tumor cells. These tests help confirm the diagnosis and distinguish endometrial clear cell carcinoma from other types of endometrial cancer that can look similar under the microscope.

Endometrial clear cell carcinoma often shows positive staining for HNF1β, napsin A, and AMACR (P504S). When present, these markers are usually positive in most tumour cells and support the diagnosis.

Estrogen receptor (ER) and progesterone receptor (PR) are usually negative or only focally positive in clear cell carcinoma. p53 staining is variable, and some tumours show an abnormal (mutation-pattern) result. Many clear cell carcinomas also show diffuse p16 staining, although p16 is not specific to this diagnosis and is interpreted in conjunction with microscopic features and other stains.

Because clear cell carcinoma can overlap with other tumour types, immunohistochemistry is often an important part of confirming the diagnosis.

FIGO grade

The FIGO grade system used for endometrial endometrioid carcinoma is based largely on the amount of solid growth. Endometrial clear cell carcinoma is considered high grade by definition, so it is not typically assigned FIGO grades 1, 2, or 3.

For this tumour type, the most important prognostic and treatment information is usually the stage and the presence of specific high-risk features described elsewhere in the pathology report.

Biomarkers

Biomarkers are tests performed on tumour tissue to understand better how a cancer behaves and which treatments may be most effective. These tests may include immunohistochemistry (to detect specific proteins in tumour cells) and molecular testing (to detect changes in DNA). Not all biomarkers are tested in every case.

Mismatch repair proteins (MMR)

Mismatch repair proteins help normal cells fix small mistakes that occur during DNA replication. The four most commonly tested proteins are MLH1, PMS2, MSH2, and MSH6, which work together in pairs.

Pathologists usually test MMR proteins using immunohistochemistry. Results are reported as either retained expression (normal) or loss of expression (abnormal).

Mismatch repair protein loss can be seen in a subset of clear cell carcinomas, although reported rates vary. If one or more mismatch repair proteins are lost, the tumour is described as mismatch repair–deficient. This is important because mismatch repair–deficient tumours may respond well to immunotherapy. Loss of mismatch repair proteins can also raise the possibility of Lynch syndrome, and additional testing may be recommended in the appropriate clinical setting.

Estrogen receptor (ER) and progesterone receptor (PR)

ER and PR are proteins that allow tumour cells to respond to the hormones estrogen and progesterone. These markers are tested by immunohistochemistry and reported as positive or negative, sometimes with a percentage indicating how many tumour cells express the receptor.

In endometrial clear cell carcinoma, ER and PR are usually negative or only focally positive. This pattern can help distinguish clear cell carcinoma from many low-grade endometrial endometrioid carcinomas, which are often strongly ER- and PR-positive.

p53

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

In endometrial clear cell carcinoma, p53 results are variable, and a significant subset of tumours show abnormal p53 staining. Because p53 abnormalities can overlap with those of serous carcinoma, p53 results are interpreted in conjunction with the microscopic features and other immunohistochemical stains.

POLE

POLE mutations occur in a small subset of endometrial cancers. Tumours with POLE mutations typically have many DNA mutations but are less aggressive.

POLE mutations are uncommon in endometrial clear cell carcinoma, but when present, they may be associated with a better prognosis. Results are reported as mutated or wild-type (normal).

PIK3CA

PIK3CA regulates cell growth and survival. Mutations in this gene are observed in a subset of clear cell carcinomas.

Results are usually reported as mutated or wild-type (normal). In some cases, these results may be considered when evaluating targeted therapy options, particularly in advanced or recurrent disease.

KRAS

KRAS is a gene involved in pathways that regulate cell growth. KRAS mutations can be found in a subset of clear cell carcinomas.

When present, KRAS results are reported as mutated or wild-type (normal). These results are most relevant in advanced disease when molecular profiling is used to explore treatment options.

ARID1A

ARID1A is a gene involved in regulating how DNA is packaged and read within cells. Loss of ARID1A expression can be seen in some endometrial clear cell carcinomas.

ARID1A is often assessed by immunohistochemistry and reported as retained (normal) or lost (abnormal). Some studies suggest that ARID1A loss may be associated with prognosis, though this remains an area of ongoing research.

PTEN

PTEN is a tumour suppressor gene that helps regulate cell growth. PTEN abnormalities are less common in clear cell carcinoma than in endometrioid carcinoma. When evaluated, PTEN results may be reported as retained or lost by immunohistochemistry, or as mutated or wild-type by molecular testing.

Additional molecular findings

Other genetic alterations can be seen in clear cell carcinoma, including changes involving PPP2R1A, PIK3R1, and SPOP. These results are usually identified through broader molecular profiling and are most relevant in advanced or recurrent disease.

TCGA molecular subtypes

Many endometrial cancers can be grouped into four molecular subtypes, based on large genomic studies such as those from The Cancer Genome Atlas (TCGA). The biomarkers described above help place a tumour into one of these categories, which can provide important prognostic information.

