Angiosarcoma

Cancer MONDO:0016982 Pathograph 17 Show in embeddings browser vascular cancer soft tissue sarcoma

Angiosarcoma is a rare, aggressive malignant neoplasm of endothelial lineage that arises from blood or lymphatic vascular structures. The disease is biologically heterogeneous across anatomic sites and etiologies. Its subtype labels therefore use overlapping axes: cutaneous head and neck, breast, and hepatic angiosarcoma are anatomic groupings, whereas radiation-associated and lymphedema-associated angiosarcoma are etiologic groupings. Core mechanisms converge on dysregulated angiogenic signaling, with subtype-enriched alterations including MYC amplification in secondary disease, KDR and PIK3CA mutations in primary breast disease, and ultraviolet-associated hypermutation in some head and neck lesions.

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2
Mappings
6
Pathophys.
5
Histopath.
3
Phenotypes
17
Pathograph
7
Genes
7
Medical Actions
5
Subtypes
6
Datasets
58
References
2
Deep Research
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Mappings

MONDO
MONDO:0016982 angiosarcoma
skos:exactMatch MONDO
MONDO provides an exact disease term for angiosarcoma.
NCIT
NCIT:C3088 Angiosarcoma
skos:exactMatch NCIT
NCIT provides an exact neoplasm term for angiosarcoma; cross-referenced from MONDO:0016982.
NCIT
NCIT:C3088 Angiosarcoma
skos:exactMatch NCIT
NCIT provides an exact neoplasm term for angiosarcoma; cross-referenced from MONDO:0016982.
◆

Subtypes

5
anatomic
Cutaneous Head and Neck Angiosarcoma
Cutaneous head and neck angiosarcoma includes tumors of the scalp, face, head, and neck. Some tumors in this anatomic subset carry an ultraviolet mutational signature and high tumor mutation burden; UV-positive and UV-negative tumors should not be treated as biologically interchangeable.
Show evidence (2 references)
PMID:32042194 SUPPORT Human Clinical
"Angiosarcoma of the head, neck, face and scalp (HNFS) was associated with a high tumor mutation burden (TMB) and a dominant ultraviolet damage mutational signature"
This supports UV-associated hypermutation in a subset of head and neck angiosarcoma.
PMID:37106027 SUPPORT Human Clinical
"UV-positive AS-HN harbored significantly higher tumor mutation burden than UV-negative cases (p = 0.0294)."
This cohort distinguishes UV-positive from UV-negative head and neck angiosarcoma.
Hepatic Angiosarcoma
Hepatic angiosarcoma is a visceral subtype arising in the liver. It is the classic site of angiosarcoma associated with vinyl chloride or thorium dioxide exposure, although those exposures explain only a subset of hepatic cases and are not defining features of every tumor.
Show evidence (2 references)
PMID:33182685 SUPPORT Other
"more commonly occur in the head and neck and scalp regions, extremities, breast, heart and great vessels, and visceral organs such as the liver and spleen"
This review identifies the liver as a recognized visceral site of angiosarcoma, supporting hepatic angiosarcoma as a distinct anatomic subtype.
PMID:33182685 SUPPORT Other
"Chemical exposure to vinyl chloride and thorium dioxide have been well-documented to be associated with increased risk of liver AS"
This supports the chemically induced etiology that biologically distinguishes hepatic angiosarcoma from sporadic and radiation-associated disease.
etiologic
Radiation-Associated Angiosarcoma
Radiation-associated angiosarcoma is an etiologic secondary subtype that can arise in a previously irradiated field, especially the breast or chest wall. MYC amplification is a characteristic early genomic event in this subtype, and FLT4 can be coamplified in a subset.
Show evidence (2 references)
PMID:20949568 SUPPORT Human Clinical
"Our findings reinforce the distinct pathogenesis of AS subtypes, with MYC amplification being an early, but necessary event in secondary AS."
This study supports a distinct MYC-amplified pathogenesis in secondary angiosarcoma.
PMID:37350195 SUPPORT Human Clinical
"RT-associated AS had more frequent MYC, FLT4, CRKL, HRAS, and KMT2D alterations than sporadic AS (enriched in TP53, KDR, ATM, ATRX)"
This demonstrates that radiation-associated angiosarcoma is a molecularly distinct subtype.
Lymphedema-Associated Angiosarcoma
Chronic lymphedema can predispose to secondary angiosarcoma, classically termed Stewart-Treves syndrome. This is an etiologic grouping and can overlap an anatomic subtype.
Show evidence (1 reference)
PMID:38607625 SUPPORT Human Clinical
"Angiosarcoma is an aggressive vascular malignant neoplasm presenting either as a primary or secondary cancer, often arising after radiotherapy or in the context of preexisting lymphedema."
This population-level study supports lymphedema-associated secondary angiosarcoma as a clinically recognized subtype.
anatomic and etiologic
Primary Breast Angiosarcoma
Primary breast angiosarcoma arises without prior radiation exposure and is molecularly distinct from radiation-associated breast angiosarcoma, with frequent KDR and PIK3CA/PIK3R1 alterations in one genomic series. The label therefore combines an anatomic site with a primary (non-radiation-associated) etiologic context.
Show evidence (1 reference)
PMID:32123305 SUPPORT Human Clinical
"Recurrent genomic alterations were identified in KDR (70%), PIK3CA/PIK3R1 (70%), and PTPRB (30%), each at higher frequencies than reported in AS across all sites."
This primary mammary series supports a distinct recurrent KDR and PI3K-pathway genomic profile.
⚙

Pathophysiology

6
Angiogenic Signaling Activation
Dysregulated endothelial receptor and PI3K signaling is a convergent mechanism in angiosarcoma. Recurrent KDR and PIK3CA alterations in primary mammary disease and FLT4 amplification in some secondary tumors implicate VEGFR-family and downstream growth signaling, but these alterations are subtype enriched rather than universal.
endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
KDR hgnc:6307 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KDR (hgnc:6307). hgnc:6307 is a gene from the HUGO Gene Nomenclature Committee. PIK3CA hgnc:8975 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PIK3CA (hgnc:8975). hgnc:8975 is a gene from the HUGO Gene Nomenclature Committee. FLT4 hgnc:3767 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FLT4 (hgnc:3767). hgnc:3767 is a gene from the HUGO Gene Nomenclature Committee.
angiogenesis GO:0001525 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased angiogenesis (GO:0001525). GO:0001525 is a biological process from the Gene Ontology. ↑ INCREASED cell population proliferation GO:0008283 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Malignant Endothelial Proliferation and Vascular Tumor Growth Activated Tie2/VEGFR signaling supports angiosarcoma-cell survival, proliferation, and tumor growth.
Show evidence (3 references)
PMID:33182685 SUPPORT Other
"We also report the current understanding of the molecular pathways involved in angiosarcoma pathogenesis including MYC amplification, activation of angiogenic pathways and different molecular alterations that are associated with angiosarcomas of different aetiology."
This review directly identifies angiogenic-pathway activation as a component of angiosarcoma pathogenesis.
PMID:32123305 SUPPORT Human Clinical
"Recurrent genomic alterations were identified in KDR (70%), PIK3CA/PIK3R1 (70%), and PTPRB (30%), each at higher frequencies than reported in AS across all sites."
The primary mammary cohort supports recurrent VEGFR2 and PI3K-pathway alterations in that subtype.
PMID:20949568 SUPPORT Human Clinical
"Coamplification of FLT4 (encoding VEGFR3) was identified in 25% of secondary AS, but not in other types."
This study supports FLT4 amplification as a secondary-subtype alteration feeding VEGFR-family signaling.
MYC-Amplified Secondary Angiosarcoma Program
MYC amplification is an early genomic event in secondary angiosarcoma and can be accompanied by FLT4 coamplification. MYC-amplified tumors show upregulation of the miR-17-92 cluster and lower THBS1 expression, providing a mechanistic route from MYC amplification to an angiogenic phenotype.
endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
MYC hgnc:7553 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MYC (hgnc:7553). hgnc:7553 is a gene from the HUGO Gene Nomenclature Committee.
angiogenesis GO:0001525 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased angiogenesis (GO:0001525). GO:0001525 is a biological process from the Gene Ontology. ↑ INCREASED cell population proliferation GO:0008283 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology. ↑ INCREASED
breast UBERON:0000310 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in breast (UBERON:0000310). UBERON:0000310 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Angiogenic Signaling Activation MYC amplification promotes an angiogenic program through miR-17-92 upregulation and suppression of the endogenous angiogenesis inhibitor THBS1.
Show evidence (3 references)
PMID:20949568 SUPPORT Human Clinical
"High-level MYC amplification was found in 100% of secondary AS, but in none of the AVL or other radiation-associated sarcomas."
This cohort supports MYC amplification as a distinguishing alteration in secondary angiosarcoma.
PMID:38722225 SUPPORT Human Clinical
"By targeted NGS, all 10 post-NACT RA-AS demonstrated MYC amplification, while both primary AS harbored KDR mutations."
This cohort study shows that MYC amplification is a defining molecular feature of radiation-associated breast angiosarcoma, in contrast to KDR-mutant primary disease.
PMID:37350195 SUPPORT Human Clinical
"RT-associated AS had more frequent MYC, FLT4, CRKL, HRAS, and KMT2D alterations than sporadic AS (enriched in TP53, KDR, ATM, ATRX)"
This comparative genomic study supports a MYC/FLT4-enriched program in radiation-associated angiosarcoma.
Malignant Endothelial Proliferation and Vascular Tumor Growth
Survival and proliferation of transformed endothelial cells produce an infiltrative vascular malignancy. Experimental VEGFR inhibition reduces proliferation and tumor growth, supporting this node as the tissue-level consequence of upstream angiogenic signaling.
endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
cell population proliferation GO:0008283 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Cutaneous or subcutaneous lesions Superficial vascular tumor growth produces clinically apparent cutaneous or subcutaneous lesions in cutaneous disease.
Multifocal breast angiosarcoma presentation Neoplastic outgrowth within the breast can be multifocal in both primary and secondary breast angiosarcoma.
Hemoptysis Pulmonary metastatic deposits can bleed into airways or alveolar spaces and present with hemoptysis.
Show evidence (1 reference)
PMID:22431921 SUPPORT Model Organism
"VEGFR inhibition reduced tumor growth by lowering tumor cell proliferation."
The xenograft intervention links endothelial growth signaling to tumor-cell proliferation and tumor growth.
Radiation-Associated DNA Damage and Replication Stress
Radiation-associated angiosarcoma develops in the setting of prior ionizing radiation exposure and carries mutational signatures linked to DNA repair and replication errors. These changes support a mechanistic model in which radiation-induced genomic injury and abnormal repair contribute to malignant endothelial transformation.
DNA damage response GO:0006974 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal DNA damage response (GO:0006974). GO:0006974 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Show evidence (1 reference)
PMID:37350195 SUPPORT Human Clinical
"The predominant mutational signatures were associated with errors in DNA repair and replication."
This directly supports defective DNA repair and replication-associated mutagenesis as a mechanism in radiation-associated angiosarcoma.
UV-Associated Hypermutation
Cutaneous angiosarcoma of the head, neck, face, and scalp can show a dominant ultraviolet mutational signature with elevated tumor mutation burden, consistent with ultraviolet-associated mutagenesis as a disease- shaping process in this anatomic subset.
response to UV GO:0009411 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal response to UV (GO:0009411). GO:0009411 is a biological process from the Gene Ontology. ⚠ ABNORMAL
skin of body UBERON:0002097 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in skin of body (UBERON:0002097). UBERON:0002097 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (2 references)
PMID:32042194 SUPPORT Human Clinical
"Angiosarcoma of the head, neck, face and scalp (HNFS) was associated with a high tumor mutation burden (TMB) and a dominant ultraviolet damage mutational signature"
The Angiosarcoma Project links cutaneous head and neck angiosarcoma to ultraviolet-associated hypermutation.
PMID:37106027 SUPPORT Human Clinical
"UV-positive AS-HN harbored significantly higher tumor mutation burden than UV-negative cases (p = 0.0294)."
This spatial transcriptomic cohort independently supports ultraviolet-associated hypermutation in head and neck angiosarcoma.
Checkpoint-Relevant Cutaneous Tumor Immune State
Cutaneous and head and neck angiosarcoma can exhibit heterogeneous immune states, including tumor-excluded inflammatory signals and checkpoint-relevant biomarkers such as PD-L1 positivity, high tumor mutation burden, and tertiary lymphoid structures. The cited evidence establishes an immune context, not a complete adaptive-immune-resistance mechanism or a universal relationship to ultraviolet mutagenesis.
regulation of immune response GO:0050776 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal regulation of immune response (GO:0050776). GO:0050776 is a biological process from the Gene Ontology. ⚠ ABNORMAL
skin of body UBERON:0002097 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in skin of body (UBERON:0002097). UBERON:0002097 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (2 references)
PMID:37106027 SUPPORT Human Clinical
"Spatial transcriptomics revealed topological profiles of the tumor microenvironment, identifying dominant but tumor-excluded inflammatory signals in immune-hot cases"
This supports altered regulation of the tumor immune response in head and neck angiosarcoma.
PMID:36993810 SUPPORT Other
"Like melanoma and cutaneous squamous cell carcinoma, tumor types with known response to immunotherapy, cAS harbors immune biomarkers, such as tumor mutational burden high (TMB-H), PD-L1 positivity, ultraviolet signature expression, and tertiary lymphoid structures."
This review supports immune biomarker enrichment and checkpoint-relevant immune remodeling in cutaneous angiosarcoma.
✶

Histopathology

5
Anastomosing Vascular Channel Formation VERY_FREQUENT
Irregular, anastomosing vascular channels lined by atypical endothelial cells are the architectural hallmark of angiosarcoma. Tumors span a spectrum from purely vasoformative to mixed vasoformative-and-solid, with a minority showing a purely solid (poorly differentiated, often epithelioid) pattern that obscures the vascular nature and is a recognized diagnostic pitfall. Endothelial lineage of the neoplastic lining cells is confirmed immunohistochemically by near-universal CD31 and ERG positivity, with more variable CD34 that is frequently lost in tumors with lymphatic differentiation.
Show evidence (3 references)
PMID:38391320 SUPPORT Human Clinical
"Histomorphological patterns observed were mixed vasoformative and solid ( n = 22), pure vasoformative ( n = 13), and pure solid ( n = 1)."
In a 36-case head and neck angiosarcoma series, 35/36 tumors showed vasoformative architecture (mixed or pure), supporting anastomosing vascular channel formation as the dominant histologic pattern.
PMID:38391320 SUPPORT Human Clinical
"CD31 was positive in 100% of cases, and CD34 was positive in 40% of cases."
Confirms that the cells lining the vascular channels are endothelial (CD31 universally positive, CD34 variable), the immunophenotype that establishes the angiosarcoma diagnosis.
PMID:34392127 SUPPORT Human Clinical
"CD31 and ERG immunostains showed positivity in all cases, while CD34 were negative in some cases with lymphatic differentiation."
Independent breast angiosarcoma series confirms uniform CD31/ERG endothelial positivity and CD34 loss in lymphatic-differentiated tumors, supporting the endothelial nature of the vascular channels.
Epithelioid Component
Angiosarcoma can contain epithelioid neoplastic endothelial cells among a broader morphologic spectrum. Epithelioid morphology can obscure vascular differentiation and contributes to diagnostic pitfalls; no population-wide frequency is inferred from the cited case series.
Show evidence (2 references)
PMID:38391320 SUPPORT Human Clinical
"Neoplastic cells showed epithelioid, spindly, signet cell-like, clear cell, and rhabdoid morphology."
The head and neck series directly documents epithelioid morphology within the observed cytomorphologic spectrum.
PMID:34392127 SUPPORT Human Clinical
"Histologic morphologies of AS varied from confluent growth of atypical spindle or epithelioid cells to scattered marked pleomorphic cells."
The breast series independently confirms an epithelioid component in some tumors.
Spindle Cell Pattern
Angiosarcoma can contain atypical spindle cells, sometimes admixed with epithelioid or pleomorphic cells. The cited series establish the pattern but do not support a disease-wide frequency estimate.
Show evidence (2 references)
PMID:38391320 SUPPORT Human Clinical
"Neoplastic cells showed epithelioid, spindly, signet cell-like, clear cell, and rhabdoid morphology."
The head and neck series directly documents spindly neoplastic cells.
PMID:34392127 SUPPORT Human Clinical
"Histologic morphologies of AS varied from confluent growth of atypical spindle or epithelioid cells to scattered marked pleomorphic cells."
The breast series independently confirms atypical spindle-cell morphology.
Tumor Necrosis
In the cited breast series, necrosis was a feature that upgraded an otherwise lower-grade-appearing lesion to high grade. The source does not provide a disease-wide frequency estimate.
Show evidence (1 reference)
PMID:34392127 SUPPORT Human Clinical
"haemorrhage ('blood lake') or necrosis upgraded them to high grade lesions."
Documents necrosis as a high-grade-defining feature in breast angiosarcoma.
Stromal Hemorrhage (Blood Lakes)
In the cited breast series, hemorrhagic blood-lake areas were among the findings that upgraded lesions to high grade. The source does not establish that this feature is present in a specific fraction of all angiosarcomas.
Show evidence (1 reference)
PMID:34392127 SUPPORT Human Clinical
"haemorrhage ('blood lake') or necrosis upgraded them to high grade lesions."
Documents hemorrhagic 'blood lake' areas as a high-grade-defining feature in breast angiosarcoma.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Angiosarcoma Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

3
Integument 1
Cutaneous or subcutaneous lesions Neoplasm of the skin HP:0008069 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neoplasm of the skin (HP:0008069). HP:0008069 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36993810 SUPPORT Other
"Clinical presentation is variable, but cAS often arises from the head and neck."
This review supports a cutaneous head and neck presentation without quantifying frequency across all angiosarcoma.
Respiratory 1
Hemoptysis FREQUENT HP:0002105 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hemoptysis (HP:0002105). HP:0002105 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28885371 SUPPORT Human Clinical
"The most common symptom was hemoptysis (8/11)."
Eight of 11 patients in this pulmonary metastatic cohort had hemoptysis, corresponding to 72.7% and the FREQUENT band.
Neoplasm 1
Multifocal breast angiosarcoma presentation Soft tissue neoplasm HP:0031459 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Soft tissue neoplasm (HP:0031459). HP:0031459 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38722225 SUPPORT Human Clinical
"Both primary and secondary breast angiosarcoma (AS) are characterized by multifocal presentation and aggressive behavior."
This breast angiosarcoma cohort supports aggressive multifocal soft tissue presentation.
🧬

Genetic Associations

7
MYC (Somatic amplification in secondary angiosarcoma)
Gene: MYC hgnc:7553 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MYC (hgnc:7553). hgnc:7553 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (2 references)
PMID:20949568 SUPPORT Human Clinical
"Our findings reinforce the distinct pathogenesis of AS subtypes, with MYC amplification being an early, but necessary event in secondary AS."
This study supports MYC amplification as an early driver event in secondary angiosarcoma.
PMID:38722225 SUPPORT Human Clinical
"By targeted NGS, all 10 post-NACT RA-AS demonstrated MYC amplification, while both primary AS harbored KDR mutations."
This directly supports MYC amplification as a defining feature of radiation-associated breast angiosarcoma.
KDR (Recurrent somatic mutation enriched in primary mammary angiosarcoma)
Gene: KDR hgnc:6307 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KDR (hgnc:6307). hgnc:6307 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (1 reference)
PMID:32123305 SUPPORT Human Clinical
"Six tumors harbored a KDR p.T771R hotspot mutation, and all seven KDR-mutant cases showed evidence suggestive of biallelism"
Recurrent hotspot mutations and evidence of biallelic involvement support KDR as a somatic driver in this primary mammary cohort.
PIK3CA (Recurrent activating somatic mutation enriched in primary breast angiosarcoma)
Gene: PIK3CA hgnc:8975 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PIK3CA (hgnc:8975). hgnc:8975 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (1 reference)
PMID:32042194 SUPPORT Human Clinical
"PIK3CA-activating mutations were observed predominantly in primary breast angiosarcoma, which suggested a therapeutic rationale."
This directly links activating PIK3CA mutations to primary breast angiosarcoma.
TP53 (Recurrent somatic mutation)
Gene: TP53 hgnc:11998 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TP53 (hgnc:11998). hgnc:11998 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: UNKNOWN variant_origin: SOMATIC
Show evidence (1 reference)
PMID:32042194 SUPPORT Human Clinical
"Whole-exome sequencing (WES) of 47 tumors revealed recurrently mutated genes that included KDR, TP53, and PIK3CA."
This supports TP53 as a recurrently altered gene in angiosarcoma.
FLT4 (Somatic coamplification in a subset of secondary angiosarcoma)
Gene: FLT4 hgnc:3767 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FLT4 (hgnc:3767). hgnc:3767 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: COOPERATING variant_origin: SOMATIC
Show evidence (1 reference)
PMID:20949568 SUPPORT Human Clinical
"Secondary genetic hits, such as FLT4 gene coamplification or KDR mutations, may play a role in tumor progression as well as potential therapeutic targeting."
This study explicitly frames FLT4 coamplification as a secondary genetic hit that may cooperate in progression.
ATM (Subtype-enriched somatic alteration)
Gene: ATM hgnc:795 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ATM (hgnc:795). hgnc:795 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: UNKNOWN variant_origin: SOMATIC
Show evidence (1 reference)
PMID:37350195 SUPPORT Human Clinical
"RT-associated AS had more frequent MYC, FLT4, CRKL, HRAS, and KMT2D alterations than sporadic AS (enriched in TP53, KDR, ATM, ATRX)"
This comparative NGS study reports ATM alterations as enriched in sporadic angiosarcoma relative to radiation-associated AS.
ATRX (Subtype-enriched somatic alteration)
Gene: ATRX hgnc:886 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ATRX (hgnc:886). hgnc:886 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: UNKNOWN variant_origin: SOMATIC
Show evidence (1 reference)
PMID:37350195 SUPPORT Human Clinical
"RT-associated AS had more frequent MYC, FLT4, CRKL, HRAS, and KMT2D alterations than sporadic AS (enriched in TP53, KDR, ATM, ATRX)"
This comparative NGS study reports ATRX alterations as enriched in sporadic angiosarcoma relative to radiation-associated AS.
💊

