by Jason Wasserman MD PhD FRCPC
March 4, 2026
Dedifferentiated carcinoma of the endometrium is an aggressive type of cancer that starts in the endometrium, the inner lining of the uterus. It is called “dedifferentiated” because the tumour comprises two components: an undifferentiated carcinoma component and a second differentiated component. The differentiated component is most often a low-grade form of endometrial endometrioid carcinoma (FIGO grade 1 or 2).
The undifferentiated component is important because it is associated with a more aggressive clinical course. Even if the undifferentiated component makes up only a small part of the tumour, it can still affect prognosis and treatment decisions. For this reason, it is important to distinguish dedifferentiated carcinoma from other high-grade endometrial cancers.
What are the symptoms of dedifferentiated carcinoma of the endometrium?
The most common symptom of dedifferentiated carcinoma of the endometrium is abnormal vaginal bleeding, especially bleeding after menopause. Some people also notice unusual vaginal discharge.
A minority of patients report abdominal or pelvic pain, especially if the tumour is large. Because bleeding after menopause is not normal, it should always be evaluated.
What causes dedifferentiated carcinoma of the endometrium?
The exact cause is not fully understood. In dedifferentiated carcinoma of the endometrium, the undifferentiated carcinoma component is clonally related to the accompanying differentiated carcinoma component. This means that both components come from the same original tumour, and the undifferentiated component develops through a process called dedifferentiation, in which a more typical endometrial cancer changes over time and loses its recognizable features.
Dedifferentiation appears to occur more often in tumours that are mismatch repair–deficient (also called microsatellite unstable). In fact, about half to two-thirds of dedifferentiated carcinomas show mismatch repair deficiency. An association with Lynch syndrome has been suggested in some patients, particularly when a mismatch repair deficiency is present.
Other genetic changes can also contribute. Many tumours have alterations in the PI3K pathway (for example, PTEN, PIK3CA, and PIK3R1), and some have abnormalities in proteins of the SWI/SNF complex. Loss of SWI/SNF proteins is strongly associated with dedifferentiation and is discussed further in the biomarkers section.
How is this diagnosis made?
The diagnosis of dedifferentiated carcinoma of the endometrium 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
Dedifferentiated carcinoma is diagnosed when two components are identified.
The differentiated component is most often a FIGO grade 1 or 2 endometrioid carcinoma. This component forms glands and resembles typical low-grade endometrioid carcinoma.
The undifferentiated component comprises sheets of tumour cells that do not form glands. The tumour cells often appear discohesive, meaning they do not stick together well and may appear as single cells or loose groups. The cells are usually small to intermediate in size and can be relatively uniform, although they are clearly malignant.
Mitotic figures (dividing cells) are typically very frequent, reflecting a fast-growing tumour. Areas of necrosis (tumour cell death) are common. Tumour-infiltrating lymphocytes, which are immune cells within the tumour, are often numerous. Some tumours show rhabdoid features, and some show a myxoid background.
The boundary between the differentiated and undifferentiated components can be abrupt, creating a striking biphasic appearance. In other cases, the two components may be mixed, and multiple tissue sections may be required to identify both.
Immunohistochemistry
Immunohistochemistry is a laboratory test that uses antibodies to detect specific proteins inside tumor cells. These tests are important in dedifferentiated carcinoma because the undifferentiated component can resemble other cancers, such as high-grade endometrioid carcinoma, serous carcinoma, neuroendocrine carcinoma, lymphoma, or sarcoma.
The undifferentiated component usually shows only limited evidence of epithelial (carcinoma) differentiation. Tumour cells often show very focal but intense staining for epithelial markers such as epithelial membrane antigen (EMA) and cytokeratins. The staining may be dot-like and concentrated around the nucleus. Diffuse strong pancytokeratin staining is not typical, and pancytokeratin can be completely negative. For this reason, pathologists often use more than one epithelial marker, and markers such as CK8/18 and EMA are frequently the most helpful.
The tumour cells in the undifferentiated component typically express vimentin and are usually negative for estrogen receptor (ER) and progesterone receptor (PR). E-cadherin is typically absent. PAX8 is usually negative but may show focal staining in scattered cells or small clusters.
Neuroendocrine markers such as synaptophysin or chromogranin may be positive in a small minority of tumour cells, usually less than 10%. This limited staining helps distinguish dedifferentiated carcinoma from true neuroendocrine carcinoma, which typically shows more diffuse staining.
Loss of SWI/SNF complex proteins may also be evaluated by immunohistochemistry. Loss of SMARCA4 (BRG1), SMARCB1 (INI1), or combined loss of ARID1A and ARID1B in the undifferentiated component supports the diagnosis and is discussed further in the biomarkers section.