Unlike serous carcinoma, which almost always falls into the p53-abnormal (copy-number high) group, endometrial clear cell carcinoma is more heterogeneous. Different tumours may fall into different TCGA categories.

Some clear cell carcinomas fall into the p53-abnormal (copy-number high) subtype, particularly those with abnormal p53 staining. Some fall into the mismatch repair–deficient subtype when mismatch repair proteins are lost. A small number fall into the POLE-ultramutated subtype when a POLE mutation is present. Other tumours may fall into the no specific molecular profile (NSMP) group.

Understanding which molecular subtype a tumour belongs to helps doctors better estimate prognosis and choose the most appropriate treatment.

Other features to look for in your pathology report

Myometrial invasion

Myometrial invasion describes how deeply the tumor has grown into the muscle wall of the uterus.

The uterus is made up of an inner lining (the endometrium) and a thick outer muscle layer called the myometrium. When the tumor spreads from the lining into this muscle, it is called myometrial invasion.

Pathologists measure the depth of invasion in millimetres and often report it as a percentage of the total thickness of the myometrium. Invasion of less than 50% of the myometrial thickness is associated with a lower risk. Invasion of 50% or more is associated with a higher risk of lymph node spread.

This measurement is critical because it directly affects the tumor stage.

Cervical stromal invasion

Cervical stromal invasion means the tumor has grown from the body of the uterus into the supportive tissue of the cervix.

The cervix is the lower part of the uterus that connects to the vagina. If the tumor involves only the surface lining of the cervix, this does not change the stage. However, if it invades the deeper cervical stroma, the stage increases.

This finding may influence the need for additional treatment such as radiation therapy.

Invasion of surrounding organs or tissues

The uterus is closely connected to several other organs and tissues, such as the ovaries, fallopian tubes, vagina, bladder, and rectum. The term “adnexa” refers to the fallopian tubes, ovaries, and ligaments directly linked to the uterus.

As a tumour grows, it can spread into any of these organs or tissues. In such cases, some parts of these organs or tissues may have to be removed along with the uterus. A pathologist will thoroughly examine these organs or tissues for tumour cells, and the findings will be detailed in your pathology report.

The presence of tumour cells in other organs or tissues raises the pathologic tumour stage and is linked with a poorer prognosis.

Lymphatic and vascular invasion

Lymphatic and vascular invasion means tumor cells are seen inside small lymphatic channels or blood vessels.

Lymphatic vessels are part of the immune system and allow fluid to drain from tissues. Blood vessels carry blood throughout the body. When tumor cells enter these channels, they have a pathway to spread to lymph nodes or distant organs.

Pathologists look for tumour cells inside these channels under the microscope. This finding does not mean the tumour has already spread, but it does increase the risk of spread. Because of this, lymphatic and vascular invasion is considered a high-risk feature and may lead your doctor to recommend additional treatment after surgery.

Margins

A margin refers to the edge of the tissue removed during surgery, such as a hysterectomy. After the surgery, pathologists examine the tissue margins under a microscope to check for any remaining cancer cells. In the case of endometrial clear cell carcinoma, several specific margins are carefully evaluated:

1. Cervical margin: This is the edge where the uterus meets the cervix. Pathologists examine this margin to see if the cancer has spread into or beyond the cervix.

2. Vaginal cuff margin: If the top portion of the vagina is removed along with the uterus, the pathologist will check the vaginal cuff margin to ensure no cancer cells are present at the surgical edge.

3. Parametrial margin: This margin includes the tissue around the uterus, including ligaments and connective tissue. It is examined to see if cancer has spread into these areas.

4. Peritoneal margin: If the peritoneum (the lining of the abdominal cavity) is removed, it will be examined to check for cancer cells in this area.

If any of these margins contain cancer cells, it is referred to as a positive margin, which may mean that some tumour cells were left behind after surgery. A negative margin means no cancer cells were found at the edges, suggesting that the tumour was completely removed. Clear margins are important for reducing the risk of the cancer returning, and positive margins may lead to recommendations for additional treatments, such as radiation therapy.

Lymph nodes

Lymph nodes are small, bean-shaped structures in the lymphatic system that help fight infection and remove waste from the body. Lymph nodes contain immune cells that filter lymph fluid as it travels through lymphatic vessels and help trap harmful substances such as bacteria or cancer cells.

In endometrial clear cell carcinoma, lymph nodes are examined because this type of cancer can spread beyond the uterus. During surgery, lymph nodes from the pelvis and sometimes the abdomen may be removed and sent to a pathologist. Each lymph node is examined under the microscope to look for metastatic cancer, meaning cancer cells that have spread from the uterus.

Examining lymph nodes is important for determining the stage of the cancer, guiding treatment decisions, and estimating prognosis. If cancer cells are found in the lymph nodes, your doctor may recommend additional treatment such as chemotherapy, radiation therapy, or other systemic therapies.

