Definition/General
Introduction:
Endometrial angiosarcoma is an extremely rare malignant vascular tumor of the uterus
It represents less than 1% of all uterine sarcomas
It shows endothelial differentiation with vascular channel formation
It has an aggressive clinical course with poor prognosis.
Origin:
Arises from endometrial blood vessels or lymphatic vessels
May develop from pre-existing vascular malformations
Can occur as primary endometrial tumor
May arise in the context of radiation-induced sarcoma
Rarely occurs as part of carcinosarcoma.
Classification:
Classified as vascular tumor by WHO classification
High-grade malignant vascular neoplasm
May show epithelioid or spindle cell morphology
Primary vs metastatic distinction important
Associated with radiation-induced sarcomas.
Epidemiology:
Extremely rare tumor
Peak incidence in 6th-7th decades
Postmenopausal women predominantly affected
Strong association with previous pelvic radiation
Latency period of 10-20 years after radiation
May occur in lymphedema settings.
Clinical Features
Presentation:
Abnormal uterine bleeding (most common)
Rapidly enlarging uterine mass
Postmenopausal bleeding
Pelvic pain and pressure
Hemorrhagic discharge
Systemic symptoms in advanced cases.
Symptoms:
Heavy bleeding (90% cases)
Pelvic pain
Rapid symptom onset
Abdominal distension
Fatigue and weakness (due to bleeding)
Weight loss
Dyspnea (pulmonary metastases).
Risk Factors:
Previous pelvic radiation (strongest risk factor)
Chronic lymphedema
Previous chemotherapy with alkylating agents
Genetic predisposition (rare)
Age >60 years
Immunosuppression.
Screening:
No specific screening recommendations
High suspicion in radiation-exposed patients
Regular follow-up after pelvic radiation therapy
Imaging surveillance in high-risk patients
Prompt evaluation of new symptoms.
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Gross Description
Appearance:
Hemorrhagic, spongy mass with cystic spaces
Dark red to purple cut surface
Soft, friable consistency
Areas of necrosis and hemorrhage
May show cavernous appearance.
Characteristics:
Size ranges from 2-12 cm
Well-demarcated to infiltrative margins
Cut surface shows blood-filled spaces
Solid and cystic areas
Extensive hemorrhage
May rupture easily during handling.
Size Location:
Variable size at presentation
Mean size 6-8 cm
Involves endometrial cavity
May extend to myometrium
Parametrial involvement possible
Vascular invasion common.
Multifocality:
Usually unifocal at presentation
Extensive vascular invasion
May show satellite nodules
Lymphatic spread common
Multiple hemorrhagic foci.
Microscopic Description
Histological Features:
Malignant endothelial cells lining vascular channels
Irregular, anastomosing channels
Solid sheets of atypical cells
High mitotic activity
Nuclear pleomorphism
Areas of necrosis and hemorrhage.
Cellular Characteristics:
Enlarged endothelial cells with hyperchromatic nuclei
Prominent nucleoli
Increased nuclear-to-cytoplasmic ratio
Epithelioid or spindle cell morphology
Mitotic figures abundant
Atypical mitoses present.
Architectural Patterns:
Vasoformative pattern with irregular channels
Solid pattern with sheets of cells
Papillary projections into vascular spaces
Sinusoidal pattern
Areas of geographic necrosis.
Grading Criteria:
All cases considered high-grade by definition
Mitotic count >5/10 HPF
Marked nuclear atypia
Necrosis present
Solid growth pattern indicates higher grade.
Immunohistochemistry
Positive Markers:
CD31 (positive, specific for endothelium)
CD34 (positive in well-differentiated areas)
FLI-1 (nuclear staining)
ERG (nuclear, highly specific)
Vimentin
VEGFR (may be positive).
Negative Markers:
Cytokeratins (negative)
Desmin (negative)
Smooth muscle actin (negative)
S-100 (negative)
CD117 (negative)
Factor VIII (variable).
Diagnostic Utility:
CD31 and ERG confirm endothelial differentiation
CD34 may be lost in high-grade areas
FLI-1 supports vascular origin
Negative epithelial markers exclude carcinoma
Endothelial markers distinguish from other sarcomas.
Molecular Subtypes:
MYC amplification in radiation-associated cases
KDR (VEGFR2) expression
PDGFRA mutations rare
TP53 mutations common
RB1 alterations.
Molecular/Genetic
Genetic Mutations:
TP53 mutations (60-80% cases)
MYC amplification (radiation-associated)
RB1 pathway alterations
CDKN2A deletions
PTEN loss
KIT mutations (rare).
Molecular Markers:
p53 overexpression (majority of cases)
MYC overexpression
Loss of RB expression
High Ki-67 index (>30%)
VEGF overexpression
Chromosomal instability.
Prognostic Significance:
TP53 mutations indicate poor prognosis
MYC amplification associated with aggressive behavior
High-grade morphology correlates with poor outcome
Size >5 cm indicates poor prognosis
Radiation-associated tumors have worse outcome.
Therapeutic Targets:
Anti-angiogenic agents (bevacizumab, pazopanib)
Multi-kinase inhibitors
mTOR inhibitors
Immunotherapy (pembrolizumab)
Combination chemotherapy
Targeted therapy based on molecular profile.
Differential Diagnosis
Similar Entities:
Hemangioma (benign vascular proliferation)
Epithelioid hemangioendothelioma (intermediate-grade)
Kaposi sarcoma (HHV-8 positive)
Carcinosarcoma (epithelial component)
Metastatic angiosarcoma.
Distinguishing Features:
Hemangioma: Benign endothelium
Hemangioma: Low mitotic rate
Epithelioid hemangioendothelioma: Intermediate-grade
Kaposi sarcoma: HHV-8 positive
Angiosarcoma: High-grade endothelium
Angiosarcoma: CD31/ERG positive.
Diagnostic Challenges:
Distinguishing from poorly differentiated carcinoma
Recognizing solid growth patterns
Identifying vascular differentiation
Excluding metastatic disease
Immunohistochemistry essential for diagnosis.
Rare Variants:
Epithelioid angiosarcoma
Spindle cell angiosarcoma
Lymphangiosarcoma
Hemangiosarcoma
Mixed angiosarcoma patterns.
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, hemorrhagic appearance
Diagnosis
Angiosarcoma of the endometrium
Classification
WHO Classification: High-grade vascular sarcoma
Histological Features
Malignant vascular tumor with endothelial differentiation, mitoses: [count]/10 HPF
Vascular Pattern
Pattern: [vasoformative/solid/mixed], anastomosing channels [present/absent]
Grade
Grade: High-grade angiosarcoma
Clinical History
Previous pelvic radiation: [yes/no/unknown]
Immunohistochemistry
Endothelial markers: CD31 [+/-], ERG [+/-], CD34 [+/-]
Negative: Cytokeratins, Desmin, SMA
Ki-67: [percentage]%
Final Diagnosis
High-grade angiosarcoma of endometrium [radiation-associated/primary]