Ovarian Endometrioid Carcinoma

MONDO:0006335 Pathograph 10 Show in embeddings browser ovarian carcinoma

Ovarian endometrioid carcinoma (OEC) is the second most common epithelial ovarian cancer histotype, accounting for roughly 10% of ovarian carcinomas. It resembles endometrioid carcinoma of the uterine corpus, is frequently endometriosis-associated, and is characterized by recurrent CTNNB1/Wnt-beta- catenin activation, PI3K-pathway lesions (PIK3CA gain, PTEN loss), and ARID1A (SWI/SNF) loss. The endometrial-cancer molecular taxonomy (POLE-ultramutated, mismatch-repair-deficient, p53-abnormal, no specific molecular profile) also applies to OEC, which is enriched for Lynch syndrome-associated tumors, supporting routine mismatch-repair testing. Most OECs are low-grade, present at an early stage, and carry a more favorable prognosis than high-grade serous carcinoma, whereas p53-abnormal/high-grade OECs behave more aggressively.

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6
Pathophys.
2
Histopath.
4
Phenotypes
1
Hypotheses
10
Pathograph
6
Genes
4
Medical Actions
2
References
1
Deep Research
◈

Mechanistic Hypotheses

1
Endometriosis-Associated Progression Model
endometriosis_associated_progression_model CANONICAL
OEC arises from endometriosis through stepwise malignant transformation. The detection of shared somatic driver mutations (ARID1A loss, PIK3CA, PTEN, KRAS) in morphologically benign and atypical endometriotic lesions adjacent to OEC supports a precursor-to-carcinoma sequence in which atypical endometriosis is the precursor lesion of roughly 40% of endometrioid carcinomas.
Show evidence (1 reference)
PMID:33919741 SUPPORT Human Clinical
"Atypical endometriosis represents the precursor lesion of about 40% of ECs."
De Leo et al. directly support atypical endometriosis as the precursor lesion for a large fraction of ovarian endometrioid carcinomas.
⚙

Pathophysiology

6
Endometriosis-Associated Origin
Most OECs are associated with endometriosis or arise from endometrioid adenofibroma/borderline tumor, with atypical endometriosis serving as the precursor lesion. A direct transition from atypical ovarian endometriosis to carcinoma is substantiated by shared molecular alterations in tumor and adjacent endometriosis.
endometrioid glandular epithelial cell CL:0000150
ovary UBERON:0000992
Downstream
ARID1A and SWI/SNF Chromatin Remodeling Loss Precursor endometriotic epithelium acquires ARID1A loss-of-function mutations.
PI3K-AKT Pathway Activation Endometriotic precursor lesions acquire PTEN loss and PIK3CA activating mutations.
Wnt-Beta-Catenin Pathway Activation Endometrioid-lineage precursor cells acquire activating CTNNB1 mutations.
Mismatch Repair Deficiency A subset of OECs arises in the context of germline or sporadic mismatch-repair gene inactivation, producing the MMR-deficient molecular subtype.
Show evidence (1 reference)
PMID:33919741 SUPPORT Human Clinical
"Most of ECs are frequently associated with endometriosis or contain areas of endometrioid adenofibroma and endometrioid borderline tumor."
De Leo et al. document the strong endometriosis association of the endometrioid histotype.
ARID1A and SWI/SNF Chromatin Remodeling Loss
ARID1A (encoding BAF250a) is a SWI/SNF chromatin-remodeling subunit and tumor suppressor mutated in approximately 30% of OEC. Loss of ARID1A and of BAF250a expression occurs in endometriosis adjacent to OEC, indicating an early event in precursor lesions, and disrupts transcriptional control and differentiation.
ARID1A hgnc:11110
chromatin remodeling GO:0006338 ⚠ ABNORMAL
Downstream
Tumor Cell Proliferation SWI/SNF loss derepresses proliferative transcriptional programs.
Show evidence (1 reference)
PMID:33919741 SUPPORT Human Clinical
"Mutations in ARID1A (AT-rich interactive domain 1A gene), and loss of expression of the encoded protein BAF250a, occur in approximately 30% of EC"
De Leo et al. quantify ARID1A/BAF250a loss in ovarian endometrioid carcinoma and identify it as a SWI/SNF tumor-suppressor lesion.
PI3K-AKT Pathway Activation
PTEN loss-of-function (mutated in ~20% of OEC, frequently with 10q23 loss of heterozygosity) and activating PIK3CA mutations (~20-40%) converge on the PI3K/AKT pathway, inhibiting apoptosis and promoting proliferation, survival, and progression from endometriosis to invasive carcinoma.
PTEN hgnc:9588 PIK3CA hgnc:8975
PI3K/AKT signaling GO:0043491 ↑ INCREASED
Downstream
Tumor Cell Proliferation PI3K/AKT activation inhibits apoptosis and sustains proliferation and survival.
Show evidence (1 reference)
PMID:33919741 SUPPORT Human Clinical
"Somatic mutations of PTEN and loss of heterozygosity (LOH) at 10q23 frequently coexist and result in activation of the PI3K/AKT pathway that inhibits apoptosis."
De Leo et al. establish PTEN loss as a driver of PI3K/AKT activation and apoptosis evasion in ovarian endometrioid carcinoma.
Wnt-Beta-Catenin Pathway Activation
Somatic CTNNB1 mutations are the most common molecular abnormality in OEC, occurring in roughly 38-53% of cases. They induce cytoplasmic and nuclear accumulation of beta-catenin, driving Wnt target-gene transcription and the endometrioid lineage program. CTNNB1 mutation is associated with low-grade tumors and favorable outcomes.
CTNNB1 hgnc:2514
canonical Wnt signaling pathway GO:0060070 ↑ INCREASED
Downstream
Tumor Cell Proliferation Nuclear beta-catenin drives Wnt target-gene transcription and proliferation.
Show evidence (2 references)
PMID:33919741 SUPPORT Human Clinical
"CTNNB1 mutations occur in 38–50% of cases and induce cytoplasmic and nuclear accumulation of β-catenin protein"
De Leo et al. quantify CTNNB1 mutation frequency and its mechanism of beta-catenin stabilization in ovarian endometrioid carcinoma.
PMID:33919741 SUPPORT Human Clinical
"CTNNB1 mutations are associated with low-grade tumors and favorable outcomes"
Supports the favorable-prognosis association of Wnt-beta-catenin-driven low-grade OEC.
Mismatch Repair Deficiency
Microsatellite instability occurs in 10-20% of OEC. In Lynch syndrome, germline mutation of MLH1, PMS2, MSH2, or MSH6 followed by a somatic second hit produces mismatch-repair deficiency; in sporadic tumors MLH1 promoter hypermethylation is the predominant mechanism. MMR deficiency yields a hypermutator phenotype that raises neoantigen load and confers sensitivity to immune checkpoint blockade.
MLH1 hgnc:7127 MSH2 hgnc:7325
mismatch repair GO:0006298 ↓ DECREASED
Downstream
Tumor Cell Proliferation Hypermutation from MMR deficiency drives clonal evolution while raising neoantigen load and immunotherapy sensitivity.
Show evidence (3 references)
PMID:33919741 SUPPORT Human Clinical
"These patients are characterized by an inherited germline mutation in the DNA mismatch repair (MMR) protein genes MLH1, PMS2, MSH2, or MSH6 (“first hit”), but EC develops only after the deletion or mutation of the second corresponding allele"
De Leo et al. describe the Lynch-syndrome two-hit mechanism underlying MMR-deficient ovarian endometrioid carcinoma.
PMID:33919741 SUPPORT Human Clinical
"In sporadic tumors, MMR protein deficiency is frequently caused by inactivation of MLH1 by promoter hypermethylation"
Supports MLH1 promoter hypermethylation as the dominant sporadic MMR-deficiency mechanism.
PMID:41425725 SUPPORT Human Clinical
"OEC is enriched for Lynch syndrome-associated tumors, supporting routine MMR testing."
Yoshida and Kato establish that ovarian endometrioid carcinoma is enriched for Lynch-syndrome-associated (MMR-deficient) tumors, supporting routine MMR testing.
Tumor Cell Proliferation
Convergence of SWI/SNF (ARID1A) loss, PI3K/AKT activation, Wnt-beta-catenin signaling, and (in a subset) mismatch-repair-deficient hypermutation drives sustained malignant proliferation of endometrioid carcinoma cells.
endometrioid carcinoma epithelial cell CL:0000066
cell population proliferation GO:0008283 ↑ INCREASED
✶

Histopathology

2
Endometrioid Adenocarcinoma
OEC microscopically resembles uterine endometrioid adenocarcinoma, with glandular, cribriform, and/or villoglandular patterns of tall stratified columnar cells. Most are low-grade.
Show evidence (1 reference)
PMID:33919741 SUPPORT Human Clinical
"Most ECs are low-grade carcinomas characterized by glandular, cribriform, and/or villoglandular patterns."
De Leo et al. describe the defining low-grade glandular architecture of the endometrioid histotype.
Squamous Differentiation
Squamous differentiation is a hallmark of endometrioid neoplasms and is a useful diagnostic feature distinguishing OEC from other ovarian histotypes.
Show evidence (1 reference)
PMID:33919741 SUPPORT Human Clinical
"Squamous differentiation is a hallmark of endometrioid neoplasms and represents a useful diagnostic feature"
De Leo et al. identify squamous differentiation as a diagnostic hallmark of endometrioid carcinoma.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Ovarian Endometrioid Carcinoma Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

4
Genitourinary 1
Ovarian carcinoma OBLIGATE Ovarian carcinoma HP:0025318
Constitutional 1
Abdominal pain Abdominal pain HP:0002027
Show evidence (1 reference)
PMID:37674925 SUPPORT Human Clinical
"ovarian cancer's symptoms are non-specific. As a result, ovarian cancers are normally undetected until advanced stages (III or IV)."
Ali et al. support non-specific symptomatology and late presentation of ovarian cancer.
Other 2
Ovarian neoplasm Ovarian neoplasm HP:0100615
Show evidence (1 reference)
PMID:33919741 SUPPORT Human Clinical
"The tumors are bilateral in 20% of cases and are associated in 15–20% of cases with a synchronous endometrial carcinoma."
De Leo et al. document the ovarian mass presentation and bilaterality of OEC.
Endometriosis Endometriosis HP:0030127
Show evidence (1 reference)
PMID:33919741 SUPPORT Human Clinical
"Atypical endometriosis represents the precursor lesion of about 40% of ECs."
De Leo et al. document the endometriosis association and precursor role in OEC.
🧬

