Endometrial Cancer

Synonyms: -

Material:

FFPE tissue sections

TAT:

varies depending on the anlysis

Method:

NGS

Overview

Endometrial carcinoma is the most common gynecological malignancy in many high-income countries. According to GLOBOCAN 2024, an estimated 434,620 new cases of cancer of the corpus uteri and 100,680 associated deaths occurred worldwide in 2024, making corpus uteri cancer the 16th most frequently diagnosed cancer globally. Comprehensive genomic analysis by The Cancer Genome Atlas (TCGA) identified four molecular groups of endometrial carcinoma: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Clinically applicable surrogate classifiers subsequently enabled assignment to four corresponding molecular subtypes: POLE-mutated, mismatch-repair-deficient, p53-abnormal, and no specific molecular profile. Molecular classification complements histopathological assessment and contributes to integrated prognostic risk stratification and treatment planning.

Clinical background and relevance

Molecular classification is performed on representative tumour tissue. The standard pathological classifier combines POLE exonuclease-domain mutation analysis with assessment of MMR protein expression and p53 expression. MSI analysis, MLH1 promoter methylation testing, and targeted sequencing may provide complementary information within an integrated diagnostic workflow.

POLE-mutated

Pathogenic or likely pathogenic POLE exonuclease-domain mutations associated with the ultramutated phenotype define the POLE-mutated subtype. POLE-mutated endometrial carcinomas are generally associated with an excellent prognosis, particularly in early-stage disease. Not every POLE variant is subtype-defining; variants must therefore be interpreted using validated molecular and clinical criteria.

Mismatch-repair-deficient

MMR-deficient endometrial carcinomas show loss of functional mismatch-repair activity. MMR status is generally assessed by immunohistochemistry for MLH1, PMS2, MSH2, and MSH6. Defective mismatch repair may also be identified through MSI testing or a validated molecular-profiling assay. In tumours with loss of MLH1 and PMS2 expression, MLH1 promoter methylation analysis helps distinguish likely sporadic MLH1 silencing from cases requiring further assessment for Lynch syndrome. Methylation results must be interpreted together with the immunohistochemical findings, personal and family history, and, where indicated, constitutional genetic testing.

p53-abnormal

The p53-abnormal subtype is defined by an abnormal p53 immunohistochemical expression pattern in the absence of a subtype-defining POLE mutation or MMR deficiency. Abnormal patterns include diffuse strong nuclear overexpression, complete absence of tumour-cell staining with an appropriate internal positive control, and unequivocal cytoplasmic staining. TP53 sequencing can provide complementary information in selected cases. p53-abnormal endometrial carcinomas are commonly associated with aggressive pathological features and have the least favourable prognosis among the four principal molecular classes. Prognosis and treatment nevertheless remain dependent on stage and other clinicopathological factors.

No specific molecular profile

The no specific molecular profile (NSMP) subtype comprises carcinomas without a subtype-defining pathogenic POLE exonuclease-domain mutation, without MMR deficiency, and without a p53-abnormal phenotype. NSMP is a large and biologically heterogeneous category with generally intermediate outcomes. ER status and clinicopathological variables can provide further prognostic information within this group.

Multiple-classifier tumours

A small proportion of endometrial carcinomas show more than one classifier feature. Integrated subtype assignments should follow a validated classification algorithm. Tumours with a subtype-defining pathogenic POLE mutation are generally assigned to the POLE-mutated group, including those with concurrent p53-abnormality. Tumours with MMR deficiency and concurrent p53-abnormality are generally assigned to the MMR-deficient group. A single-classifier p53-abnormal designation is used when no subtype-defining POLE mutation or MMR deficiency is present. Discordant, unusual, or subclonal findings require specialist pathological and molecular review.

Additional testing

HER2 assessment is separate from the four-group molecular classification. HER2 immunohistochemistry, with appropriate reflex in situ hybridisation for equivocal results, may identify patients eligible for HER2-directed therapy in defined clinical settings. Current NCCN guidance recommends HER2 testing for p53-aberrant carcinomas and for metastatic or recurrent endometrial carcinoma.

Separate from molecular classification, NTRK1, NTRK2, and NTRK3 fusion analysis may be performed on tumour tissue when identification of a tumour-agnostic therapeutic target is clinically relevant. NTRK fusions are rare in unselected adult solid tumours. Adult pan-cancer prevalence estimates range from approximately 0.03% to 0.70%, with variation according to tumour type, patient selection, and assay methodology. Detection of a qualifying NTRK fusion may identify a patient as a candidate for TRK-inhibitor therapy, subject to the applicable regulatory indication and clinical circumstances.

Table 1: Classification of endometrial carcinomas

Molecular subtype	Defining molecular finding	Principal analysis
POLE-mutated (POLEmut)	Subtype-defining pathogenic or likely pathogenic mutation in the POLE exonuclease domain	POLE sequencing
Mismatch-repair-deficient (MMRd)	Loss of expression of one or more MMR proteins; MSI	MMR immunohistochemistry; MSI analysis; MLH1 promoter methylation when MLH1/PMS2 loss is present
P53-abnormal (p53abn)	Abnormal p53 immunohistochemical expression pattern, in the absence of a subtype-defining POLE mutation or MMR deficiency	P53 immunohistochemistry; TP53 sequencing in selected cases
No specific molecular profile (NSMP)	No subtype-defining POLE mutation, no MMR deficiency, and no p53 abnormal phenotype	Integrated exclusion of the other three classes; ER immunohistochemistry for risk refinement according to the applicable guidelines

Available tests

The analyses listed below may be ordered individually or, where applicable, as part of a combined molecular analysis. Molecular classification requires integration of molecular results with histopathological findings and relevant immunohistochemical results.

Single-method analysis	Panel	Gene scope	Purpose
Sequencing	Panel00694	POLE, TP53	Detection of somatic sequence variants in the tumour
Fusion gene analysis	Panel00692	NTRK1, NTRK2, NTRK3	Identification of NTRK gene fusions in the tumour
MLH1 promoter methylation	Panel00706	MLH1	Assessment of MLH1 promoter methylation in tumours with MLH1/PMS2 loss to support distinction between likely sporadic MLH1 silencing and cases requiring further evaluation for Lynch syndrome.
Microsatellite instability (MSI)	Panel00693	Microsatellite marker panel	Determination of microsatellite instability (MSI)

	Panel	Analytical components
Combined molecular analysis	Panel00532	DNA sequence analysis: POLE, TP53 Fusion analysis: NTRK1, NTRK2, NTRK3 MSI analysis: microsatellite marker panel

Additional molecular genetic analyses on tumour tissue, e.g., the determination of tumour mutational burden (TMB) and homologous recombination deficiency (HRD) are also available (see Panel 00617 – ).

Evaluation of inherited cancer risk is a separate component of the diagnostic pathway. Germline testing should be considered according to the clinical and family history and tumour findings. Genetic counselling is strongly recommended when a germline alteration is suspected. A strong family history of endometrial or colorectal cancer warrants genetic evaluation irrespective of tumour MMR or MLH1 promoter methylation results.

Therapy

References

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Our editorial team consists of medical specialists and scientists in the field of human genetics. All content is created and reviewed in accordance with current scientific standards.

Last Update : 24.09.2026

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