Definition/General
Introduction:
Primary ovarian angiosarcoma is an extremely rare malignant vascular tumor representing less than 0.1% of ovarian malignancies
Characterized by endothelial cell proliferation forming vascular channels
Most ovarian angiosarcomas are metastatic from other sites
Highly aggressive tumor with poor prognosis.
Origin:
Arises from ovarian vascular endothelium (blood or lymphatic vessels)
May arise de novo or from pre-existing vascular malformations
Radiation-associated cases reported (post-radiation for other malignancies)
Chemical exposure (vinyl chloride, arsenic) associated
Chronic lymphedema may predispose (Stewart-Treves syndrome)
Genetic alterations in angiogenesis pathways.
Classification:
WHO 2020 soft tissue tumor classification applies: Well-differentiated angiosarcoma - obvious vascular channels
Poorly differentiated angiosarcoma - solid growth, minimal vascular differentiation
Epithelioid angiosarcoma - epithelioid morphology
Primary vs secondary - clinical correlation essential
Hemangioendothelioma - intermediate-grade vascular tumor.
Epidemiology:
Extremely rare - fewer than 30 primary cases reported
Age range 20-70 years (mean 45 years)
No gender predilection in ovary (unlike other sites)
Bilateral involvement rare (suggests metastatic disease)
Associated with radiation exposure in 20% cases
Poor prognosis - 5-year survival <20%
Indian population - case reports only.
Clinical Features
Presentation:
Rapidly enlarging pelvic mass with hemorrhagic ascites
Acute abdominal pain due to hemorrhage or rupture (40% cases)
Hemoperitoneum from tumor rupture
Constitutional symptoms prominent due to aggressive nature
Anemia from chronic bleeding
Advanced stage at presentation common.
Symptoms:
Severe pelvic/abdominal pain (80% cases)
Abdominal distension with hemorrhagic ascites
Acute onset symptoms from rupture/bleeding
Fatigue and weakness from anemia
Weight loss and constitutional symptoms
Dyspnea if pleural involvement
Shock if massive hemoperitoneum.
Risk Factors:
Previous radiation therapy (pelvic radiation for other cancers)
Chemical exposure - vinyl chloride, arsenic, thorium dioxide
Chronic lymphedema (Stewart-Treves syndrome)
Genetic syndromes - neurofibromatosis, Klippel-Trenaunay syndrome
Immunosuppression
Vascular malformations
Age 40-60 years.
Screening:
No specific screening due to extreme rarity
High-risk patients (post-radiation) need regular follow-up
Complete blood count - anemia common
Coagulation studies - DIC may occur
Imaging shows highly vascular mass
Angiography may demonstrate tumor vascularity
Tissue diagnosis essential but biopsy risky due to bleeding.
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Gross Description
Appearance:
Hemorrhagic, spongy masses with blood-filled spaces
Dark red to purple coloration
Friable, soft consistency
Extensive hemorrhage and necrosis
Cystic spaces filled with blood
Surface involvement with tumor rupture common
Adherent blood clots on surface.
Characteristics:
Soft, spongy consistency
Dark red to purple cut surface
Blood-filled cystic spaces
Extensive hemorrhage and necrosis
Friable texture that bleeds easily
Variegated appearance
May be partly solid.
Size Location:
Variable size (5-20 cm, average 10-12 cm)
Unilateral involvement typical for primary tumors
Bilateral suggests metastatic disease
May involve ovarian surface
Adherent to surrounding structures
Peritoneal implants possible.
Multifocality:
Usually solitary when primary
Multiple lesions suggest metastatic disease
Hematogenous spread to lungs, liver common
Peritoneal dissemination may occur
Lymph node involvement uncommon
Direct extension to adjacent organs.
Microscopic Description
Histological Features:
Anastomosing vascular channels lined by atypical endothelial cells
Vasoformative pattern with recognizable vascular lumens
Solid areas with spindled or epithelioid cells
Extensive hemorrhage and necrosis
Mitotic activity prominent
Nuclear atypia in endothelial cells.
Cellular Characteristics:
Atypical endothelial cells with enlarged, hyperchromatic nuclei
Prominent nucleoli
Abundant eosinophilic cytoplasm
Pleomorphic nuclear morphology
High mitotic rate (>5/10 HPF)
Multilayering of endothelial cells
Epithelioid morphology in some areas.
Architectural Patterns:
Vasoformative pattern - obvious vascular channels
Solid pattern - sheets of atypical cells
Papillary pattern projecting into vascular lumens
Sinusoidal pattern
Cavernous spaces filled with blood
Infiltrative growth into ovarian stroma.
Grading Criteria:
Well-differentiated: obvious vascular channels, mild atypia
Moderately differentiated: mix of vascular and solid areas
Poorly differentiated: predominantly solid, minimal vascular differentiation
High mitotic count (>10/10 HPF) indicates high grade
Necrosis extent correlates with grade.