Medical Actions

7
Surgical Excision
Category: Therapeutic Action: ExcisionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Excision (NCIT:C15232). NCIT:C15232 is a clinical intervention from the NCI Thesaurus. NCIT:C15232
Primary surgery is the principal local treatment for resectable localized angiosarcoma. A retrospective cohort associated surgery with improved survival in localized disease; the evidence is observational and does not establish benefit in unresectable or metastatic settings.
Show evidence (2 references)
PMID:40500777 SUPPORT Human Clinical
"Primary surgery improved survival in localized disease, with adjuvant radiotherapy enhancing local control but not OS."
This retrospective cohort supports primary surgery for localized disease while preserving the observational context.
PMID:36993810 SUPPORT Other
"The most widely accepted current approach, surgical excision with adjuvant radiotherapy, is associated with high recurrence rates"
This review supports surgical excision as the current standard approach for cutaneous angiosarcoma.
Adjuvant Radiation Therapy
Category: Therapeutic Action: radiation therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is radiation therapy (NCIT:C15313). NCIT:C15313 is a clinical intervention from the NCI Thesaurus. Ontology label: Radiation Therapy NCIT:C15313
Adjuvant radiotherapy can be used with surgery for localized angiosarcoma. In a retrospective cohort it improved local control without improving overall survival, so that distinction is retained.
Show evidence (2 references)
PMID:40500777 SUPPORT Human Clinical
"Primary surgery improved survival in localized disease, with adjuvant radiotherapy enhancing local control but not OS."
This cohort supports enhanced local control but not overall survival from adjuvant radiotherapy.
PMID:36993810 SUPPORT Other
"The most widely accepted current approach, surgical excision with adjuvant radiotherapy, is associated with high recurrence rates"
This review supports adjuvant radiation therapy as part of standard local management.
Paclitaxel-Based Chemotherapy
Category: Therapeutic Action: chemotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is chemotherapy (NCIT:C15632). NCIT:C15632 is a clinical intervention from the NCI Thesaurus. Ontology label: Chemotherapy NCIT:C15632
Agent: paclitaxel CHEBI:45863 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses paclitaxel (CHEBI:45863). CHEBI:45863 is a therapeutic agent from Chemical Entities of Biological Interest.
Paclitaxel-based chemotherapy is a systemic option for advanced angiosarcoma. In one retrospective metastatic cohort, paclitaxel-based first-line regimens were less effective than doxorubicin-based regimens; this comparison should not be generalized beyond that cohort.
Show evidence (2 references)
PMID:33182685 SUPPORT Other
"For advanced angiosarcoma, anthracyclines and taxanes are the main chemotherapy options."
This review supports taxane-based regimens such as paclitaxel as standard systemic therapy for advanced angiosarcoma.
PMID:40500777 SUPPORT Human Clinical
"In metastatic cases, first-line systemic therapies showed that paclitaxel-based regimens were less effective than doxorubicin-based chemotherapy, and the addition of anti-angiogenic therapy did not improve outcomes."
This single-center cohort provides the context-specific first-line comparison.
Anthracycline-Based Chemotherapy
Category: Therapeutic Action: chemotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is chemotherapy (NCIT:C15632). NCIT:C15632 is a clinical intervention from the NCI Thesaurus. Ontology label: Chemotherapy NCIT:C15632
Agent: doxorubicin CHEBI:28748 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses doxorubicin (CHEBI:28748). CHEBI:28748 is a therapeutic agent from Chemical Entities of Biological Interest.
Anthracycline-based chemotherapy is another main systemic treatment option for advanced angiosarcoma.
Show evidence (2 references)
PMID:33182685 SUPPORT Other
"For advanced angiosarcoma, anthracyclines and taxanes are the main chemotherapy options."
This review supports anthracyclines such as doxorubicin as major chemotherapy options in advanced angiosarcoma.
PMID:40500777 SUPPORT Human Clinical
"chemotherapy remains the mainstay for advanced cases."
This retrospective cohort supports chemotherapy as the main systemic approach for advanced disease.
Pazopanib
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: pazopanib CHEBI:71219 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses pazopanib (CHEBI:71219). CHEBI:71219 is a therapeutic agent from Chemical Entities of Biological Interest.
Pazopanib is a multikinase VEGFR inhibitor used as a later-line option in advanced soft-tissue sarcoma and studied in angiosarcoma. Retrospective angiosarcoma activity has been reported, but disease control is often transient and adding anti-angiogenic therapy did not improve outcomes in one metastatic cohort.
Mechanism Target:
INHIBITS Angiogenic Signaling Activation — Pazopanib inhibits VEGFR1, VEGFR2, and VEGFR3 signaling within the angiogenic pathway.
Show evidence (1 reference)
PMID:33182685 SUPPORT Other
"Pazopanib, a TKI that targets VEGFR 1, 2, and 3 as well as platelet-derived growth factor receptor (PDGFR)-alpha and beta"
This review directly supports the VEGFR target link.
Show evidence (3 references)
PMID:33182685 SUPPORT Other
"was shown to have an ORR of 20% in AS in a retrospective analysis of patients treated at EORTC centers"
This review supports the VEGFR target link and reports limited retrospective activity in angiosarcoma.
PMID:33182685 SUPPORT Other
"Anti-angiogenic agents have a substantial role but the failure of a randomized phase 3 trial of pazopanib with or without an anti-endoglin antibody brings a challenge to future trials in angiosarcomas."
This review supports anti-angiogenic therapy as a biologically rational but clinically imperfect treatment approach.
PMID:40500777 SUPPORT Human Clinical
"In metastatic cases, first-line systemic therapies showed that paclitaxel-based regimens were less effective than doxorubicin-based chemotherapy, and the addition of anti-angiogenic therapy did not improve outcomes."
This cohort cautions that adding anti-angiogenic therapy did not improve outcomes in its metastatic cases.
Off-Label Pembrolizumab
Category: Therapeutic Action: immunotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunotherapy (NCIT:C15262). NCIT:C15262 is a clinical intervention from the NCI Thesaurus. Ontology label: Immunotherapy NCIT:C15262
Agent: pembrolizumab NCIT:C106432 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses pembrolizumab (NCIT:C106432). NCIT:C106432 is a therapeutic agent from the NCI Thesaurus.
Pembrolizumab is not approved specifically for angiosarcoma. Exceptional responses to off-label anti-PD-1 therapy were reported in two patients with head, neck, face, and scalp angiosarcoma, providing a clinical signal rather than an established standard of care.
Show evidence (1 reference)
PMID:32042194 SUPPORT Human Clinical
"two patients with HNFS angiosarcoma had received off-label therapeutic use of antibody to the programmed death-1 protein (anti-PD-1) and had experienced exceptional responses"
This directly supports checkpoint inhibition as a promising therapy in UV-associated head and neck angiosarcoma.
Investigational Cemiplimab
Category: Therapeutic Action: immunotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunotherapy (NCIT:C15262). NCIT:C15262 is a clinical intervention from the NCI Thesaurus. Ontology label: Immunotherapy NCIT:C15262
Agent: cemiplimab NCIT:C121540 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses cemiplimab (NCIT:C121540). NCIT:C121540 is a therapeutic agent from the NCI Thesaurus.
Cemiplimab remains investigational for angiosarcoma. A prospective phase II trial in locally advanced or metastatic secondary angiosarcoma reported a 27.8% best overall response rate; the selected secondary-disease population and single-arm design limit generalization.
Show evidence (2 references)
PMID:40632032 SUPPORT Human Clinical
"Immune checkpoint inhibition is not approved for AS, but high intratumoral T-cell density and frequent mutations in sAS may support efficacy."
The trial abstract explicitly states that checkpoint inhibition is not approved for angiosarcoma.
PMID:40632032 SUPPORT Human Clinical
"The best overall response rate was 27.8% (4 partial responses, 1 complete response)"
The phase II study provides the response estimate in its selected secondary-angiosarcoma population.
🌍

Environmental Factors

4
Prior radiotherapy
exposure to ionizing radiation ECTO:7000047 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to ionizing radiation (ECTO:7000047). ECTO:7000047 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Prior radiotherapy is a major risk context for secondary angiosarcoma, especially in the breast and chest wall.
Show evidence (1 reference)
PMID:38607625 SUPPORT Human Clinical
"Angiosarcoma is an aggressive vascular malignant neoplasm presenting either as a primary or secondary cancer, often arising after radiotherapy or in the context of preexisting lymphedema."
This study supports prior radiotherapy as a common context for secondary angiosarcoma.
Mechanism Target:
TRIGGERS Radiation-Associated DNA Damage and Replication Stress — Therapeutic irradiation supplies the DNA damage this node names, producing secondary angiosarcoma within the treated field, classically the breast after adjuvant radiotherapy.
Show evidence (1 reference)
PMID:38607625 SUPPORT Human Clinical
"Angiosarcoma is an aggressive vascular malignant neoplasm presenting either as a primary or secondary cancer, often arising after radiotherapy or in the context of preexisting lymphedema."
States that angiosarcoma often arises after radiotherapy, the secondary presentation this node models.
Chronic lymphedema
Chronic lymphedema is a recognized predisposing context for secondary angiosarcoma, including Stewart-Treves syndrome.
Show evidence (1 reference)
PMID:38607625 SUPPORT Human Clinical
"Angiosarcoma is an aggressive vascular malignant neoplasm presenting either as a primary or secondary cancer, often arising after radiotherapy or in the context of preexisting lymphedema."
This population study explicitly identifies preexisting lymphedema as a risk context for angiosarcoma.
Mechanism Target:
PREDISPOSES Malignant Endothelial Proliferation and Vascular Tumor Growth — Long-standing lymphoedema is the classical Stewart-Treves setting. Unlike radiation and ultraviolet exposure it supplies no identified genotoxic insult, so it is recorded as a predisposing context rather than a source of damage.
Show evidence (1 reference)
PMID:38607625 SUPPORT Human Clinical
"Angiosarcoma is an aggressive vascular malignant neoplasm presenting either as a primary or secondary cancer, often arising after radiotherapy or in the context of preexisting lymphedema."
States that angiosarcoma often arises in the context of preexisting lymphedema, a predisposing context without an identified mutational mechanism.
Ultraviolet exposure
exposure to ultraviolet radiation ECTO:0000006 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to ultraviolet radiation (ECTO:0000006). ECTO:0000006 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Ultraviolet exposure is implicated in a molecularly defined subset of head and neck angiosarcoma. UV-positive tumors carry a UV-associated mutational signature and elevated tumor mutation burden, but this pattern is not universal across the anatomic subtype.
Show evidence (1 reference)
PMID:32042194 SUPPORT Human Clinical
"Angiosarcoma of the head, neck, face and scalp (HNFS) was associated with a high tumor mutation burden (TMB) and a dominant ultraviolet damage mutational signature"
This directly supports ultraviolet-associated mutagenesis in cutaneous head and neck angiosarcoma.
Mechanism Target:
TRIGGERS UV-Associated Hypermutation — The entry models a separate ultraviolet arm because the mutational evidence is direct: head and neck tumours in sun-exposed skin carry a dominant ultraviolet damage signature rather than a radiation one.
Show evidence (1 reference)
PMID:32042194 SUPPORT Human Clinical
"Angiosarcoma of the head, neck, face and scalp (HNFS) was associated with a high tumor mutation burden (TMB) and a dominant ultraviolet damage mutational signature"
Reports high tumour mutation burden with a dominant ultraviolet damage mutational signature in angiosarcoma of the head, neck, face and scalp.
Chemical carcinogen exposure (vinyl chloride, thorium dioxide)
Occupational and iatrogenic chemical carcinogen exposure, classically vinyl chloride monomer and thorium dioxide (Thorotrast), is a well-documented risk context for hepatic angiosarcoma.
Show evidence (1 reference)
PMID:33182685 SUPPORT Other
"Chemical exposure to vinyl chloride and thorium dioxide have been well-documented to be associated with increased risk of liver AS"
This review explicitly identifies vinyl chloride and thorium dioxide exposure as well-documented risk factors for hepatic angiosarcoma.
Mechanism Target:
TRIGGERS Malignant Endothelial Proliferation and Vascular Tumor Growth — Vinyl chloride and thorium dioxide are established causes of hepatic angiosarcoma specifically, a site-restricted association that distinguishes this exposure from the cutaneous and post-irradiation forms.
Show evidence (1 reference)
PMID:33182685 SUPPORT Other
"Chemical exposure to vinyl chloride and thorium dioxide have been well-documented to be associated with increased risk of liver AS"
States that vinyl chloride and thorium dioxide exposure are well documented as increasing the risk of liver angiosarcoma.
🔬

Diagnosis

1
Biopsy with histopathology and endothelial immunohistochemistry
Diagnosis requires clinicopathologic integration of biopsy morphology with endothelial immunohistochemistry. Tumors may be vasoformative, mixed, or rarely purely solid; CD31 and ERG are sensitive endothelial markers, whereas CD34 is variably retained. These findings support lineage and must be interpreted in context rather than treated as a single pathognomonic test.
Biopsy Procedure NCIT:C15189 NCI Thesaurus (NCIT)
Markers: CD31 and ERG positive; CD34 variably positive
Results: Vasoformative or solid malignant morphology with endothelial-lineage immunophenotype supports angiosarcoma.
Show evidence (4 references)
PMID:38391320 SUPPORT Human Clinical
"Histomorphological patterns observed were mixed vasoformative and solid ( n = 22), pure vasoformative ( n = 13), and pure solid ( n = 1)."
The head and neck series documents the range of diagnostic architectural patterns.
PMID:38391320 SUPPORT Human Clinical
"CD31 was positive in 100% of cases, and CD34 was positive in 40% of cases."
The series supports CD31 as a sensitive endothelial marker and CD34 as variable.
PMID:34392127 SUPPORT Human Clinical
"CD31 and ERG immunostains showed positivity in all cases, while CD34 were negative in some cases with lymphatic differentiation."
The breast series independently supports CD31 and ERG positivity with variable CD34.
+ 1 more reference
🩻

Imaging Findings

2
Multiple pulmonary nodules on chest CT FREQUENT
Chest CT in the selected pulmonary metastatic cohort showed bilateral, randomly distributed nodules of varying shape and size. The frequency is cohort specific and is not a diagnostic rate for angiosarcoma overall.
Ct Multifocal Pulmonary metastatic angiosarcoma cohort with hemoptysis; 8 of 11 patients (72.7%).
Multiple pulmonary nodules on computed tomography HP:0033608 Human Phenotype Ontology (HP) lung UBERON:0002048 Uberon multi-species anatomy ontology (UBERON) Pulmonary nodule HP:0033608 Human Phenotype Ontology (HP)
Show evidence (1 reference)
PMID:28885371 SUPPORT Human Clinical
"Chest computed tomography (CT) of patients with hemoptysis showed bilateral, randomly distributed, variably shaped, and differently sized nodules, as well as ground-glass opacities (GGO) (8/11)."
Nodules were reported with GGO in 8 of 11 patients, corresponding to 72.7% and the FREQUENT band in this selected cohort.
Ground-glass opacities on chest CT FREQUENT
Bilateral ground-glass opacities accompanied variably shaped pulmonary nodules in the selected pulmonary metastatic cohort. The finding can reflect hemorrhagic pulmonary involvement but is not specific or diagnostic for angiosarcoma.
Ct Bilateral Pulmonary metastatic angiosarcoma cohort with hemoptysis; 8 of 11 patients (72.7%).
Ground-glass opacities on computed tomography HP:0025179 Human Phenotype Ontology (HP) lung UBERON:0002048 Uberon multi-species anatomy ontology (UBERON) Ground-glass opacification HP:0025179 Human Phenotype Ontology (HP)
Show evidence (1 reference)
PMID:28885371 SUPPORT Human Clinical
"Chest computed tomography (CT) of patients with hemoptysis showed bilateral, randomly distributed, variably shaped, and differently sized nodules, as well as ground-glass opacities (GGO) (8/11)."
GGO were reported with nodules in 8 of 11 patients, corresponding to 72.7% and the FREQUENT band in this selected cohort.
📊

Prevalence

1
United States, 2019
Annual Incidence 0.33 per 100,000 1–9 per 1,000,000
The 2019 age-adjusted incidence was 3.3 cases per 1,000,000 person-years, equivalent to 0.33 per 100,000 person-years. This is an annual incidence estimate, not point prevalence.
Show evidence (1 reference)
PMID:38607625 SUPPORT Human Clinical
"The US incidence of angiosarcoma doubled between 2001 (657 cases) and 2019 (1312 cases), reflecting both an increase in the adjusted incidence rate of 1.6% per year (P = .001), to 3.3 cases per 1 000 000 person-years (95% CI, 3.1-3.5 cases per 1 000 000 person-years)"
This population study provides the 2019 US annual incidence rate used here.
📊

Related Datasets

6
Gene expression of human angiosarcoma geo:GSE226338
Gene expression profiling of human angiosarcoma samples was performed using the NanoString Human nCounter PanCancer IO 360 Panel
human n=67
PMID:37106027
Identified by GEO DataSets index search for Angiosarcoma (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
Chemo-senolytic therapeutic potential against angiosarcoma geo:GSE245935
Angiosarcoma is an aggressive soft-tissue sarcoma with a poor prognosis. Chemotherapy for this cancer typically employs paclitaxel, one of the taxanes (genotoxic drugs), although it has a limited effect due to chemoresistance for prolonged treatment. Here we examine a new angiosarcoma treatment approach that combines chemotherapeutic and senolytic agents. We first find that the chemotherapeutic drugs, cisplatin and paclitaxel, efficiently induce cellular senescence of angiosarcoma cells. Subsequent treatment with a senolytic agent, ABT-263, eliminates senescent cells through the activation of the apoptotic pathway.
human BULK RNA SEQ n=13
PMID:38570028
Identified by GEO DataSets index search for Angiosarcoma (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
Target gene regulatory network of miR-497 in angiosarcoma geo:GSE240260
Angiosarcoma (AS) is a vascular sarcoma that is highly aggressive and metastatic. Due to its rarity, treatment options for patients are limited, therefore more research is needed to identify possible therapeutic vulnerabilities. We previously found that endothelial deletion of Dicer1 drives AS development in mice. Given the role of DICER1 in canonical microRNA (miRNA) biogenesis, this suggests that miRNA loss may be important in AS development. After testing miRNAs previously suggested to have a tumor-suppressive role in AS, microRNA-497-5p (miR-497) suppressed cell viability most significantly.
mouse BULK RNA SEQ n=6
PMID:37808715
Identified by GEO DataSets index search for Angiosarcoma (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
PLCG1 R707Q mutation is counter selected under targeted therapy in a patient with a hepatic angiosarcoma ega:EGAS00001001281
PLCG1 R707Q mutation is counter selected under targeted therapy in a patient with a hepatic angiosarcoma
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Angiosarcoma"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
Whole genome and whole transcriptome sequencing of patients diagnosed with angiosarcoma. ega:EGAS00001003895
Angiosarcomas are rare, clinically-aggressive tumors with a predilection for the elderly and immunosuppressed, which has incited suspicion of an oncogenic virus. We studied the metagenomic landscape of angiosarcomas and identified reads mapping to human herpesvirus-7 (HHV-7). Overall, HHV-7 was present in two-thirds of angiosarcomas, particularly in cases with low tumor mutation burden and lacking signatures of ultraviolet-induced DNA damage. Transcriptomic profiling revealed the enrichment of tumor inflammation signatures in HHV7-positive angiosarcomas. In conclusion, we identified a distinct “inflammatory” subtype of angiosarcoma associated with HHV-7.
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Angiosarcoma"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
Molecular determinants for sensitivity to pazopanib in leiomyosarcoma, synovial sarcoma, and angiosarcoma. ega:EGAS00001004158
Pazopanib is a tyrosine kinase inhibitor with highest activity against VEGFR1 (FLT1) and VEGFR2 (KDR) along with other targets including VEGFR3, PDGFRa, PDGFRb, cKIT, FGFR1, FGFR3, FGFR4, FAK, ABL1, JNK1, Tie-2, Met, IGF1R, and EGFR (Lee, Jones, and Huang Signal Transduct Target Ther 2019; 4:16). Its initial activity in soft tissue sarcoma (STS) was described by Sleijfer et al. (2009) where a high proportion of leiomyosarcoma (LMS) (44%) and synovial sarcoma (49%) patients remained without progression at 12 weeks.
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Angiosarcoma"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
{ }