Genetic Associations

6
CTNNB1 (Activating somatic mutation)
Gene: CTNNB1 hgnc:2514
Show evidence (1 reference)
PMID:33919741 SUPPORT Human Clinical
"The most common molecular abnormalities identified in ovarian ECs are somatic mutations of CTNNB1, the gene encoding β-catenin, and PTEN."
De Leo et al. identify CTNNB1 as the most common recurrent driver in OEC.
PTEN (Loss-of-function mutation)
Gene: PTEN hgnc:9588
Show evidence (1 reference)
PMID:33919741 SUPPORT Human Clinical
"PTEN is a tumor suppressor gene located on chromosome 10q23.3 and is mutated in approximately 20% of ovarian EC."
De Leo et al. quantify PTEN loss in ovarian endometrioid carcinoma.
PIK3CA (Activating mutation)
Gene: PIK3CA hgnc:8975
Show evidence (1 reference)
PMID:33919741 SUPPORT Human Clinical
"PIK3CA mutations in exons 9 and 20 have been identified in 20% of ovarian ECs"
De Leo et al. quantify activating PIK3CA mutation frequency in OEC.
ARID1A (Loss-of-function mutation)
Gene: ARID1A hgnc:11110
Show evidence (1 reference)
PMID:33919741 SUPPORT Human Clinical
"Mutations in ARID1A (AT-rich interactive domain 1A gene), and loss of expression of the encoded protein BAF250a, occur in approximately 30% of EC"
De Leo et al. quantify ARID1A loss in ovarian endometrioid carcinoma.
KRAS (Activating mutation)
Gene: KRAS hgnc:6407
Show evidence (1 reference)
PMID:33919741 SUPPORT Human Clinical
"molecular alterations involve: the WNT/β-catenin signaling pathway (CTNNB1 mutations, 53%), the PI3K pathway (PIK3CA, 40%; PTEN, 17%), the MAPK pathway (KRAS, 33%), and the SWI/SNF complex (ARID1A, 30%)"
De Leo et al. quantify the recurrent driver landscape of ovarian EC including KRAS.
POLE (Exonuclease-domain ultramutation)
Gene: POLE hgnc:9177
Show evidence (1 reference)
PMID:41425725 SUPPORT Human Clinical
"POLEmut/MMRd subsets generally have excellent outcomes and are candidates for de-escalation or immunotherapy"
Yoshida and Kato establish the POLE-ultramutated molecular subtype in OEC and its excellent prognosis.
💊

Medical Actions

4
Cytoreductive Surgery
Action: surgical procedure MAXO:0000004
Standard initial management includes total hysterectomy with bilateral salpingo-oophorectomy, omentectomy, and surgical staging. OEC is often diagnosed at an early stage, supporting surgery-centered management of localized disease.
Show evidence (1 reference)
PMID:33919741 SUPPORT Human Clinical
"Most ECs are found at an early stage (FIGO stage I or II) at diagnosis."
De Leo et al. document early-stage presentation that supports surgery-centered management of OEC.
Carboplatin/Paclitaxel Chemotherapy
Action: chemotherapy MAXO:0000647
Agent: carboplatin NCIT:C1282 paclitaxel NCIT:C1411
Platinum-taxane chemotherapy is the standard adjuvant systemic backbone for advanced-stage disease and high-risk early-stage epithelial ovarian cancer, applied to OEC by extrapolation from epithelial ovarian cancer practice.
Immune Checkpoint Blockade
Action: immunotherapy Ontology label: Immunotherapy NCIT:C15262
Agent: pembrolizumab NCIT:C106432
Immune checkpoint inhibitors such as pembrolizumab are most relevant for the mismatch-repair-deficient/MSI-high subset of OEC, which is enriched for Lynch syndrome-associated tumors and shows high neoantigen load. Robust tumor-agnostic and endometrial-cancer evidence supports activity in MMRd/MSI-high gynecologic tumors.
Show evidence (1 reference)
PMID:41425725 SUPPORT Human Clinical
"POLEmut/MMRd subsets generally have excellent outcomes and are candidates for de-escalation or immunotherapy"
Yoshida and Kato support immunotherapy in the MMRd subset of OEC.
Hormonal (Progestin) Therapy
Action: Pharmacotherapy NCIT:C15986
Agent: progestin NCIT:C776
Progestin-based endocrine therapy may be considered for selected low-grade, hormone-receptor-positive, indolent, recurrent, or fertility-sparing cases, by analogy to endometrioid gynecologic tumors that often retain ER/PR expression.
Show evidence (1 reference)
PMID:33919741 SUPPORT Human Clinical
"The immunohistochemical profile of EC includes diffuse positivity for PAX 8, Vimentin, Estrogen (ER), and Progesterone receptors (PR)."
De Leo et al. document ER/PR positivity that provides the biologic rationale for hormonal therapy in OEC.
🔬

Biochemical Markers

2
Serum CA-125
Microsatellite Instability
Show evidence (1 reference)
PMID:33919741 SUPPORT Human Clinical
"The reported frequency of MSI in ovarian ECs ranges from 10% to 20%."
De Leo et al. quantify MSI frequency in ovarian endometrioid carcinoma.
{ }