Isolated tumour cells (ITCs)

Pathologists use the term “isolated tumour cells” to describe a group of tumour cells measuring 0.2 mm or less and found in a lymph node. If only isolated tumour cells are found in all the lymph nodes examined, the pathologic nodal stage is pN1mi.

Micrometastasis

Micrometastasis is a group of tumour cells measuring 0.2-2 mm found in a lymph node. If only micrometastases are found in all the lymph nodes examined, the pathologic nodal stage is pN1mi.

Macrometastasis

Macrometastasis is a group of tumour cells measuring more than 2 mm in a lymph node. Macrometastases are associated with a worse prognosis and often lead to recommendations for additional treatment.

Pathologic stage (pTNM)

The pathologic stage for endometrial clear cell carcinoma is based on the TNM staging system, an internationally recognized system created by the American Joint Committee on Cancer. This system uses information about the primary tumour (T), lymph nodes (N), and distant metastatic disease (M) to determine the complete pathologic stage (pTNM). Your pathologist will examine the submitted tissue and assign each part a number.

In general, a higher number means a more advanced disease and a worse prognosis.

Tumour stage (pT) for endometrial clear cell carcinoma

Endometrial clear cell carcinoma is given a tumour stage between T1 and T4 based on the depth of myometrial invasion and growth of the tumour outside of the uterus.

• T1 – The tumour only involves the uterus.

• T2 – The tumour has grown to involve the cervical stroma.

• T3 – The tumour has grown through the wall of the uterus and is now on the outer surface of the uterus, OR it has grown to involve the fallopian tubes or ovaries.

• T4 – The tumour has grown directly into the bladder or the colon.

Nodal stage (pN) for endometrial clear cell carcinoma

Based on examination of lymph nodes from the pelvis and abdomen, endometrial clear cell carcinoma is staged from N0 to N2.

• N0 – No tumour cells were found in any lymph nodes examined.

• N1mi – Tumour cells were found in at least one lymph node from the pelvis, but the area with cancer cells was not larger than 2 millimetres (only isolated cancer cells or micrometastasis).

• N1a – Tumour cells were found in at least one lymph node from the pelvis, and the area with cancer cells was greater than 2 millimetres (macrometastasis).

• N2mi – Tumour cells were found in at least one lymph node outside the pelvis, but the area with cancer cells was not larger than 2 millimetres (only isolated cancer cells or micrometastasis).

• N2a – Tumour cells were found in at least one lymph node outside the pelvis, and the area with cancer cells was greater than 2 millimetres (macrometastasis).

• NX – No lymph nodes were sent for examination.

FIGO stage

The FIGO staging system, developed by the International Federation of Gynecology and Obstetrics, is a standardized method for classifying endometrial cancers based on their extent of spread. This system is important because it helps doctors determine the extent of the cancer, plan appropriate treatment, and estimate the prognosis (the likely disease outcome).

• Stage I: The cancer is confined to the uterus.
  • IA: The cancer is limited to the endometrium or has invaded less than halfway into the myometrium.
    Prognosis: Cancers in Stage IA have an excellent prognosis, with a high likelihood of being successfully treated through surgery alone.
  • IB: The cancer has invaded more than halfway into the myometrium.
    Prognosis: Although Stage IB is more advanced than Stage IA, it generally has a good prognosis, especially if treated promptly.
• Stage II: The cancer has spread from the uterus to the cervix but has not gone beyond the uterus.
  Prognosis: Stage II cancers are more likely to require additional treatments, such as radiation or chemotherapy, but many patients still have a favourable outcome with appropriate treatment.
• Stage III: The cancer has spread beyond the uterus but is still within the pelvis.
  • IIIA: The cancer has spread to the outer surface of the uterus or to nearby tissues.
  • IIIB: The cancer has spread to the vagina or the pelvic wall.
  • IIIC: The cancer has spread to the lymph nodes.
    Prognosis: Stage III cancers are more advanced and often require a combination of surgery, radiation, and chemotherapy. The prognosis is more guarded, but treatment can still be effective in many cases.
• Stage IV: The cancer has spread to distant organs, such as the bladder, bowel, or lungs.
  • IVA: The cancer has spread to nearby organs such as the bladder or rectum.
  • IVB: The cancer has spread to distant organs, such as the lungs or liver.
    Prognosis: Stage IV cancers are the most advanced and carry a more serious prognosis. Treatment at this stage is usually focused on managing symptoms and slowing disease progression.

Questions to ask your doctor

• What is my stage?

• Was the tumour confined to the uterus or had it spread beyond the uterus?

• How deeply did the tumor invade the myometrium?

• Were lymph nodes involved?

• Was lymphatic and vascular invasion present?

• Were biomarker tests performed, and do any results affect treatment options?

• What does my stage and TCGA molecular subtype mean for my prognosis?