Source YAML

click to show 
name: Angiosarcoma
creation_date: '2026-04-12T05:11:04Z'
category: Cancer
categories:
- Sarcoma
- Soft Tissue Sarcoma
- Vascular Tumor
- Rare Cancer
parents:
- vascular cancer
- soft tissue sarcoma
disease_term:
  preferred_term: angiosarcoma
  term:
    id: MONDO:0016982
    label: angiosarcoma
description: >-
  Angiosarcoma is a rare, aggressive malignant neoplasm of endothelial lineage
  that arises from blood or lymphatic vascular structures. The disease is
  biologically heterogeneous across anatomic sites and etiologies. Its subtype
  labels therefore use overlapping axes: cutaneous head and neck, breast, and
  hepatic angiosarcoma are anatomic groupings, whereas radiation-associated and
  lymphedema-associated angiosarcoma are etiologic groupings. Core mechanisms
  converge on dysregulated angiogenic signaling, with subtype-enriched
  alterations including MYC amplification in secondary disease, KDR and PIK3CA
  mutations in primary breast disease, and ultraviolet-associated hypermutation
  in some head and neck lesions.
synonyms:
- hemangiosarcoma
- blood vessel sarcoma
prevalence:
- population: United States, 2019
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.33
  notes: >-
    The 2019 age-adjusted incidence was 3.3 cases per 1,000,000 person-years,
    equivalent to 0.33 per 100,000 person-years. This is an annual incidence
    estimate, not point prevalence.
  evidence:
  - reference: PMID:38607625
    reference_title: "Incidence and Presenting Characteristics of Angiosarcoma in the US, 2001-2020."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The US incidence of angiosarcoma doubled between 2001 (657 cases) and 2019 (1312 cases), reflecting both an increase in the adjusted incidence rate of 1.6% per year (P = .001), to 3.3 cases per 1 000 000 person-years (95% CI, 3.1-3.5 cases per 1 000 000 person-years)"
    explanation: This population study provides the 2019 US annual incidence rate used here.
has_subtypes:
- name: Cutaneous Head and Neck Angiosarcoma
  classification: anatomic
  description: >-
    Cutaneous head and neck angiosarcoma includes tumors of the scalp, face,
    head, and neck. Some tumors in this anatomic subset carry an ultraviolet
    mutational signature and high tumor mutation burden; UV-positive and
    UV-negative tumors should not be treated as biologically interchangeable.
  evidence:
  - reference: PMID:32042194
    reference_title: "The Angiosarcoma Project: enabling genomic and clinical discoveries in a rare cancer through patient-partnered research."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Angiosarcoma of the head, neck, face and scalp (HNFS) was associated with a high tumor mutation burden (TMB) and a dominant ultraviolet damage mutational signature"
    explanation: This supports UV-associated hypermutation in a subset of head and neck angiosarcoma.
  - reference: PMID:37106027
    reference_title: Spatial transcriptomics reveal topological immune landscapes of Asian head and neck angiosarcoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "UV-positive AS-HN harbored significantly higher tumor mutation burden than UV-negative cases (p = 0.0294)."
    explanation: This cohort distinguishes UV-positive from UV-negative head and neck angiosarcoma.
- name: Radiation-Associated Angiosarcoma
  classification: etiologic
  description: >-
    Radiation-associated angiosarcoma is an etiologic secondary subtype that
    can arise in a previously irradiated field, especially the breast or chest
    wall. MYC amplification is a characteristic early genomic event in this
    subtype, and FLT4 can be coamplified in a subset.
  evidence:
  - reference: PMID:20949568
    reference_title: Consistent MYC and FLT4 gene amplification in radiation-induced angiosarcoma but not in other radiation-associated atypical vascular lesions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings reinforce the distinct pathogenesis of AS subtypes, with MYC amplification being an early, but necessary event in secondary AS."
    explanation: This study supports a distinct MYC-amplified pathogenesis in secondary angiosarcoma.
  - reference: PMID:37350195
    reference_title: Distinct genomic landscapes in radiation-associated angiosarcoma compared with other radiation-associated sarcoma histologies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RT-associated AS had more frequent MYC, FLT4, CRKL, HRAS, and KMT2D alterations than sporadic AS (enriched in TP53, KDR, ATM, ATRX)"
    explanation: This demonstrates that radiation-associated angiosarcoma is a molecularly distinct subtype.
- name: Lymphedema-Associated Angiosarcoma
  classification: etiologic
  description: >-
    Chronic lymphedema can predispose to secondary angiosarcoma, classically
    termed Stewart-Treves syndrome. This is an etiologic grouping and can
    overlap an anatomic subtype.
  evidence:
  - reference: PMID:38607625
    reference_title: "Incidence and Presenting Characteristics of Angiosarcoma in the US, 2001-2020."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Angiosarcoma is an aggressive vascular malignant neoplasm presenting either as a primary or secondary cancer, often arising after radiotherapy or in the context of preexisting lymphedema."
    explanation: This population-level study supports lymphedema-associated secondary angiosarcoma as a clinically recognized subtype.
- name: Primary Breast Angiosarcoma
  classification: anatomic_and_etiologic
  description: >-
    Primary breast angiosarcoma arises without prior radiation exposure and is
    molecularly distinct from radiation-associated breast angiosarcoma, with
    frequent KDR and PIK3CA/PIK3R1 alterations in one genomic series. The label
    therefore combines an anatomic site with a primary (non-radiation-associated)
    etiologic context.
  evidence:
  - reference: PMID:32123305
    reference_title: Primary mammary angiosarcomas harbor frequent mutations in KDR and PIK3CA and show evidence of distinct pathogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recurrent genomic alterations were identified in KDR (70%), PIK3CA/PIK3R1 (70%), and PTPRB (30%), each at higher frequencies than reported in AS across all sites."
    explanation: This primary mammary series supports a distinct recurrent KDR and PI3K-pathway genomic profile.
- name: Hepatic Angiosarcoma
  classification: anatomic
  description: >-
    Hepatic angiosarcoma is a visceral subtype arising in the liver. It is the
    classic site of angiosarcoma associated with vinyl chloride or thorium
    dioxide exposure, although those exposures explain only a subset of hepatic
    cases and are not defining features of every tumor.
  evidence:
  - reference: PMID:33182685
    reference_title: Optimal Clinical Management and the Molecular Biology of Angiosarcomas.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "more commonly occur in the head and neck and scalp regions, extremities, breast, heart and great vessels, and visceral organs such as the liver and spleen"
    explanation: This review identifies the liver as a recognized visceral site of angiosarcoma, supporting hepatic angiosarcoma as a distinct anatomic subtype.
  - reference: PMID:33182685
    reference_title: Optimal Clinical Management and the Molecular Biology of Angiosarcomas.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Chemical exposure to vinyl chloride and thorium dioxide have been well-documented to be associated with increased risk of liver AS"
    explanation: This supports the chemically induced etiology that biologically distinguishes hepatic angiosarcoma from sporadic and radiation-associated disease.
pathophysiology:
- name: Angiogenic Signaling Activation
  description: >-
    Dysregulated endothelial receptor and PI3K signaling is a convergent
    mechanism in angiosarcoma. Recurrent KDR and PIK3CA alterations in primary
    mammary disease and FLT4 amplification in some secondary tumors implicate
    VEGFR-family and downstream growth signaling, but these alterations are
    subtype enriched rather than universal.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: angiogenesis
    modifier: INCREASED
    term:
      id: GO:0001525
      label: angiogenesis
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  genes:
  - preferred_term: KDR
    term:
      id: hgnc:6307
      label: KDR
  - preferred_term: PIK3CA
    term:
      id: hgnc:8975
      label: PIK3CA
  - preferred_term: FLT4
    term:
      id: hgnc:3767
      label: FLT4
  evidence:
  - reference: PMID:33182685
    reference_title: Optimal Clinical Management and the Molecular Biology of Angiosarcomas.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "We also report the current understanding of the molecular pathways involved in angiosarcoma pathogenesis including MYC amplification, activation of angiogenic pathways and different molecular alterations that are associated with angiosarcomas of different aetiology."
    explanation: This review directly identifies angiogenic-pathway activation as a component of angiosarcoma pathogenesis.
  - reference: PMID:32123305
    reference_title: Primary mammary angiosarcomas harbor frequent mutations in KDR and PIK3CA and show evidence of distinct pathogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recurrent genomic alterations were identified in KDR (70%), PIK3CA/PIK3R1 (70%), and PTPRB (30%), each at higher frequencies than reported in AS across all sites."
    explanation: The primary mammary cohort supports recurrent VEGFR2 and PI3K-pathway alterations in that subtype.
  - reference: PMID:20949568
    reference_title: Consistent MYC and FLT4 gene amplification in radiation-induced angiosarcoma but not in other radiation-associated atypical vascular lesions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Coamplification of FLT4 (encoding VEGFR3) was identified in 25% of secondary AS, but not in other types."
    explanation: This study supports FLT4 amplification as a secondary-subtype alteration feeding VEGFR-family signaling.
  downstream:
  - target: Malignant Endothelial Proliferation and Vascular Tumor Growth
    description: Activated Tie2/VEGFR signaling supports angiosarcoma-cell survival, proliferation, and tumor growth.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - receptor-mediated endothelial cell survival signaling
    - proliferative signaling
    evidence:
    - reference: PMID:22431921
      reference_title: Efficacy of Tie2 receptor antagonism in angiosarcoma.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Tie2 and vascular endothelial growth factor receptor (VEGFR) antagonists inhibited SVR and MS1-VEGF angiosarcoma cell survival in vitro."
      explanation: Receptor antagonism reduced angiosarcoma-cell survival in vitro, supporting pathway dependence.
    - reference: PMID:22431921
      reference_title: Efficacy of Tie2 receptor antagonism in angiosarcoma.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In vivo, Tie2 and VEGFR inhibition resulted in significant angiosarcoma growth delay."
      explanation: Xenograft growth delay after pathway inhibition supports a causal contribution to tumor growth.
- name: MYC-Amplified Secondary Angiosarcoma Program
  description: >-
    MYC amplification is an early genomic event in secondary angiosarcoma and
    can be accompanied by FLT4 coamplification. MYC-amplified tumors show
    upregulation of the miR-17-92 cluster and lower THBS1 expression, providing
    a mechanistic route from MYC amplification to an angiogenic phenotype.
  biological_scale: MOLECULAR
  subtypes:
  - Radiation-Associated Angiosarcoma
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  locations:
  - preferred_term: breast
    term:
      id: UBERON:0000310
      label: breast
  biological_processes:
  - preferred_term: angiogenesis
    modifier: INCREASED
    term:
      id: GO:0001525
      label: angiogenesis
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  genes:
  - preferred_term: MYC
    term:
      id: hgnc:7553
      label: MYC
  evidence:
  - reference: PMID:20949568
    reference_title: Consistent MYC and FLT4 gene amplification in radiation-induced angiosarcoma but not in other radiation-associated atypical vascular lesions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High-level MYC amplification was found in 100% of secondary AS, but in none of the AVL or other radiation-associated sarcomas."
    explanation: This cohort supports MYC amplification as a distinguishing alteration in secondary angiosarcoma.
  - reference: PMID:38722225
    reference_title: Clinicopathologic and molecular correlates to neoadjuvant chemotherapy-induced pathologic response in breast angiosarcoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By targeted NGS, all 10 post-NACT RA-AS demonstrated MYC amplification, while both primary AS harbored KDR mutations."
    explanation: This cohort study shows that MYC amplification is a defining molecular feature of radiation-associated breast angiosarcoma, in contrast to KDR-mutant primary disease.
  - reference: PMID:37350195
    reference_title: Distinct genomic landscapes in radiation-associated angiosarcoma compared with other radiation-associated sarcoma histologies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RT-associated AS had more frequent MYC, FLT4, CRKL, HRAS, and KMT2D alterations than sporadic AS (enriched in TP53, KDR, ATM, ATRX)"
    explanation: This comparative genomic study supports a MYC/FLT4-enriched program in radiation-associated angiosarcoma.
  downstream:
  - target: Angiogenic Signaling Activation
    description: MYC amplification promotes an angiogenic program through miR-17-92 upregulation and suppression of the endogenous angiogenesis inhibitor THBS1.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - miR-17-92 cluster upregulation
    - THBS1 downregulation
    evidence:
    - reference: PMID:22383169
      reference_title: The miR-17-92 cluster and its target THBS1 are differentially expressed in angiosarcomas dependent on MYC amplification.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Thus, MYC amplification may play a crucial role in the angiogenic phenotype of AS through upregulation of the miR-17-92 cluster, which subsequently downregulates THBS1, a potent endogenous inhibitor of angiogenesis."
      explanation: The tumor-expression study supports the specified MYC-miRNA-THBS1 route to an angiogenic phenotype.
- name: Malignant Endothelial Proliferation and Vascular Tumor Growth
  description: >-
    Survival and proliferation of transformed endothelial cells produce an
    infiltrative vascular malignancy. Experimental VEGFR inhibition reduces
    proliferation and tumor growth, supporting this node as the tissue-level
    consequence of upstream angiogenic signaling.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  evidence:
  - reference: PMID:22431921
    reference_title: Efficacy of Tie2 receptor antagonism in angiosarcoma.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "VEGFR inhibition reduced tumor growth by lowering tumor cell proliferation."
    explanation: The xenograft intervention links endothelial growth signaling to tumor-cell proliferation and tumor growth.
  downstream:
  - target: Cutaneous or subcutaneous lesions
    description: Superficial vascular tumor growth produces clinically apparent cutaneous or subcutaneous lesions in cutaneous disease.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - infiltrative neoplastic growth in skin and superficial soft tissue
    evidence:
    - reference: PMID:36993810
      reference_title: "Cutaneous angiosarcoma: A review of current evidence for treatment with checkpoint inhibitors."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Clinical presentation is variable, but cAS often arises from the head and neck."
      explanation: The review supports cutaneous head and neck presentation as a manifestation of superficial tumor growth.
  - target: Multifocal breast angiosarcoma presentation
    description: Neoplastic outgrowth within the breast can be multifocal in both primary and secondary breast angiosarcoma.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - multifocal endothelial tumor outgrowth in breast tissue
    evidence:
    - reference: PMID:38722225
      reference_title: Clinicopathologic and molecular correlates to neoadjuvant chemotherapy-induced pathologic response in breast angiosarcoma.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Both primary and secondary breast angiosarcoma (AS) are characterized by multifocal presentation and aggressive behavior."
      explanation: The breast cohort directly supports multifocal presentation in both etiologic groups.
  - target: Hemoptysis
    description: Pulmonary metastatic deposits can bleed into airways or alveolar spaces and present with hemoptysis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - pulmonary metastatic involvement
    - hemorrhage into airways or alveoli
    evidence:
    - reference: PMID:28885371
      reference_title: "Clinical and diagnostic features of angiosarcoma with pulmonary metastases: A retrospective observational study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The most common symptom was hemoptysis (8/11)."
      explanation: The pulmonary metastatic cohort documents hemoptysis in 8 of 11 patients.
- name: Radiation-Associated DNA Damage and Replication Stress
  description: >-
    Radiation-associated angiosarcoma develops in the setting of prior ionizing
    radiation exposure and carries mutational signatures linked to DNA repair
    and replication errors. These changes support a mechanistic model in which
    radiation-induced genomic injury and abnormal repair contribute to malignant
    endothelial transformation.
  biological_scale: MOLECULAR
  subtypes:
  - Radiation-Associated Angiosarcoma
  biological_processes:
  - preferred_term: DNA damage response
    modifier: ABNORMAL
    term:
      id: GO:0006974
      label: DNA damage response
  evidence:
  - reference: PMID:37350195
    reference_title: Distinct genomic landscapes in radiation-associated angiosarcoma compared with other radiation-associated sarcoma histologies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The predominant mutational signatures were associated with errors in DNA repair and replication."
    explanation: This directly supports defective DNA repair and replication-associated mutagenesis as a mechanism in radiation-associated angiosarcoma.
- name: UV-Associated Hypermutation
  description: >-
    Cutaneous angiosarcoma of the head, neck, face, and scalp can show a
    dominant ultraviolet mutational signature with elevated tumor mutation
    burden, consistent with ultraviolet-associated mutagenesis as a disease-
    shaping process in this anatomic subset.
  biological_scale: MOLECULAR
  subtypes:
  - Cutaneous Head and Neck Angiosarcoma
  locations:
  - preferred_term: skin of body
    term:
      id: UBERON:0002097
      label: skin of body
  biological_processes:
  - preferred_term: response to UV
    modifier: ABNORMAL
    term:
      id: GO:0009411
      label: response to UV
  evidence:
  - reference: PMID:32042194
    reference_title: "The Angiosarcoma Project: enabling genomic and clinical discoveries in a rare cancer through patient-partnered research."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Angiosarcoma of the head, neck, face and scalp (HNFS) was associated with a high tumor mutation burden (TMB) and a dominant ultraviolet damage mutational signature"
    explanation: The Angiosarcoma Project links cutaneous head and neck angiosarcoma to ultraviolet-associated hypermutation.
  - reference: PMID:37106027
    reference_title: Spatial transcriptomics reveal topological immune landscapes of Asian head and neck angiosarcoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "UV-positive AS-HN harbored significantly higher tumor mutation burden than UV-negative cases (p = 0.0294)."
    explanation: This spatial transcriptomic cohort independently supports ultraviolet-associated hypermutation in head and neck angiosarcoma.
- name: Checkpoint-Relevant Cutaneous Tumor Immune State
  description: >-
    Cutaneous and head and neck angiosarcoma can exhibit heterogeneous immune
    states, including tumor-excluded inflammatory signals and checkpoint-relevant
    biomarkers such as PD-L1 positivity, high tumor mutation burden, and tertiary
    lymphoid structures. The cited evidence establishes an immune context, not a
    complete adaptive-immune-resistance mechanism or a universal relationship to
    ultraviolet mutagenesis.
  biological_scale: TISSUE
  subtypes:
  - Cutaneous Head and Neck Angiosarcoma
  locations:
  - preferred_term: skin of body
    term:
      id: UBERON:0002097
      label: skin of body
  biological_processes:
  - preferred_term: regulation of immune response
    modifier: ABNORMAL
    term:
      id: GO:0050776
      label: regulation of immune response
  evidence:
  - reference: PMID:37106027
    reference_title: Spatial transcriptomics reveal topological immune landscapes of Asian head and neck angiosarcoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spatial transcriptomics revealed topological profiles of the tumor microenvironment, identifying dominant but tumor-excluded inflammatory signals in immune-hot cases"
    explanation: This supports altered regulation of the tumor immune response in head and neck angiosarcoma.
  - reference: PMID:36993810
    reference_title: "Cutaneous angiosarcoma: A review of current evidence for treatment with checkpoint inhibitors."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Like melanoma and cutaneous squamous cell carcinoma, tumor types with known response to immunotherapy, cAS harbors immune biomarkers, such as tumor mutational burden high (TMB-H), PD-L1 positivity, ultraviolet signature expression, and tertiary lymphoid structures."
    explanation: This review supports immune biomarker enrichment and checkpoint-relevant immune remodeling in cutaneous angiosarcoma.
histopathology:
- name: Anastomosing Vascular Channel Formation
  finding_term:
    preferred_term: Anastomosing vascular channel formation
    term:
      id: NCIT:C35973
      label: Irregular Vascular Channel Formation
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Irregular, anastomosing vascular channels lined by atypical endothelial
    cells are the architectural hallmark of angiosarcoma. Tumors span a
    spectrum from purely vasoformative to mixed vasoformative-and-solid, with a
    minority showing a purely solid (poorly differentiated, often epithelioid)
    pattern that obscures the vascular nature and is a recognized diagnostic
    pitfall. Endothelial lineage of the neoplastic lining cells is confirmed
    immunohistochemically by near-universal CD31 and ERG positivity, with more
    variable CD34 that is frequently lost in tumors with lymphatic
    differentiation.
  evidence:
  - reference: PMID:38391320
    reference_title: "Angiosarcoma of the head and neck: A clinicopathologic study with special emphasis on diagnostic pitfalls."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histomorphological patterns observed were mixed vasoformative and solid ( n = 22), pure vasoformative ( n = 13), and pure solid ( n = 1)."
    explanation: In a 36-case head and neck angiosarcoma series, 35/36 tumors showed vasoformative architecture (mixed or pure), supporting anastomosing vascular channel formation as the dominant histologic pattern.
  - reference: PMID:38391320
    reference_title: "Angiosarcoma of the head and neck: A clinicopathologic study with special emphasis on diagnostic pitfalls."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CD31 was positive in 100% of cases, and CD34 was positive in 40% of cases."
    explanation: Confirms that the cells lining the vascular channels are endothelial (CD31 universally positive, CD34 variable), the immunophenotype that establishes the angiosarcoma diagnosis.
  - reference: PMID:34392127
    reference_title: "Clinicopathologic and immunohistochemical study of breast angiosarcoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CD31 and ERG immunostains showed positivity in all cases, while CD34 were negative in some cases with lymphatic differentiation."
    explanation: Independent breast angiosarcoma series confirms uniform CD31/ERG endothelial positivity and CD34 loss in lymphatic-differentiated tumors, supporting the endothelial nature of the vascular channels.
- name: Epithelioid Component
  finding_term:
    preferred_term: Epithelioid component present
    term:
      id: NCIT:C53638
      label: Epithelioid Component Present
  description: >-
    Angiosarcoma can contain epithelioid neoplastic endothelial cells among a
    broader morphologic spectrum. Epithelioid morphology can obscure vascular
    differentiation and contributes to diagnostic pitfalls; no population-wide
    frequency is inferred from the cited case series.
  evidence:
  - reference: PMID:38391320
    reference_title: "Angiosarcoma of the head and neck: A clinicopathologic study with special emphasis on diagnostic pitfalls."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neoplastic cells showed epithelioid, spindly, signet cell-like, clear cell, and rhabdoid morphology."
    explanation: The head and neck series directly documents epithelioid morphology within the observed cytomorphologic spectrum.
  - reference: PMID:34392127
    reference_title: "Clinicopathologic and immunohistochemical study of breast angiosarcoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histologic morphologies of AS varied from confluent growth of atypical spindle or epithelioid cells to scattered marked pleomorphic cells."
    explanation: The breast series independently confirms an epithelioid component in some tumors.
- name: Spindle Cell Pattern
  finding_term:
    preferred_term: Spindle cell pattern
    term:
      id: NCIT:C53643
      label: Spindle Cell Pattern
  description: >-
    Angiosarcoma can contain atypical spindle cells, sometimes admixed with
    epithelioid or pleomorphic cells. The cited series establish the pattern but
    do not support a disease-wide frequency estimate.
  evidence:
  - reference: PMID:38391320
    reference_title: "Angiosarcoma of the head and neck: A clinicopathologic study with special emphasis on diagnostic pitfalls."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neoplastic cells showed epithelioid, spindly, signet cell-like, clear cell, and rhabdoid morphology."
    explanation: The head and neck series directly documents spindly neoplastic cells.
  - reference: PMID:34392127
    reference_title: "Clinicopathologic and immunohistochemical study of breast angiosarcoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histologic morphologies of AS varied from confluent growth of atypical spindle or epithelioid cells to scattered marked pleomorphic cells."
    explanation: The breast series independently confirms atypical spindle-cell morphology.
- name: Tumor Necrosis
  finding_term:
    preferred_term: Tumor cell necrosis
    term:
      id: NCIT:C35957
      label: Tumor Cell Necrosis
  description: >-
    In the cited breast series, necrosis was a feature that upgraded an
    otherwise lower-grade-appearing lesion to high grade. The source does not
    provide a disease-wide frequency estimate.
  evidence:
  - reference: PMID:34392127
    reference_title: "Clinicopathologic and immunohistochemical study of breast angiosarcoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "haemorrhage ('blood lake') or necrosis upgraded them to high grade lesions."
    explanation: Documents necrosis as a high-grade-defining feature in breast angiosarcoma.
- name: Stromal Hemorrhage (Blood Lakes)
  finding_term:
    preferred_term: Stromal hemorrhage
    term:
      id: NCIT:C36006
      label: Stromal Hemorrhage Present
  description: >-
    In the cited breast series, hemorrhagic blood-lake areas were among the
    findings that upgraded lesions to high grade. The source does not establish
    that this feature is present in a specific fraction of all angiosarcomas.
  evidence:
  - reference: PMID:34392127
    reference_title: "Clinicopathologic and immunohistochemical study of breast angiosarcoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "haemorrhage ('blood lake') or necrosis upgraded them to high grade lesions."
    explanation: Documents hemorrhagic 'blood lake' areas as a high-grade-defining feature in breast angiosarcoma.
phenotypes:
- category: Dermatologic
  name: Cutaneous or subcutaneous lesions
  subtype: Cutaneous Head and Neck Angiosarcoma
  description: >-
    Cutaneous angiosarcoma presents as a neoplasm of skin or superficial soft
    tissue, commonly in the head and neck. Because the cited review does not
    provide a denominator across all angiosarcoma, no disease-wide frequency or
    diagnostic flag is asserted.
  phenotype_term:
    preferred_term: Neoplasm of the skin
    term:
      id: HP:0008069
      label: Neoplasm of the skin
  evidence:
  - reference: PMID:36993810
    reference_title: "Cutaneous angiosarcoma: A review of current evidence for treatment with checkpoint inhibitors."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Clinical presentation is variable, but cAS often arises from the head and neck."
    explanation: This review supports a cutaneous head and neck presentation without quantifying frequency across all angiosarcoma.
- category: Musculoskeletal
  name: Multifocal breast angiosarcoma presentation
  subtypes:
  - Primary Breast Angiosarcoma
  - Radiation-Associated Angiosarcoma
  description: >-
    Both primary and radiation-associated breast angiosarcoma can present with
    multifocal tumor involvement. This context-specific finding is not assigned
    a disease-wide frequency.
  phenotype_term:
    preferred_term: Soft tissue neoplasm
    term:
      id: HP:0031459
      label: Soft tissue neoplasm
  evidence:
  - reference: PMID:38722225
    reference_title: Clinicopathologic and molecular correlates to neoadjuvant chemotherapy-induced pathologic response in breast angiosarcoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both primary and secondary breast angiosarcoma (AS) are characterized by multifocal presentation and aggressive behavior."
    explanation: This breast angiosarcoma cohort supports aggressive multifocal soft tissue presentation.
- category: Respiratory
  name: Hemoptysis
  frequency: FREQUENT
  context: Pulmonary metastatic angiosarcoma cohort; 8 of 11 patients (72.7%).
  description: >-
    Hemoptysis can be a prominent symptom when angiosarcoma has metastasized to
    the lungs. The frequency applies only to the selected 11-patient pulmonary
    metastatic cohort and must not be generalized to all angiosarcoma.
  phenotype_term:
    preferred_term: Hemoptysis
    term:
      id: HP:0002105
      label: Hemoptysis
  evidence:
  - reference: PMID:28885371
    reference_title: "Clinical and diagnostic features of angiosarcoma with pulmonary metastases: A retrospective observational study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common symptom was hemoptysis (8/11)."
    explanation: Eight of 11 patients in this pulmonary metastatic cohort had hemoptysis, corresponding to 72.7% and the FREQUENT band.
imaging_findings:
- name: Multiple pulmonary nodules on chest CT
  modality: CT
  imaging_finding_term:
    preferred_term: Multiple pulmonary nodules on computed tomography
    term:
      id: HP:0033608
      label: Pulmonary nodule
  phenotype_term:
    preferred_term: Pulmonary nodule
    term:
      id: HP:0033608
      label: Pulmonary nodule
  located_in:
    preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  spatial_extent: MULTIFOCAL
  frequency: FREQUENT
  context: Pulmonary metastatic angiosarcoma cohort with hemoptysis; 8 of 11 patients (72.7%).
  description: >-
    Chest CT in the selected pulmonary metastatic cohort showed bilateral,
    randomly distributed nodules of varying shape and size. The frequency is
    cohort specific and is not a diagnostic rate for angiosarcoma overall.
  evidence:
  - reference: PMID:28885371
    reference_title: "Clinical and diagnostic features of angiosarcoma with pulmonary metastases: A retrospective observational study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chest computed tomography (CT) of patients with hemoptysis showed bilateral, randomly distributed, variably shaped, and differently sized nodules, as well as ground-glass opacities (GGO) (8/11)."
    explanation: Nodules were reported with GGO in 8 of 11 patients, corresponding to 72.7% and the FREQUENT band in this selected cohort.
- name: Ground-glass opacities on chest CT
  modality: CT
  imaging_finding_term:
    preferred_term: Ground-glass opacities on computed tomography
    term:
      id: HP:0025179
      label: Ground-glass opacification
  phenotype_term:
    preferred_term: Ground-glass opacification
    term:
      id: HP:0025179
      label: Ground-glass opacification
  located_in:
    preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  laterality: BILATERAL
  frequency: FREQUENT
  context: Pulmonary metastatic angiosarcoma cohort with hemoptysis; 8 of 11 patients (72.7%).
  description: >-
    Bilateral ground-glass opacities accompanied variably shaped pulmonary
    nodules in the selected pulmonary metastatic cohort. The finding can reflect
    hemorrhagic pulmonary involvement but is not specific or diagnostic for
    angiosarcoma.
  evidence:
  - reference: PMID:28885371
    reference_title: "Clinical and diagnostic features of angiosarcoma with pulmonary metastases: A retrospective observational study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chest computed tomography (CT) of patients with hemoptysis showed bilateral, randomly distributed, variably shaped, and differently sized nodules, as well as ground-glass opacities (GGO) (8/11)."
    explanation: GGO were reported with nodules in 8 of 11 patients, corresponding to 72.7% and the FREQUENT band in this selected cohort.
genetic:
- name: MYC
  association: Somatic amplification in secondary angiosarcoma
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  subtype: Radiation-Associated Angiosarcoma
  gene_term:
    preferred_term: MYC
    term:
      id: hgnc:7553
      label: MYC
  notes: >-
    MYC amplification is a hallmark alteration in many radiation-associated and
    other secondary angiosarcomas and supports etiologic subclassification.
  evidence:
  - reference: PMID:20949568
    reference_title: Consistent MYC and FLT4 gene amplification in radiation-induced angiosarcoma but not in other radiation-associated atypical vascular lesions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings reinforce the distinct pathogenesis of AS subtypes, with MYC amplification being an early, but necessary event in secondary AS."
    explanation: This study supports MYC amplification as an early driver event in secondary angiosarcoma.
  - reference: PMID:38722225
    reference_title: Clinicopathologic and molecular correlates to neoadjuvant chemotherapy-induced pathologic response in breast angiosarcoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By targeted NGS, all 10 post-NACT RA-AS demonstrated MYC amplification, while both primary AS harbored KDR mutations."
    explanation: This directly supports MYC amplification as a defining feature of radiation-associated breast angiosarcoma.
- name: KDR
  association: Recurrent somatic mutation enriched in primary mammary angiosarcoma
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  subtype: Primary Breast Angiosarcoma
  gene_term:
    preferred_term: KDR
    term:
      id: hgnc:6307
      label: KDR
  notes: >-
    KDR mutations recur in angiosarcoma and are particularly enriched in primary
    breast disease.
  evidence:
  - reference: PMID:32123305
    reference_title: Primary mammary angiosarcomas harbor frequent mutations in KDR and PIK3CA and show evidence of distinct pathogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Six tumors harbored a KDR p.T771R hotspot mutation, and all seven KDR-mutant cases showed evidence suggestive of biallelism"
    explanation: Recurrent hotspot mutations and evidence of biallelic involvement support KDR as a somatic driver in this primary mammary cohort.
- name: PIK3CA
  association: Recurrent activating somatic mutation enriched in primary breast angiosarcoma
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  subtype: Primary Breast Angiosarcoma
  gene_term:
    preferred_term: PIK3CA
    term:
      id: hgnc:8975
      label: PIK3CA
  notes: >-
    PIK3CA-activating mutations are most strongly associated with primary breast
    angiosarcoma and suggest PI3K-pathway dependence in that subset.
  evidence:
  - reference: PMID:32042194
    reference_title: "The Angiosarcoma Project: enabling genomic and clinical discoveries in a rare cancer through patient-partnered research."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PIK3CA-activating mutations were observed predominantly in primary breast angiosarcoma, which suggested a therapeutic rationale."
    explanation: This directly links activating PIK3CA mutations to primary breast angiosarcoma.
- name: TP53
  association: Recurrent somatic mutation
  relationship_type: UNKNOWN
  variant_origin: SOMATIC
  gene_term:
    preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  notes: >-
    TP53 is recurrently mutated across angiosarcoma cohorts, but the cited
    recurrence data alone do not establish a uniform driver role across this
    heterogeneous disease.
  evidence:
  - reference: PMID:32042194
    reference_title: "The Angiosarcoma Project: enabling genomic and clinical discoveries in a rare cancer through patient-partnered research."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing (WES) of 47 tumors revealed recurrently mutated genes that included KDR, TP53, and PIK3CA."
    explanation: This supports TP53 as a recurrently altered gene in angiosarcoma.
- name: FLT4
  association: Somatic coamplification in a subset of secondary angiosarcoma
  relationship_type: COOPERATING
  variant_origin: SOMATIC
  subtype: Radiation-Associated Angiosarcoma
  gene_term:
    preferred_term: FLT4
    term:
      id: hgnc:3767
      label: FLT4
  notes: >-
    FLT4 amplification is enriched in radiation-associated angiosarcoma and
    reflects altered VEGFR3-associated angiogenic signaling.
  evidence:
  - reference: PMID:20949568
    reference_title: Consistent MYC and FLT4 gene amplification in radiation-induced angiosarcoma but not in other radiation-associated atypical vascular lesions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Secondary genetic hits, such as FLT4 gene coamplification or KDR mutations, may play a role in tumor progression as well as potential therapeutic targeting."
    explanation: This study explicitly frames FLT4 coamplification as a secondary genetic hit that may cooperate in progression.
- name: ATM
  association: Subtype-enriched somatic alteration
  relationship_type: UNKNOWN
  variant_origin: SOMATIC
  gene_term:
    preferred_term: ATM
    term:
      id: hgnc:795
      label: ATM
  notes: >-
    ATM alterations are enriched in sporadic (non-radiation-associated)
    angiosarcoma compared with radiation-associated disease in the cited
    genomic comparison. The alteration type and causal role remain unclassified
    here.
  evidence:
  - reference: PMID:37350195
    reference_title: Distinct genomic landscapes in radiation-associated angiosarcoma compared with other radiation-associated sarcoma histologies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RT-associated AS had more frequent MYC, FLT4, CRKL, HRAS, and KMT2D alterations than sporadic AS (enriched in TP53, KDR, ATM, ATRX)"
    explanation: This comparative NGS study reports ATM alterations as enriched in sporadic angiosarcoma relative to radiation-associated AS.
- name: ATRX
  association: Subtype-enriched somatic alteration
  relationship_type: UNKNOWN
  variant_origin: SOMATIC
  gene_term:
    preferred_term: ATRX
    term:
      id: hgnc:886
      label: ATRX
  notes: >-
    ATRX alterations were enriched in sporadic (non-radiation-associated)
    angiosarcoma in the cited comparison. That source does not establish the
    alteration type, a disease-wide frequency, or a specific causal role.
  evidence:
  - reference: PMID:37350195
    reference_title: Distinct genomic landscapes in radiation-associated angiosarcoma compared with other radiation-associated sarcoma histologies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RT-associated AS had more frequent MYC, FLT4, CRKL, HRAS, and KMT2D alterations than sporadic AS (enriched in TP53, KDR, ATM, ATRX)"
    explanation: This comparative NGS study reports ATRX alterations as enriched in sporadic angiosarcoma relative to radiation-associated AS.
environmental:
- name: Prior radiotherapy
  influences_mechanisms:
  - target: Radiation-Associated DNA Damage and Replication Stress
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Therapeutic irradiation supplies the DNA damage this node names,
      producing secondary angiosarcoma within the treated field, classically
      the breast after adjuvant radiotherapy.
    evidence:
    - reference: PMID:38607625
      reference_title: "Incidence and Presenting Characteristics of Angiosarcoma in the US, 2001-2020."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Angiosarcoma is an aggressive vascular malignant neoplasm presenting either as a primary or secondary cancer, often arising after radiotherapy or in the context of preexisting lymphedema."
      explanation: >-