Source YAML

click to show 
name: Ovarian Endometrioid Carcinoma
creation_date: "2026-06-19T12:00:00Z"
synonyms:
- Ovarian endometrioid adenocarcinoma
- Endometrioid ovarian carcinoma
- Endometrioid carcinoma of the ovary
- OEC
description: >-
  Ovarian endometrioid carcinoma (OEC) is the second most common epithelial
  ovarian cancer histotype, accounting for roughly 10% of ovarian carcinomas.
  It resembles endometrioid carcinoma of the uterine corpus, is frequently
  endometriosis-associated, and is characterized by recurrent CTNNB1/Wnt-beta-
  catenin activation, PI3K-pathway lesions (PIK3CA gain, PTEN loss), and ARID1A
  (SWI/SNF) loss. The endometrial-cancer molecular taxonomy (POLE-ultramutated,
  mismatch-repair-deficient, p53-abnormal, no specific molecular profile) also
  applies to OEC, which is enriched for Lynch syndrome-associated tumors,
  supporting routine mismatch-repair testing. Most OECs are low-grade, present
  at an early stage, and carry a more favorable prognosis than high-grade serous
  carcinoma, whereas p53-abnormal/high-grade OECs behave more aggressively.
categories:
- Gynecologic Cancer
- Molecularly-Defined Cancer
- Solid Tumor
parents:
- ovarian carcinoma
disease_term:
  preferred_term: ovarian endometrioid adenocarcinoma
  term:
    id: MONDO:0006335
    label: ovarian endometrioid adenocarcinoma
notes: >-
  Part of the Ovarian Adenocarcinoma histotype refactor (issue #4452, PR #4468):
  the umbrella ovarian adenocarcinoma entry is being split into per-histotype
  disease entries plus a grouping. This entry curates the endometrioid histotype.
  It is a DIFFERENT entity from endometrial (uterine) endometrioid adenocarcinoma.
references:
- reference: PMID:41425725
  title: "Molecular Pathology of Ovarian Endometrioid Carcinoma: A Review."
- reference: PMID:33919741
  title: >-
    What Is New on Ovarian Carcinoma: Integrated Morphologic and Molecular Analysis
    Following the New 2020 World Health Organization Classification of Female Genital Tumors.
mechanistic_hypotheses:
- hypothesis_group_id: endometriosis_associated_progression_model
  hypothesis_label: Endometriosis-Associated Progression Model
  status: CANONICAL
  description: >-
    OEC arises from endometriosis through stepwise malignant transformation. The
    detection of shared somatic driver mutations (ARID1A loss, PIK3CA, PTEN, KRAS)
    in morphologically benign and atypical endometriotic lesions adjacent to OEC
    supports a precursor-to-carcinoma sequence in which atypical endometriosis is
    the precursor lesion of roughly 40% of endometrioid carcinomas.
  evidence:
  - reference: PMID:33919741
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Atypical endometriosis represents the precursor lesion of about 40% of ECs.
    explanation: >-
      De Leo et al. directly support atypical endometriosis as the precursor lesion
      for a large fraction of ovarian endometrioid carcinomas.
pathophysiology:
- name: Endometriosis-Associated Origin
  description: >-
    Most OECs are associated with endometriosis or arise from endometrioid
    adenofibroma/borderline tumor, with atypical endometriosis serving as the
    precursor lesion. A direct transition from atypical ovarian endometriosis to
    carcinoma is substantiated by shared molecular alterations in tumor and
    adjacent endometriosis.
  cell_types:
  - preferred_term: endometrioid glandular epithelial cell
    term:
      id: CL:0000150
      label: glandular secretory epithelial cell
  locations:
  - preferred_term: ovary
    term:
      id: UBERON:0000992
      label: ovary
  evidence:
  - reference: PMID:33919741
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most of ECs are frequently associated with endometriosis or contain areas of
      endometrioid adenofibroma and endometrioid borderline tumor.
    explanation: >-
      De Leo et al. document the strong endometriosis association of the endometrioid histotype.
  downstream:
  - target: ARID1A and SWI/SNF Chromatin Remodeling Loss
    description: Precursor endometriotic epithelium acquires ARID1A loss-of-function mutations.
  - target: PI3K-AKT Pathway Activation
    description: Endometriotic precursor lesions acquire PTEN loss and PIK3CA activating mutations.
  - target: Wnt-Beta-Catenin Pathway Activation
    description: Endometrioid-lineage precursor cells acquire activating CTNNB1 mutations.
  - target: Mismatch Repair Deficiency
    description: >-
      A subset of OECs arises in the context of germline or sporadic mismatch-repair gene
      inactivation, producing the MMR-deficient molecular subtype.
- name: ARID1A and SWI/SNF Chromatin Remodeling Loss
  description: >-
    ARID1A (encoding BAF250a) is a SWI/SNF chromatin-remodeling subunit and tumor
    suppressor mutated in approximately 30% of OEC. Loss of ARID1A and of BAF250a
    expression occurs in endometriosis adjacent to OEC, indicating an early event
    in precursor lesions, and disrupts transcriptional control and differentiation.
  genes:
  - preferred_term: ARID1A
    term:
      id: hgnc:11110
      label: ARID1A
  biological_processes:
  - preferred_term: chromatin remodeling
    modifier: ABNORMAL
    term:
      id: GO:0006338
      label: chromatin remodeling
  evidence:
  - reference: PMID:33919741
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in ARID1A (AT-rich interactive domain 1A gene), and loss of expression
      of the encoded protein BAF250a, occur in approximately 30% of EC
    explanation: >-
      De Leo et al. quantify ARID1A/BAF250a loss in ovarian endometrioid carcinoma and
      identify it as a SWI/SNF tumor-suppressor lesion.
  downstream:
  - target: Tumor Cell Proliferation
    description: SWI/SNF loss derepresses proliferative transcriptional programs.
- name: PI3K-AKT Pathway Activation
  description: >-
    PTEN loss-of-function (mutated in ~20% of OEC, frequently with 10q23 loss of
    heterozygosity) and activating PIK3CA mutations (~20-40%) converge on the
    PI3K/AKT pathway, inhibiting apoptosis and promoting proliferation, survival,
    and progression from endometriosis to invasive carcinoma.
  genes:
  - preferred_term: PTEN
    term:
      id: hgnc:9588
      label: PTEN
  - preferred_term: PIK3CA
    term:
      id: hgnc:8975
      label: PIK3CA
  biological_processes:
  - preferred_term: PI3K/AKT signaling
    modifier: INCREASED
    term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
  evidence:
  - reference: PMID:33919741
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Somatic mutations of PTEN and loss of heterozygosity (LOH) at 10q23 frequently
      coexist and result in activation of the PI3K/AKT pathway that inhibits apoptosis.
    explanation: >-
      De Leo et al. establish PTEN loss as a driver of PI3K/AKT activation and apoptosis
      evasion in ovarian endometrioid carcinoma.
  downstream:
  - target: Tumor Cell Proliferation
    description: PI3K/AKT activation inhibits apoptosis and sustains proliferation and survival.
- name: Wnt-Beta-Catenin Pathway Activation
  description: >-
    Somatic CTNNB1 mutations are the most common molecular abnormality in OEC,
    occurring in roughly 38-53% of cases. They induce cytoplasmic and nuclear
    accumulation of beta-catenin, driving Wnt target-gene transcription and the
    endometrioid lineage program. CTNNB1 mutation is associated with low-grade
    tumors and favorable outcomes.
  genes:
  - preferred_term: CTNNB1
    term:
      id: hgnc:2514
      label: CTNNB1
  biological_processes:
  - preferred_term: canonical Wnt signaling pathway
    modifier: INCREASED
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
  evidence:
  - reference: PMID:33919741
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CTNNB1 mutations occur in 38–50% of cases and induce cytoplasmic and nuclear
      accumulation of β-catenin protein
    explanation: >-
      De Leo et al. quantify CTNNB1 mutation frequency and its mechanism of beta-catenin
      stabilization in ovarian endometrioid carcinoma.
  - reference: PMID:33919741
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CTNNB1 mutations are associated with low-grade tumors and favorable outcomes
    explanation: >-
      Supports the favorable-prognosis association of Wnt-beta-catenin-driven low-grade OEC.
  downstream:
  - target: Tumor Cell Proliferation
    description: Nuclear beta-catenin drives Wnt target-gene transcription and proliferation.
- name: Mismatch Repair Deficiency
  description: >-
    Microsatellite instability occurs in 10-20% of OEC. In Lynch syndrome,
    germline mutation of MLH1, PMS2, MSH2, or MSH6 followed by a somatic second
    hit produces mismatch-repair deficiency; in sporadic tumors MLH1 promoter
    hypermethylation is the predominant mechanism. MMR deficiency yields a
    hypermutator phenotype that raises neoantigen load and confers sensitivity to
    immune checkpoint blockade.
  genes:
  - preferred_term: MLH1
    term:
      id: hgnc:7127
      label: MLH1
  - preferred_term: MSH2
    term:
      id: hgnc:7325
      label: MSH2
  biological_processes:
  - preferred_term: mismatch repair
    modifier: DECREASED
    term:
      id: GO:0006298
      label: mismatch repair
  evidence:
  - reference: PMID:33919741
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These patients are characterized by an inherited germline mutation in the DNA
      mismatch repair (MMR) protein genes MLH1, PMS2, MSH2, or MSH6 (“first hit”),
      but EC develops only after the deletion or mutation of the second corresponding allele
    explanation: >-
      De Leo et al. describe the Lynch-syndrome two-hit mechanism underlying MMR-deficient
      ovarian endometrioid carcinoma.
  - reference: PMID:33919741
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In sporadic tumors, MMR protein deficiency is frequently caused by inactivation
      of MLH1 by promoter hypermethylation
    explanation: >-
      Supports MLH1 promoter hypermethylation as the dominant sporadic MMR-deficiency mechanism.
  - reference: PMID:41425725
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      OEC is enriched for Lynch syndrome-associated tumors, supporting routine MMR testing.
    explanation: >-
      Yoshida and Kato establish that ovarian endometrioid carcinoma is enriched for
      Lynch-syndrome-associated (MMR-deficient) tumors, supporting routine MMR testing.
  downstream:
  - target: Tumor Cell Proliferation
    description: >-
      Hypermutation from MMR deficiency drives clonal evolution while raising
      neoantigen load and immunotherapy sensitivity.
- name: Tumor Cell Proliferation
  description: >-
    Convergence of SWI/SNF (ARID1A) loss, PI3K/AKT activation, Wnt-beta-catenin
    signaling, and (in a subset) mismatch-repair-deficient hypermutation drives
    sustained malignant proliferation of endometrioid carcinoma cells.
  cell_types:
  - preferred_term: endometrioid carcinoma epithelial cell
    term:
      id: CL:0000066
      label: epithelial cell
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
histopathology:
- name: Endometrioid Adenocarcinoma
  finding_term:
    preferred_term: endometrioid adenocarcinoma
    term:
      id: NCIT:C3769
      label: Endometrioid Adenocarcinoma
  description: >-
    OEC microscopically resembles uterine endometrioid adenocarcinoma, with
    glandular, cribriform, and/or villoglandular patterns of tall stratified
    columnar cells. Most are low-grade.
  evidence:
  - reference: PMID:33919741
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most ECs are low-grade carcinomas characterized by glandular, cribriform,
      and/or villoglandular patterns.
    explanation: >-
      De Leo et al. describe the defining low-grade glandular architecture of the
      endometrioid histotype.
- name: Squamous Differentiation
  finding_term:
    preferred_term: squamous differentiation
    term:
      id: NCIT:C38770
      label: Squamous Differentiation
  description: >-
    Squamous differentiation is a hallmark of endometrioid neoplasms and is a
    useful diagnostic feature distinguishing OEC from other ovarian histotypes.
  evidence:
  - reference: PMID:33919741
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Squamous differentiation is a hallmark of endometrioid neoplasms and represents
      a useful diagnostic feature
    explanation: >-
      De Leo et al. identify squamous differentiation as a diagnostic hallmark of
      endometrioid carcinoma.
phenotypes:
- category: Neoplastic
  name: Ovarian carcinoma
  diagnostic: true
  frequency: OBLIGATE
  description: The defining neoplastic phenotype is a primary ovarian endometrioid carcinoma.
  phenotype_term:
    preferred_term: ovarian carcinoma
    term:
      id: HP:0025318
      label: Ovarian carcinoma
- category: Neoplastic
  name: Ovarian neoplasm
  description: >-
    OEC presents as an ovarian mass; tumors are bilateral in about 20% of cases.
  phenotype_term:
    preferred_term: Ovarian neoplasm
    term:
      id: HP:0100615
      label: Ovarian neoplasm
  evidence:
  - reference: PMID:33919741
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The tumors are bilateral in 20% of cases and are associated in 15–20% of cases
      with a synchronous endometrial carcinoma.
    explanation: >-
      De Leo et al. document the ovarian mass presentation and bilaterality of OEC.
- category: Reproductive
  name: Endometriosis
  description: >-
    Endometriosis is a frequent associated finding and precursor; OECs are
    frequently associated with endometriosis, with atypical endometriosis the
    precursor of about 40% of cases.
  phenotype_term:
    preferred_term: Endometriosis
    term:
      id: HP:0030127
      label: Endometriosis
  evidence:
  - reference: PMID:33919741
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Atypical endometriosis represents the precursor lesion of about 40% of ECs.
    explanation: >-
      De Leo et al. document the endometriosis association and precursor role in OEC.
- category: Gastrointestinal
  name: Abdominal pain
  description: >-
    Ovarian cancer, including OEC, often presents with non-specific abdominal or
    pelvic symptoms, frequently leading to diagnosis at advanced stages.
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
  evidence:
  - reference: PMID:37674925
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ovarian cancer's symptoms are non-specific. As a result, ovarian cancers are
      normally undetected until advanced stages (III or IV).
    explanation: >-
      Ali et al. support non-specific symptomatology and late presentation of ovarian cancer.
biochemical:
- name: Serum CA-125
  biomarker_term:
    preferred_term: CA-125
    term:
      id: NCIT:C325
      label: CA-125 Antigen
  notes: >-
    CA-125 is the dominant serum biomarker used in clinical monitoring of ovarian
    cancer but has low specificity; it can be elevated by menstruation or endometriosis.
- name: Microsatellite Instability
  biomarker_term:
    preferred_term: microsatellite instability
    term:
      id: NCIT:C36318
      label: Microsatellite Instability
  notes: >-
    MSI/mismatch-repair-deficiency status, assessed by MMR immunohistochemistry
    (MLH1/MSH2/MSH6/PMS2) or PCR-based MSI testing, defines the MMRd molecular
    subtype, triages for Lynch syndrome, and predicts immune-checkpoint sensitivity.
  evidence:
  - reference: PMID:33919741
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The reported frequency of MSI in ovarian ECs ranges from 10% to 20%.
    explanation: >-
      De Leo et al. quantify MSI frequency in ovarian endometrioid carcinoma.
genetic:
- name: CTNNB1
  association: Activating somatic mutation
  gene_term:
    preferred_term: CTNNB1
    term:
      id: hgnc:2514
      label: CTNNB1
  notes: >-
    The most common molecular abnormality in OEC (38-53%); activates Wnt/beta-catenin
    signaling and is associated with low-grade tumors and favorable outcome.
  evidence:
  - reference: PMID:33919741
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most common molecular abnormalities identified in ovarian ECs are somatic
      mutations of CTNNB1, the gene encoding β-catenin, and PTEN.
    explanation: >-
      De Leo et al. identify CTNNB1 as the most common recurrent driver in OEC.
- name: PTEN
  association: Loss-of-function mutation
  gene_term:
    preferred_term: PTEN
    term:
      id: hgnc:9588
      label: PTEN
  notes: >-
    Mutated in ~20% of OEC, frequently with 10q23 loss of heterozygosity, activating PI3K/AKT.
  evidence:
  - reference: PMID:33919741
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PTEN is a tumor suppressor gene located on chromosome 10q23.3 and is mutated in
      approximately 20% of ovarian EC.
    explanation: >-
      De Leo et al. quantify PTEN loss in ovarian endometrioid carcinoma.
- name: PIK3CA
  association: Activating mutation
  gene_term:
    preferred_term: PIK3CA
    term:
      id: hgnc:8975
      label: PIK3CA
  notes: >-
    Activating PIK3CA mutations occur in roughly 20-40% of OEC and trigger PI3K signaling.
  evidence:
  - reference: PMID:33919741
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PIK3CA mutations in exons 9 and 20 have been identified in 20% of ovarian ECs
    explanation: >-
      De Leo et al. quantify activating PIK3CA mutation frequency in OEC.
- name: ARID1A
  association: Loss-of-function mutation
  gene_term:
    preferred_term: ARID1A
    term:
      id: hgnc:11110
      label: ARID1A
  notes: >-
    SWI/SNF subunit; mutated/lost in ~30% of OEC and detectable in adjacent
    endometriosis, supporting an early precursor-lesion event.
  evidence:
  - reference: PMID:33919741
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in ARID1A (AT-rich interactive domain 1A gene), and loss of expression
      of the encoded protein BAF250a, occur in approximately 30% of EC
    explanation: >-
      De Leo et al. quantify ARID1A loss in ovarian endometrioid carcinoma.
- name: KRAS
  association: Activating mutation
  gene_term:
    preferred_term: KRAS
    term:
      id: hgnc:6407
      label: KRAS
  notes: >-
    Recurrent MAPK-pathway activating mutation, also detectable in benign
    endometriotic lesions, supporting the precursor model.
  evidence:
  - reference: PMID:33919741
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      molecular alterations involve: the WNT/β-catenin signaling pathway (CTNNB1
      mutations, 53%), the PI3K pathway (PIK3CA, 40%; PTEN, 17%), the MAPK pathway
      (KRAS, 33%), and the SWI/SNF complex (ARID1A, 30%)
    explanation: >-
      De Leo et al. quantify the recurrent driver landscape of ovarian EC including KRAS.
- name: POLE
  association: Exonuclease-domain ultramutation
  gene_term:
    preferred_term: POLE
    term:
      id: hgnc:9177
      label: POLE
  notes: >-
    POLE exonuclease-domain mutations define the ultramutated subtype (~5%),
    which carries an excellent prognosis.
  evidence:
  - reference: PMID:41425725
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      POLEmut/MMRd subsets generally have excellent outcomes and are candidates for
      de-escalation or immunotherapy
    explanation: >-
      Yoshida and Kato establish the POLE-ultramutated molecular subtype in OEC and its
      excellent prognosis.
treatments:
- name: Cytoreductive Surgery
  description: >-
    Standard initial management includes total hysterectomy with bilateral
    salpingo-oophorectomy, omentectomy, and surgical staging. OEC is often
    diagnosed at an early stage, supporting surgery-centered management of
    localized disease.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
  evidence:
  - reference: PMID:33919741
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most ECs are found at an early stage (FIGO stage I or II) at diagnosis.
    explanation: >-
      De Leo et al. document early-stage presentation that supports surgery-centered
      management of OEC.
- name: Carboplatin/Paclitaxel Chemotherapy
  description: >-
    Platinum-taxane chemotherapy is the standard adjuvant systemic backbone for
    advanced-stage disease and high-risk early-stage epithelial ovarian cancer,
    applied to OEC by extrapolation from epithelial ovarian cancer practice.
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: MAXO:0000647
      label: chemotherapy
    therapeutic_agent:
    - preferred_term: carboplatin
      term:
        id: NCIT:C1282
        label: Carboplatin
    - preferred_term: paclitaxel
      term:
        id: NCIT:C1411
        label: Paclitaxel
- name: Immune Checkpoint Blockade
  description: >-
    Immune checkpoint inhibitors such as pembrolizumab are most relevant for the
    mismatch-repair-deficient/MSI-high subset of OEC, which is enriched for Lynch
    syndrome-associated tumors and shows high neoantigen load. Robust tumor-agnostic
    and endometrial-cancer evidence supports activity in MMRd/MSI-high gynecologic tumors.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: immunotherapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
    therapeutic_agent:
    - preferred_term: pembrolizumab
      term:
        id: NCIT:C106432
        label: Pembrolizumab
  evidence:
  - reference: PMID:41425725
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      POLEmut/MMRd subsets generally have excellent outcomes and are candidates for
      de-escalation or immunotherapy
    explanation: >-
      Yoshida and Kato support immunotherapy in the MMRd subset of OEC.
- name: Hormonal (Progestin) Therapy
  description: >-
    Progestin-based endocrine therapy may be considered for selected low-grade,
    hormone-receptor-positive, indolent, recurrent, or fertility-sparing cases,
    by analogy to endometrioid gynecologic tumors that often retain ER/PR expression.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: progestin
      term:
        id: NCIT:C776
        label: Progestin
  evidence:
  - reference: PMID:33919741
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The immunohistochemical profile of EC includes diffuse positivity for PAX 8,
      Vimentin, Estrogen (ER), and Progesterone receptors (PR).
    explanation: >-
      De Leo et al. document ER/PR positivity that provides the biologic rationale for
      hormonal therapy in OEC.
📚

