Definition/General

Introduction:
-Endometrial undifferentiated carcinoma is a rare, highly aggressive malignant tumor that lacks morphologic differentiation
-It represents 1-2% of all endometrial carcinomas
-It is characterized by complete loss of glandular differentiation
-It often occurs in association with well-differentiated endometrioid carcinoma (dedifferentiated carcinoma).
Origin:
-Arises from endometrial epithelial cells that have lost differentiation capacity
-May develop de novo or through dedifferentiation of existing carcinoma
-Associated with defective DNA mismatch repair in many cases
-Results from accumulation of multiple genetic alterations.
Classification:
-WHO classification recognizes undifferentiated carcinoma as distinct entity
-May be pure undifferentiated or mixed with differentiated component
-Dedifferentiated carcinoma: admixture of low-grade endometrioid and undifferentiated components
-All considered high-grade tumors regardless of differentiated component grade.
Epidemiology:
-Peak incidence in 6th-7th decades
-Mean age 60-65 years
-Associated with Lynch syndrome in 30-40% cases
-Risk factors similar to endometrioid carcinoma
-Microsatellite instability common
-Better prognosis when associated with Lynch syndrome.

Clinical Features

Presentation:
-Postmenopausal bleeding (most common)
-Rapidly enlarging uterus
-Pelvic mass or pressure
-Abnormal uterine bleeding in premenopausal women
-Constitutional symptoms (weight loss, fatigue)
-Advanced stage at presentation common.
Symptoms:
-Abnormal uterine bleeding (85-90%)
-Pelvic pain
-Bulky uterine mass
-Vaginal discharge
-Abdominal distension
-Rapid symptom progression
-Bowel or bladder symptoms
-Ascites in advanced cases.
Risk Factors:
-Lynch syndrome (hereditary nonpolyposis colorectal cancer)
-Family history of Lynch-associated cancers
-MLH1 promoter hypermethylation
-Obesity
-Diabetes mellitus
-Nulliparity
-Unopposed estrogen therapy
-Tamoxifen therapy.
Screening:
-No specific screening for undifferentiated carcinoma
-Lynch syndrome screening important
-Endometrial sampling for abnormal bleeding
-Imaging studies (ultrasound, MRI)
-Genetic counseling for Lynch syndrome patients
-CA-125 often elevated.

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Gross Description

Appearance:
-Soft, fleshy, tan-gray mass with areas of hemorrhage and necrosis
-Polypoid or sessile configuration
-Cut surface shows homogeneous or heterogeneous appearance
-Size typically large at presentation.
Characteristics:
-Soft consistency with friable texture
-Extensive necrosis common
-Areas of hemorrhage
-Lack of glandular architecture on cut surface
-May show cystic degeneration
-Surface may be ulcerated.
Size Location:
-Usually involves entire endometrial cavity
-Average size 6-10 cm
-Deep myometrial invasion common
-May extend to cervix
-Extrauterine extension frequent
-Lymphovascular invasion grossly visible.
Multifocality:
-Usually unifocal but extensive
-May have areas of better differentiation (dedifferentiated pattern)
-Lymph node metastases common
-Peritoneal implants frequent
-Ovarian involvement in advanced cases.

Microscopic Description

Histological Features:
-Sheets of monotonous, undifferentiated cells without glandular architecture
-Complete absence of luminal differentiation
-Cells may be small, medium, or large
-High nuclear-to-cytoplasmic ratio
-Absence of squamous or other specific differentiation.
Cellular Characteristics:
-Uniform, primitive-appearing cells
-Round to oval nuclei with coarse chromatin
-Prominent nucleoli
-Scanty cytoplasm
-High mitotic activity (>10 mitoses/10 HPF)
-Numerous apoptotic cells
-Tumor giant cells may be present.
Architectural Patterns:
-Solid sheets of undifferentiated cells
-Lack of organized architecture
-No glandular formation
-No squamous differentiation
-Desmoplastic stroma may be present
-Areas of necrosis and hemorrhage
-Lymphovascular invasion common.
Grading Criteria:
-All undifferentiated carcinomas are high-grade by definition
-No grading system applicable
-Mitotic count typically very high (>20/10 HPF)
-Ki-67 proliferation index usually >70%
-Necrosis almost always present.

