Definition/General
Introduction:
Undifferentiated uterine sarcoma (UUS) is a rare, highly aggressive malignant neoplasm
It represents less than 5% of all uterine sarcomas
It lacks specific differentiation features
It is characterized by primitive undifferentiated cells
It has the worst prognosis among uterine sarcomas.
Origin:
Arises from the endometrial stroma or myometrium
It may arise from pre-existing benign lesions
It can develop de novo
The cellular origin remains uncertain
It shows complete lack of lineage-specific differentiation.
Classification:
Classified as high-grade uterine sarcoma by WHO classification
It is categorized under mesenchymal tumors of the uterus
It is distinguished from endometrial stromal sarcoma
It lacks specific histological patterns
It requires immunohistochemical studies for diagnosis.
Epidemiology:
Peak incidence in 5th-6th decades
Mean age is 55-65 years
It accounts for less than 1% of all uterine malignancies
African American women have higher incidence
Risk factors include prior pelvic radiation
Previous tamoxifen therapy may increase risk.
Clinical Features
Presentation:
Abnormal uterine bleeding (80-90% cases)
Rapidly enlarging uterus
Pelvic mass or pressure symptoms
Postmenopausal bleeding (most common)
Menorrhagia in premenopausal women
Pelvic pain and discomfort
Weight loss in advanced cases.
Symptoms:
Heavy menstrual bleeding
Intermenstrual bleeding
Postmenopausal bleeding
Pelvic pressure or fullness
Urinary frequency
Constipation
Abdominal distension
Rapid symptom progression.
Risk Factors:
Age >50 years
Previous pelvic radiation
Prior tamoxifen therapy
Obesity
Unopposed estrogen exposure
Lynch syndrome (possible association)
Family history of sarcomas.
Screening:
No specific screening recommendations
High clinical suspicion for rapidly growing uterine mass
Imaging studies for evaluation
Tissue sampling essential for diagnosis
Genetic counseling for familial cases.
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Gross Description
Appearance:
Large, bulky mass filling the uterine cavity
Tan-gray to yellow cut surface
Areas of hemorrhage and necrosis
Soft, fleshy consistency
Irregular margins with myometrial invasion.
Characteristics:
Mass ranges from 5-20 cm in size
Cut surface shows variegated appearance
Extensive necrosis (50-80% of tumor)
Hemorrhagic areas
Cystic degeneration may be present
Infiltrative growth pattern.
Size Location:
Usually large at presentation
Mean size 8-12 cm
Primarily involves uterine corpus
May extend to cervix
Extrauterine spread common
Rapid growth pattern.
Multifocality:
Usually unifocal at presentation
Extensive local invasion
Myometrial infiltration common
Vascular invasion frequent
Extrauterine extension in 40-60% cases at diagnosis.
Microscopic Description
Histological Features:
Sheets of primitive undifferentiated cells
High nuclear-to-cytoplasmic ratio
Marked nuclear pleomorphism
Prominent nucleoli
Abundant mitotic figures (>20/10 HPF)
Extensive necrosis
Lack of specific architectural patterns.
Cellular Characteristics:
Large, pleomorphic cells with oval to round nuclei
Vesicular chromatin
Prominent nucleoli
Scanty to moderate cytoplasm
Bizarre multinucleated cells
High mitotic rate
Atypical mitoses common.
Architectural Patterns:
Diffuse growth pattern without specific organization
Sheets and clusters of cells
Lack of glandular formation
No specific stromal patterns
Geographic necrosis
Hemorrhage and cystic change.
Grading Criteria:
All cases are considered high-grade by definition
Mitotic count >20/10 HPF
Marked nuclear atypia
Extensive necrosis
FNCLCC grading system may be applied.
Immunohistochemistry
Positive Markers:
Vimentin (positive in most cases)
CD10 (may be positive)
p53 (often overexpressed)
Ki-67 (high proliferation index >50%)
Cyclin D1 (may be positive)
p16 (may show diffuse staining).
Negative Markers:
CD117 (c-kit) negative
Desmin negative
Smooth muscle actin negative
S-100 negative
Cytokeratins negative
Calretinin negative
ER and PR typically negative
Inhibin negative.
Diagnostic Utility:
Immunohistochemistry used to exclude other sarcomas
Negative panel helps rule out leiomyosarcoma
Negative cytokeratins exclude carcinosarcoma
Negative CD117 excludes GIST
High Ki-67 supports aggressive behavior.
Molecular Subtypes:
No established molecular subtypes
Complex karyotype with multiple chromosomal abnormalities
TP53 mutations common
Microsatellite instability rare
PTEN loss may be present.
Molecular/Genetic
Genetic Mutations:
TP53 mutations (60-80% cases)
Complex chromosomal abnormalities
Aneuploidy common
RB1 pathway alterations
p16/CDKN2A deletions
MYC amplification may be present.
Molecular Markers:
High proliferation index (Ki-67 >50%)
p53 overexpression (50-70%)
Loss of RB expression
Cyclin D1 overexpression
p16 expression variable
Chromosomal instability.
Prognostic Significance:
TP53 mutations associated with poor prognosis
High Ki-67 correlates with aggressive behavior
Complex karyotype indicates poor outcome
p53 overexpression linked to chemoresistance
BRCA pathway alterations may predict treatment response.
Therapeutic Targets:
PARP inhibitors for BRCA-deficient tumors
Checkpoint inhibitors for mismatch repair deficient cases
Anti-angiogenic agents
Aurora kinase inhibitors
Cell cycle checkpoint inhibitors
Combination chemotherapy remains standard.
Differential Diagnosis
Similar Entities:
Leiomyosarcoma (smooth muscle differentiation)
Endometrial stromal sarcoma (low-grade stromal features)
Carcinosarcoma (epithelial component)
Adenosarcoma (benign epithelial component)
Metastatic sarcoma from other sites.
Distinguishing Features:
Leiomyosarcoma: Smooth muscle actin positive
Leiomyosarcoma: Spindle cell morphology
ESS: CD10 positive, ER/PR positive
ESS: Low mitotic rate
Carcinosarcoma: Cytokeratin positive component
Adenosarcoma: Benign glandular component
UUS: Complete lack of differentiation.
Diagnostic Challenges:
Distinguishing from poorly differentiated carcinosarcoma
Excluding metastatic sarcoma
Differentiating from high-grade ESS
Ruling out dedifferentiated endometrial carcinoma
Extensive sampling required for accurate diagnosis.
Rare Variants:
Giant cell variant with multinucleated cells
Myxoid variant with myxoid stroma
Rhabdoid features may be present
Pleomorphic variant with marked nuclear atypia
Mixed patterns may occur.
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 type], measuring [size] cm in greatest dimension
Diagnosis
Undifferentiated uterine sarcoma
Classification
WHO Classification: High-grade undifferentiated sarcoma
Histological Features
Sheets of primitive undifferentiated cells with high nuclear grade and mitotic activity >20/10 HPF
Size and Extent
Size: [X] cm, myometrial invasion: [depth/percentage]
Necrosis
Necrosis: [percentage]% of tumor
Lymphovascular Invasion
Lymphovascular invasion: [present/absent]
Margins
Margins: [involved/uninvolved]
Immunohistochemistry
Positive: Vimentin, Ki-67 (high)
Negative: Desmin, SMA, Cytokeratins, CD117
p53: [overexpressed/wild-type pattern]
FIGO Stage
FIGO Stage: [I/II/III/IV] ([substage])
Final Diagnosis
Undifferentiated uterine sarcoma, high-grade, FIGO Stage [stage]