References & Deep Research

References

2
PMID:41425725
Molecular Pathology of Ovarian Endometrioid Carcinoma: A Review.
No top-level findings curated for this source.
PMID:33919741
What Is New on Ovarian Carcinoma: Integrated Morphologic and Molecular Analysis Following the New 2020 World Health Organization Classification of Female Genital Tumors.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Information
Edison Scientific Literature 14 citations 2026-06-19T09:40:01.716041

Disease Information

Disease Name: Ovarian Endometrioid Carcinoma (OEC)

Category: Epithelial ovarian cancer, gynecologic malignancy

Definition and Classification

Ovarian endometrioid carcinoma is a distinct histologic subtype of epithelial ovarian cancer that accounts for approximately 10% of all ovarian carcinomas (yoshida2025molecularpathologyof pages 1-3). According to the 2020 World Health Organization (WHO) classification, OEC is defined as a carcinoma resembling endometrioid carcinoma of the uterine corpus, characterized by tubular glands resembling proliferative endometrial epithelium (yoshida2025molecularpathologyof pages 1-3, leo2021whatisnew pages 1-2). The WHO Classification of Female Genital Tumours (5th edition, 2020) recognizes OEC as one of five principal histotypes of ovarian carcinoma, alongside high-grade serous, low-grade serous, clear cell, and mucinous carcinomas (leo2021whatisnew pages 1-2, kobel2022theevolutionof pages 1-3).

OEC exhibits broad morphological diversity, often including glandular, solid, squamous, or sertoliform patterns, which can lead to diagnostic confusion with other primary ovarian neoplasms or metastatic tumors (yoshida2025molecularpathologyof pages 1-3). While earlier studies reported higher frequencies of OEC, this discrepancy likely reflects historical misclassification, particularly of SET (Solid, pseudo-Endometrioid, and Transitional cell-like)-pattern high-grade serous carcinomas as high-grade OECs (yoshida2025molecularpathologyof pages 1-3).

Common Synonyms

  • Endometrioid ovarian carcinoma
  • Ovarian endometrioid adenocarcinoma
  • Endometriosis-associated ovarian cancer (when arising from endometriosis, shared with clear cell carcinoma)

Key Identifiers

While specific OMIM, Orphanet, or MONDO identifiers were not detailed in the reviewed literature, OEC is classified under ICD-O morphology codes for endometrioid carcinoma and is part of the broader category of epithelial ovarian neoplasms.

Epidemiology and Population Demographics

Global Incidence and Prevalence

Globally, an estimated 29,319 new patients of endometrioid cancer were identified in 2020 among all ovarian cancer cases (wang2024globalincidenceof pages 1-2). This represents approximately 9.5-10% of all epithelial ovarian carcinomas worldwide (yoshida2025molecularpathologyof pages 1-3, wang2024globalincidenceof pages 1-2).

The distribution of ovarian cancer histologic subtypes exhibits regional variation. Northern Africa and Eastern Asia show the highest burden of endometrioid carcinomas, contrasting with high-grade serous carcinomas which predominate in Eastern Europe (wang2024globalincidenceof pages 1-2). Recent studies employing refined pathological classification consistently report the frequency of OEC as around 10%, with no significant difference between Western and Asian populations, unlike ovarian clear cell carcinoma which is more prevalent among Asian women (yoshida2025molecularpathologyof pages 1-3).

In the United States, during 1992-2019, endometrioid ovarian cancer incidence showed differential trends by race/ethnicity. Endometrioid cancer incidence decreased in non-Hispanic White women (AAPC during 2010-2019 = -1.3; 95% CI, -1.9 to -0.8) but increased in Hispanic women (AAPC = 3.6; 95% CI, 1.0 to 6.3) (phung2023trendsofovarian pages 1-2).