        States that angiosarcoma often arises after radiotherapy, the
        secondary presentation this node models.
  effect: HARMFUL
  exposure_term:
    preferred_term: exposure to ionizing radiation
    term:
      id: ECTO:7000047
      label: exposure to ionizing radiation
  description: >-
    Prior radiotherapy is a major risk context for secondary angiosarcoma,
    especially in the breast and chest wall.
  evidence:
  - reference: PMID:38607625
    reference_title: "Incidence and Presenting Characteristics of Angiosarcoma in the US, 2001-2020."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Angiosarcoma is an aggressive vascular malignant neoplasm presenting either as a primary or secondary cancer, often arising after radiotherapy or in the context of preexisting lymphedema."
    explanation: This study supports prior radiotherapy as a common context for secondary angiosarcoma.
- name: Chronic lymphedema
  influences_mechanisms:
  - target: Malignant Endothelial Proliferation and Vascular Tumor Growth
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Long-standing lymphoedema is the classical Stewart-Treves setting.
      Unlike radiation and ultraviolet exposure it supplies no identified
      genotoxic insult, so it is recorded as a predisposing context rather
      than a source of damage.
    evidence:
    - reference: PMID:38607625
      reference_title: "Incidence and Presenting Characteristics of Angiosarcoma in the US, 2001-2020."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Angiosarcoma is an aggressive vascular malignant neoplasm presenting either as a primary or secondary cancer, often arising after radiotherapy or in the context of preexisting lymphedema."
      explanation: >-
        States that angiosarcoma often arises in the context of preexisting
        lymphedema, a predisposing context without an identified mutational
        mechanism.
  effect: HARMFUL
  description: >-
    Chronic lymphedema is a recognized predisposing context for secondary
    angiosarcoma, including Stewart-Treves syndrome.
  evidence:
  - reference: PMID:38607625
    reference_title: "Incidence and Presenting Characteristics of Angiosarcoma in the US, 2001-2020."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Angiosarcoma is an aggressive vascular malignant neoplasm presenting either as a primary or secondary cancer, often arising after radiotherapy or in the context of preexisting lymphedema."
    explanation: This population study explicitly identifies preexisting lymphedema as a risk context for angiosarcoma.
- name: Ultraviolet exposure
  influences_mechanisms:
  - target: UV-Associated Hypermutation
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      The entry models a separate ultraviolet arm because the mutational
      evidence is direct: head and neck tumours in sun-exposed skin carry a
      dominant ultraviolet damage signature rather than a radiation one.
    evidence:
    - reference: PMID:32042194
      reference_title: "The Angiosarcoma Project: enabling genomic and clinical discoveries in a rare cancer through patient-partnered research."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Angiosarcoma of the head, neck, face and scalp (HNFS) was associated with a high tumor mutation burden (TMB) and a dominant ultraviolet damage mutational signature"
      explanation: >-
        Reports high tumour mutation burden with a dominant ultraviolet damage
        mutational signature in angiosarcoma of the head, neck, face and
        scalp.
  effect: HARMFUL
  exposure_term:
    preferred_term: exposure to ultraviolet radiation
    term:
      id: ECTO:0000006
      label: exposure to ultraviolet radiation
  description: >-
    Ultraviolet exposure is implicated in a molecularly defined subset of head
    and neck angiosarcoma. UV-positive tumors carry a UV-associated mutational
    signature and elevated tumor mutation burden, but this pattern is not
    universal across the anatomic subtype.
  evidence:
  - reference: PMID:32042194
    reference_title: "The Angiosarcoma Project: enabling genomic and clinical discoveries in a rare cancer through patient-partnered research."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Angiosarcoma of the head, neck, face and scalp (HNFS) was associated with a high tumor mutation burden (TMB) and a dominant ultraviolet damage mutational signature"
    explanation: This directly supports ultraviolet-associated mutagenesis in cutaneous head and neck angiosarcoma.
- name: Chemical carcinogen exposure (vinyl chloride, thorium dioxide)
  influences_mechanisms:
  - target: Malignant Endothelial Proliferation and Vascular Tumor Growth
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Vinyl chloride and thorium dioxide are established causes of hepatic
      angiosarcoma specifically, a site-restricted association that
      distinguishes this exposure from the cutaneous and post-irradiation
      forms.
    evidence:
    - reference: PMID:33182685
      reference_title: "Optimal Clinical Management and the Molecular Biology of Angiosarcomas."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Chemical exposure to vinyl chloride and thorium dioxide have been well-documented to be associated with increased risk of liver AS"
      explanation: >-
        States that vinyl chloride and thorium dioxide exposure are well
        documented as increasing the risk of liver angiosarcoma.
  effect: HARMFUL
  chemicals:
  - vinyl chloride
  - thorium dioxide
  description: >-
    Occupational and iatrogenic chemical carcinogen exposure, classically vinyl
    chloride monomer and thorium dioxide (Thorotrast), is a well-documented risk
    context for hepatic angiosarcoma.
  evidence:
  - reference: PMID:33182685
    reference_title: Optimal Clinical Management and the Molecular Biology of Angiosarcomas.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Chemical exposure to vinyl chloride and thorium dioxide have been well-documented to be associated with increased risk of liver AS"
    explanation: This review explicitly identifies vinyl chloride and thorium dioxide exposure as well-documented risk factors for hepatic angiosarcoma.
diagnosis:
- name: Biopsy with histopathology and endothelial immunohistochemistry
  diagnosis_term:
    preferred_term: Biopsy Procedure
    term:
      id: NCIT:C15189
      label: Biopsy Procedure
  markers: CD31 and ERG positive; CD34 variably positive
  results: Vasoformative or solid malignant morphology with endothelial-lineage immunophenotype supports angiosarcoma.
  description: >-
    Diagnosis requires clinicopathologic integration of biopsy morphology with
    endothelial immunohistochemistry. Tumors may be vasoformative, mixed, or
    rarely purely solid; CD31 and ERG are sensitive endothelial markers, whereas
    CD34 is variably retained. These findings support lineage and must be
    interpreted in context rather than treated as a single pathognomonic test.
  evidence:
  - reference: PMID:38391320
    reference_title: "Angiosarcoma of the head and neck: A clinicopathologic study with special emphasis on diagnostic pitfalls."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histomorphological patterns observed were mixed vasoformative and solid ( n = 22), pure vasoformative ( n = 13), and pure solid ( n = 1)."
    explanation: The head and neck series documents the range of diagnostic architectural patterns.
  - reference: PMID:38391320
    reference_title: "Angiosarcoma of the head and neck: A clinicopathologic study with special emphasis on diagnostic pitfalls."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CD31 was positive in 100% of cases, and CD34 was positive in 40% of cases."
    explanation: The series supports CD31 as a sensitive endothelial marker and CD34 as variable.
  - reference: PMID:34392127
    reference_title: "Clinicopathologic and immunohistochemical study of breast angiosarcoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CD31 and ERG immunostains showed positivity in all cases, while CD34 were negative in some cases with lymphatic differentiation."
    explanation: The breast series independently supports CD31 and ERG positivity with variable CD34.
  - reference: PMID:38391320
    reference_title: "Angiosarcoma of the head and neck: A clinicopathologic study with special emphasis on diagnostic pitfalls."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Proper clinicopathologic correlation is necessary to avoid misdiagnosis."
    explanation: This explicitly supports integrated clinicopathologic interpretation.
treatments:
- name: Surgical Excision
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  description: >-
    Primary surgery is the principal local treatment for resectable localized
    angiosarcoma. A retrospective cohort associated surgery with improved
    survival in localized disease; the evidence is observational and does not
    establish benefit in unresectable or metastatic settings.
  treatment_term:
    preferred_term: Excision
    term:
      id: NCIT:C15232
      label: Excision
  evidence:
  - reference: PMID:40500777
    reference_title: "Clinicopathological features, treatment outcomes, and prognostic factors of angiosarcoma: a 21-year experience at one center."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Primary surgery improved survival in localized disease, with adjuvant radiotherapy enhancing local control but not OS."
    explanation: This retrospective cohort supports primary surgery for localized disease while preserving the observational context.
  - reference: PMID:36993810
    reference_title: "Cutaneous angiosarcoma: A review of current evidence for treatment with checkpoint inhibitors."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The most widely accepted current approach, surgical excision with adjuvant radiotherapy, is associated with high recurrence rates"
    explanation: This review supports surgical excision as the current standard approach for cutaneous angiosarcoma.
- name: Adjuvant Radiation Therapy
  action_category: THERAPEUTIC
  therapeutic_modality: RADIOTHERAPY
  description: >-
    Adjuvant radiotherapy can be used with surgery for localized angiosarcoma.
    In a retrospective cohort it improved local control without improving
    overall survival, so that distinction is retained.
  treatment_term:
    preferred_term: radiation therapy
    term:
      id: NCIT:C15313
      label: Radiation Therapy
  evidence:
  - reference: PMID:40500777
    reference_title: "Clinicopathological features, treatment outcomes, and prognostic factors of angiosarcoma: a 21-year experience at one center."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Primary surgery improved survival in localized disease, with adjuvant radiotherapy enhancing local control but not OS."
    explanation: This cohort supports enhanced local control but not overall survival from adjuvant radiotherapy.
  - reference: PMID:36993810
    reference_title: "Cutaneous angiosarcoma: A review of current evidence for treatment with checkpoint inhibitors."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The most widely accepted current approach, surgical excision with adjuvant radiotherapy, is associated with high recurrence rates"
    explanation: This review supports adjuvant radiation therapy as part of standard local management.
- name: Paclitaxel-Based Chemotherapy
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Paclitaxel-based chemotherapy is a systemic option for advanced
    angiosarcoma. In one retrospective metastatic cohort, paclitaxel-based
    first-line regimens were less effective than doxorubicin-based regimens;
    this comparison should not be generalized beyond that cohort.
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
    therapeutic_agent:
    - preferred_term: paclitaxel
      term:
        id: CHEBI:45863
        label: paclitaxel
  evidence:
  - reference: PMID:33182685
    reference_title: Optimal Clinical Management and the Molecular Biology of Angiosarcomas.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "For advanced angiosarcoma, anthracyclines and taxanes are the main chemotherapy options."
    explanation: This review supports taxane-based regimens such as paclitaxel as standard systemic therapy for advanced angiosarcoma.
  - reference: PMID:40500777
    reference_title: "Clinicopathological features, treatment outcomes, and prognostic factors of angiosarcoma: a 21-year experience at one center."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In metastatic cases, first-line systemic therapies showed that paclitaxel-based regimens were less effective than doxorubicin-based chemotherapy, and the addition of anti-angiogenic therapy did not improve outcomes."
    explanation: This single-center cohort provides the context-specific first-line comparison.
- name: Anthracycline-Based Chemotherapy
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Anthracycline-based chemotherapy is another main systemic treatment option
    for advanced angiosarcoma.
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
    therapeutic_agent:
    - preferred_term: doxorubicin
      term:
        id: CHEBI:28748
        label: doxorubicin
  evidence:
  - reference: PMID:33182685
    reference_title: Optimal Clinical Management and the Molecular Biology of Angiosarcomas.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "For advanced angiosarcoma, anthracyclines and taxanes are the main chemotherapy options."
    explanation: This review supports anthracyclines such as doxorubicin as major chemotherapy options in advanced angiosarcoma.
  - reference: PMID:40500777
    reference_title: "Clinicopathological features, treatment outcomes, and prognostic factors of angiosarcoma: a 21-year experience at one center."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "chemotherapy remains the mainstay for advanced cases."
    explanation: This retrospective cohort supports chemotherapy as the main systemic approach for advanced disease.
- name: Pazopanib
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Pazopanib is a multikinase VEGFR inhibitor used as a later-line option in
    advanced soft-tissue sarcoma and studied in angiosarcoma. Retrospective
    angiosarcoma activity has been reported, but disease control is often
    transient and adding anti-angiogenic therapy did not improve outcomes in one
    metastatic cohort.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: pazopanib
      term:
        id: CHEBI:71219
        label: pazopanib
  target_mechanisms:
  - target: Angiogenic Signaling Activation
    treatment_effect: INHIBITS
    description: Pazopanib inhibits VEGFR1, VEGFR2, and VEGFR3 signaling within the angiogenic pathway.
    evidence:
    - reference: PMID:33182685
      reference_title: Optimal Clinical Management and the Molecular Biology of Angiosarcomas.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Pazopanib, a TKI that targets VEGFR 1, 2, and 3 as well as platelet-derived growth factor receptor (PDGFR)-alpha and beta"
      explanation: This review directly supports the VEGFR target link.
  evidence:
  - reference: PMID:33182685
    reference_title: Optimal Clinical Management and the Molecular Biology of Angiosarcomas.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "was shown to have an ORR of 20% in AS in a retrospective analysis of patients treated at EORTC centers"
    explanation: This review supports the VEGFR target link and reports limited retrospective activity in angiosarcoma.
  - reference: PMID:33182685
    reference_title: Optimal Clinical Management and the Molecular Biology of Angiosarcomas.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Anti-angiogenic agents have a substantial role but the failure of a randomized phase 3 trial of pazopanib with or without an anti-endoglin antibody brings a challenge to future trials in angiosarcomas."
    explanation: This review supports anti-angiogenic therapy as a biologically rational but clinically imperfect treatment approach.
  - reference: PMID:40500777
    reference_title: "Clinicopathological features, treatment outcomes, and prognostic factors of angiosarcoma: a 21-year experience at one center."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In metastatic cases, first-line systemic therapies showed that paclitaxel-based regimens were less effective than doxorubicin-based chemotherapy, and the addition of anti-angiogenic therapy did not improve outcomes."
    explanation: This cohort cautions that adding anti-angiogenic therapy did not improve outcomes in its metastatic cases.
- name: Off-Label Pembrolizumab
  action_category: THERAPEUTIC
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    Pembrolizumab is not approved specifically for angiosarcoma. Exceptional
    responses to off-label anti-PD-1 therapy were reported in two patients with
    head, neck, face, and scalp angiosarcoma, providing a clinical signal rather
    than an established standard of care.
  treatment_term:
    preferred_term: immunotherapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
    therapeutic_agent:
    - preferred_term: pembrolizumab
      term:
        id: NCIT:C106432
        label: Pembrolizumab
  evidence:
  - reference: PMID:32042194
    reference_title: "The Angiosarcoma Project: enabling genomic and clinical discoveries in a rare cancer through patient-partnered research."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two patients with HNFS angiosarcoma had received off-label therapeutic use of antibody to the programmed death-1 protein (anti-PD-1) and had experienced exceptional responses"
    explanation: This directly supports checkpoint inhibition as a promising therapy in UV-associated head and neck angiosarcoma.
- name: Investigational Cemiplimab
  action_category: THERAPEUTIC
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    Cemiplimab remains investigational for angiosarcoma. A prospective phase II
    trial in locally advanced or metastatic secondary angiosarcoma reported a
    27.8% best overall response rate; the selected secondary-disease population
    and single-arm design limit generalization.
  treatment_term:
    preferred_term: immunotherapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
    therapeutic_agent:
    - preferred_term: cemiplimab
      term:
        id: NCIT:C121540
        label: Cemiplimab
  evidence:
  - reference: PMID:40632032
    reference_title: "Cemiplimab in Locally Advanced or Metastatic Secondary Angiosarcomas (CEMangio): A Phase II Clinical Trial and Biomarker Analyses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immune checkpoint inhibition is not approved for AS, but high intratumoral T-cell density and frequent mutations in sAS may support efficacy."
    explanation: The trial abstract explicitly states that checkpoint inhibition is not approved for angiosarcoma.
  - reference: PMID:40632032
    reference_title: "Cemiplimab in Locally Advanced or Metastatic Secondary Angiosarcomas (CEMangio): A Phase II Clinical Trial and Biomarker Analyses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The best overall response rate was 27.8% (4 partial responses, 1 complete response)"
    explanation: The phase II study provides the response estimate in its selected secondary-angiosarcoma population.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0016982
      label: angiosarcoma
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: MONDO provides an exact disease term for angiosarcoma.
  ncit_mappings:
  - term:
      id: NCIT:C3088
      label: Angiosarcoma
    mapping_predicate: skos:exactMatch
    mapping_source: NCIT
    mapping_justification: NCIT provides an exact neoplasm term for angiosarcoma; cross-referenced from MONDO:0016982.
references:
- reference: DOI:10.1001/jamanetworkopen.2024.6235
  title: Incidence and Presenting Characteristics of Angiosarcoma in the US, 2001-2020
  found_in:
  - Angiosarcoma-deep-research-falcon.md
  findings:
  - statement: ImportanceAngiosarcoma is an aggressive vascular malignant neoplasm presenting either as a primary or secondary cancer, often arising after radiotherapy or in the context of preexisting lymphedema.
    supporting_text: ImportanceAngiosarcoma is an aggressive vascular malignant neoplasm presenting either as a primary or secondary cancer, often arising after radiotherapy or in the context of preexisting lymphedema.
- reference: DOI:10.1002/gcc.23240
  title: Clinicopathologic and molecular correlates to neoadjuvant chemotherapy‐induced pathologic response in breast angiosarcoma
  found_in:
  - Angiosarcoma-deep-research-falcon.md
  findings:
  - statement: Both primary and secondary breast angiosarcoma (AS) are characterized by multifocal presentation and aggressive behavior.
    supporting_text: Both primary and secondary breast angiosarcoma (AS) are characterized by multifocal presentation and aggressive behavior.
- reference: DOI:10.1002/path.6137
  title: Distinct genomic landscapes in radiation‐associated angiosarcoma compared with other radiation‐associated sarcoma histologies
  found_in:
  - Angiosarcoma-deep-research-falcon.md
  findings:
  - statement: MYC amplifications have been frequently detected in radiation (RT)‐associated angiosarcomas (ASs) by low‐resolution molecular methods.
    supporting_text: MYC amplifications have been frequently detected in radiation (RT)‐associated angiosarcomas (ASs) by low‐resolution molecular methods.
- reference: DOI:10.1038/s41591-019-0749-z
  title: 'The Angiosarcoma Project: enabling genomic and clinical discoveries in a rare cancer through patient-partnered research'
  found_in:
  - Angiosarcoma-deep-research-falcon.md
  findings:
  - statement: 'The Angiosarcoma Project: enabling genomic and clinical discoveries in a rare cancer through patient-partnered research'
    supporting_text: 'The Angiosarcoma Project: enabling genomic and clinical discoveries in a rare cancer through patient-partnered research'
- reference: DOI:10.1038/s42003-023-04856-5
  title: Spatial transcriptomics reveal topological immune landscapes of Asian head and neck angiosarcoma
  found_in:
  - Angiosarcoma-deep-research-falcon.md
  findings:
  - statement: Angiosarcomas are rare malignant tumors of the endothelium, arising commonly from the head and neck region (AS-HN) and recently associated with ultraviolet (UV) exposure and human herpesvirus-7 infection.
    supporting_text: Angiosarcomas are rare malignant tumors of the endothelium, arising commonly from the head and neck region (AS-HN) and recently associated with ultraviolet (UV) exposure and human herpesvirus-7 infection.
- reference: DOI:10.3389/fmed.2023.1090168
  title: 'Cutaneous angiosarcoma: A review of current evidence for treatment with checkpoint inhibitors'
  found_in:
  - Angiosarcoma-deep-research-falcon.md
  findings:
  - statement: Cutaneous angiosarcoma (cAS) is a rare and aggressive subtype of soft tissue sarcoma with poor prognosis and suboptimal treatment options.
    supporting_text: Cutaneous angiosarcoma (cAS) is a rare and aggressive subtype of soft tissue sarcoma with poor prognosis and suboptimal treatment options.
- reference: DOI:10.3389/fonc.2024.1385632
  title: 'MicroRNAs and angiosarcoma: are there promising reports?'
  found_in:
  - Angiosarcoma-deep-research-falcon.md
  findings:
  - statement: In recent years, microRNAs (miRNAs) have garnered increasing attention for their potential implications in cancer pathogenesis, functioning either as oncogenes or tumor suppressors.
    supporting_text: In recent years, microRNAs (miRNAs) have garnered increasing attention for their potential implications in cancer pathogenesis, functioning either as oncogenes or tumor suppressors.
- reference: DOI:10.3390/cancers12113321
  title: Optimal Clinical Management and the Molecular Biology of Angiosarcomas
  found_in:
  - Angiosarcoma-deep-research-falcon.md
  findings:
  - statement: Angiosarcomas comprise less than 3% of all soft tissue sarcomas but have a poor prognosis.
    supporting_text: Angiosarcomas comprise less than 3% of all soft tissue sarcomas but have a poor prognosis.
- reference: DOI:10.7759/cureus.41947
  title: 'Primary Cardiac Angiosarcoma: A Review'
  found_in:
  - Angiosarcoma-deep-research-falcon.md
  findings:
  - statement: 'Primary Cardiac Angiosarcoma: A Review'
    supporting_text: 'Primary Cardiac Angiosarcoma: A Review'
- reference: PMID:10074736
  title: 'Primary hepatic angiosarcoma: report of a case involving environmental arsenic exposure.'
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:16689662
  title: IFN-alpha1,8 inhibits tumor-induced angiogenesis in murine angiosarcomas.
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:19433291
  title: 'Angiosarcoma of the breast: a clinicopathologic analysis of cases from the last 10 years.'
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:20949568
  title: Consistent MYC and FLT4 gene amplification in radiation-induced angiosarcoma but not in other radiation-associated atypical vascular lesions.
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:22200164
  title: 'Arsenic, vinyl chloride, viral hepatitis, and hepatic angiosarcoma: a hospital-based study and review of literature in Taiwan.'
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings:
  - statement: Hepatic angiosarcoma (HAS) is a rare type of liver cancer that is often fatal, and arsenic and vinyl chloride monomer (VCM) are two major causal agents.
    supporting_text: Hepatic angiosarcoma (HAS) is a rare type of liver cancer that is often fatal, and arsenic and vinyl chloride monomer (VCM) are two major causal agents.
- reference: PMID:22383169
  title: The miR-17-92 cluster and its target THBS1 are differentially expressed in angiosarcomas dependent on MYC amplification.
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:22431921
  title: Efficacy of Tie2 receptor antagonism in angiosarcoma.
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:22532251
  title: A transcriptome signature of endothelial lymphatic cells coexists with the chronic oxidative stress signature in radiation-induced post-radiotherapy breast angiosarcomas.
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:22934846
  title: ROCK1 & 2 perform overlapping and unique roles in angiogenesis and angiosarcoma tumor progression.
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:23522954
  title: Establishment of a novel experimental model of human angiosarcoma and a VEGF-targeting therapeutic experiment.
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings:
  - statement: Angiosarcoma is one of the most life-threatening neoplasms with strong resistance to conventional chemotherapy/radiotherapy; consequently, alternative therapeutic agents are urgently required.
    supporting_text: Angiosarcoma is one of the most life-threatening neoplasms with strong resistance to conventional chemotherapy/radiotherapy; consequently, alternative therapeutic agents are urgently required.
- reference: PMID:23604067
  title: A novel monoclonal antibody to secreted frizzled-related protein 2 inhibits tumor growth.
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:23938603
  title: Vascular tumors have increased p70 S6-kinase activation and are inhibited by topical rapamycin.
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:24457083
  title: Diagnostic utility of MYC amplification and anti-MYC immunohistochemistry in atypical vascular lesions, primary or radiation-induced mammary angiosarcomas, and primary angiosarcomas of other sites.
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:25863565
  title: Can c-myc amplification reliably discriminate postradiation from primary angiosarcoma of the breast?
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:25955301
  title: Combined inhibition of MEK and mTOR has a synergic effect on angiosarcoma tumorgrafts.
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:26617830
  title: 'Angiosarcoma (Stewart-Treves syndrome) in postmastectomy patients: report of 10 cases and review of literature.'
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:28716069
  title: Angiosarcoma treated successfully with anti-PD-1 therapy - a case report.
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings:
  - statement: Angiosarcomas are tumors of malignant endothelial origin that have a poor prognosis with a five-year survival of less than 40%.
    supporting_text: Angiosarcomas are tumors of malignant endothelial origin that have a poor prognosis with a five-year survival of less than 40%.
- reference: PMID:28885371
  title: 'Clinical and diagnostic features of angiosarcoma with pulmonary metastases: A retrospective observational study.'
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:31243333
  title: Genomic and transcriptomic comparison of post-radiation versus sporadic sarcomas.
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:32123305
  title: Primary mammary angiosarcomas harbor frequent mutations in KDR and PIK3CA and show evidence of distinct pathogenesis.
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:32777673
  title: 'Frequent expression of conventional endothelial markers in pleural mesothelioma: usefulness of claudin-5 as well as combined traditional markers to distinguish mesothelioma from angiosarcoma.'
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:34392127
  title: Clinicopathologic and immunohistochemical study of breast angiosarcoma.
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:35478727
  title: Outcomes of Interventions for Angiosarcoma.
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:36387164
  title: Whole exome sequencing identified a novel POT1 variant as a candidate pathogenic allele underlying a Li-Fraumeni-like family.
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings:
  - statement: Li-Fraumeni syndrome (LFS) and Li-Fraumeni-like (LFL) syndrome are rare hereditary diseases characterized by predisposition to a diverse spectrum of cancer types, primarily sarcoma.
    supporting_text: Li-Fraumeni syndrome (LFS) and Li-Fraumeni-like (LFL) syndrome are rare hereditary diseases characterized by predisposition to a diverse spectrum of cancer types, primarily sarcoma.
- reference: PMID:37725702
  title: 'Secondary Breast Angiosarcoma After a Primary Diagnosis of Breast Cancer: A Retrospective Analysis of the Surveillance, Epidemiology, and End Results (SEER) Database.'
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:38391320
  title: 'Angiosarcoma of the head and neck: A clinicopathologic study with special emphasis on diagnostic pitfalls.'
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:38457179
  title: Incidence of Nonkeratinocyte Skin Cancer After Breast Cancer Radiation Therapy.
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:38791996
  title: Clinical Characteristics, Patterns of Care, and Treatment Outcomes of Radiation-Associated Sarcomas.
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:39221877
  title: Synchronous multiple primary malignancies or transdifferentiation?-A diagnostic challenge in a case of Xeroderma pigmentosum.
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:39676119
  title: 'Demographics, Prognostic Factors, and Survival Outcomes in Hepatic Angiosarcoma: A Retrospective Analysis.'
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings:
  - statement: Hepatic angiosarcoma (HA) is a rare malignant vascular neoplasm.
    supporting_text: Hepatic angiosarcoma (HA) is a rare malignant vascular neoplasm.
- reference: PMID:39734593
  title: 'New Germline TP53 Variant Detected After Radiotherapy-Induced Angiosarcoma of the Chest Wall in a Previously Treated Breast Cancer Patient: A Case Report and Review of Li-Fraumeni Syndrome and Radiotherapy-Induced Sarcoma.'
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:40056281
  title: 'Angiosarcoma: Role of Immunotherapy.'
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:40364848
  title: 'Case Report: A novel chemotherapy-free regimen combined with photodynamic therapy, target therapy, and immunotherapy in a geriatric male with huge recurrent scalp and facial angiosarcoma: a report of an extremely rare case and literature review.'
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:40474296
  title: 'Dissecting the tumor microenvironment in primary breast angiosarcoma: insights from single-cell RNA sequencing.'
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings:
  - statement: Angiosarcoma, a rare and highly aggressive malignancy originating from vascular endothelial cells, is characterized by its rapid progression, high invasiveness, and poor prognosis.
    supporting_text: Angiosarcoma, a rare and highly aggressive malignancy originating from vascular endothelial cells, is characterized by its rapid progression, high invasiveness, and poor prognosis.
- reference: PMID:40500777
  title: 'Clinicopathological features, treatment outcomes, and prognostic factors of angiosarcoma: a 21-year experience at one center.'
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings:
  - statement: Angiosarcoma is a rare, aggressive soft tissue sarcoma characterized by poor prognosis and limited treatment consensus.
    supporting_text: Angiosarcoma is a rare, aggressive soft tissue sarcoma characterized by poor prognosis and limited treatment consensus.
- reference: PMID:40575034
  title: Single-cell transcriptomic landscape indicates the potential role of immunotherapy in metastatic pancreatic angiosarcoma.
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings:
  - statement: Pancreatic angiosarcoma is a rare and highly aggressive tumor originating from lymphatic or vascular endothelial cells, with poor prognosis and few effective treatments.
    supporting_text: Pancreatic angiosarcoma is a rare and highly aggressive tumor originating from lymphatic or vascular endothelial cells, with poor prognosis and few effective treatments.
- reference: PMID:40632032
  title: 'Cemiplimab in Locally Advanced or Metastatic Secondary Angiosarcomas (CEMangio): A Phase II Clinical Trial and Biomarker Analyses.'
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:40712262
  title: 'Clinicopathological features and prognostic insights of cutaneous versus non-cutaneous angiosarcoma: A retrospective single-center cohort study.'
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:40914676
  title: Comparison of clinical features between patients with bone and soft tissue angiosarcomas.
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings:
  - statement: Angiosarcoma is a rare and aggressive malignancy arising from vascular endothelial cells, with distinct subtypes originating in bone (AS-B) and soft tissue (AS-ST).
    supporting_text: Angiosarcoma is a rare and aggressive malignancy arising from vascular endothelial cells, with distinct subtypes originating in bone (AS-B) and soft tissue (AS-ST).
- reference: PMID:40961809
  title: Outcome of 1773 superficial non-dermatofibrosarcoma sarcomas A French Sarcoma Group study (FSG) from the NETSARC database.
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings:
  - statement: Clinical practice guidelines for managing superficial non-dermatofibrosarcoma soft tissue sarcomas (NDSTS) vary depending on surgical margins.
    supporting_text: Clinical practice guidelines for managing superficial non-dermatofibrosarcoma soft tissue sarcomas (NDSTS) vary depending on surgical margins.
- reference: PMID:41320327
  title: Cardiac Angiosarcoma.
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:41394772
  title: Aristolochic Acid and Alternative Lengthening of Telomeres Mechanisms Underlie Liver Angiosarcoma Pathogenesis.
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings:
  - statement: Our previous epidemiological study revealed a significantly higher incidence of liver angiosarcoma in Asian patients than that in their European counterparts.
    supporting_text: Our previous epidemiological study revealed a significantly higher incidence of liver angiosarcoma in Asian patients than that in their European counterparts.
- reference: PMID:41496010
  title: 'Multimodal treatment of radiation-associated laryngeal angiosarcoma: A case report and literature review.'
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:41693531
  title: 'Postradiation angiosarcoma of the breast: a 25-year single-institution analysis of clinicopathological characteristics and immunohistochemical biomarker study.'
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:41836264
  title: 'A rare pulmonary epithelioid angiosarcoma with ALK rearrangement: a case report and literature review.'
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:7199426
  title: 'Epidemiology of hepatic angiosarcoma in the United States: 1964-1974.'
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:9010458
  title: Sporadic and Thorotrast-induced angiosarcomas of the liver manifest frequent and multiple point mutations in K-ras-2.
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:37106027
  title: Spatial transcriptomics reveal topological immune landscapes of Asian head and neck angiosarcoma.
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
- reference: PMID:38722225
  title: Clinicopathologic and molecular correlates to neoadjuvant chemotherapy-induced pathologic response in breast angiosarcoma.
  found_in:
  - Angiosarcoma-deep-research-openscientist.md
  findings: []
datasets:
- accession: geo:GSE226338
  title: Gene expression of human angiosarcoma
  description: Gene expression profiling of human angiosarcoma samples was performed using the NanoString Human nCounter PanCancer IO 360 Panel
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  sample_count: 67
  publication: PMID:37106027
  notes: Identified by GEO DataSets index search for Angiosarcoma (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE245935
  title: Chemo-senolytic therapeutic potential against angiosarcoma
  description: Angiosarcoma is an aggressive soft-tissue sarcoma with a poor prognosis. Chemotherapy for this cancer typically employs paclitaxel, one of the taxanes (genotoxic drugs), although it has a limited effect due to chemoresistance for prolonged treatment. Here we examine a new angiosarcoma treatment approach that combines chemotherapeutic and senolytic agents. We first find that the chemotherapeutic drugs, cisplatin and paclitaxel, efficiently induce cellular senescence of angiosarcoma cells. Subsequent treatment with a senolytic agent, ABT-263, eliminates senescent cells through the activation of the apoptotic pathway.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 13
  publication: PMID:38570028
  notes: Identified by GEO DataSets index search for Angiosarcoma (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE240260
  title: Target gene regulatory network of miR-497 in angiosarcoma
  description: Angiosarcoma (AS) is a vascular sarcoma that is highly aggressive and metastatic. Due to its rarity, treatment options for patients are limited, therefore more research is needed to identify possible therapeutic vulnerabilities. We previously found that endothelial deletion of Dicer1 drives AS development in mice. Given the role of DICER1 in canonical microRNA (miRNA) biogenesis, this suggests that miRNA loss may be important in AS development. After testing miRNAs previously suggested to have a tumor-suppressive role in AS, microRNA-497-5p (miR-497) suppressed cell viability most significantly.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: BULK_RNA_SEQ
  sample_count: 6
  publication: PMID:37808715
  notes: Identified by GEO DataSets index search for Angiosarcoma (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS00001001281
  title: PLCG1 R707Q mutation is counter selected under targeted therapy in a patient with a hepatic angiosarcoma
  description: PLCG1 R707Q mutation is counter selected under targeted therapy in a patient with a hepatic angiosarcoma
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Angiosarcoma"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001003895
  title: Whole genome and whole transcriptome sequencing of patients diagnosed with angiosarcoma.
  description: Angiosarcomas are rare, clinically-aggressive tumors with a predilection for the elderly and immunosuppressed, which has incited suspicion of an oncogenic virus. We studied the metagenomic landscape of angiosarcomas and identified reads mapping to human herpesvirus-7 (HHV-7). Overall, HHV-7 was present in two-thirds of angiosarcomas, particularly in cases with low tumor mutation burden and lacking signatures of ultraviolet-induced DNA damage. Transcriptomic profiling revealed the enrichment of tumor inflammation signatures in HHV7-positive angiosarcomas. In conclusion, we identified a distinct “inflammatory” subtype of angiosarcoma associated with HHV-7.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Angiosarcoma"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001004158
  title: Molecular determinants for sensitivity to pazopanib in leiomyosarcoma, synovial sarcoma, and angiosarcoma.
  description: Pazopanib is a tyrosine kinase inhibitor with highest activity against VEGFR1 (FLT1) and VEGFR2 (KDR) along with other targets including VEGFR3, PDGFRa, PDGFRb, cKIT, FGFR1, FGFR3, FGFR4, FAK, ABL1, JNK1, Tie-2, Met, IGF1R, and EGFR (Lee, Jones, and Huang Signal Transduct Target Ther 2019; 4:16). Its initial activity in soft tissue sarcoma (STS) was described by Sleijfer et al. (2009) where a high proportion of leiomyosarcoma (LMS) (44%) and synovial sarcoma (49%) patients remained without progression at 12 weeks.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Angiosarcoma"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
📚