Immunohistochemistry
Positive Markers:
CD31 (90-95% positive)
CD34 (70-80% positive)
ERG (nuclear staining, 85-90%)
FLI1 (nuclear staining, 80-85%)
Factor VIII (70% positive)
D2-40 (lymphatic endothelium)
Vimentin (100% positive).
Negative Markers:
Cytokeratins (negative)
PAX8 (negative)
WT1 (negative)
Calretinin (negative)
Inhibin (negative)
S-100 (negative)
Desmin (negative)
SMA (negative in tumor cells).
Diagnostic Utility:
Endothelial markers essential for diagnosis
CD31 and ERG most reliable markers
Negative epithelial markers exclude carcinoma
Ki-67 shows high proliferation (>30%)
p53 may be positive (associated with aggressive behavior)
Panel approach necessary for definitive diagnosis.
Molecular Subtypes:
Primary angiosarcoma: complex karyotype, various mutations
Radiation-induced: specific chromosomal aberrations
KDR/VEGFR2 amplification in some cases
FLT4 amplification (lymphangiosarcoma)
MYC amplification (secondary angiosarcomas).
Molecular/Genetic
Genetic Mutations:
TP53 mutations (60% of cases)
VEGFR2/KDR amplification (40%)
FLT4 amplification (lymphatic differentiation)
MYC amplification (radiation-induced cases)
PLCG1 mutations (20%)
PTPRB mutations (15%)
Complex chromosomal rearrangements common.
Molecular Markers:
Ki-67 proliferation index (typically >50%)
p53 overexpression (mutant pattern)
VEGF expression (angiogenesis marker)
CD31 expression (endothelial marker)
Survivin expression (apoptosis resistance)
HIF-1α expression (hypoxia response).
Prognostic Significance:
Stage most important prognostic factor
Size >5 cm poor prognosis
High mitotic count (>10/10 HPF) adverse factor
p53 mutations associated with aggressive behavior
Grade correlates with outcome
Age >60 years worse prognosis
Radiation-induced typically more aggressive.
Therapeutic Targets:
VEGFR inhibitors: sorafenib, sunitinib
mTOR inhibitors: sirolimus
Anti-angiogenic agents: bevacizumab
Immunotherapy: checkpoint inhibitors under investigation
Tyrosine kinase inhibitors: pazopanib
Combination chemotherapy: doxorubicin-based regimens.
Differential Diagnosis
Similar Entities:
Hemangioendothelioma (epithelioid or kaposiform)
Hemangioma (cavernous or capillary)
Metastatic angiosarcoma (from other sites)
Poorly differentiated carcinoma
Malignant mixed Müllerian tumor
Kaposi sarcoma
Hemangiopericytoma.
Distinguishing Features:
Angiosarcoma: CD31+, ERG+, high-grade, infiltrative
Hemangioendothelioma: intermediate-grade, less atypia
Hemangioma: benign, well-formed vessels, no atypia
Metastatic: clinical history, bilateral
Carcinoma: cytokeratin+, PAX8+
Kaposi: HHV8+, spindle cells.
Diagnostic Challenges:
Distinguishing primary from metastatic angiosarcoma
Poorly differentiated areas may lack vascular features
Extensive necrosis obscuring morphology
Sampling adequacy important
Frozen section interpretation difficult due to hemorrhage
Biopsy bleeding risk.
Rare Variants:
Epithelioid angiosarcoma (epithelioid morphology)
Lymphangiosarcoma (lymphatic differentiation, D2-40+)
Radiation-induced angiosarcoma (post-radiation therapy)
Well-differentiated angiosarcoma (obvious vascular channels)
Angiosarcomatous transformation of hemangioma.
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
[Laterality] salpingo-oophorectomy, measuring [size] cm
Diagnosis
[Primary/Metastatic] angiosarcoma of ovary
Classification and Grade
Angiosarcoma, [well/moderately/poorly] differentiated
Histological Features
Shows [vasoformative/solid] pattern with atypical endothelial cells, mitotic count [X]/10 HPF, necrosis [X]%
Size and Extent
Tumor size: [X] cm, [confined to ovary/extraovarian extension], hemorrhage present
Surgical Margins
Surgical margins: [clear/involved/cannot be assessed due to friability]
Lymphovascular Invasion
Lymphovascular invasion: [present/absent/cannot be assessed - tumor is vascular]
Lymph Node Status
Lymph nodes: [X] examined, [X] positive
Special Studies
IHC: CD31 (+), ERG (+), CD34 (+), cytokeratins (-), Ki-67 [X]%
Molecular: VEGFR2 [result], p53 [result] if performed
Clinical correlation needed to exclude metastatic angiosarcoma
Prognostic Factors
Grade: [differentiation]; Size: [X] cm; Mitoses: [X]/10 HPF; Necrosis: [present/absent]
Final Diagnosis
[Primary/Metastatic] angiosarcoma of [laterality] ovary, [grade]