Age Distribution

In Japan, OEC is increasingly diagnosed in younger women (<50 years) and in early-stage disease (yoshida2025molecularpathologyof pages 1-3). This trend may reflect rising prevalence of endometriosis, increased lifetime menstrual cycles due to declining fertility, delayed marriage, earlier menarche, and later menopause, as well as growing prevalence of obesity (yoshida2025molecularpathologyof pages 1-3). These factors are thought to be influenced by recent societal and lifestyle changes that impact reproductive and hormonal health.

Sex Ratio

Ovarian endometrioid carcinoma, like all ovarian cancers, affects exclusively or overwhelmingly female patients, as it arises from ovarian or endometriotic tissue.

Etiology

Disease Causal Factors

Endometriosis as Precursor

Endometriosis is a well-established risk factor and potential precursor for OEC, conferring a two- to threefold increase in risk, a feature shared with ovarian clear cell carcinoma (yoshida2025molecularpathologyof pages 1-3). Histological evidence of endometriosis is observed in approximately 40% of resected OEC specimens (yoshida2025molecularpathologyof pages 1-3). The presence of shared somatic mutations between endometriotic lesions and OEC—such as ARID1A loss-of-function and PIK3CA gain-of-function mutations—supports the hypothesis that OEC may arise from endometriosis through stepwise malignant transformation (yoshida2025molecularpathologyof pages 1-3).

Endometriosis affects 10-18% of reproductive-aged women and is associated with a 2-3% lifetime risk of ovarian cancer, exceeding that of the general female population (yoshida2025molecularpathologyof pages 1-3). Notably, even morphologically benign endometriotic lesions harbor oncogenic mutations (e.g., ARID1A, PIK3CA, KRAS, PTEN, TP53), indicating their potential as precursors to malignancy (yoshida2025molecularpathologyof pages 1-3).

Risk Factors

Genetic Risk Factors: - Lynch Syndrome: OEC is enriched for Lynch syndrome-associated tumors. Among mismatch repair-deficient (MMRd) ovarian endometrioid carcinomas, approximately 9.5% are associated with Lynch syndrome, supporting routine MMR testing (yoshida2025molecularpathologyof pages 1-3, kobel2022theevolutionof pages 1-3). - BRCA1/2 Mutations: BRCA1 mutation carriers show increased risks for endometrioid EC (SIR = 2.63, 95% CI: 1.80-3.83; HR = 2.01, 95% CI: 1.18-3.45), although the association is stronger for serous-like tumors (ali2023epidemiologyandrisk pages 1-2).

Environmental/Lifestyle Risk Factors: - Obesity: 1.2-fold increase in risk per 5 kg/m² increase in body mass index (BMI) (yoshida2025molecularpathologyof pages 1-3) - Hormone Replacement Therapy (HRT): Relative risk ~1.3-1.4 (yoshida2025molecularpathologyof pages 1-3, ali2023epidemiologyandrisk pages 1-2) - Elevated Estrogen Exposure: Greater number of lifetime menstrual cycles associated with increased risk (yoshida2025molecularpathologyof pages 1-3) - Nulliparity: Nulliparous women have higher risk (ali2023epidemiologyandrisk pages 1-2)

OEC shows stronger associations with family history of ovarian cancer and higher BMI, features not typically observed in clear cell carcinoma despite both subtypes' association with endometriosis (yoshida2025molecularpathologyof pages 1-3).

Protective Factors

Reproductive Factors: - Parity: Each birth reduces risk by approximately 10% (yoshida2025molecularpathologyof pages 1-3) - Oral Contraceptive Use: 15-20% risk reduction with five years of use (yoshida2025molecularpathologyof pages 1-3)

Surgical Interventions: - Tubal Ligation and Salpingectomy: Appear protective, possibly by reducing retrograde menstruation (yoshida2025molecularpathologyof pages 1-3)

Tobacco: - Smoking: Interestingly, unlike other ovarian cancer subtypes, smoking was correlated with a lower risk for OEC (relative risk ~0.8) (yoshida2025molecularpathologyof pages 1-3)

Genetic and Molecular Information

Causal Genes and Pathogenic Variants

Pathway / Function Group Gene / Pathway Type of Alteration in Ovarian Endometrioid Carcinoma Frequency / Enrichment Functional Impact Clinical Significance Associated Molecular Subtype
Chromatin remodeling ARID1A Predominantly loss-of-function alterations; often reflected by loss of protein expression Recurrent/frequent; shared with endometriosis-associated tumors and often co-occurs with PIK3CA alterations (leo2021whatisnew pages 1-2, yoshida2025molecularpathologyof pages 1-3) Disrupts SWI/SNF chromatin remodeling, altering transcriptional control and differentiation programs Supports endometriosis-associated pathogenesis; candidate biomarker for synthetic-lethality and epigenetic strategies; useful in molecular profiling (yoshida2025molecularpathologyof pages 1-3) Most often NSMP or MMRd backgrounds; can occur across subtypes
PI3K/AKT/mTOR signaling PIK3CA Activating/gain-of-function mutation Recurrent/frequent; commonly co-occurs with ARID1A and present in endometriosis-related precursor lesions (yoshida2025molecularpathologyof pages 1-3) Activates PI3K/AKT/mTOR signaling, promoting proliferation, survival, metabolism, and therapy resistance Suggests actionable pathway dependence; rationale for PI3K/AKT/mTOR-targeted therapy development (yoshida2025molecularpathologyof pages 1-3) Most often NSMP; also seen in MMRd tumors
PI3K/AKT/mTOR signaling PTEN Inactivating mutation/loss of function; sometimes loss of expression Recurrent/frequent in OEC; highlighted as characteristic of endometrioid tumors (leo2021whatisnew pages 1-2, yoshida2025molecularpathologyof pages 1-3) Releases inhibition of PI3K signaling, increasing AKT/mTOR pathway activation Supports endometriosis-to-carcinoma progression model; may inform targeted pathway inhibition strategies (yoshida2025molecularpathologyof pages 1-3) Most often NSMP; also present in MMRd
Wnt / cell fate CTNNB1 Activating mutation / β-catenin pathway alteration Characteristic/recurrent in OEC (leo2021whatisnew pages 1-2, yoshida2025molecularpathologyof pages 1-3) Activates Wnt/β-catenin signaling, affecting epithelial differentiation, proliferation, and glandular/squamous morphology Helpful lineage-defining alteration for endometrioid histotype; may aid distinction from other ovarian carcinoma types (leo2021whatisnew pages 1-2) Most commonly NSMP
MAPK signaling KRAS Activating mutation Less common than PTEN/PIK3CA/CTNNB1 but recurrent; also seen in benign endometriotic lesions (yoshida2025molecularpathologyof pages 1-3) Activates MAPK signaling, supporting growth and clonal evolution from precursor lesions Supports precursor-lesion model and molecular heterogeneity; potential entry point for pathway-based trials in selected tumors Usually NSMP
DNA mismatch repair MLH1 Loss of protein expression from mutation or promoter hypermethylation Present in the MMRd subset; sporadic cases often involve promoter hypermethylation (yoshida2025molecularpathologyof pages 1-3) Causes mismatch-repair deficiency, hypermutation, and microsatellite instability Important for Lynch syndrome triage when unmethylated; predicts eligibility/relevance for immune checkpoint blockade in MMRd disease (yoshida2025molecularpathologyof pages 1-3) MMRd
DNA mismatch repair MSH2 Loss-of-function germline or somatic alteration with loss of protein expression Enriched in Lynch-associated OEC within the MMRd subset (yoshida2025molecularpathologyof pages 1-3) Defective mismatch repair leading to MSI and increased neoantigen load Strong Lynch syndrome implication; triggers genetic counseling and germline testing; may predict immunotherapy sensitivity (yoshida2025molecularpathologyof pages 1-3) MMRd
DNA mismatch repair MSH6 Loss-of-function germline or somatic alteration with loss of protein expression Enriched in Lynch-associated OEC within the MMRd subset (yoshida2025molecularpathologyof pages 1-3) Defective mismatch repair with hypermutator phenotype Supports Lynch syndrome diagnosis and ICI consideration; should be included in routine MMR IHC panels (yoshida2025molecularpathologyof pages 1-3) MMRd
DNA mismatch repair PMS2 Loss-of-function germline or somatic alteration with loss of protein expression Present in MMRd tumors, either isolated or paired with MLH1 loss depending on mechanism (yoshida2025molecularpathologyof pages 1-3) Defective mismatch repair and MSI development Lynch screening relevance; contributes to molecular classification and therapeutic stratification (yoshida2025molecularpathologyof pages 1-3) MMRd
Replication proofreading POLE Pathogenic exonuclease-domain mutation causing ultramutation Uncommon but clinically important subset; specifically recognized in OEC molecular classification (yoshida2025molecularpathologyof pages 1-3, kobel2022theevolutionof pages 1-3) Causes defective proofreading during DNA replication, producing ultrahigh tumor mutational burden Associated with excellent prognosis; may justify treatment de-escalation in some contexts and may enhance immunotherapy responsiveness (yoshida2025molecularpathologyof pages 1-3) POLE-ultramutated
Genome stability / TP53 axis p53 pathway Abnormal p53 pattern / TP53 alteration in a minority, especially high-grade cases Minority subset; defines biologically aggressive p53-abnormal OECs (yoshida2025molecularpathologyof pages 1-3, kobel2022theevolutionof pages 1-3) Genomic instability and more aggressive tumor biology Associated with poorer prognosis and need for intensified management relative to POLEmut/MMRd subsets (yoshida2025molecularpathologyof pages 1-3) p53-abnormal
Integrated molecular classification MMR pathway (overall) Deficiency detected by IHC/MSI testing rather than a single-gene event Clinically meaningful subset; OEC is enriched for Lynch-associated tumors, supporting routine MMR testing (yoshida2025molecularpathologyof pages 1-3, kobel2022theevolutionof pages 1-3) Hypermutation, MSI, immune activation potential Essential for universal screening workflows, prognostic stratification, and selection for checkpoint inhibition (yoshida2025molecularpathologyof pages 1-3) MMRd
Integrated molecular classification PI3K/AKT/mTOR pathway (overall) Combined activation through PIK3CA gain and/or PTEN loss One of the dominant pathway-level themes in OEC and endometriosis-associated ovarian cancer (yoshida2025molecularpathologyof pages 1-3) Promotes survival, proliferation, metabolic rewiring, and progression from endometriosis Major translational target class; links precursor lesions to invasive carcinoma (yoshida2025molecularpathologyof pages 1-3) Mostly NSMP, also across other subtypes
Integrated molecular classification Wnt/β-catenin pathway (overall) Pathway activation mainly through CTNNB1 alteration Characteristic of endometrioid differentiation (leo2021whatisnew pages 1-2, yoshida2025molecularpathologyof pages 1-3) Reinforces endometrioid lineage program and tumor growth Useful for histotype assignment and biologic interpretation of morphology Mostly NSMP

Table: This table summarizes the major recurrent molecular alterations and pathway-level abnormalities reported in ovarian endometrioid carcinoma, including their biologic effects and clinical implications. It is useful for linking histology, molecular subtype, prognosis, and potential therapeutic opportunities.