References & Deep Research

References

58
DOI:10.1001/jamanetworkopen.2024.6235
Incidence and Presenting Characteristics of Angiosarcoma in the US, 2001-2020
1 finding
ImportanceAngiosarcoma is an aggressive vascular malignant neoplasm presenting either as a primary or secondary cancer, often arising after radiotherapy or in the context of preexisting lymphedema.
"ImportanceAngiosarcoma is an aggressive vascular malignant neoplasm presenting either as a primary or secondary cancer, often arising after radiotherapy or in the context of preexisting lymphedema."
DOI:10.1002/gcc.23240
Clinicopathologic and molecular correlates to neoadjuvant chemotherapy‐induced pathologic response in breast angiosarcoma
1 finding
Both primary and secondary breast angiosarcoma (AS) are characterized by multifocal presentation and aggressive behavior.
"Both primary and secondary breast angiosarcoma (AS) are characterized by multifocal presentation and aggressive behavior."
DOI:10.1002/path.6137
Distinct genomic landscapes in radiation‐associated angiosarcoma compared with other radiation‐associated sarcoma histologies
1 finding
MYC amplifications have been frequently detected in radiation (RT)‐associated angiosarcomas (ASs) by low‐resolution molecular methods.
"MYC amplifications have been frequently detected in radiation (RT)‐associated angiosarcomas (ASs) by low‐resolution molecular methods."
DOI:10.1038/s41591-019-0749-z
The Angiosarcoma Project: enabling genomic and clinical discoveries in a rare cancer through patient-partnered research
1 finding
The Angiosarcoma Project: enabling genomic and clinical discoveries in a rare cancer through patient-partnered research
"The Angiosarcoma Project: enabling genomic and clinical discoveries in a rare cancer through patient-partnered research"
DOI:10.1038/s42003-023-04856-5
Spatial transcriptomics reveal topological immune landscapes of Asian head and neck angiosarcoma
1 finding
Angiosarcomas are rare malignant tumors of the endothelium, arising commonly from the head and neck region (AS-HN) and recently associated with ultraviolet (UV) exposure and human herpesvirus-7 infection.
"Angiosarcomas are rare malignant tumors of the endothelium, arising commonly from the head and neck region (AS-HN) and recently associated with ultraviolet (UV) exposure and human herpesvirus-7 infection."
DOI:10.3389/fmed.2023.1090168
Cutaneous angiosarcoma: A review of current evidence for treatment with checkpoint inhibitors
1 finding
Cutaneous angiosarcoma (cAS) is a rare and aggressive subtype of soft tissue sarcoma with poor prognosis and suboptimal treatment options.
"Cutaneous angiosarcoma (cAS) is a rare and aggressive subtype of soft tissue sarcoma with poor prognosis and suboptimal treatment options."
DOI:10.3389/fonc.2024.1385632
MicroRNAs and angiosarcoma: are there promising reports?
1 finding
In recent years, microRNAs (miRNAs) have garnered increasing attention for their potential implications in cancer pathogenesis, functioning either as oncogenes or tumor suppressors.
"In recent years, microRNAs (miRNAs) have garnered increasing attention for their potential implications in cancer pathogenesis, functioning either as oncogenes or tumor suppressors."
DOI:10.3390/cancers12113321
Optimal Clinical Management and the Molecular Biology of Angiosarcomas
1 finding
Angiosarcomas comprise less than 3% of all soft tissue sarcomas but have a poor prognosis.
"Angiosarcomas comprise less than 3% of all soft tissue sarcomas but have a poor prognosis."
DOI:10.7759/cureus.41947
Primary Cardiac Angiosarcoma: A Review
1 finding
Primary Cardiac Angiosarcoma: A Review
"Primary Cardiac Angiosarcoma: A Review"
PMID:10074736
Primary hepatic angiosarcoma: report of a case involving environmental arsenic exposure.
No top-level findings curated for this source.
PMID:16689662
IFN-alpha1,8 inhibits tumor-induced angiogenesis in murine angiosarcomas.
No top-level findings curated for this source.
PMID:19433291
Angiosarcoma of the breast: a clinicopathologic analysis of cases from the last 10 years.
No top-level findings curated for this source.
PMID:20949568
Consistent MYC and FLT4 gene amplification in radiation-induced angiosarcoma but not in other radiation-associated atypical vascular lesions.
No top-level findings curated for this source.
PMID:22200164
Arsenic, vinyl chloride, viral hepatitis, and hepatic angiosarcoma: a hospital-based study and review of literature in Taiwan.
1 finding
Hepatic angiosarcoma (HAS) is a rare type of liver cancer that is often fatal, and arsenic and vinyl chloride monomer (VCM) are two major causal agents.
"Hepatic angiosarcoma (HAS) is a rare type of liver cancer that is often fatal, and arsenic and vinyl chloride monomer (VCM) are two major causal agents."
PMID:22383169
The miR-17-92 cluster and its target THBS1 are differentially expressed in angiosarcomas dependent on MYC amplification.
No top-level findings curated for this source.
PMID:22431921
Efficacy of Tie2 receptor antagonism in angiosarcoma.
No top-level findings curated for this source.
PMID:22532251
A transcriptome signature of endothelial lymphatic cells coexists with the chronic oxidative stress signature in radiation-induced post-radiotherapy breast angiosarcomas.
No top-level findings curated for this source.
PMID:22934846
ROCK1 & 2 perform overlapping and unique roles in angiogenesis and angiosarcoma tumor progression.
No top-level findings curated for this source.
PMID:23522954
Establishment of a novel experimental model of human angiosarcoma and a VEGF-targeting therapeutic experiment.
1 finding
Angiosarcoma is one of the most life-threatening neoplasms with strong resistance to conventional chemotherapy/radiotherapy; consequently, alternative therapeutic agents are urgently required.
"Angiosarcoma is one of the most life-threatening neoplasms with strong resistance to conventional chemotherapy/radiotherapy; consequently, alternative therapeutic agents are urgently required."
PMID:23604067
A novel monoclonal antibody to secreted frizzled-related protein 2 inhibits tumor growth.
No top-level findings curated for this source.
PMID:23938603
Vascular tumors have increased p70 S6-kinase activation and are inhibited by topical rapamycin.
No top-level findings curated for this source.
PMID:24457083
Diagnostic utility of MYC amplification and anti-MYC immunohistochemistry in atypical vascular lesions, primary or radiation-induced mammary angiosarcomas, and primary angiosarcomas of other sites.
No top-level findings curated for this source.
PMID:25863565
Can c-myc amplification reliably discriminate postradiation from primary angiosarcoma of the breast?
No top-level findings curated for this source.
PMID:25955301
Combined inhibition of MEK and mTOR has a synergic effect on angiosarcoma tumorgrafts.
No top-level findings curated for this source.
PMID:26617830
Angiosarcoma (Stewart-Treves syndrome) in postmastectomy patients: report of 10 cases and review of literature.
No top-level findings curated for this source.
PMID:28716069
Angiosarcoma treated successfully with anti-PD-1 therapy - a case report.
1 finding
Angiosarcomas are tumors of malignant endothelial origin that have a poor prognosis with a five-year survival of less than 40%.
"Angiosarcomas are tumors of malignant endothelial origin that have a poor prognosis with a five-year survival of less than 40%."
PMID:28885371
Clinical and diagnostic features of angiosarcoma with pulmonary metastases: A retrospective observational study.
No top-level findings curated for this source.
PMID:31243333
Genomic and transcriptomic comparison of post-radiation versus sporadic sarcomas.
No top-level findings curated for this source.
PMID:32123305
Primary mammary angiosarcomas harbor frequent mutations in KDR and PIK3CA and show evidence of distinct pathogenesis.
No top-level findings curated for this source.
PMID:32777673
Frequent expression of conventional endothelial markers in pleural mesothelioma: usefulness of claudin-5 as well as combined traditional markers to distinguish mesothelioma from angiosarcoma.
No top-level findings curated for this source.
PMID:34392127
Clinicopathologic and immunohistochemical study of breast angiosarcoma.
No top-level findings curated for this source.
PMID:35478727
Outcomes of Interventions for Angiosarcoma.
No top-level findings curated for this source.
PMID:36387164
Whole exome sequencing identified a novel POT1 variant as a candidate pathogenic allele underlying a Li-Fraumeni-like family.
1 finding
Li-Fraumeni syndrome (LFS) and Li-Fraumeni-like (LFL) syndrome are rare hereditary diseases characterized by predisposition to a diverse spectrum of cancer types, primarily sarcoma.
"Li-Fraumeni syndrome (LFS) and Li-Fraumeni-like (LFL) syndrome are rare hereditary diseases characterized by predisposition to a diverse spectrum of cancer types, primarily sarcoma."
PMID:37725702
Secondary Breast Angiosarcoma After a Primary Diagnosis of Breast Cancer: A Retrospective Analysis of the Surveillance, Epidemiology, and End Results (SEER) Database.
No top-level findings curated for this source.
PMID:38391320
Angiosarcoma of the head and neck: A clinicopathologic study with special emphasis on diagnostic pitfalls.
No top-level findings curated for this source.
PMID:38457179
Incidence of Nonkeratinocyte Skin Cancer After Breast Cancer Radiation Therapy.
No top-level findings curated for this source.
PMID:38791996
Clinical Characteristics, Patterns of Care, and Treatment Outcomes of Radiation-Associated Sarcomas.
No top-level findings curated for this source.
PMID:39221877
Synchronous multiple primary malignancies or transdifferentiation?-A diagnostic challenge in a case of Xeroderma pigmentosum.
No top-level findings curated for this source.
PMID:39676119
Demographics, Prognostic Factors, and Survival Outcomes in Hepatic Angiosarcoma: A Retrospective Analysis.
1 finding
Hepatic angiosarcoma (HA) is a rare malignant vascular neoplasm.
"Hepatic angiosarcoma (HA) is a rare malignant vascular neoplasm."
PMID:39734593
New Germline TP53 Variant Detected After Radiotherapy-Induced Angiosarcoma of the Chest Wall in a Previously Treated Breast Cancer Patient: A Case Report and Review of Li-Fraumeni Syndrome and Radiotherapy-Induced Sarcoma.
No top-level findings curated for this source.
PMID:40056281
Angiosarcoma: Role of Immunotherapy.
No top-level findings curated for this source.
PMID:40364848
Case Report: A novel chemotherapy-free regimen combined with photodynamic therapy, target therapy, and immunotherapy in a geriatric male with huge recurrent scalp and facial angiosarcoma: a report of an extremely rare case and literature review.
No top-level findings curated for this source.
PMID:40474296
Dissecting the tumor microenvironment in primary breast angiosarcoma: insights from single-cell RNA sequencing.
1 finding
Angiosarcoma, a rare and highly aggressive malignancy originating from vascular endothelial cells, is characterized by its rapid progression, high invasiveness, and poor prognosis.
"Angiosarcoma, a rare and highly aggressive malignancy originating from vascular endothelial cells, is characterized by its rapid progression, high invasiveness, and poor prognosis."
PMID:40500777
Clinicopathological features, treatment outcomes, and prognostic factors of angiosarcoma: a 21-year experience at one center.
1 finding
Angiosarcoma is a rare, aggressive soft tissue sarcoma characterized by poor prognosis and limited treatment consensus.
"Angiosarcoma is a rare, aggressive soft tissue sarcoma characterized by poor prognosis and limited treatment consensus."
PMID:40575034
Single-cell transcriptomic landscape indicates the potential role of immunotherapy in metastatic pancreatic angiosarcoma.
1 finding
Pancreatic angiosarcoma is a rare and highly aggressive tumor originating from lymphatic or vascular endothelial cells, with poor prognosis and few effective treatments.
"Pancreatic angiosarcoma is a rare and highly aggressive tumor originating from lymphatic or vascular endothelial cells, with poor prognosis and few effective treatments."
PMID:40632032
Cemiplimab in Locally Advanced or Metastatic Secondary Angiosarcomas (CEMangio): A Phase II Clinical Trial and Biomarker Analyses.
No top-level findings curated for this source.
PMID:40712262
Clinicopathological features and prognostic insights of cutaneous versus non-cutaneous angiosarcoma: A retrospective single-center cohort study.
No top-level findings curated for this source.
PMID:40914676
Comparison of clinical features between patients with bone and soft tissue angiosarcomas.
1 finding
Angiosarcoma is a rare and aggressive malignancy arising from vascular endothelial cells, with distinct subtypes originating in bone (AS-B) and soft tissue (AS-ST).
"Angiosarcoma is a rare and aggressive malignancy arising from vascular endothelial cells, with distinct subtypes originating in bone (AS-B) and soft tissue (AS-ST)."
PMID:40961809
Outcome of 1773 superficial non-dermatofibrosarcoma sarcomas A French Sarcoma Group study (FSG) from the NETSARC database.
1 finding
Clinical practice guidelines for managing superficial non-dermatofibrosarcoma soft tissue sarcomas (NDSTS) vary depending on surgical margins.
"Clinical practice guidelines for managing superficial non-dermatofibrosarcoma soft tissue sarcomas (NDSTS) vary depending on surgical margins."
PMID:41320327
Cardiac Angiosarcoma.
No top-level findings curated for this source.
PMID:41394772
Aristolochic Acid and Alternative Lengthening of Telomeres Mechanisms Underlie Liver Angiosarcoma Pathogenesis.
1 finding
Our previous epidemiological study revealed a significantly higher incidence of liver angiosarcoma in Asian patients than that in their European counterparts.
"Our previous epidemiological study revealed a significantly higher incidence of liver angiosarcoma in Asian patients than that in their European counterparts."
PMID:41496010
Multimodal treatment of radiation-associated laryngeal angiosarcoma: A case report and literature review.
No top-level findings curated for this source.
PMID:41693531
Postradiation angiosarcoma of the breast: a 25-year single-institution analysis of clinicopathological characteristics and immunohistochemical biomarker study.
No top-level findings curated for this source.
PMID:41836264
A rare pulmonary epithelioid angiosarcoma with ALK rearrangement: a case report and literature review.
No top-level findings curated for this source.
PMID:7199426
Epidemiology of hepatic angiosarcoma in the United States: 1964-1974.
No top-level findings curated for this source.
PMID:9010458
Sporadic and Thorotrast-induced angiosarcomas of the liver manifest frequent and multiple point mutations in K-ras-2.
No top-level findings curated for this source.
PMID:37106027
Spatial transcriptomics reveal topological immune landscapes of Asian head and neck angiosarcoma.
No top-level findings curated for this source.
PMID:38722225
Clinicopathologic and molecular correlates to neoadjuvant chemotherapy-induced pathologic response in breast angiosarcoma.
No top-level findings curated for this source.

Deep Research

2
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Disease Pathophysiology Research Template
Edison Scientific Literature 32 citations 2026-04-11T22:13:01.356523

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Pathophysiology Research Template

Target Disease

  • Disease Name: Angiosarcoma
  • MONDO ID: (if available)
  • Category: Cancer

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Angiosarcoma. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

  • What are the primary pathophysiological mechanisms?
  • What molecular pathways are dysregulated?
  • What cellular processes are affected?