Immunohistochemistry

Positive Markers:
-Cytokeratins (AE1/AE3, CAM5.2) - may be focal or weak
-EMA - often patchy
-PAX8 - supports müllerian origin
-p53 - wild-type or mutant pattern
-Vimentin - may be positive
-p16 - often diffusely positive.
Negative Markers:
-Hormone receptors (ER, PR) - typically negative
-Specific differentiation markers - negative by definition
-CD10 - helps exclude endometrial stromal sarcoma
-Desmin - excludes smooth muscle differentiation
-Myogenin - excludes rhabdomyosarcoma.
Diagnostic Utility:
-Cytokeratins confirm epithelial origin
-PAX8 positivity supports müllerian origin
-Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2) - loss indicates Lynch syndrome
-p53 staining pattern helps distinguish from other tumors
-Negative differentiation markers confirm undifferentiated nature.
Molecular Subtypes:
-Microsatellite instable (MSI-high) - Lynch syndrome or sporadic
-Microsatellite stable (MSS) - usually p53-mutant
-POLE-mutated - rare, better prognosis
-p53-abnormal - poor prognosis
-Copy number low (MSI) vs high (p53-mutant).

Molecular/Genetic

Genetic Mutations:
-Mismatch repair gene mutations (MLH1, MSH2, MSH6, PMS2) in Lynch syndrome
-MLH1 promoter hypermethylation in sporadic cases
-p53 mutations in microsatellite stable cases
-PTEN mutations common
-PIK3CA mutations
-KRAS mutations.
Molecular Markers:
-Microsatellite instability (30-40% cases)
-High tumor mutational burden in MSI cases
-p53 overexpression in MSS cases
-Loss of mismatch repair proteins
-High Ki-67 proliferation index
-Chromosomal instability in p53-mutant cases.
Prognostic Significance:
-MSI-high tumors have better prognosis
-Lynch syndrome associated tumors respond better to treatment
-p53-mutant tumors have poor prognosis
-POLE mutations predict excellent prognosis
-High tumor mutational burden predicts immunotherapy response.
Therapeutic Targets:
-Immunotherapy (PD-1/PD-L1 inhibitors) for MSI-high tumors
-PARP inhibitors for homologous recombination deficiency
-PI3K/AKT inhibitors for PIK3CA mutations
-MDM2 antagonists for p53 wild-type tumors
-Combination chemotherapy remains standard.

Differential Diagnosis

Similar Entities:
-Endometrial stromal sarcoma (high-grade)
-Leiomyosarcoma
-Carcinosarcoma (sarcomatous component)
-Lymphoma
-Metastatic undifferentiated carcinoma
-Poorly differentiated endometrioid carcinoma.
Distinguishing Features:
-Undifferentiated carcinoma: Cytokeratin positive
-Undifferentiated carcinoma: PAX8 positive
-Undifferentiated carcinoma: Epithelial origin
-ESS: CD10 positive
-ESS: Endometrial stromal differentiation
-Leiomyosarcoma: Smooth muscle markers positive
-Lymphoma: Leukocyte common antigen positive
-Lymphoma: Cytokeratin negative.
Diagnostic Challenges:
-Distinguishing from high-grade endometrial stromal sarcoma
-Separating from poorly differentiated endometrioid carcinoma
-Recognition of dedifferentiated pattern
-Excluding metastatic carcinoma
-Distinguishing from lymphoma or melanoma.
Rare Variants:
-Small cell variant (overlap with neuroendocrine carcinoma)
-Large cell variant
-Rhabdoid features
-Giant cell variant
-Mixed with other specific types
-Spindle cell areas (exclude carcinosarcoma).

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

Hysterectomy specimen measuring [X x Y x Z] cm, weighing [X] grams

Diagnosis

Endometrial undifferentiated carcinoma

Classification

WHO Classification: Undifferentiated carcinoma, FIGO Grade: High-grade

Histological Features

Sheets of undifferentiated cells lacking glandular or specific differentiation

Associated Differentiated Component

[Present/Absent]: [type if present] ([percentage]%)

Size and Extent

Tumor size: [X] cm, myometrial invasion: [depth/total thickness], [percent]%

Margins

Margins: [involved/uninvolved], closest margin: [X] mm

Lymphovascular Invasion

Lymphovascular invasion: [present/absent]

Cervical Involvement

Cervical involvement: [present/absent]

Special Studies

IHC: Cytokeratins: [result], PAX8: [result], p53: [pattern]

Mismatch repair proteins: MLH1: [result], MSH2: [result], MSH6: [result], PMS2: [result]

Molecular studies: [if performed]

Microsatellite Instability

MSI status: [MSI-high/MSS/not tested]

FIGO Staging

FIGO Stage: [stage] ([staging criteria])

Prognostic Factors

High-grade tumor, Stage: [X], MSI status: [status]

Final Diagnosis

Endometrial undifferentiated carcinoma, FIGO Stage [X]