Definition/General

Introduction:
-Endometrial adenocarcinoma is the most common gynecologic malignancy in developed countries, arising from the endometrial epithelium
-It represents >95% of endometrial cancers and shows two distinct pathogenetic pathways (Type I and Type II).
Origin:
-Arises from endometrial glandular epithelium
-Type I tumors develop from atypical hyperplasia
-Type II tumors arise de novo from atrophic endometrium or endometrial polyps.
Classification:
-WHO 2020 recognizes endometrioid, serous, clear cell, mucinous, and other rare types
-TCGA molecular classification: POLE-mutated, MMR-deficient, p53-abnormal, p53-wild type.
Epidemiology:
-Most common gynecologic cancer in developed countries
-Peak incidence 60-70 years
-Type I: 80% of cases, better prognosis
-Type II: 20% of cases, aggressive behavior.

Clinical Features

Presentation:
-Abnormal vaginal bleeding (90% of cases)
-Postmenopausal bleeding most common presentation
-Abnormal menstrual cycles in premenopausal women
-Pelvic pain in advanced cases.
Symptoms:
-Vaginal bleeding (key symptom)
-Vaginal discharge (watery, blood-tinged)
-Pelvic pain or pressure
-Abdominal distention
-Weight loss in advanced disease.
Risk Factors:
-Obesity (major risk factor)
-Diabetes mellitus
-Hypertension
-Nulliparity
-Late menopause
-Estrogen therapy
-Tamoxifen use
-Lynch syndrome
-PCOS.
Screening:
-No routine screening for average-risk women
-Endometrial biopsy for abnormal bleeding
-Transvaginal ultrasound for endometrial thickness
-Lynch syndrome surveillance.

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Gross Description

Appearance:
-Polypoid, exophytic mass protruding into endometrial cavity
-May show necrosis and hemorrhage
-Firm to soft consistency
-Gray-white to tan coloration.
Characteristics:
-Size variable (few cm to filling entire cavity)
-Friable surface
-May show cystic areas
-Hemorrhage and necrosis common
-May extend into cervix.
Size Location:
-Usually involves endometrial cavity
-May extend into lower uterine segment
-Myometrial invasion variable
-Cervical extension in advanced cases.
Multifocality:
-May be multifocal within endometrium
-Entire endometrium may be involved
-Skip lesions possible
-Associated with hyperplasia in Type I tumors.

Microscopic Description

Histological Features:
-Invasive glandular structures with loss of normal endometrial architecture
-Varies from well-differentiated glands to solid sheets
-Stromal invasion with desmoplastic response.
Cellular Characteristics:
-Enlarged, hyperchromatic nuclei
-Loss of nuclear polarity
-Prominent nucleoli
-Increased mitotic activity
-Cellular pleomorphism varies with grade.
Architectural Patterns:
-Glandular pattern predominant in low grade
-Solid areas increase with higher grade
-Back-to-back glands
-Cribriform pattern
-Papillary architecture possible.
Grading Criteria:
-FIGO grading: Grade 1 (<5% solid), Grade 2 (6-50% solid), Grade 3 (>50% solid)
-Nuclear grade also considered
-High-grade nuclei upgrade by one grade.

Immunohistochemistry

Positive Markers:
-PAX8 positive
-CK7 positive
-ER and PR positive (especially Type I)
-CEA may be positive
-Vimentin positive.
Negative Markers:
-CK20 negative
-CDX2 negative
-TTF-1 negative
-p16 patchy or negative (unlike cervical)
-WT1 negative.
Diagnostic Utility:
-PAX8 confirms Müllerian origin
-ER/PR positivity supports Type I tumors
-p53 immunostain for molecular classification
-MMR proteins for Lynch syndrome.
Molecular Subtypes:
-MMR-intact vs MMR-deficient
-p53 wild-type vs p53-mutant
-POLE-mutated (ultramutated)
-Different therapeutic implications.

Molecular/Genetic

Genetic Mutations:
-PTEN mutations (Type I)
-PIK3CA mutations
-KRAS mutations
-TP53 mutations (Type II)
-POLE mutations (hypermutated)
-MMR gene alterations.
Molecular Markers:
-Microsatellite instability (MSI) in MMR-deficient tumors
-p53 overexpression or null pattern
-POLE mutations in 7-10% of cases
-High tumor mutational burden.
Prognostic Significance:
-POLE-mutated: Excellent prognosis
-MMR-deficient: Intermediate prognosis
-p53-abnormal: Poor prognosis
-Molecular classification guides treatment.
Therapeutic Targets:
-Immune checkpoint inhibitors (MSI-high tumors)
-mTOR inhibitors
-CDK4/6 inhibitors
-Hormonal therapy for ER/PR-positive tumors.

Differential Diagnosis

Similar Entities:
-Atypical hyperplasia
-Cervical adenocarcinoma
-Ovarian adenocarcinoma
-Metastatic adenocarcinoma
-Endometrial polyp
-Complex hyperplasia.
Distinguishing Features:
-Endometrial carcinoma: PAX8+, stromal invasion
-Cervical origin: p16+, HPV+
-Ovarian origin: WT1+, different clinical presentation.
Diagnostic Challenges:
-Distinction from atypical hyperplasia
-Assessment of myometrial invasion
-Determining grade in mixed tumors
-Small biopsy interpretation.
Rare Variants:
-Serous carcinoma
-Clear cell carcinoma
-Carcinosarcoma
-Undifferentiated carcinoma
-Mixed carcinoma
-Secretory carcinoma.

Sample Pathology Report

Template Format

Sample Pathology Report

Complete Report: This is an example of how the final pathology report should be structured for this condition.

Specimen Information

Specimen: [Endometrial biopsy/Hysterectomy]\nUterus Size: [X x Y x Z cm]\nEndometrial Thickness: [X mm]

Diagnosis

Endometrial adenocarcinoma\nHistologic Type: [Endometrioid/Serous/Clear cell/Mixed]

Tumor Characteristics

Tumor Size: [X.X cm] (largest dimension)\nLocation: [Fundus/Body/Lower uterine segment]\nGrowth Pattern: [Exophytic/Infiltrative]

Histologic Grade (FIGO)

Architectural Grade: [1/2/3]\nSolid Component: [<5%/6-50%/>50%]\nNuclear Grade: [1/2/3]\nOverall Grade: [1/2/3]

Myometrial Invasion

Myometrial Invasion: [Present/Absent]\nDepth of Invasion: [X mm] or [<50%/>50% of wall thickness]\nLymphovascular Invasion: [Present/Absent]

Molecular Studies

Mismatch Repair Proteins:\nMLH1: [Retained/Lost]\nPMS2: [Retained/Lost]\nMSH2: [Retained/Lost]\nMSH6: [Retained/Lost]

p53 Immunohistochemistry:\np53: [Wild-type pattern/Overexpression/Null pattern]\nInterpretation: [Normal/Abnormal]

Staging (FIGO 2009)

Primary Tumor (T): [T1a/T1b/T2/T3a/T3b/T4]\nFIGO Stage: [IA/IB/II/IIIA/IIIB/IIIC1/IIIC2/IVA/IVB]\nComment: Clinical correlation required

Additional Findings

Background Endometrium: [Atrophic/Hyperplastic/Polyp]\nCervical Involvement: [Present/Absent]\nAdnexal Involvement: [Present/Absent/Not sampled]

Comments

This endometrial adenocarcinoma shows [grade and type]. Molecular studies show [MMR status and p53 status]. [Additional findings]. Consider molecular classification for prognostic stratification and treatment planning. Oncology consultation recommended for staging and adjuvant therapy.