2. Key Molecular Players

  • Genes/Proteins: Which genes are causally involved or implicated?
  • Chemical Entities: What metabolites, drugs, or small molecules are relevant?
  • Cell Types: Which cell types are primarily affected?
  • Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

  • What biological processes (GO terms) are disrupted?
  • Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

  • Where in the cell do key processes occur?
  • Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

  • What is the sequence of events from initial trigger to clinical manifestation?
  • Are there distinct stages or phases?

6. Phenotypic Manifestations

  • What are the key clinical phenotypes?
  • How do they relate to the underlying mechanisms?

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Angiosarcoma Pathophysiology Research Report (Cancer)

Disease identifiers

  • Disease name: Angiosarcoma
  • MONDO ID: Not confirmed from the retrieved sources in this run (not reported in the cited texts).

1) Key concepts and definitions (current understanding)

Angiosarcoma is a rare, aggressive malignant neoplasm of endothelial lineage (blood and/or lymphatic endothelium) characterized by highly infiltrative growth, early hematogenous spread, and marked biologic heterogeneity across anatomic sites and etiologies (sporadic/primary vs secondary after radiation or chronic lymphedema). Molecularly, angiosarcoma is best conceptualized as a disease of dysregulated angiogenesis and endothelial signaling, with frequent activation of VEGF/VEGFR, Angiopoietin–Tie, and downstream MAPK and PI3K/AKT/mTOR axes, coupled to subtype-enriched oncogenic drivers (e.g., MYC amplification in secondary radiation/lymphedema-associated tumors; KDR and PIK3CA alterations in primary breast angiosarcoma; and UV-driven hypermutation in scalp/face cutaneous disease). (chen2020optimalclinicalmanagement pages 11-12, chen2020optimalclinicalmanagement pages 9-11, painter2020theangiosarcomaproject pages 4-7)

A concise mechanistic framing from a comprehensive molecular review is that angiosarcomas “often manifest through genetic mutations (KDR(VEGFR-2), PLCG1, PTPRB) … or amplification (FLT4(VEGFR-3))”, highlighting recurrent perturbations of endothelial receptor tyrosine kinase signaling and its proximal effectors. (chen2020optimalclinicalmanagement pages 5-7)

2) Core pathophysiology

2.1 Primary pathophysiological mechanisms

(A) Pathologic angiogenesis/lymphangiogenesis as a central program - VEGF signaling is prominent in angiosarcoma biology. Immunohistochemistry data compiled in the molecular review show high expression of VEGF pathway components (e.g., VEGF-A/VEGFRs) across cases, consistent with a phenotype dependent on endothelial growth factor signaling. (chen2020optimalclinicalmanagement pages 9-11) - The Angiopoietin–Tie axis contributes to vascular maturation/maintenance and appears biologically relevant in angiosarcoma; Tie/Ang proteins were detected in substantial fractions of cases by immunohistochemistry (e.g., Tie-2, Ang-1/2), and expression levels correlated with survival in at least one cohort. (chen2020optimalclinicalmanagement pages 11-12)

(B) Oncogenic rewiring downstream of endothelial receptors - Downstream signaling nodes repeatedly implicated include FAK, MAPK, and PI3K/AKT/mTOR, which couple extracellular pro-angiogenic signals to proliferation, survival, migration, and invasion. (chen2020optimalclinicalmanagement pages 11-12, kumari2023primarycardiacangiosarcoma pages 3-4)

(C) DNA damage/etiology-specific mutagenesis shapes subtype biology - Radiation-associated angiosarcoma (RT-AS) exhibits features of ionizing radiation damage and distinct genomic landscapes compared with sporadic angiosarcoma, with mutational patterns consistent with error-prone repair of DNA double-strand breaks (microhomology-mediated mechanisms and/or non-homologous end joining). (dermawan2023distinctgenomiclandscapes pages 8-10, dermawan2023distinctgenomiclandscapes pages 1-3) - UV-associated cutaneous angiosarcoma (scalp/face) displays a UV mutational signature and high tumor mutational burden (TMB), supporting a causative role for UV damage in a clinically important subset. (painter2020theangiosarcomaproject pages 4-7, painter2020theangiosarcomaproject pages 7-11)

2.2 Dysregulated molecular pathways

VEGF/VEGFR signaling (KDR/FLT4 and effectors) - Activating or recurrent alterations affecting VEGFR signaling include KDR (VEGFR2) mutations and FLT4 (VEGFR3) amplifications, with subtype-specific enrichment (e.g., KDR in primary breast; FLT4 often co-amplified with MYC in radiation-associated breast angiosarcoma). (chen2020optimalclinicalmanagement pages 9-11, chang2024clinicopathologicandmolecular pages 10-11)

Angiopoietin–Tie / vascular stability signaling (TIE2 pathway) - Loss-of-function PTPRB mutations are proposed to deregulate Tie-2 and VEGFR2 signaling (removing phosphatase “braking” on endothelial receptor pathways). (chen2020optimalclinicalmanagement pages 11-12)

MAPK pathway - PLCG1 activating mutations (e.g., R707Q) can increase IP3 generation and activate MAPK signaling, and PLCG1 mutations may be mutually exclusive with VEGFR2/KDR mutations in some series—supporting alternative, convergent mechanisms to activate downstream growth pathways. (chen2020optimalclinicalmanagement pages 11-12)

PI3K pathway - In primary breast angiosarcoma, activating PIK3CA mutations are strongly enriched and functionally activating, indicating PI3K pathway dependence in this subtype and a plausible vulnerability to PI3Kα inhibition. (painter2020theangiosarcomaproject pages 4-7)

MYC-driven transcriptional/angiogenic programs (secondary disease) - Secondary angiosarcomas (especially radiation- or lymphedema-associated cutaneous/breast/chest wall tumors) show frequent high-level MYC amplification and MYC-associated transcriptional changes (including miRNA programs) linked to a pro-angiogenic state. (chen2020optimalclinicalmanagement pages 9-11, chang2024clinicopathologicandmolecular pages 10-11)

3) Key molecular players

3.1 Genes/proteins (HGNC symbols)

Subtype-enriched genomic alterations with statistics

Primary breast angiosarcoma (sporadic) - KDR (VEGFR2): 8/12 (66.7%) in a 2024 breast angiosarcoma cohort, including hotspot p.T771 in multiple cases. (chang2024clinicopathologicandmolecular pages 10-11) - PIK3CA: 5/12 (41.7%) in the same cohort; Angiosarcoma Project WES found primary breast angiosarcoma significantly enriched for PIK3CA mutations (9/18 vs 1/29; p=0.0003). (chang2024clinicopathologicandmolecular pages 10-11, painter2020theangiosarcomaproject pages 4-7) - TP53: 3/12 (25%) in the same cohort. (chang2024clinicopathologicandmolecular pages 10-11) - Mechanistic interpretation: Angiosarcoma Project identified TP53 (25%; 9/36 patients) and KDR (22%; 8/36 patients) as significantly mutated above background and mutually exclusive (p=0.02); KDR alterations were concentrated in primary breast tumors. (painter2020theangiosarcomaproject pages 4-7)

Radiation-associated breast/chest wall angiosarcoma (secondary) - MYC amplification: 89/97 (91.8%) in a large 2024 breast radiation-associated series; in the neoadjuvant-treated subset, all 10 sequenced radiation-associated cases showed MYC amplification. (chang2024clinicopathologicandmolecular pages 10-11, chang2024clinicopathologicandmolecular pages 1-3) - FLT4 amplification: 10/74 (13.5%) in the same report, often co-amplified with MYC. (chang2024clinicopathologicandmolecular pages 10-11) - PTPRB: loss-of-function mutations reported in 10/39 secondary angiosarcomas in a prior mechanistic review. (chen2020optimalclinicalmanagement pages 11-12) - Distinct radiation-associated genomic landscape: radiation-associated angiosarcoma was reported enriched for MYC, FLT4, CRKL, HRAS, KMT2D compared with sporadic angiosarcoma, whereas sporadic tumors were enriched for TP53, KDR, ATM, ATRX. (dermawan2023distinctgenomiclandscapes pages 1-3)

UV-associated cutaneous angiosarcoma (head/neck/face/scalp; HNFS) - Angiosarcoma Project: HNFS tumors had much higher median TMB (20.7 muts/Mb vs 2.8 non-HNFS) and a dominant UV mutational signature in 10/12 HNFS samples. (painter2020theangiosarcomaproject pages 4-7) - Exceptional immunotherapy responses were linked to very high TMB and UV signature in individual HNFS cases treated with pembrolizumab (durable >2 years off therapy). (painter2020theangiosarcomaproject pages 7-11) - Spatial multi-omic profiling of Asian head/neck angiosarcoma reported recurrent mutations in CSMD3 (18%), LRP1B (18%), MUC16 (18%), POT1 (16%), TP53 (16%), and higher TMB in UV-positive disease (p=0.0294). (loh2023spatialtranscriptomicsreveal pages 1-2)

Other recurrent/functional drivers (across angiosarcoma) - PLCG1 (e.g., R707Q): reported recurrently (e.g., 3/34 in one cohort; also present in larger series), functionally de-repressing PLCγ1 and activating MAPK signaling; may confer resistance to therapies targeting VEGF/KDR in some contexts. (chen2020optimalclinicalmanagement pages 11-12, kumari2023primarycardiacangiosarcoma pages 3-4) - TP53: variable alteration rates across series; functional role supported by animal/endothelial models where TP53 alterations can lead to angiosarcoma-like tumors. (chen2020optimalclinicalmanagement pages 9-11, chen2020optimalclinicalmanagement pages 7-8)

3.2 Chemical entities (therapeutically relevant; CHEBI)

Angiosarcoma treatments are not purely “pathophysiology,” but many clinical implementations directly target core dysregulated pathways: - Anti-angiogenic / VEGF-axis agents: bevacizumab, sorafenib, pazopanib, regorafenib (and others) are used clinically; reported activity is modest in unselected disease (e.g., bevacizumab ORR 9% (2/23); sorafenib ORR 15–23% with median PFS ~3 months; pazopanib ORR ~20% in retrospective data). (chen2020optimalclinicalmanagement pages 5-7) - Immune checkpoint inhibitors (ICIs): pembrolizumab and other anti–PD-1/PD-L1 regimens show notable activity in select cutaneous/UV-high disease and variable responses otherwise. (painter2020theangiosarcomaproject pages 7-11, chen2020optimalclinicalmanagement pages 5-7)

3.3 Cell types (CL) and anatomical locations (UBERON)

Key cell types involved - Endothelial tumor cells (blood and/or lymphatic endothelium) are the malignant compartment. (chen2020optimalclinicalmanagement pages 11-12, kumari2023primarycardiacangiosarcoma pages 3-4) - Immune microenvironment cell types repeatedly implicated include CD8+ T cells, macrophages (CD68+), neutrophils (CD15+), and FOXP3+ regulatory T cells, varying by immune-hot vs immune-cold spatial phenotypes. (loh2023spatialtranscriptomicsreveal pages 1-2)

Common anatomical sites / subtype anchors - Cutaneous/subcutaneous disease dominates population incidence datasets (majority of cases). (wagner2024incidenceandpresenting pages 1-2) - Scalp/face (UV-exposed head/neck) are key for the UV/TMB-high subtype. (painter2020theangiosarcomaproject pages 4-7, painter2020theangiosarcomaproject pages 7-11) - Breast/chest wall are key for radiation-associated secondary angiosarcoma after breast irradiation. (wagner2024incidenceandpresenting pages 1-2, chang2024clinicopathologicandmolecular pages 10-11)

4) Biological processes (GO-oriented pathophysiology mapping)

The evidence supports disruption of the following GO-relevant process classes: - Angiogenesis / vasculature development (VEGF/VEGFR, Ang/Tie). (chen2020optimalclinicalmanagement pages 11-12, chen2020optimalclinicalmanagement pages 9-11) - Endothelial cell proliferation, migration, and sprouting driven by VEGF receptor activation and downstream PI3K/MAPK cascades. (kumari2023primarycardiacangiosarcoma pages 3-4) - Response to hypoxia (e.g., endoglin upregulation under hypoxia; pro-angiogenic remodeling). (chen2020optimalclinicalmanagement pages 5-7) - DNA damage response / double-strand break repair and mutational processes specific to radiation-associated tumors. (dermawan2023distinctgenomiclandscapes pages 8-10, dermawan2023distinctgenomiclandscapes pages 1-3) - Response to ultraviolet light / UV-induced mutagenesis in HNFS tumors. (painter2020theangiosarcomaproject pages 4-7, painter2020theangiosarcomaproject pages 7-11) - Immune response / tumor inflammation programs (immune-hot vs cold; tumor inflammation signature differences). (loh2023spatialtranscriptomicsreveal pages 1-2)

5) Cellular components (where key processes occur)

Mechanistic events described in the evidence primarily map to: - Plasma membrane receptor complexes (VEGFR2/KDR, VEGFR3/FLT4, Tie receptors) initiating signaling. (kumari2023primarycardiacangiosarcoma pages 3-4, chen2020optimalclinicalmanagement pages 5-7) - Cytosolic signaling complexes (PLCγ1-mediated phosphoinositide signaling, MAPK and PI3K/AKT/mTOR cascades). (chen2020optimalclinicalmanagement pages 11-12, kumari2023primarycardiacangiosarcoma pages 3-4) - Nuclear transcriptional programs (MYC-driven transcription and miRNA programs). (chen2020optimalclinicalmanagement pages 9-11, chang2024clinicopathologicandmolecular pages 10-11) - Tumor microenvironment compartments with spatially organized immune infiltration/exclusion patterns. (loh2023spatialtranscriptomicsreveal pages 1-2)

6) Disease progression model (sequence of events)

6.1 Etiology-dependent initiation → transformation

  1. Initiating insult or predisposition
  2. UV exposure for HNFS cutaneous angiosarcoma, associated with UV mutational signatures and high TMB. (painter2020theangiosarcomaproject pages 4-7, painter2020theangiosarcomaproject pages 7-11)
  3. Ionizing radiation for secondary breast/chest wall angiosarcoma, with latency on the order of years and distinct genomic landscapes consistent with radiation-induced DNA damage and repair. (dermawan2023distinctgenomiclandscapes pages 1-3, wagner2024incidenceandpresenting pages 1-2)

  4. Chronic lymphedema and other secondary contexts are recognized risk settings and molecularly associated with MYC amplification in secondary disease. (wagner2024incidenceandpresenting pages 1-2, chen2020optimalclinicalmanagement pages 9-11)

  5. Early molecular driver acquisition and lineage program

  6. Secondary radiation/lymphedema-associated lesions frequently acquire MYC amplification, driving a pro-angiogenic transcriptional program (including miRNA changes and reduced anti-angiogenic factors). (chen2020optimalclinicalmanagement pages 9-11, chang2024clinicopathologicandmolecular pages 10-11)

  7. Primary breast tumors show KDR and PIK3CA activation, linking endothelial growth factor sensing directly to proliferative survival signaling (PI3K pathway). (painter2020theangiosarcomaproject pages 4-7, chang2024clinicopathologicandmolecular pages 10-11)

  8. Progression: signaling convergence, invasion, and metastasis

  9. Across subtypes, signaling converges on MAPK and PI3K/AKT/mTOR to support proliferation/survival and the invasive vascular phenotype. (chen2020optimalclinicalmanagement pages 11-12, kumari2023primarycardiacangiosarcoma pages 3-4)
  10. Radiation-associated tumors may acquire additional co-alterations (e.g., FLT4, HRAS, KMT2D) consistent with progression and genomic instability. (dermawan2023distinctgenomiclandscapes pages 1-3, chang2024clinicopathologicandmolecular pages 10-11)

6.2 Distinct “immune phenotypes” influence clinical behavior and treatment sensitivity

  • UV/TMB-high HNFS tumors can be particularly immunogenic, and exceptional responses to PD-1 blockade have been observed in that context, supporting immune selection/escape as part of progression. (painter2020theangiosarcomaproject pages 7-11)
  • Spatial profiling reveals immune-hot cases may exhibit tumor-excluded inflammation (immune cells present but spatially segregated), potentially contributing to variable responses. (loh2023spatialtranscriptomicsreveal pages 1-2)

7) Phenotypic manifestations (HP-oriented)

Although detailed HP-term enumerations were not provided explicitly in the retrieved texts, the evidence supports the following phenotype classes: - Aggressive local infiltration and high recurrence risk, particularly in cutaneous and radiation-associated breast/chest wall disease. (wagner2024incidenceandpresenting pages 1-2, chen2020optimalclinicalmanagement pages 5-7) - Early metastasis with poor prognosis overall; cutaneous angiosarcoma review reports mean 5-year survival ~33.5%. (guan2023cutaneousangiosarcomaa pages 1-2) - Site-specific presentations: UV-exposed scalp/face lesions (often misrecognized early) and post-radiation chest wall/breast cutaneous nodules in the irradiated field. (wagner2024incidenceandpresenting pages 1-2, dermawan2023distinctgenomiclandscapes pages 1-3)

8) Recent developments and latest research (prioritizing 2023–2024)

8.1 Population-level epidemiology (2024)

A US population-based analysis (USCS NPCR–SEER combined) identified 19,289 cases (2001–2020) and reported that “angiosarcoma incidence doubled from 657 cases in 2001 to 1312 in 2019”, with increasing incidence particularly driven by secondary breast/chest-wall disease in women. (JAMA Network Open, 2024-04; https://doi.org/10.1001/jamanetworkopen.2024.6235) (wagner2024incidenceandpresenting pages 1-2)

8.2 High-resolution subtype genomics and precision targets (2023–2024)

  • Radiation-associated angiosarcoma shows a distinct landscape compared with other radiation-associated sarcomas and compared with sporadic angiosarcoma, with enrichment for MYC/FLT4/HRAS/KMT2D and relative depletion of TP53 alterations in the radiation-associated setting. (The Journal of Pathology, 2023-06; https://doi.org/10.1002/path.6137) (dermawan2023distinctgenomiclandscapes pages 1-3)
  • Breast angiosarcoma (2024): a large molecular cohort quantified near-ubiquitous MYC amplification in radiation-associated breast angiosarcoma (91.8%) and high prevalence of KDR and PIK3CA alterations in primary breast disease, strengthening the biologic separation of these entities and supporting subtype-tailored therapeutic hypotheses. (Genes Chromosomes Cancer, 2024-05; https://doi.org/10.1002/gcc.23240) (chang2024clinicopathologicandmolecular pages 10-11)
  • Spatial transcriptomics in head/neck angiosarcoma (2023): defines immune-hot/intermediate/cold clusters and shows higher TMB in UV-positive cases, providing a framework for immunotherapy stratification beyond histology alone. (Communications Biology, 2023-04; https://doi.org/10.1038/s42003-023-04856-5) (loh2023spatialtranscriptomicsreveal pages 1-2)

8.3 Immunotherapy biomarker synthesis (2023)

A 2023 review of checkpoint inhibitors in cutaneous angiosarcoma collates evidence that cAS can display TMB-H, PD-L1 positivity, UV mutational signature, tertiary lymphoid structures, and abundant CD8+ TILs, providing mechanistic rationale for immunotherapy in selected patients. (Frontiers in Medicine, 2023-03; https://doi.org/10.3389/fmed.2023.1090168) (guan2023cutaneousangiosarcomaa pages 1-2)

9) Current applications and real-world implementations

9.1 Diagnostic and subclassification biomarkers

  • MYC amplification testing (FISH) and/or MYC IHC is widely used to support diagnosis of secondary radiation- or lymphedema-associated angiosarcoma and to distinguish from benign/atypical post-radiation vascular lesions, consistent with the strong enrichment of MYC amplification in radiation-associated breast disease. (chen2020optimalclinicalmanagement pages 9-11, chang2024clinicopathologicandmolecular pages 10-11)
  • Molecular subclassification has direct clinical implications: primary breast angiosarcoma (KDR/PIK3CA-driven) differs biologically and therapeutically from radiation-associated breast angiosarcoma (MYC-amplified). (painter2020theangiosarcomaproject pages 4-7, chang2024clinicopathologicandmolecular pages 10-11)

9.2 Therapeutic implementations linked to pathophysiology

  • VEGF/angiogenesis pathway targeting is a rational strategy but shows heterogeneous and often modest efficacy in unselected populations (e.g., bevacizumab ORR 9%; sorafenib ORR 15–23%; pazopanib ORR ~20% in retrospective series), implying that pathway activation alone is insufficient as a biomarker and that subtype/driver selection is important. (chen2020optimalclinicalmanagement pages 5-7)
  • Immune checkpoint blockade appears most compelling in UV/TMB-high cutaneous HNFS angiosarcoma, where durable, exceptional responses have been documented, consistent with the UV-driven hypermutated state and increased neoantigen burden. (painter2020theangiosarcomaproject pages 7-11)

10) Expert opinions and analysis (authoritative sources)

  • The angiosarcoma field increasingly treats the disease as a set of molecularly distinct entities rather than one tumor type, supported by population-level subtype shifts (secondary breast/chest wall) and by strong subtype-enrichment of drivers such as MYC (secondary) vs KDR/PIK3CA (primary breast) vs UV/TMB-high HNFS disease. (wagner2024incidenceandpresenting pages 1-2, painter2020theangiosarcomaproject pages 4-7, chang2024clinicopathologicandmolecular pages 10-11)
  • Mechanistic reviews emphasize angiogenesis signaling (VEGF/VEGFR, Tie/Ang) as central but also highlight why anti-angiogenic monotherapy is often insufficient: convergent downstream signaling (MAPK/PI3K), pathway redundancy, and genetically distinct etiologic subtypes. (chen2020optimalclinicalmanagement pages 11-12, chen2020optimalclinicalmanagement pages 5-7)

11) Relevant statistics and data (recent studies)

Epidemiology and incidence

  • US (2001–2020): 19,289 cases; incidence doubled from 657 (2001) to 1312 (2019); adjusted annual increase leading to ~3.3 per 1,000,000 person-years (peak stated in the study excerpt), and most tumors were cutaneous/subcutaneous/breast (72.3%). (wagner2024incidenceandpresenting pages 1-2)

Genomics and biomarkers (selected quantitative findings)

  • Radiation-associated breast angiosarcoma: MYC amplification 89/97 (91.8%); FLT4 amplification 10/74 (13.5%). (chang2024clinicopathologicandmolecular pages 10-11)
  • Primary breast angiosarcoma: KDR 8/12 (66.7%), PIK3CA 5/12 (41.7%), TP53 3/12 (25%). (chang2024clinicopathologicandmolecular pages 10-11)
  • Angiosarcoma Project WES: TP53 25% (9/36), KDR 22% (8/36), mutually exclusive (p=0.02); HNFS median TMB 20.7 muts/Mb vs 2.8 non-HNFS; UV signature in 10/12 HNFS. (painter2020theangiosarcomaproject pages 4-7)
  • Cutaneous head/neck angiosarcoma immune biomarker compilation: PD-L1 positivity 33% (head/neck cAS in cited cohort) and UV signature 9/18 in one head/neck series. (guan2023cutaneousangiosarcomaa pages 1-2)

12) Knowledge base–ready annotation blocks

12.1 Pathophysiology description (narrative)

Angiosarcoma is an endothelial malignancy in which dysregulated angiogenesis/lymphangiogenesis is central. Key oncogenic events frequently occur at the level of endothelial receptor signaling (KDR/VEGFR2, FLT4/VEGFR3, Tie/Ang pathways) or in proximal effectors (PLCG1, PTPRB), converging on MAPK and PI3K/AKT/mTOR. Etiology strongly shapes pathophysiology: UV-driven HNFS tumors show UV mutational signatures and high TMB with immune responsiveness in select cases; radiation-associated breast/chest wall tumors show MYC amplification (often with FLT4 co-amplification) and radiation-associated mutational processes; and primary breast tumors are enriched for KDR and activating PIK3CA mutations. (chen2020optimalclinicalmanagement pages 5-7, painter2020theangiosarcomaproject pages 4-7, chang2024clinicopathologicandmolecular pages 10-11)

12.2 Gene/protein annotations (HGNC + mechanism + evidence)

  • MYC (HGNC:7553) — amplification/overexpression in secondary (radiation-associated) angiosarcoma; linked to pro-angiogenic transcriptional and miRNA programs; near-ubiquitous in radiation-associated breast angiosarcoma cohorts. (chen2020optimalclinicalmanagement pages 9-11, chang2024clinicopathologicandmolecular pages 10-11)
  • KDR (HGNC:6307; VEGFR2) — recurrent mutations enriched in primary breast angiosarcoma; significant driver in Angiosarcoma Project; activates angiogenic RTK signaling leading to PI3K/MAPK activation. (painter2020theangiosarcomaproject pages 4-7, chang2024clinicopathologicandmolecular pages 10-11, kumari2023primarycardiacangiosarcoma pages 3-4)
  • PIK3CA (HGNC:8975) — activating mutations enriched in primary breast angiosarcoma and functionally activating; implies PI3K pathway dependence. (painter2020theangiosarcomaproject pages 4-7, chang2024clinicopathologicandmolecular pages 10-11)
  • FLT4 (HGNC:3767; VEGFR3) — amplification in radiation-associated breast angiosarcoma (subset; often co-amplified with MYC), and in radiation-associated angiosarcoma more broadly. (chang2024clinicopathologicandmolecular pages 10-11, dermawan2023distinctgenomiclandscapes pages 1-3)
  • PTPRB (HGNC:9668) — loss-of-function mutations in secondary angiosarcoma; proposed to deregulate Tie2/VEGFR2 signaling. (chen2020optimalclinicalmanagement pages 11-12)
  • PLCG1 (HGNC:9065) — activating mutations (e.g., R707Q) increase phosphoinositide signaling and MAPK activation; may be mutually exclusive with KDR mutations in some cohorts. (chen2020optimalclinicalmanagement pages 11-12)
  • TP53 (HGNC:11998) — recurrent driver, variable frequency by subtype; significant in Angiosarcoma Project and supported by animal models. (painter2020theangiosarcomaproject pages 4-7, chen2020optimalclinicalmanagement pages 7-8)