The molecular landscape of OEC is characterized by recurrent alterations in chromatin remodeling genes, the PI3K/AKT/mTOR signaling pathway, and DNA mismatch repair genes. Key findings include:

ARID1A (AT-rich Interaction Domain 1A): - Frequent loss-of-function alterations, often reflected by loss of protein expression on immunohistochemistry - Disrupts SWI/SNF chromatin remodeling complex - Often co-occurs with PIK3CA mutations - Shared between endometriotic lesions and OEC, supporting progression model (yoshida2025molecularpathologyof pages 1-3, leo2021whatisnew pages 1-2)

PIK3CA (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha): - Activating/gain-of-function mutations - Frequently co-occurs with ARID1A loss - Present in endometriosis-related precursor lesions - Activates PI3K/AKT/mTOR signaling pathway (yoshida2025molecularpathologyof pages 1-3, leo2021whatisnew pages 1-2)

PTEN (Phosphatase and Tensin Homolog): - Inactivating mutations/loss of function - Characteristic of endometrioid tumors - Releases inhibition of PI3K signaling - Frequently present in OEC (leo2021whatisnew pages 1-2, yoshida2025molecularpathologyof pages 1-3)

CTNNB1 (Catenin Beta 1): - Activating mutations leading to β-catenin pathway alterations - Characteristic/recurrent in OEC - Helpful lineage-defining alteration for endometrioid histotype (leo2021whatisnew pages 1-2, yoshida2025molecularpathologyof pages 1-3)

KRAS: - Activating mutations, less common than PTEN/PIK3CA/CTNNB1 - Also seen in benign endometriotic lesions (yoshida2025molecularpathologyof pages 1-3)

MMR Genes (MLH1, MSH2, MSH6, PMS2): - Loss of expression from germline or somatic mutations, or MLH1 promoter hypermethylation - Define the MMRd molecular subtype (25-30% of OEC) - Enriched for Lynch syndrome-associated tumors - Confer microsatellite instability (MSI) and hypermutation (yoshida2025molecularpathologyof pages 1-3, kobel2022theevolutionof pages 1-3)

POLE (DNA Polymerase Epsilon, Catalytic Subunit): - Pathogenic exonuclease-domain mutations causing ultramutation - Uncommon but clinically important subset - Associated with excellent prognosis (yoshida2025molecularpathologyof pages 1-3, kobel2022theevolutionof pages 1-3)

Molecular Subtypes

Recent data demonstrate that the endometrial cancer molecular taxonomy applies to OEC, enabling classification into four molecular subtypes (yoshida2025molecularpathologyof pages 1-3, kobel2022theevolutionof pages 1-3):

  1. POLE-ultramutated: Excellent prognosis, candidates for treatment de-escalation
  2. Mismatch Repair-Deficient (MMRd): Generally excellent outcomes, immunotherapy-sensitive, enriched for Lynch syndrome
  3. p53-abnormal: Poorer prognosis, warrant intensified management
  4. No Specific Molecular Profile (NSMP): Heterogeneous, often enriched for PI3K/Wnt pathway alterations

Allele Frequencies

Specific population allele frequencies were not detailed in the reviewed literature, though mutations are predominantly somatic rather than germline (except in Lynch syndrome and hereditary cancer predisposition syndromes).

Mechanism / Pathophysiology

Molecular Pathways

PI3K/AKT/mTOR Pathway: The PI3K/AKT/mTOR pathway is aberrantly activated in OEC, driven by PIK3CA gain-of-function mutations and/or PTEN loss. This pathway activation promotes cell proliferation, survival, metabolic rewiring, and progression from endometriosis to invasive carcinoma (yoshida2025molecularpathologyof pages 1-3). The pathway represents a major translational target, with PI3K/AKT/mTOR inhibitors under investigation (yoshida2025molecularpathologyof pages 1-3).

Wnt/β-Catenin Pathway: CTNNB1 alterations activate Wnt/β-catenin signaling, affecting epithelial differentiation, proliferation, and glandular/squamous morphology. This pathway reinforces the endometrioid lineage program and is characteristic of endometrioid differentiation (leo2021whatisnew pages 1-2, yoshida2025molecularpathologyof pages 1-3).

DNA Mismatch Repair Pathway: MMR deficiency in approximately 25-30% of OEC leads to microsatellite instability (MSI) and hypermutation, creating high tumor mutational burden and neoantigen load. This confers sensitivity to immune checkpoint inhibitors (yoshida2025molecularpathologyof pages 1-3, kobel2022theevolutionof pages 1-3).

Chromatin Remodeling: ARID1A loss disrupts the SWI/SNF chromatin remodeling complex, altering transcriptional control and differentiation programs. This creates vulnerability to synthetic lethal approaches including ATR inhibitors and epigenetic modulators (yoshida2025molecularpathologyof pages 1-3).

Cellular Processes

Stepwise Malignant Transformation: The progression from benign endometriosis to atypical endometriosis to invasive OEC is supported by the presence of shared mutations (ARID1A, PIK3CA) in morphologically benign endometriotic lesions, indicating their potential as precursors (yoshida2025molecularpathologyof pages 1-3). This model suggests that oncogenic alterations accumulate progressively, with inflammatory signaling and oxidative stress in the endometriotic microenvironment contributing to transformation.

Epigenetic Changes: In sporadic MMRd cases, MLH1 promoter hypermethylation is the predominant mechanism of MMR deficiency, contrasting with germline mutations in Lynch syndrome-associated cases (yoshida2025molecularpathologyof pages 1-3).

Tumor Microenvironment

The tumor immune microenvironment differs between OEC and high-grade serous ovarian cancer, with endometrioid ovarian cancer potentially more conducive to immunotherapy due to lower levels of immune exclusion and T cell exhaustion (kobel2022theevolutionof pages 1-3).

Suggested Ontology Terms

Gene Ontology (GO) Terms: - GO:0006281 (DNA repair) - GO:0006974 (cellular response to DNA damage stimulus) - GO:0006281 (DNA mismatch repair) - GO:0016568 (chromatin modification) - GO:0006338 (chromatin remodeling) - GO:0007049 (cell cycle) - GO:0016310 (phosphorylation) - GO:0043066 (negative regulation of apoptotic process) - GO:0071310 (cellular response to organic substance)

Cell Type (CL) Terms: - CL:0002319 (neural cell) - CL:0000066 (epithelial cell) - CL:0000583 (glandular epithelial cell) - CL:0002293 (epithelial cell of endometrium)

Anatomical Structures Affected

Organ and Tissue Level

Primary Site: - Ovary (UBERON:0000992): Primary organ of tumor development - Endometriotic tissue: When arising from endometriosis, can involve peritoneum, fallopian tubes, bowel surfaces, and other pelvic structures

Associated with Endometriosis: Approximately 40% of OEC cases show histological evidence of associated endometriosis. Endometriosis can involve ovarian endometriomas (cysts), peritoneal implants, and deep infiltrating lesions (yoshida2025molecularpathologyof pages 1-3).

Secondary Involvement: - Pelvic peritoneum - Omentum - Pelvic and para-aortic lymph nodes (in advanced/metastatic disease) - Less commonly: liver, lungs, and other distant sites

Cellular Level

OEC arises from epithelial cells, specifically glandular epithelial cells that resemble endometrial-type epithelium. The tumor is characterized by tubular glands resembling proliferative endometrial epithelium, with variable solid, squamous, or sertoliform differentiation patterns (yoshida2025molecularpathologyof pages 1-3, leo2021whatisnew pages 1-2).

Suggested CL Terms: - CL:0000066 (epithelial cell) - CL:0000583 (glandular epithelial cell) - CL:0002293 (epithelial cell of endometrium)

Subcellular Level

GO Cellular Component Terms: - GO:0005634 (nucleus) - site of chromatin remodeling defects and p53 alterations - GO:0005886 (plasma membrane) - location of receptor signaling - GO:0005737 (cytoplasm) - site of PI3K/AKT/mTOR signaling - GO:0000228 (nuclear chromosome) - affected by chromatin remodeling defects

Temporal Development

Onset

Age of Onset: OEC typically presents in adult women, with increasing diagnosis in younger women (<50 years) in some populations like Japan (yoshida2025molecularpathologyof pages 1-3). The median age at diagnosis for ovarian cancer overall is around 63 years, though OEC may present somewhat earlier given its association with endometriosis, which affects reproductive-age women (ali2023epidemiologyandrisk pages 1-2).

Onset Pattern: Generally insidious, as ovarian cancer often presents with non-specific symptoms and is frequently diagnosed at advanced stages (III or IV) (ali2023epidemiologyandrisk pages 1-2). However, OEC is more often diagnosed at earlier stages compared to high-grade serous carcinoma (hayashi2023molecularhistopathologyfor pages 1-2, yoshida2025molecularpathologyof pages 1-3).

Progression

Disease Course: OEC typically follows a progressive course from precursor endometriotic lesions (in endometriosis-associated cases) through atypical endometriosis to invasive carcinoma. OEC is typically of low grade with a generally favorable prognosis compared to high-grade serous carcinoma, though high-grade/p53-abnormal OEC behaves more aggressively (hayashi2023molecularhistopathologyfor pages 1-2, yoshida2025molecularpathologyof pages 1-3).

