Endometrial Carcinoma Molecular Classification and Staging
On this page
Direct answer
Endometrial carcinoma is classified into four molecular groups: POLE-mutated, mismatch repair deficient, p53 abnormal, and no specific molecular profile (NSMP). FIGO 2023 uses these groups alongside anatomical stage, because the molecular group predicts prognosis more reliably than histology alone. POLE-mutated disease has the best outlook and p53-abnormal disease the worst.
What you must remember
- POLE-mutated: A pathogenic mutation in the POLE exonuclease domain causes an ultramutated tumour with the most favourable prognosis.
- MMR deficient: Loss of MLH1, MSH2, MSH6 or PMS2 on immunohistochemistry indicates microsatellite instability and an intermediate prognosis.
- p53 abnormal: Strong diffuse or complete absence of p53 staining signals TP53 abnormality, and this group has the poorest prognosis.
- NSMP: Tumours with none of the above features form the commonest group, with an intermediate prognosis.
- Serous and clear cell: These histologies are usually p53 abnormal, so histology and molecular class must be read together.
- Lynch link: MMR deficiency can reflect a germline mutation, so germline testing is considered for suspected Lynch syndrome.
- Hierarchy: POLE-mutated status takes precedence, then MMR deficiency, then p53 abnormality, then NSMP.
- FIGO 2023: The revised system adds molecular class to anatomical stage to refine risk and sometimes change the stage assigned.
A pathway from histology to molecular class
Molecular classification follows a fixed hierarchy, so the order of testing matters. Each step either assigns a group or passes the tumour to the next test.
- Start with histology: Endometrioid, serous and clear cell types are identified first. Serous and clear cell histology is usually p53 abnormal, which guides the testing that follows.
- Sequence POLE first: A pathogenic exonuclease domain mutation classes the tumour as POLE-mutated, even if MMR or p53 is abnormal, because this group has the best prognosis.
- Test for MMR proteins: Immunohistochemistry for MLH1, MSH2, MSH6 and PMS2 identifies MMR-deficient tumours. Loss of any of these proteins classes the tumour as MMR deficient.
- Stain for p53: Strong diffuse or complete loss of p53 staining classes the tumour as p53 abnormal. This group is assigned after POLE and MMR status are known.
- Assign NSMP: Tumours without POLE mutation, MMR deficiency or abnormal p53 fall into the NSMP group.
- Stage with FIGO 2023: The anatomical stage is combined with the molecular class to refine risk and guide adjuvant treatment.
- Refer for germline testing: MMR-deficient tumours should prompt evaluation for Lynch syndrome, particularly when MLH1 promoter methylation is absent.
Traps students fall into
Molecular questions test the hierarchy and the prognosis attached to each group.
- Trap: Calling POLE-mutated disease high-risk because the tumour looks high grade. Correct: POLE-mutated tumours have an excellent prognosis even when they appear high grade.
- Trap: Assuming MMR deficiency always means sporadic disease. Correct: Germline mutations cause some MMR-deficient cancers, so germline testing is needed in selected patients.
- Trap: Treating an endometrioid tumour as low-risk without checking p53. Correct: A p53-abnormal tumour carries a higher risk regardless of its endometrioid appearance.
Frequently asked questions
What are the four molecular groups of endometrial carcinoma?
The four molecular groups of endometrial carcinoma are POLE-mutated, mismatch repair deficient, p53 abnormal and no specific molecular profile. They are assigned in a fixed hierarchy, with POLE-mutated status taking precedence. FIGO 2023 uses these groups to refine the stage and risk of endometrial carcinoma.
Why is the POLE-mutated group favourable in endometrial carcinoma?
POLE-mutated endometrial carcinoma has an ultramutated genome caused by defective proofreading of the POLE exonuclease domain. Its prognosis is the most favourable of the four groups, and this often holds even when the tumour looks high grade. Recognising this group prevents over-treatment.
How does FIGO 2023 use molecular classification in endometrial carcinoma?
FIGO 2023 keeps the anatomical stages and adds molecular class to refine them, so the same anatomical extent can carry different risk. p53-abnormal disease is treated as higher risk, while POLE-mutated disease is often treated as lower risk. Molecular testing is therefore part of staging for endometrial carcinoma.
Why should mismatch repair deficient endometrial carcinoma prompt germline testing?
Mismatch repair deficiency can result from a germline MLH1, MSH2, MSH6 or PMS2 mutation, which indicates Lynch syndrome. Testing distinguishes a germline cause from a sporadic one, which matters for family surveillance. Relatives may need colonic and gynaecological screening if Lynch syndrome is confirmed.
What is the NSMP group in endometrial carcinoma?
The no specific molecular profile group contains tumours without POLE mutation, MMR deficiency or abnormal p53. It is the commonest of the four groups, with an intermediate prognosis. Grade, stage and histology guide the management of NSMP endometrial carcinoma.