12.3 Cell-type involvement (CL)

  • Endothelial cell (blood/lymphatic): malignant compartment; angiogenic signaling dependence. (kumari2023primarycardiacangiosarcoma pages 3-4, chen2020optimalclinicalmanagement pages 5-7)
  • CD8+ T cell, macrophage, neutrophil, Treg (FOXP3+): immune microenvironment components with spatially organized “immune-hot/cold” patterns in head/neck disease. (loh2023spatialtranscriptomicsreveal pages 1-2)

12.4 Anatomical locations (UBERON)

  • Skin of scalp/face/head & neck: enriched for UV signature/high TMB subtype. (painter2020theangiosarcomaproject pages 4-7, painter2020theangiosarcomaproject pages 7-11)
  • Breast/chest wall (irradiated field): enriched for radiation-associated MYC-amplified subtype. (wagner2024incidenceandpresenting pages 1-2, chang2024clinicopathologicandmolecular pages 10-11)

12.5 Chemical entities (CHEBI; examples linked to mechanisms)

  • Bevacizumab (anti-VEGF-A), pazopanib/sorafenib/regorafenib (multi-kinase VEGFR inhibitors) as real-world angiogenesis-directed agents with modest response rates in unselected populations. (chen2020optimalclinicalmanagement pages 5-7)
  • Pembrolizumab (anti–PD-1) as an immunotherapy option with strongest mechanistic support in UV/TMB-high cutaneous HNFS disease. (painter2020theangiosarcomaproject pages 7-11, guan2023cutaneousangiosarcomaa pages 1-2)

13) Summary table (mechanisms, subtype biology, and immune features)

Subtype/trigger Key genomic alterations (with frequencies) Dysregulated pathways/cellular processes Immune/TME features Clinical/phenotypic notes Key references (PMID if known, otherwise DOI; year)
UV-associated cutaneous head/neck/face/scalp (HNFS/cAS) TP53 25% overall cohort (9/36 patients) and KDR 22% (8/36) in Angiosarcoma Project; HNFS specifically showed dominant UV mutational signature in 10/12 cases and markedly higher median TMB 20.7 muts/Mb vs 2.8 in non-HNFS; in Asian AS-HN, recurrent mutations included CSMD3 18%, LRP1B 18%, MUC16 18%, POT1 16%, TP53 16%; review cites UV signatures in 9/18 head/neck cAS (painter2020theangiosarcomaproject pages 4-7, loh2023spatialtranscriptomicsreveal pages 1-2, guan2023cutaneousangiosarcomaa pages 1-2) UV-mediated mutagenesis; high neoantigen load/TMB; endothelial malignant transformation with angiogenic dependence including VEGF signaling in angiosarcoma broadly (painter2020theangiosarcomaproject pages 7-11, guan2023cutaneousangiosarcomaa pages 1-2, chen2020optimalclinicalmanagement pages 5-7) Immune-hot/intermediate/cold clusters identified; highest TIS in immune-hot tumors (7.82 vs 7.49 vs 5.90, p=0.00021); CD8+ T cells, neutrophils, macrophages, FOXP3+ Tregs correlated with immune clusters; PD-L1 positivity reported in 33% of head/neck cAS; tertiary lymphoid structures and abundant CD8+ TILs reported in cAS review (loh2023spatialtranscriptomicsreveal pages 1-2, guan2023cutaneousangiosarcomaa pages 1-2) Commonly arises on sun-exposed scalp/face; older patients, median age 77 in cAS review; poor prognosis with mean 5-year survival ~33.5%; exceptional anti-PD-1 responses seen in very high-TMB/UV-signature HNFS tumors (2 durable responses among 3 HNFS treated off-label) (guan2023cutaneousangiosarcomaa pages 1-2, painter2020theangiosarcomaproject pages 7-11) DOI:10.1038/s41591-019-0749-z (2020); DOI:10.1038/s42003-023-04856-5 (2023); DOI:10.3389/fmed.2023.1090168 (2023)
Radiation-associated breast/chest wall MYC amplification is the hallmark: ~55-57% of secondary AS in review; 50-100% secondary AS in summary table; in breast RA-AS, MYC amplification 89/97 (91.8%); all 10 post-NACT RA-AS in sequenced subset had MYC amplification; FLT4 amplification 10/74 (13.5%), sometimes co-amplified with MYC; PTPRB loss-of-function 10/39 secondary AS; RT-AS enriched for MYC, FLT4, CRKL, HRAS, KMT2D, whereas sporadic AS enriched for TP53, KDR, ATM, ATRX (chen2020optimalclinicalmanagement pages 9-11, chang2024clinicopathologicandmolecular pages 10-11, chang2024clinicopathologicandmolecular pages 1-3, chen2020optimalclinicalmanagement pages 11-12, dermawan2023distinctgenomiclandscapes pages 1-3) MYC-driven pro-angiogenic program with miR-17-92 upregulation and reduced THBS1/CTGF; dysregulated VEGF/VEGFR and Tie2 signaling; PTPRB loss may unleash Tie-2/VEGFR-2 signaling; radiation-associated transcriptomic profile shows lymphatic markers PDPN and PROX1; DNA damage/repair error signatures after ionizing radiation (chen2020optimalclinicalmanagement pages 9-11, chen2020optimalclinicalmanagement pages 11-12, dermawan2023distinctgenomiclandscapes pages 1-3) Generally not characterized by high UV-TMB phenotype; RT-sarcomas show mutational signatures linked to DNA repair/replication defects and increased indel/substitution ratio; PD-L1 in cutaneous AS overall around 40% in older review, but subtype-specific RA-AS immune data remain limited in provided evidence (dermawan2023distinctgenomiclandscapes pages 1-3, chen2020optimalclinicalmanagement pages 5-7) Typically high-grade cutaneous nodules of chest wall after breast irradiation; median latency ~8.0 years after radiation in RT-AS cohort and 64 months in single-institution RIBAS series; secondary breast angiosarcoma incidence rising; local recurrence frequent (77.8% in one recent series) (dermawan2023distinctgenomiclandscapes pages 1-3, wagner2024incidenceandpresenting pages 1-2) DOI:10.1002/path.6137 (2023); DOI:10.1002/gcc.23240 (2024); DOI:10.3390/cancers12113321 (2020)
Primary breast angiosarcoma KDR mutations enriched: 8/12 (66.7%) in one breast series, including five p.T771 cases; Angiosarcoma Project found KDR 22% overall and 89% of KDR missense mutations in primary breast AS; PIK3CA 5/12 (41.7%) in breast series and 9/18 primary breast AS in Angiosarcoma Project (significantly enriched vs non-breast, p=0.0003); TP53 3/12 (25%); both primary AS cases in post-NACT sequenced subset harbored KDR mutations (chang2024clinicopathologicandmolecular pages 10-11, painter2020theangiosarcomaproject pages 4-7, chang2024clinicopathologicandmolecular pages 5-6) VEGFR2/KDR-driven angiogenic signaling; PI3K pathway activation via activating PIK3CA variants; downstream PI3K/AKT/mTOR and MAPK signaling implicated in angiosarcoma biology (painter2020theangiosarcomaproject pages 4-7, chen2020optimalclinicalmanagement pages 9-11, chen2020optimalclinicalmanagement pages 11-12) Not a classic high-TMB/UV subtype; in breast NACT study, TMB was low (<10 mt/Mb) and did not correlate with response (chang2024clinicopathologicandmolecular pages 5-6) Distinct from radiation-associated breast AS by younger age and lack of pervasive MYC amplification; primary breast tumors in NACT cohort had poor histologic response and high distant metastatic rate (chang2024clinicopathologicandmolecular pages 5-6, chang2024clinicopathologicandmolecular pages 10-11) DOI:10.1038/s41591-019-0749-z (2020); DOI:10.1002/gcc.23240 (2024); DOI:10.3390/cancers12113321 (2020)
Other/secondary etiologies (lymphedema-associated, mixed secondary, non-breast/post-radiation) MYC amplification characteristic of irradiation- and lymphedema-associated secondary AS; VEGFR3/FLT4 amplification 18-25% in secondary AS; PTPRB mutations 10/39 secondary AS; PLCG1 R707Q in 3/34 and 8/116 overall series; CIC missense mutations 8/100, mostly primary rather than secondary; RT-AS composition in one 120-case study: 61% primary, 28% radiation-associated, 11% lymphedema-associated (chen2020optimalclinicalmanagement pages 7-8, chen2020optimalclinicalmanagement pages 11-12) Dysregulated angiogenesis centered on VEGF/VEGFR, Tie/Ang, MAPK, and PI3K/AKT/mTOR; PLCG1 activation increases IP3/MAPK signaling and may be mutually exclusive with VEGFR2 mutation; lymphedema/radiation-associated tumors may show lymphatic differentiation markers (PDPN, PROX1) (chen2020optimalclinicalmanagement pages 11-12, chen2020optimalclinicalmanagement pages 9-11) Immune data are less well resolved by subtype in provided evidence; checkpoint responses appear variable outside UV-high cutaneous disease; occasional CD4+/CD8+ memory T cells reported across AS and PD-L1 around 40% in cutaneous AS overall (chen2020optimalclinicalmanagement pages 5-7) Secondary angiosarcoma associated with chronic lymphedema/Stewart-Treves syndrome, prior radiotherapy, foreign material, and other carcinogenic exposures; molecular heterogeneity supports etiologic subclassification and biomarker-guided therapy (wagner2024incidenceandpresenting pages 1-2, chahardehi2024micrornasandangiosarcoma pages 3-4, chen2020optimalclinicalmanagement pages 11-12) DOI:10.3390/cancers12113321 (2020); DOI:10.3389/fonc.2024.1385632 (2024); DOI:10.1001/jamanetworkopen.2024.6235 (2024)

Table: This table summarizes angiosarcoma pathophysiology by major etiologic and clinical subtypes, highlighting subtype-enriched genomic alterations, pathway dysregulation, immune features, and clinical correlates. It is useful for linking disease mechanisms to diagnostic stratification and therapeutic hypotheses.

14) Evidence items (PMID-first, if available)

The retrieved full-text snippets frequently provided DOI/Journal/Year but did not reliably include PMIDs in the tool outputs for all sources. Key evidence items (with DOI and date): - Wagner MJ et al. JAMA Network Open 2024-04. “Incidence…US, 2001–2020.” https://doi.org/10.1001/jamanetworkopen.2024.6235 (wagner2024incidenceandpresenting pages 1-2) - Chang H-Y et al. Genes Chromosomes Cancer 2024-05. Breast angiosarcoma subtype genomics (MYC in radiation-associated; KDR/PIK3CA in primary). https://doi.org/10.1002/gcc.23240 (chang2024clinicopathologicandmolecular pages 10-11) - Loh JW et al. Communications Biology 2023-04. Spatial transcriptomics/immune landscapes in head & neck angiosarcoma. https://doi.org/10.1038/s42003-023-04856-5 (loh2023spatialtranscriptomicsreveal pages 1-2) - Dermawan JK et al. The Journal of Pathology 2023-06. Radiation-associated angiosarcoma genomic landscape. https://doi.org/10.1002/path.6137 (dermawan2023distinctgenomiclandscapes pages 1-3) - Guan L et al. Frontiers in Medicine 2023-03. Checkpoint inhibitor evidence in cutaneous angiosarcoma. https://doi.org/10.3389/fmed.2023.1090168 (guan2023cutaneousangiosarcomaa pages 1-2) - Chen TWW et al. Cancers 2020-11. Molecular biology and clinical management (VEGF/Tie, PTPRB/PLCG1, therapy response statistics). https://doi.org/10.3390/cancers12113321 (chen2020optimalclinicalmanagement pages 5-7) - Painter CA et al. Nature Medicine 2020-02. Angiosarcoma Project WES, UV/TMB findings, KDR/TP53/PIK3CA. https://doi.org/10.1038/s41591-019-0749-z (painter2020theangiosarcomaproject pages 4-7)

References

  1. (chen2020optimalclinicalmanagement pages 11-12): Tom Wei-Wu Chen, Jessica Burns, Robin L. Jones, and Paul H. Huang. Optimal clinical management and the molecular biology of angiosarcomas. Cancers, 12:3321, Nov 2020. URL: https://doi.org/10.3390/cancers12113321, doi:10.3390/cancers12113321. This article has 27 citations.

  2. (chen2020optimalclinicalmanagement pages 9-11): Tom Wei-Wu Chen, Jessica Burns, Robin L. Jones, and Paul H. Huang. Optimal clinical management and the molecular biology of angiosarcomas. Cancers, 12:3321, Nov 2020. URL: https://doi.org/10.3390/cancers12113321, doi:10.3390/cancers12113321. This article has 27 citations.

  3. (painter2020theangiosarcomaproject pages 4-7): Corrie A. Painter, Esha Jain, Brett N. Tomson, Michael Dunphy, Rachel E. Stoddard, Beena S. Thomas, Alyssa L. Damon, Shahrayz Shah, Dewey Kim, Jorge Gómez Tejeda Zañudo, Jason L. Hornick, Yen-Lin Chen, Priscilla Merriam, Chandrajit P. Raut, George D. Demetri, Brian A. Van Tine, Eric S. Lander, Todd R. Golub, and Nikhil Wagle. The angiosarcoma project: enabling genomic and clinical discoveries in a rare cancer through patient-partnered research. Feb 2020. URL: https://doi.org/10.1038/s41591-019-0749-z, doi:10.1038/s41591-019-0749-z. This article has 291 citations and is from a highest quality peer-reviewed journal.

  4. (chen2020optimalclinicalmanagement pages 5-7): Tom Wei-Wu Chen, Jessica Burns, Robin L. Jones, and Paul H. Huang. Optimal clinical management and the molecular biology of angiosarcomas. Cancers, 12:3321, Nov 2020. URL: https://doi.org/10.3390/cancers12113321, doi:10.3390/cancers12113321. This article has 27 citations.

  5. (kumari2023primarycardiacangiosarcoma pages 3-4): Naina Kumari, Sagar Bhandari, Anzal Ishfaq, Samia Rauf R Butt, Chukwuyem Ekhator, Amanda Karski, Bijan Kadel, Mohamedalamin Alnoor Altayb Ismail, Tenzin N Sherpa, Ahmed Al Khalifa, Bashar Khalifah, Nhan Nguyen, Slobodan Lazarevic, Mohammad Uzair Zaman, Ashraf Ullah, and Vikas Yadav. Primary cardiac angiosarcoma: a review. Cureus, Jul 2023. URL: https://doi.org/10.7759/cureus.41947, doi:10.7759/cureus.41947. This article has 47 citations.

  6. (dermawan2023distinctgenomiclandscapes pages 8-10): Josephine K Dermawan, Ping Chi, William D Tap, Evan Rosenbaum, Sandra D'Angelo, Kaled M Alektiar, and Cristina R Antonescu. Distinct genomic landscapes in radiation‐associated angiosarcoma compared with other radiation‐associated sarcoma histologies. The Journal of Pathology, 260:465-477, Jun 2023. URL: https://doi.org/10.1002/path.6137, doi:10.1002/path.6137. This article has 17 citations.

  7. (dermawan2023distinctgenomiclandscapes pages 1-3): Josephine K Dermawan, Ping Chi, William D Tap, Evan Rosenbaum, Sandra D'Angelo, Kaled M Alektiar, and Cristina R Antonescu. Distinct genomic landscapes in radiation‐associated angiosarcoma compared with other radiation‐associated sarcoma histologies. The Journal of Pathology, 260:465-477, Jun 2023. URL: https://doi.org/10.1002/path.6137, doi:10.1002/path.6137. This article has 17 citations.

  8. (painter2020theangiosarcomaproject pages 7-11): Corrie A. Painter, Esha Jain, Brett N. Tomson, Michael Dunphy, Rachel E. Stoddard, Beena S. Thomas, Alyssa L. Damon, Shahrayz Shah, Dewey Kim, Jorge Gómez Tejeda Zañudo, Jason L. Hornick, Yen-Lin Chen, Priscilla Merriam, Chandrajit P. Raut, George D. Demetri, Brian A. Van Tine, Eric S. Lander, Todd R. Golub, and Nikhil Wagle. The angiosarcoma project: enabling genomic and clinical discoveries in a rare cancer through patient-partnered research. Feb 2020. URL: https://doi.org/10.1038/s41591-019-0749-z, doi:10.1038/s41591-019-0749-z. This article has 291 citations and is from a highest quality peer-reviewed journal.

  9. (chang2024clinicopathologicandmolecular pages 10-11): Hsin‐Yi Chang, Josephine K. Dermawan, Maria Gabriela Kuba, Aimee M. Crago, Samuel Singer, William Tap, Ping Chi, Sandra D'Angelo, Evan Rosenbaum, and Cristina R. Antonescu. Clinicopathologic and molecular correlates to neoadjuvant chemotherapy‐induced pathologic response in breast angiosarcoma. Genes, May 2024. URL: https://doi.org/10.1002/gcc.23240, doi:10.1002/gcc.23240. This article has 6 citations.

  10. (chang2024clinicopathologicandmolecular pages 1-3): Hsin‐Yi Chang, Josephine K. Dermawan, Maria Gabriela Kuba, Aimee M. Crago, Samuel Singer, William Tap, Ping Chi, Sandra D'Angelo, Evan Rosenbaum, and Cristina R. Antonescu. Clinicopathologic and molecular correlates to neoadjuvant chemotherapy‐induced pathologic response in breast angiosarcoma. Genes, May 2024. URL: https://doi.org/10.1002/gcc.23240, doi:10.1002/gcc.23240. This article has 6 citations.

  11. (loh2023spatialtranscriptomicsreveal pages 1-2): Jui Wan Loh, Jing Yi Lee, Abner Herbert Lim, Peiyong Guan, Boon Yee Lim, Bavani Kannan, Elizabeth Chun Yong Lee, Ning Xin Gu, Tun Kiat Ko, Cedric Chuan-Young Ng, Jeffrey Chun Tatt Lim, Joe Yeong, Jing Quan Lim, Choon Kiat Ong, Bin Tean Teh, and Jason Yongsheng Chan. Spatial transcriptomics reveal topological immune landscapes of asian head and neck angiosarcoma. Communications Biology, Apr 2023. URL: https://doi.org/10.1038/s42003-023-04856-5, doi:10.1038/s42003-023-04856-5. This article has 27 citations and is from a peer-reviewed journal.

  12. (chen2020optimalclinicalmanagement pages 7-8): Tom Wei-Wu Chen, Jessica Burns, Robin L. Jones, and Paul H. Huang. Optimal clinical management and the molecular biology of angiosarcomas. Cancers, 12:3321, Nov 2020. URL: https://doi.org/10.3390/cancers12113321, doi:10.3390/cancers12113321. This article has 27 citations.

  13. (wagner2024incidenceandpresenting pages 1-2): Michael J. Wagner, Vinod Ravi, Stephanie K. Schaub, Ed Y. Kim, Jeremy Sharib, Harveshp Mogal, Min Park, Michaela Tsai, Daniela Duarte-Bateman, Anthony Tufaro, Elizabeth T. Loggers, Lee D. Cranmer, Bonny Chau, Michael J. Hassett, Juneko Grilley-Olson, and Kelly G. Paulson. Incidence and presenting characteristics of angiosarcoma in the us, 2001-2020. JAMA Network Open, 7:e246235, Apr 2024. URL: https://doi.org/10.1001/jamanetworkopen.2024.6235, doi:10.1001/jamanetworkopen.2024.6235. This article has 38 citations and is from a peer-reviewed journal.

  14. (guan2023cutaneousangiosarcomaa pages 1-2): Lucy Guan, Marisa Palmeri, and Roman Groisberg. Cutaneous angiosarcoma: a review of current evidence for treatment with checkpoint inhibitors. Frontiers in Medicine, Mar 2023. URL: https://doi.org/10.3389/fmed.2023.1090168, doi:10.3389/fmed.2023.1090168. This article has 28 citations.

  15. (chang2024clinicopathologicandmolecular pages 5-6): Hsin‐Yi Chang, Josephine K. Dermawan, Maria Gabriela Kuba, Aimee M. Crago, Samuel Singer, William Tap, Ping Chi, Sandra D'Angelo, Evan Rosenbaum, and Cristina R. Antonescu. Clinicopathologic and molecular correlates to neoadjuvant chemotherapy‐induced pathologic response in breast angiosarcoma. Genes, May 2024. URL: https://doi.org/10.1002/gcc.23240, doi:10.1002/gcc.23240. This article has 6 citations.

  16. (chahardehi2024micrornasandangiosarcoma pages 3-4): Amir Modarresi Chahardehi, Arya Afrooghe, Nikoo Emtiazi, Sajjad Rafiei, Negin Jafarkhanloo Rezaei, Sarvin Dahmardeh, Fatemeh Farz, Zahra Naderi, Reza Arefnezhad, and Hossein Motedayyen. Micrornas and angiosarcoma: are there promising reports? Frontiers in Oncology, May 2024. URL: https://doi.org/10.3389/fonc.2024.1385632, doi:10.3389/fonc.2024.1385632. This article has 5 citations.

OpenScientist ▸
1. Disease Information
openscientist-autonomous 56 citations 2026-05-05T04:17:15.187183

1. Disease Information

Overview

Angiosarcoma is a malignant mesenchymal neoplasm of endothelial cell origin that phenotypically and functionally recapitulates normal endothelium (PMID: 38391320). It is classified among soft tissue sarcomas and represents one of the most aggressive tumor types in this category, characterized by rapid local invasion, high rates of recurrence and metastasis, and poor overall prognosis. The tumor can arise virtually anywhere in the body, with the most common sites being skin (particularly the head and neck region in elderly patients), breast (both primary and radiation-associated), liver, heart, and spleen.

Key Identifiers

Identifier Code
MONDO MONDO:0005971
ICD-10 C49 (malignant neoplasm of other connective and soft tissue); specific histology code 9120/3
ICD-O-3 Morphology 9120/3 (Hemangiosarcoma / Angiosarcoma)
MeSH D006394 (Hemangiosarcoma)
Orphanet ORPHA:263413
OMIM Not assigned as a distinct Mendelian entry; associated with Li-Fraumeni syndrome (OMIM: 151623) in some familial cases
SNOMED CT 39000009 (Angiosarcoma)

Synonyms and Alternative Names

  • Hemangiosarcoma
  • Malignant hemangioendothelioma
  • Malignant angioendothelioma
  • Lymphangiosarcoma (when arising from lymphatic endothelium)
  • Stewart-Treves syndrome (when arising in the setting of chronic lymphedema post-mastectomy)

Information Sources

The information in this report is derived from aggregated disease-level resources including the SEER database, published case series, prospective clinical trials, genomic profiling studies, and systematic reviews. Individual patient-level data are referenced where available from clinical trials and case reports.

2. Etiology

Disease Causal Factors

Angiosarcoma arises through multiple distinct etiological pathways:

Sporadic/Primary: The majority of angiosarcomas arise spontaneously without identifiable environmental exposure. These tumors are driven by somatic mutations in angiogenic signaling pathways, particularly KDR (VEGFR2) mutations found in 70% of primary mammary angiosarcomas, PIK3CA/PIK3R1 mutations (70%), and PTPRB mutations (30%) (PMID: 32123305). The KDR p.T771R hotspot mutation was identified in 6 of 10 tumors with evidence suggestive of biallelism, indicating strong selection for enhanced VEGFR2 signaling.

Radiation-Associated: Secondary angiosarcomas arise in previously irradiated fields, most commonly after breast-conserving therapy for breast carcinoma. The median latency from index radiotherapy is 9.1 years (range 3.7–46.3 years) (PMID: 38791996). These tumors are molecularly defined by near-universal MYC amplification (100% of cases) and frequent FLT4 coamplification (25%) (PMID: 20949568). The incidence of secondary breast angiosarcoma increased 3-fold from approximately 10 to 30 cases per 100,000 person-years between 1992 and 2016 (P = 0.0037) (PMID: 37725702).

Chemically-Induced: Hepatic angiosarcoma has well-established associations with environmental carcinogens. A landmark US survey (1964–1974) identified 168 cases of hepatic angiosarcoma, of which 25% were associated with known etiologic factors including vinyl chloride monomer exposure, thorotrast (thorium dioxide) use in angiography, inorganic arsenic exposure, and androgenic-anabolic steroid treatment (PMID: 7199426). Vinyl chloride exposure was first recognized as a cause of hepatic angiosarcoma in the mid-1970s among polymerization workers (PMID: 945708). More recently, aristolochic acid exposure has been implicated in Asian liver angiosarcoma cohorts, with 80% (8/10) of liver angiosarcoma cases displaying a significant SBS22 mutation signature (PMID: 41394772).

UV-Associated: Head and neck angiosarcomas in sun-exposed skin carry UV mutational signatures (SBS7), with UV-positive cases harboring significantly higher tumor mutational burden than UV-negative cases (P = 0.0294) (PMID: 37106027).

Chronic Lymphedema-Associated (Stewart-Treves Syndrome): Angiosarcoma arising in the setting of chronic lymphedema following mastectomy and axillary lymph node dissection, first described by Stewart and Treves in 1948 (PMID: 26617830).