Disease Staging: The FIGO 2023 staging system for endometrial cancer integrates molecular classification, and similar principles are being applied to ovarian endometrioid carcinoma. Staging includes assessment of: - Stage I: Tumor confined to ovaries - Stage II: Tumor involves one or both ovaries with pelvic extension - Stage III: Tumor involves one or both ovaries with peritoneal implants outside pelvis and/or lymph node metastases - Stage IV: Distant metastases (kobel2022theevolutionof pages 1-3)

Molecular Subtype and Prognosis: - POLE-mutated and MMRd subsets: Generally excellent outcomes - p53-abnormal/high-grade tumors: Poorer prognosis requiring intensified management - NSMP: Intermediate prognosis (yoshida2025molecularpathologyof pages 1-3, kobel2022theevolutionof pages 1-3)

Diagnostics

Clinical Tests and Biomarkers

Serum Biomarkers: - CA125: Elevated in many ovarian cancers but with low specificity - HE4 (Human Epididymis Protein 4): Combined with CA125 improves detection sensitivity and specificity for ovarian cancer (kobel2022theevolutionof pages 1-3)

Imaging Studies

MRI (Magnetic Resonance Imaging): MRI is valuable for characterizing ovarian masses. MRI-based radiomics analysis can differentiate ovarian clear cell carcinoma from endometrioid carcinoma with high accuracy (kobel2022theevolutionof pages 1-3).

Histopathology

Microscopic Features: - Tubular glands resembling proliferative endometrial epithelium - Variable patterns: glandular, solid, squamous, sertoliform - May show squamous metaplasia (yoshida2025molecularpathologyof pages 1-3, leo2021whatisnew pages 1-2)

Immunohistochemical Markers: A four-marker IHC panel (WT1/p53/napsin A/PR) can distinguish the five principal ovarian carcinoma histotypes with high accuracy: - WT1: Typically negative in OEC (positive in serous) - p53: Variable; abnormal pattern in p53-abnormal molecular subtype - Napsin A: Negative in OEC (positive in clear cell) - PR (Progesterone Receptor): Often positive in OEC (kobel2022theevolutionof pages 1-3)

Genetic and Molecular Testing

MMR Immunohistochemistry (Routine Recommended): Assessment of MLH1, MSH2, MSH6, and PMS2 protein expression is recommended for all OEC cases to: - Identify MMRd molecular subtype - Screen for Lynch syndrome - Predict immunotherapy sensitivity (yoshida2025molecularpathologyof pages 1-3, kobel2022theevolutionof pages 1-3)

MSI Testing: PCR-based microsatellite instability analysis using NCI-recommended loci can confirm MMRd status (kobel2022theevolutionof pages 1-3).

MLH1 Promoter Methylation Testing: For cases with MLH1/PMS2 loss, methylation testing helps distinguish sporadic (hypermethylated) from Lynch-associated (unmethylated) cases (yoshida2025molecularpathologyof pages 1-3, kobel2022theevolutionof pages 1-3).

Molecular Subtyping (POLE, MMR, p53, NSMP): Using IHC surrogates and/or sequencing to classify into four molecular subtypes for prognostic stratification and therapeutic selection (yoshida2025molecularpathologyof pages 1-3, kobel2022theevolutionof pages 1-3).

Germline Testing: Indicated for MMRd cases (especially if MLH1 unmethylated) and cases with family history suggestive of hereditary cancer syndromes (yoshida2025molecularpathologyof pages 1-3, kobel2022theevolutionof pages 1-3).

Differential Diagnosis

OEC must be distinguished from: - High-grade serous carcinoma (especially SET pattern) - Clear cell carcinoma - Mucinous carcinoma - Metastatic endometrial carcinoma - Metastatic gastrointestinal carcinoma

Immunohistochemical panels, molecular testing, and clinical correlation are essential for accurate diagnosis (leo2021whatisnew pages 1-2, kobel2022theevolutionof pages 1-3).

Outcome / Prognosis

Survival and Prognosis

OEC generally has a more favorable prognosis compared to high-grade serous carcinoma, particularly when diagnosed at early stages (hayashi2023molecularhistopathologyfor pages 1-2, yoshida2025molecularpathologyof pages 1-3). Prognosis varies significantly by molecular subtype:

By Molecular Subtype: - POLE-mutated: Excellent prognosis, may justify treatment de-escalation - MMRd: Generally excellent outcomes - NSMP: Intermediate prognosis - p53-abnormal/high-grade: Poorer prognosis, requires intensified management (yoshida2025molecularpathologyof pages 1-3, kobel2022theevolutionof pages 1-3)

Lynch Syndrome-Associated OEC: Among mismatch repair-deficient endometrial cancers (which share biological features with MMRd OEC), patients with Lynch syndrome showed a trend towards better recurrence-free survival compared with MLH1-hypermethylated MMRd cases. Five-year recurrence-free survival was 91.7% (95% CI = 83.1%-100%) for Lynch syndrome cases versus 78.6% (95% CI = 73.8%-83.7%) for MLH1-hypermethylated MMRd cases (kobel2022theevolutionof pages 1-3).

Subsequent Cancer Risk: Patients with Lynch syndrome-associated OEC have increased risk of subsequent cancers. The probability of subsequent Lynch-associated cancer at 10 years was 11.6% (95% CI = 0.0%-24.7%) in the Lynch syndrome group (kobel2022theevolutionof pages 1-3).

Prognostic Factors

  • Stage at diagnosis: Earlier stage associated with better outcomes
  • Tumor grade: Low-grade tumors have better prognosis
  • Molecular subtype: POLE-mutated and MMRd subtypes favorable; p53-abnormal unfavorable
  • Age: Younger age at diagnosis may be associated with better outcomes
  • Residual disease after surgery: Complete cytoreduction associated with improved survival

Treatment

Treatment Modality Specific Agents / Approaches Indications Efficacy Data (if available) Molecular Stratification
Surgery Primary cytoreductive surgery; total hysterectomy with bilateral salpingo-oophorectomy; omentectomy; peritoneal staging/biopsies; lymph node assessment in selected early-stage cases Standard initial management for most resectable OEC; also used for diagnosis, staging, and tumor debulking OEC is often diagnosed at earlier stage than high-grade serous carcinoma and generally has a more favorable prognosis, supporting surgery-centered management in localized disease (hayashi2023molecularhistopathologyfor pages 1-2, yoshida2025molecularpathologyof pages 1-3) Not molecularly restricted, but stage, grade, and histotype remain key determinants; p53-abnormal/high-grade tumors may warrant more aggressive multimodality treatment (yoshida2025molecularpathologyof pages 1-3, kobel2022theevolutionof pages 1-3)
Adjuvant / First-line chemotherapy Carboplatin + paclitaxel Standard systemic therapy after surgery for advanced-stage disease and many high-risk early-stage cases Standard ovarian cancer backbone regimen; in mixed epithelial ovarian cohorts remains the default comparator and routine regimen. OEC generally has better outcomes than HGSC, but high-grade/p53-abnormal OEC behaves more aggressively (hayashi2023molecularhistopathologyfor pages 1-2, yoshida2025molecularpathologyof pages 1-3) Used across molecular subtypes; potential relative de-escalation interest in POLE-mutated tumors and intensification interest in p53-abnormal tumors are emerging concepts rather than established standards (yoshida2025molecularpathologyof pages 1-3, kobel2022theevolutionof pages 1-3)
Neoadjuvant chemotherapy Carboplatin + paclitaxel followed by interval debulking surgery Patients with bulky, unresectable, or medically high-risk advanced disease No OEC-specific trial data in available contexts; approach extrapolated from epithelial ovarian cancer practice (hayashi2023molecularhistopathologyfor pages 1-2) Not subtype-specific; tumor burden and surgical feasibility drive use
Immunotherapy + chemotherapy Pembrolizumab + carboplatin/paclitaxel, followed by pembrolizumab maintenance Advanced or recurrent MMR-deficient/dMMR tumors; increasingly relevant where OEC shows MMRd enrichment In NRG-GY018 endometrial cancer, 12-month PFS in dMMR disease was 74% with pembrolizumab-chemotherapy vs 38% with placebo-chemotherapy; in pMMR disease median PFS was 13.1 vs 8.7 months (kobel2022theevolutionof pages 1-3) Most compelling in MMRd/MSI-H OEC; OEC is enriched for Lynch-associated/MMRd tumors, supporting biomarker-driven use of checkpoint inhibitors (yoshida2025molecularpathologyof pages 1-3, kobel2022theevolutionof pages 1-3)
Immune checkpoint inhibitor monotherapy Pembrolizumab; dostarlimab Recurrent/metastatic MMRd/MSI-H disease after prior therapy, or when chemotherapy is unsuitable Robust tumor-agnostic and endometrial-cancer evidence supports activity in MMRd/MSI-H gynecologic tumors; OEC-specific efficacy data were not reported in the available contexts (yoshida2025molecularpathologyof pages 1-3, kobel2022theevolutionof pages 1-3) Best suited to MMRd/MSI-H tumors, including Lynch syndrome-associated OEC (yoshida2025molecularpathologyof pages 1-3)
Hormonal therapy Progestins; other endocrine therapy approaches used by analogy to endometrioid gynecologic tumors Selected low-grade, hormone receptor-positive, indolent, recurrent, or fertility-/toxicity-sensitive settings Direct OEC efficacy data not provided in the available contexts; biologic rationale exists because endometrioid tumors may retain hormone receptor expression (kobel2022theevolutionof pages 1-3, yoshida2025molecularpathologyof pages 1-3) Most plausible in ER/PR-positive, low-grade, NSMP-type tumors rather than p53-abnormal tumors
Targeted therapy: PI3K/AKT/mTOR axis Investigational PI3K, AKT, or mTOR inhibitors Recurrent or refractory tumors with PIK3CA activation and/or PTEN loss Pathway is a major driver in OEC and endometriosis-associated ovarian cancer; clinical benefit remains investigational in available sources (yoshida2025molecularpathologyof pages 1-3) Best rationalized for PIK3CA-mutant and PTEN-deficient tumors; often overlaps with NSMP tumors (yoshida2025molecularpathologyof pages 1-3)
Targeted therapy: ARID1A-directed synthetic lethality ATR inhibitors; epigenetic/synthetic-lethal strategies under investigation Recurrent ARID1A-deficient tumors in trials or precision-oncology settings Preclinical and translational rationale is strong, but no definitive OEC-specific efficacy data were reported in the available contexts (yoshida2025molecularpathologyof pages 1-3) ARID1A-loss tumors, often with coexisting PI3K-pathway alterations (yoshida2025molecularpathologyof pages 1-3)
Targeted therapy: PARP inhibitors Olaparib and related PARP inhibitors Selected tumors with homologous recombination deficiency or pathogenic BRCA alterations; less established in typical OEC than in HGSC In ovarian cancer organoid models, a BRCA1-mutant endometrioid organoid showed increased olaparib sensitivity relative to non-BRCA models (kobel2022theevolutionof pages 1-3) Most relevant to BRCA1/2-mutant or HRD tumors; likely a minority of OECs compared with HGSC
Molecularly adapted management POLE/MMRd/NSMP/p53-abnormal classification integrated with histology and stage Risk stratification, prognosis, trial selection, and tailoring of adjuvant/systemic therapy POLE-mutated and MMRd subsets generally show excellent outcomes, while p53-abnormal/high-grade tumors have poorer prognosis and may merit intensified management (yoshida2025molecularpathologyof pages 1-3, kobel2022theevolutionof pages 1-3) POLE-mutated: favorable prognosis; MMRd: immunotherapy-sensitive; p53-abnormal: highest-risk biology; NSMP: heterogeneous, often enriched for PI3K/Wnt alterations (yoshida2025molecularpathologyof pages 1-3, kobel2022theevolutionof pages 1-3)
Precision preclinical testing Patient-derived organoids (drug screening with platinum, taxane, olaparib); xenografts Research use; potential future patient-specific therapy selection Ovarian cancer organoids preserved histopathology/genomics and showed drug-response patterns correlating with clinical course in small series (kobel2022theevolutionof pages 1-3) Enables individualized testing across BRCA-mutant, platinum-sensitive/resistant, and pathway-defined tumors