FIGO grade
The FIGO grade system used for endometrial endometrioid carcinoma is based largely on the amount of solid growth. Dedifferentiated carcinoma includes an undifferentiated carcinoma component; for this reason, it is considered high grade by definition and is not managed like low-grade endometrioid carcinoma.
Your pathology report may include a FIGO grade for the differentiated endometrioid component (for example, FIGO grade 1 or 2). However, the presence of the undifferentiated component is the most important prognostic and treatment-planning feature, regardless of the percentage of undifferentiated carcinoma present.
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).
Loss of mismatch repair proteins is common in dedifferentiated carcinoma. 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 in advanced or recurrent disease. Mismatch repair deficiency can also raise the possibility of Lynch syndrome, and additional testing may be recommended in the appropriate clinical setting.
POLE
POLE mutations occur in a small subset of endometrial cancers. Tumours with POLE mutations typically have many DNA mutations but can behave less aggressively.
POLE mutations are uncommon in dedifferentiated carcinoma, but when present, they are associated with a favourable prognosis. Results are reported as mutated or wild-type (normal).
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. Some dedifferentiated carcinomas show abnormal p53, while others do not. p53 results are interpreted in conjunction with microscopic features and other biomarker results.
SWI/SNF complex proteins (SMARCA4, SMARCB1, ARID1A, ARID1B)
The SWI/SNF complex is a group of proteins that helps control how DNA is packaged inside cells and how genes are turned on and off. Inactivating mutations affecting SWI/SNF proteins are strongly associated with dedifferentiation in many tumours.
Pathologists may evaluate these proteins by immunohistochemistry. Results are reported as retained expression (normal) or loss of expression (abnormal). Loss of SMARCA4 (BRG1), loss of SMARCB1 (INI1), or combined loss of ARID1A and ARID1B in the undifferentiated component supports the diagnosis of dedifferentiated carcinoma and may be associated with more aggressive behaviour.
PTEN, PIK3CA, and PIK3R1
These genes are involved in the PI3K pathway, which regulates cell growth and survival. Alterations in this pathway are common in dedifferentiated carcinoma and often present in both the differentiated and undifferentiated components, supporting the notion that the two components are related.
Results are usually reported as mutated or wild-type (normal). These findings are most relevant when molecular profiling is performed 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.
Dedifferentiated carcinomas are most commonly found in the mismatch repair–deficient group. However, they can also arise in other molecular settings. Some tumours fall into the no specific molecular profile (NSMP) category, some are p53-abnormal, and a small subset are POLE-ultramutated.
This information is important because the molecular subtype can affect prognosis and may influence treatment decisions. For example, POLE-ultramutated tumours tend to have a favourable prognosis, while p53-abnormal tumours tend to behave more aggressively. Mismatch repair–deficient tumours may be eligible for immunotherapy in advanced disease.
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 dedifferentiated carcinoma of the endometrium, several specific margins are carefully evaluated:
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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.
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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.
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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.
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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 dedifferentiated carcinoma of the endometrium, lymph nodes are examined because this type of cancer is generally aggressive and 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, and, in some cases, immunotherapy, depending on the biomarker results.
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 dedifferentiated carcinoma of the endometrium 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 dedifferentiated carcinoma of the endometrium
Dedifferentiated carcinoma of the endometrium 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.
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T1 – The tumour only involves the uterus.
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T2 – The tumour has grown to involve the cervical stroma.
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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.
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T4 – The tumour has grown directly into the bladder or the colon.
Nodal stage (pN) for dedifferentiated carcinoma of the endometrium
Based on examination of lymph nodes from the pelvis and abdomen, dedifferentiated carcinoma of the endometrium is staged from N0 to N2.
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N0 – No tumour cells were found in any lymph nodes examined.
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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).
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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).
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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).
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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).
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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.
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: Stage IA dedifferentiated carcinoma has a better prognosis than higher stages, but the presence of an undifferentiated carcinoma component is associated with aggressive behaviour, and additional therapy is often recommended even when the tumour appears confined to the uterus.
IB: The cancer has invaded more than halfway into the myometrium.
Prognosis: Stage IB disease carries a higher risk of spread and recurrence than Stage IA and usually requires additional therapy.
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 and chemotherapy.
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 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 some 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
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What is my stage?
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Was the tumour confined to the uterus or had it spread beyond the uterus?
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How deeply did the tumor invade the myometrium?
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Were lymph nodes involved?
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Was lymphatic and vascular invasion present?
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Were biomarker tests performed, and do any results affect treatment options?
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What does my stage and TCGA molecular subtype mean for my prognosis?
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