Table: This table summarizes current and emerging treatment strategies for ovarian endometrioid carcinoma, linking each modality to its main indications, available efficacy evidence, and relevant molecular subgroups. It is useful for mapping standard care alongside biomarker-driven precision approaches.

Surgery

Primary Cytoreductive Surgery: Standard initial management includes total hysterectomy with bilateral salpingo-oophorectomy, omentectomy, peritoneal staging/biopsies, and lymph node assessment in selected cases. OEC is often diagnosed at earlier stage than high-grade serous carcinoma, supporting surgery-centered management in localized disease (hayashi2023molecularhistopathologyfor pages 1-2, kobel2022theevolutionof pages 1-3, yoshida2025molecularpathologyof pages 1-3).

Chemotherapy

Standard Regimen: Carboplatin plus paclitaxel is the standard adjuvant chemotherapy for advanced-stage disease and high-risk early-stage cases (hayashi2023molecularhistopathologyfor pages 1-2, kobel2022theevolutionof pages 1-3, yoshida2025molecularpathologyof pages 1-3).

Immunotherapy

Checkpoint Inhibitors: Immune checkpoint inhibitors (pembrolizumab, dostarlimab) have demonstrated remarkable efficacy in MMRd/dMMR tumors:

  • In the NRG-GY018 trial in endometrial cancer, 12-month progression-free survival in dMMR disease was 74% with pembrolizumab-chemotherapy versus 38% with placebo-chemotherapy (hazard ratio 0.30; 95% CI, 0.19-0.48; P<0.001) (kobel2022theevolutionof pages 1-3)
  • In pMMR disease, median PFS was 13.1 months with pembrolizumab versus 8.7 months with placebo (hazard ratio 0.54; 95% CI, 0.41-0.71; P<0.001) (kobel2022theevolutionof pages 1-3)

The combination of immune checkpoint inhibitors with chemotherapy is now standard for advanced or recurrent MMRd disease. OEC's enrichment for Lynch syndrome-associated/MMRd tumors makes this particularly relevant (yoshida2025molecularpathologyof pages 1-3, kobel2022theevolutionof pages 1-3).

Relevant MAXO Terms: - MAXO:0001175 (chemotherapy) - MAXO:0001479 (immunotherapy) - MAXO:0000571 (surgical procedure)

Targeted Therapy

PI3K/AKT/mTOR Inhibitors: Under investigation for tumors with PIK3CA mutations and/or PTEN loss, which are common in OEC. The PI3K/AKT/mTOR pathway is a major driver and translational target (yoshida2025molecularpathologyof pages 1-3).

ARID1A-Directed Synthetic Lethality: ATR inhibitors and epigenetic modulators are being investigated for ARID1A-deficient tumors, which are frequent in OEC (yoshida2025molecularpathologyof pages 1-3).

PARP Inhibitors: Potential utility in tumors with homologous recombination deficiency or BRCA1/2 mutations. In preclinical models, a BRCA1-mutant endometrioid organoid showed increased olaparib sensitivity (kobel2022theevolutionof pages 1-3).

Hormonal Therapy

Progestin-based therapy may be considered for selected low-grade, hormone receptor-positive, indolent, recurrent, or fertility-sparing cases, by analogy to endometrioid gynecologic tumors (kobel2022theevolutionof pages 1-3, yoshida2025molecularpathologyof pages 1-3).

Molecularly Stratified Treatment

Molecular classification enables risk-stratified management: - POLE-mutated: Excellent prognosis, potential treatment de-escalation - MMRd: Immunotherapy-sensitive - p53-abnormal: Highest-risk biology, intensified management - NSMP: Heterogeneous, often enriched for PI3K/Wnt alterations, potential targets for pathway inhibitors (yoshida2025molecularpathologyof pages 1-3, kobel2022theevolutionof pages 1-3)

Prevention

Primary Prevention

Risk Factor Modification: - Oral Contraceptive Use: 15-20% risk reduction with 5 years of use (yoshida2025molecularpathologyof pages 1-3) - Achieving/Maintaining Healthy Weight: Obesity increases risk; weight management may reduce risk (yoshida2025molecularpathologyof pages 1-3) - Breastfeeding and Parity: Each birth reduces risk by ~10% (yoshida2025molecularpathologyof pages 1-3)

Secondary Prevention

Surgical Risk Reduction: - Tubal Ligation/Salpingectomy: Protective, possibly by reducing retrograde menstruation (yoshida2025molecularpathologyof pages 1-3) - Risk-Reducing Salpingo-Oophorectomy: Considered in high-risk populations (BRCA1/2 carriers, Lynch syndrome) (ali2023epidemiologyandrisk pages 1-2)

Genetic Screening and Counseling

Lynch Syndrome Screening: Universal MMR immunohistochemistry testing of all OEC cases is recommended to identify Lynch syndrome carriers, enabling: - Genetic counseling and germline testing - Surveillance for other Lynch-associated cancers - Cascade testing of at-risk family members (yoshida2025molecularpathologyof pages 1-3, kobel2022theevolutionof pages 1-3)

BRCA1/2 Testing: Consideration of genetic testing in cases with family history of breast/ovarian cancer or personal history suggestive of hereditary cancer syndrome (ali2023epidemiologyandrisk pages 1-2).

Model Organisms and Experimental Models

Patient-Derived Organoids (PDOs)

Patient-derived organoids have been successfully established from OEC tissues, preserving histopathology, molecular subtype characteristics, and genetic profiles including POLE, MMR, p53 status, and pathway alterations (kobel2022theevolutionof pages 1-3). OEC organoids enable: - Drug sensitivity testing (carboplatin, paclitaxel, olaparib) - Correlation with clinical responses - Precision medicine applications (kobel2022theevolutionof pages 1-3)

Patient-Derived Xenografts (PDX)

PDX models in immunodeficient mice (NOD-SCID, NSG) using: - Subcutaneous implantation: Easier monitoring, higher engraftment rates - Orthotopic implantation: Better recapitulates tumor microenvironment and metastatic patterns (kobel2022theevolutionof pages 1-3)

Orthotopic organoid-based PDX (O-PDX) models maintain tissue architecture, biomarker expression, and genetic profiles of original tumors, proving useful for preclinical therapeutic evaluation (kobel2022theevolutionof pages 1-3).

Genetically Engineered Mouse Models (GEMMs)

Models with relevant mutations (Tp53, Pten, Arid1a combinations) have been developed. Syngeneic models from murine fallopian tube organoids with defined genetic alterations enable immunotherapy studies in immunocompetent hosts (kobel2022theevolutionof pages 1-3).

Cell Lines

Limited endometrioid-specific ovarian cancer cell lines are available, making patient-derived models particularly valuable for OEC research (kobel2022theevolutionof pages 1-3).

Applications: - Drug screening and therapeutic response prediction - Mechanistic studies of pathway dependencies - Biomarker validation - Precision medicine approaches

Summary and Clinical Implications

Ovarian endometrioid carcinoma represents approximately 10% of epithelial ovarian cancers and is distinguished by:

  1. Strong association with endometriosis (40% of cases), suggesting a progression model from benign to malignant disease
  2. Characteristic molecular alterations including ARID1A loss, PIK3CA/PTEN mutations, CTNNB1 alterations, and enrichment for MMR deficiency
  3. Four molecular subtypes (POLE-ultramutated, MMRd, p53-abnormal, NSMP) with distinct prognoses and therapeutic implications
  4. Enrichment for Lynch syndrome, necessitating universal MMR testing
  5. Generally favorable prognosis compared to high-grade serous carcinoma, especially in POLE-mutated and MMRd subtypes
  6. Emerging immunotherapy opportunities, particularly for MMRd tumors showing dramatic responses to checkpoint inhibitors
  7. Multiple targetable pathways including PI3K/AKT/mTOR, chromatin remodeling, and DNA repair mechanisms

Integrating morphology with molecular classification refines diagnosis and prognostication. Routine MMR immunohistochemistry with reflex germline testing improves Lynch syndrome detection. Future priorities include prospective validation of molecular stratification, multi-omics refinement of NSMP tumors, and development of targeted therapeutic strategies for pathway-driven disease.

Suggested MONDO ID: MONDO:0003573 (ovarian endometrioid adenocarcinoma)

This comprehensive report synthesizes current evidence on ovarian endometrioid carcinoma, providing a foundation for clinical care, research prioritization, and therapeutic development.

References

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