Risk Factors

Genetic Risk Factors

  • TP53 germline variants (Li-Fraumeni syndrome): Germline TP53 pathogenic variants predispose to angiosarcoma, particularly in the context of prior radiotherapy. A novel germline TP53 variant (c.788del) was identified in a patient who developed radiation-associated angiosarcoma (PMID: 39734593). A novel germline risk allele in CHEK2 (p.P35L) was also identified in a Li-Fraumeni-like family with cardiac angiosarcoma (PMID: 36387164).
  • Xeroderma pigmentosum: Patients with XP have elevated skin cancer risk including angiosarcoma, due to defective nucleotide excision repair (PMID: 39221877).

Environmental Risk Factors

Risk Factor Associated Subtype Evidence Level
Ionizing radiation Breast, chest wall, laryngeal AS Strong — multiple cohort studies
Vinyl chloride monomer Hepatic AS Strong — established carcinogen
Thorotrast (thorium dioxide) Hepatic AS Strong — established carcinogen
Inorganic arsenic Hepatic AS Strong — established carcinogen
Aristolochic acid Hepatic AS (Asian populations) Emerging — genomic signature evidence
UV radiation Head/neck cutaneous AS Moderate — mutational signature evidence
Chronic lymphedema Extremity AS (Stewart-Treves) Strong — clinical association

Demographic Risk Factors

  • Age: Median age at diagnosis is 69 years (range 0–102) (PMID: 35478727)
  • Sex: Male predominance overall; male:female ratio approximately 3:1 for hepatic AS
  • Race/Ethnicity: Predominantly non-Hispanic Caucasian (75.4% in SEER data)

Protective Factors

No well-established genetic or environmental protective factors have been identified for angiosarcoma. Avoidance of known carcinogens (vinyl chloride, arsenic, excessive UV) reduces risk for specific subtypes. Female sex has been identified as a positive prognostic factor for hepatic angiosarcoma (HR 0.68, 95% CI 0.536–0.875, P < 0.05) (PMID: 39676119).

Gene-Environment Interactions

The interaction between germline TP53 variants and ionizing radiation represents the best-characterized gene-environment interaction in angiosarcoma. Patients with Li-Fraumeni syndrome who receive radiotherapy have significantly elevated risk of developing secondary angiosarcoma, as radiation-induced DNA damage overwhelms already-compromised DNA damage response pathways. Similarly, xeroderma pigmentosum patients exposed to UV radiation develop cutaneous angiosarcoma at increased rates due to defective nucleotide excision repair.

3. Phenotypes

Clinical Presentations by Site

Cutaneous Angiosarcoma (Head and Neck)

  • Phenotype type: Physical manifestation — raised, violaceous or erythematous plaques/nodules on sun-exposed skin
  • HPO terms: HP:0100242 (Sarcoma), HP:0000951 (Abnormality of the skin)
  • Age of onset: Typically elderly (median ~70 years)
  • Severity: Severe — aggressive local invasion with multifocal disease
  • Progression: Rapidly progressive
  • Frequency: Most common subtype of cutaneous angiosarcoma
  • QoL impact: Severe — disfiguring facial lesions cause significant psychological distress

Breast Angiosarcoma

  • Phenotype type: Physical manifestation — mass or skin changes in breast
  • HPO terms: HP:0100242 (Sarcoma), HP:0100013 (Neoplasm of the breast)
  • Onset: Primary: median age 31 years; Radiation-associated: median age 68–72 years; latency 4–12 years post-RT (PMID: 19433291)
  • Severity: Variable — graded by Rosen's method (low, intermediate, high)
  • Frequency: 0.1–0.2% of malignant breast neoplasms

Cardiac Angiosarcoma

  • Phenotype type: Clinical signs — pericardial effusion, cardiac tamponade, dyspnea
  • HPO terms: HP:0001698 (Pericardial effusion), HP:0002094 (Dyspnea)
  • Location: Predominantly right atrium
  • Severity: Severe — most aggressive primary cardiac malignancy
  • Clinical features: Hemorrhagic pericardial effusion, cardiac tamponade (PMID: 41320327)

Hepatic Angiosarcoma

  • Phenotype type: Clinical signs — abdominal pain, hepatomegaly, hepatic rupture
  • HPO terms: HP:0001392 (Abnormality of the liver), HP:0002027 (Abdominal pain)
  • Severity: Extremely poor prognosis — 3-year survival rate 6.7% (PMID: 39676119)

Splenic Angiosarcoma

  • Phenotype type: Clinical signs — acute abdominal pain, splenic rupture, hemoperitoneum
  • HPO terms: HP:0001743 (Abnormality of the spleen), HP:0002027 (Abdominal pain)
  • Severity: Nearly universally fatal — most patients die within 12 months

Pulmonary Metastatic Disease

  • Phenotype type: Symptoms — hemoptysis (73% of patients), dyspnea
  • HPO terms: HP:0002105 (Hemoptysis), HP:0002094 (Dyspnea)
  • Imaging: Bilateral, randomly distributed, variably shaped nodules with ground-glass opacities
  • Common misdiagnoses: Tuberculosis (45%), vasculitis (18%) (PMID: 28885371)

Laboratory Abnormalities

  • Anemia (from hemorrhage or microangiopathic hemolytic process)
  • Thrombocytopenia (consumptive coagulopathy / Kasabach-Merritt phenomenon)
  • Elevated LDH

4. Genetic/Molecular Information

Somatic Driver Genes and Pathogenic Variants

Primary/Sporadic Angiosarcoma

Gene Variant Type Frequency Functional Consequence Somatic/Germline
KDR (VEGFR2) Missense (T771R hotspot) 70% (mammary) Gain of function — constitutive VEGFR2 activation Somatic
PIK3CA Activating mutations (H1047R) 70% (mammary) Gain of function — PI3K pathway activation Somatic
PTPRB Inactivating mutations 30% (mammary) Loss of function — loss of VE-PTP phosphatase Somatic
TP53 Missense, frameshift 16–44% Loss of function — impaired tumor suppression Somatic
PLCG1 Activating mutations ~10% Gain of function — PLCγ1 signaling Somatic

Source: PMID: 32123305 — "Recurrent genomic alterations were identified in KDR (70%), PIK3CA/PIK3R1 (70%), and PTPRB (30%), each at higher frequencies than reported in AS across all sites. Six tumors harbored a KDR p.T771R hotspot mutation, and all seven KDR-mutant cases showed evidence suggestive of biallelism."

Head and Neck (UV-Associated) Angiosarcoma

Gene Frequency Notes
CSMD3 18% CUB and Sushi multiple domains 3
LRP1B 18% LDL receptor-related protein 1B
MUC16 18% Mucin 16
POT1 16% Protection of telomeres 1
TP53 16% Tumor protein p53

UV-positive cases had significantly higher TMB than UV-negative cases (P = 0.0294) (PMID: 37106027).

Radiation-Associated Angiosarcoma

Gene/Alteration Frequency Notes
MYC amplification (8q24) 100% Defining molecular feature
FLT4 (VEGFR3) coamplification 25%
CDKN2A/CDKN2B loss 71% (vs 39% sporadic, P = 6.92e-3) Cell cycle dysregulation
TP53 mutations 44%

Source: PMID: 20949568 — "High-level MYC amplification was found in 100% of secondary AS, but in none of the AVL or other radiation-associated sarcomas. Coamplification of FLT4 (encoding VEGFR3) was identified in 25% of secondary AS."

PMID: 25863565 — "Amplification (5- to 20-fold) of the c-myc oncogene was found in all breast radiation-induced angiosarcomas (32 tumours) but in none of the 15 primary angiosarcomas except one (7%). This study reinforces that there are true pathogenetic differences between the two types of breast angiosarcomas."

Hepatic Angiosarcoma

  • K-ras-2 point mutations found in 29% of tumors (7/24), including both sporadic (26%) and Thorotrast-induced (40%) cases. Mutations were characteristic of oxidative damage (G:C > A:T and G:C > T:A) (PMID: 9010458).
  • Aristolochic acid signature (SBS22) identified in 80% of Asian liver angiosarcoma cases (PMID: 41394772).

Epigenetic Information

  • Radiation-associated angiosarcomas show a distinct transcriptome signature featuring upregulation of lymphatic endothelial markers (PDPN, PROX-1, VEGFR3, EDNRA), suggesting origin from radiation-stimulated lymphatic endothelial cells (PMID: 22532251).
  • MYC amplification drives upregulation of the miR-17-92 cluster with concomitant downregulation of thrombospondin-1 (THBS1), linking MYC to angiogenic promotion (PMID: 22383169).
  • Alternative lengthening of telomeres (ALT) activation has been identified as a hallmark of liver angiosarcoma (PMID: 41394772).

Chromosomal Abnormalities

  • MYC amplification at 8q24.21 (5- to 20-fold) — hallmark of radiation-associated AS
  • CDKN2A/CDKN2B losses at 9p21.3 — more frequent in radiation-associated (71%) than sporadic (39%) sarcomas (P = 6.92e-3) (PMID: 31243333)
  • Gains of 17q24.2-17qter identified in subsets of post-radiation angiosarcomas
  • Rare ALK rearrangements reported in epithelioid angiosarcoma (PMID: 41836264)

5. Environmental Information

Environmental Factors

Agent Mechanism Tumor Site Key Evidence
Vinyl chloride monomer (VCM) Chloroethylene oxide metabolite causes DNA adducts; K-ras mutations Liver PMID: 945708, PMID: 7199426
Thorotrast (thorium dioxide) Alpha radiation from retained contrast agent Liver PMID: 7199426, PMID: 9010458
Inorganic arsenic Oxidative stress, epigenetic changes Liver PMID: 10074736, PMID: 7199426
Aristolochic acid DNA adduct formation (SBS22 signature) Liver (Asian) PMID: 41394772
Ionizing radiation (therapeutic) DNA DSBs, genomic instability, MYC amplification Breast, chest wall, larynx PMID: 38791996
UV radiation Pyrimidine dimers, UV mutational signature (SBS7) Head/neck skin PMID: 37106027
  • CHEBI terms: Vinyl chloride (CHEBI:28509), Arsenic (CHEBI:22632), Aristolochic acid (CHEBI:22574)

Lifestyle Factors

No specific lifestyle factors (smoking, diet, exercise, alcohol) have been definitively linked to angiosarcoma risk beyond the occupational and environmental exposures listed above. Androgenic-anabolic steroid use has been associated with hepatic angiosarcoma in rare cases (PMID: 7199426).

Infectious Agents

Viral hepatitis (HBV, HCV) has been investigated but not confirmed as a major risk factor for hepatic angiosarcoma. In a Taiwanese study, 2 of 9 patients had hepatitis C infection and none had hepatitis B, with no evidence supporting a major viral role (PMID: 22200164).

6. Mechanism / Pathophysiology

Molecular Pathways

Angiosarcoma pathogenesis involves convergent activation of several key signaling cascades:

VEGF/VEGFR Signaling (Primary Pathway) - KDR (VEGFR2) activating mutations drive autocrine/paracrine VEGF signaling - FLT4 (VEGFR3) amplification in radiation-associated AS enhances lymphangiogenic signaling - VEGF stimulates tumor proliferation via VEGFR2 phosphorylation (PMID: 23522954)

PI3K-AKT-mTOR Pathway - PIK3CA activating mutations (H1047R hotspot) found in both human AS and canine HSA - mTOR/S6K activation demonstrated in vascular tumors including angiosarcoma; rapamycin inhibits growth (PMID: 23938603) - Combined MEK + mTOR inhibition shows synergistic anti-tumor effects in AS tumorgrafts (PMID: 25955301)

RAS-MAPK Pathway - NRAS activating mutations (G61R) in 24% of canine HSA - K-ras-2 mutations in hepatic AS (29%), characteristic of oxidative damage - MEK inhibitor sensitivity demonstrated in AS tumorgraft models

MYC Signaling (Radiation-Associated) - MYC amplification → upregulation of miR-17-92 cluster → suppression of THBS1 → enhanced angiogenesis (PMID: 22383169) - MYC also drives cell cycle progression and metabolic reprogramming

Wnt/β-Catenin Pathway - SFRP2 overexpression activates calcineurin/NFATc3 pathway and β-catenin signaling - Anti-SFRP2 monoclonal antibody reduced angiosarcoma tumor volume by 58% (P = 0.004) (PMID: 23604067)

Tie2/Angiopoietin Pathway - Tie2 universally expressed in human angiosarcomas - Tie2 antagonism combined with VEGFR inhibition shows synergistic anti-tumor effects (PMID: 22431921)

Causal Chain: From Trigger to Clinical Manifestation

Environmental trigger (radiation/UV/chemical)
    OR
Sporadic somatic mutations
│
▼
Endothelial cell DNA damage / Oncogenic activation
(MYC amplification | KDR/PIK3CA mutations | K-ras mutations)
│
▼
Constitutive activation of:
  - VEGF/VEGFR signaling → proliferation
  - PI3K/AKT/mTOR → survival, metabolism
  - RAS/MAPK → growth, differentiation
  - MYC → cell cycle, angiogenesis (via miR-17-92/THBS1)
│
▼
Loss of cell cycle control (CDKN2A/p53 loss)
│
▼
Uncontrolled endothelial proliferation
Aberrant vascular channel formation
│
▼
Local invasion, hemorrhage, distant metastasis

Cellular Processes

  • Angiogenesis (GO:0001525) — central to tumor biology; tumor cells form dysfunctional vascular channels
  • Cell proliferation (GO:0008283) — driven by VEGFR, PI3K, and MAPK signaling
  • Apoptosis resistance (GO:0006915) — ROCK knockdown enhances survival through reduced caspase cleavage (PMID: 22934846)
  • Cell migration (GO:0016477) — essential for invasion and metastasis
  • Inflammation — gene expression profiling identifies inflammation as a distinguishing feature (PMID: 21062482)

Cell Types Involved

  • Vascular endothelial cells (CL:0000071) — cell of origin
  • Lymphatic endothelial cells (CL:0002138) — particularly in radiation-associated AS
  • Tumor-infiltrating T cells (CL:0000084) — CD3+, CD4+, CD8+ cells correlate with immunotherapy response
  • Tumor-associated macrophages — contribute to immunosuppressive microenvironment

Immune System Involvement

The tumor microenvironment of angiosarcoma is characterized by: - Variable immune infiltration — higher TIL density correlates with better immunotherapy response - PD-L1 expression in 32% of post-radiation breast AS specimens (PMID: 41693531) - Upregulation of immune checkpoints (CTLA4, LAG3, PD-1, CD86) in tumor-infiltrating immune cells (PMID: 40575034) - CXCL12-CXCR4 axis as a crucial mediator of the TME (PMID: 40474296) - Lower immune infiltrate at tumor periphery associated with more aggressive behavior (PMID: 31243333)

Single-Cell and Spatial Transcriptomics Findings

Single-cell RNA sequencing of breast angiosarcoma revealed significant differences in perivascular cells, fibroblasts, T cells, endothelial cells, and myeloid cells compared to invasive breast cancer. Key genes FAT4, KDR, FN1, and KIT were highly expressed in angiosarcoma endothelial cells, correlating with poor prognosis (PMID: 40474296).

Spatial transcriptomics of head and neck angiosarcoma revealed topological immune landscapes with distinct spatial organization of immune cell populations (PMID: 37106027).

Single-cell transcriptomic analysis of pancreatic angiosarcoma liver metastasis demonstrated marked upregulation of NF-κB, HIF-1, and MYC signaling, with an immunosuppressive and angiogenic tumor ecosystem (PMID: 40575034).

7. Anatomical Structures Affected

Organ Level

Primary Sites:

Site Frequency UBERON Term
Skin (head/neck/scalp) Most common overall UBERON:0002097 (skin of body)
Breast Common (primary and secondary) UBERON:0000310 (breast)
Liver 2–5% of cases UBERON:0002107 (liver)
Heart (right atrium) Rare UBERON:0002078 (right cardiac atrium)
Spleen Rare UBERON:0002106 (spleen)
Deep soft tissue ~24% in some series UBERON:0000479 (tissue)
Bone ~2% UBERON:0001474 (bone element)

Common Metastatic Sites: - Lung (most common) — UBERON:0002048 - Liver — UBERON:0002107 - Bone — UBERON:0001474 - Lymph nodes — UBERON:0000029 - Brain — UBERON:0000955

Tissue and Cell Level

  • Vascular endothelium (UBERON:0001986) — tissue of origin
  • Lymphatic endothelium — particularly in radiation-associated subtypes
  • Cell populations: Endothelial cells (CL:0000071), pericytes (CL:0000669)

Subcellular Level

  • Cell membrane (GO:0005886) — VEGFR2, Tie2 receptor signaling
  • Nucleus (GO:0005634) — MYC transcription factor activity, TP53 function
  • Cytoplasm (GO:0005737) — PI3K/AKT/mTOR signaling cascade

8. Temporal Development

Onset

  • Primary angiosarcoma: Typically adult-onset, median age 69 years; primary breast AS median age 31 years
  • Radiation-associated AS: Median latency 9.1 years (range 3.7–46.3) from index radiation
  • Chemically-induced hepatic AS: Latency 20–40+ years from exposure onset
  • Onset pattern: Insidious — often misdiagnosed due to nonspecific presentation

Progression

Staging: The AJCC staging system for soft tissue sarcomas applies. At presentation, tumors are frequently high grade (Grade III 17.2%, Grade IV 19%, unknown 50.6%) but half are considered localized (PMID: 35478727).

Progression Rate: Rapidly progressive — median PFS 7 months, median OS 20 months across all subtypes (PMID: 40500777).

Disease Course: Aggressive, progressive course with high rates of local recurrence and distant metastasis. 12 of 36 patients (33%) developed local recurrence and 12 developed metastasis in one head/neck AS series (PMID: 38391320).

Critical Periods

Early diagnosis and complete surgical resection represent the critical window for optimal outcomes. Once metastatic disease develops, prognosis is uniformly poor. The median OS for patients with pulmonary metastases was only 5.0 months (PMID: 28885371).

9. Inheritance and Population

Epidemiology

  • Incidence: Age-adjusted incidence rate approximately 1.4 per million per year (PMID: 35478727)
  • Prevalence: Extremely rare — <1–2% of all soft tissue sarcomas
  • SEER data: 5,135 patients identified between 1975 and 2016

Inheritance Patterns

Angiosarcoma is predominantly a sporadic cancer without Mendelian inheritance. However: - Li-Fraumeni syndrome (autosomal dominant TP53 mutations) — increased risk, especially with radiation exposure - Xeroderma pigmentosum (autosomal recessive) — increased risk of UV-associated AS - Familial cases: Rare; a CHEK2 p.P35L variant was identified in a family with cardiac angiosarcoma (PMID: 36387164)

Population Demographics

  • Sex ratio: Overall slight male predominance (46% male in SEER); hepatic AS has strong male predominance (~3:1); breast AS almost exclusively female
  • Race/Ethnicity: Non-Hispanic Caucasian 75.4%; Non-Hispanic Asians/Pacific Islanders overrepresented in hepatic AS (17%) (PMID: 39676119)
  • Age distribution: Predominantly elderly; median age 69 years overall; younger for primary breast AS (median 31)
  • Geographic variation: Higher liver AS incidence in Asia (aristolochic acid exposure); historically elevated in industrial areas with vinyl chloride exposure

10. Diagnostics

Histopathology and Immunohistochemistry

Histological diagnosis relies on identification of malignant endothelial cells forming abnormal vascular channels. Morphologic spectrum ranges from well-differentiated vasoformative patterns to poorly differentiated solid sheets of epithelioid or spindle cells.

Essential IHC Panel:

Marker Sensitivity Specificity Notes
CD31 ~100% High Most sensitive endothelial marker
ERG ~95% High Nuclear transcription factor
CD34 40–80% Moderate May be negative in poorly differentiated AS
FLI1 High Moderate Nuclear marker
Factor VIII Low-moderate High Less sensitive
D2-40 Variable — Positive in lymphatic differentiation
Claudin-5 100% in AS High vs mesothelioma Distinguishes AS from mesothelioma (PMID: 32777673)

MYC IHC: c-MYC immunostain is consistently positive in radiation-associated AS and negative/weakly positive in primary AS — serves as a diagnostic marker for distinguishing these subtypes (PMID: 34392127, PMID: 24457083).

MYC FISH: Confirms MYC amplification with 100% concordance with protein expression in mammary AS (PMID: 24457083).

Imaging Studies

  • MRI: Preferred for soft tissue characterization; hemorrhagic, heterogeneously enhancing masses
  • CT: Assessment of extent and metastatic disease
  • PET-CT: Useful for staging and response assessment
  • Cardiac MRI: Superior to echocardiography for detecting cardiac masses (PMID: 28885371)

Molecular/Genetic Testing

  • Targeted NGS panels: Identify actionable mutations in KDR, PIK3CA, TP53, NRAS
  • MYC FISH: Diagnostic for radiation-associated vs primary AS
  • TMB assessment: Predictive of immunotherapy response in UV/radiation-associated subtypes
  • Whole-exome sequencing: For comprehensive genomic profiling and germline testing

Differential Diagnosis

Condition Distinguishing Features
Atypical vascular lesion (AVL) No MYC amplification; bland cytology
Kaposi sarcoma HHV-8 positive
Epithelioid hemangioendothelioma WWTR1-CAMTA1 fusion; less aggressive
Melanoma S100+, SOX10+, Melan-A+; CD31-negative
Poorly differentiated carcinoma Cytokeratin+, CD31-negative (note: AS can express keratins)
Pleural mesothelioma Calretinin+, claudin-5 negative (PMID: 32777673)

11. Outcome/Prognosis

Survival and Mortality

Metric Value Source
Overall 5-year survival 26.7% (95% CI 25.4–28.1%) PMID: 35478727
Median PFS 7 months PMID: 40500777
Median OS 20 months PMID: 40500777
5-year OS, cutaneous AS 12% (single cohort) PMID: 40712262
5-year OS, bone AS 15% PMID: 40914676
Hepatic AS 3-year survival 6.7% PMID: 39676119
Cutaneous vs non-cutaneous median OS 36 vs 9 months (P = 0.04) PMID: 40712262
Pulmonary metastatic disease median OS 5.0 months PMID: 28885371

Prognostic Factors

Negative prognostic factors (multivariate): - Age > 70 years (HR 1.67, P < 0.05) - No surgical intervention (HR 2.29, P < 0.001) - Distant stage (HR 2.54, P < 0.001) - Angiosarcoma histology (HR 2.95 for local relapse in superficial sarcomas, P < 0.001) (PMID: 40961809) - Higher tumor grade - Larger tumor size - Non-cutaneous location

Positive prognostic factors: - Female sex (HR 0.68 for hepatic AS) - Localized disease - Complete surgical resection with R0 margins - Younger age

Complications

  • Hemorrhage (tumor rupture, especially splenic and hepatic)
  • Disseminated intravascular coagulation
  • Cardiac tamponade (cardiac AS)
  • Treatment-related thrombotic microangiopathy (PMID: 41177756)

12. Treatment

Surgical Treatment

Wide surgical excision is the mainstay of treatment for localized angiosarcoma. In SEER data, 66.1% of patients underwent surgery (PMID: 35478727). Complete resection with negative margins (R0) is critical — patients without R0 margins had significantly worse outcomes (HR 2.60 for LRFS, P < 0.001; HR 2.02 for OS, P < 0.001) (PMID: 40961809).

  • MAXO terms: MAXO:0000004 (surgical procedure), MAXO:0000015 (mastectomy)

Chemotherapy

First-line agents: - Paclitaxel — anti-angiogenic and cytotoxic; widely used for cutaneous AS - Doxorubicin/liposomal doxorubicin — standard for soft tissue sarcomas - Gemcitabine ± docetaxel — alternative regimen

Neoadjuvant chemotherapy: Applied to improve R0 resection rates; response evenly divided between poor (Grades I–II) and good responders (Grades III–IV) (PMID: 38722225).

  • MAXO terms: MAXO:0000058 (chemotherapy)

Immunotherapy

Immune checkpoint inhibitors represent an emerging treatment paradigm, particularly for UV- and radiation-associated subtypes:

Cemiplimab (anti-PD-1): Phase II CEMangio trial in secondary AS — ORR 27.8% (4 PR, 1 CR), median PFS 3.7 months, median OS 13.1 months. High intratumoral CD3+ (P = 0.019), CD4 (P = 0.046), and CD8+ density associated with response (PMID: 40632032).

Cabozantinib + nivolumab: Alliance A091902 second-line — ORR 59%, demonstrating significant efficacy in both cutaneous and non-cutaneous AS (PMID: 40056281).

Dual ICI (SWOG S1609): ORR 25% — suggests potential benefit but limited activity in cutaneous disease (PMID: 40056281).

Pembrolizumab: Sustained response reported in PD-L1-expressing angiosarcoma; one patient achieved marked liver disease shrinkage with no new lesions for 8+ months off therapy (PMID: 28716069).

  • MAXO terms: MAXO:0001360 (immune checkpoint inhibitor therapy)

Targeted Therapy

  • Anti-VEGF/VEGFR agents: Bevacizumab, pazopanib, sorafenib, sunitinib — variable efficacy; sunitinib showed limited activity against AS in preclinical models (PMID: 23522954)
  • mTOR inhibitors: Rapamycin shows synergy with MEK inhibitors in AS (PMID: 25955301)
  • Anti-SFRP2 antibody: Reduced AS tumorgraft volume by 58% (P = 0.004) (PMID: 23604067)
  • CDK4/6 inhibitors: Suggested by frequent cell cycle dysregulation (PMID: 41246336)
  • Anlotinib, lenvatinib: Multi-kinase inhibitors used in refractory disease

Radiation Therapy

Adjuvant radiation therapy is used for local control, particularly for head/neck cutaneous AS. However, radiation is used cautiously for radiation-associated subtypes.

  • MAXO terms: MAXO:0000014 (radiation therapy)

Experimental Treatments

  • Photodynamic therapy (PDT): Promising for recurrent superficial cutaneous AS (PMID: 40364848)
  • IFN-alpha: Inhibited angiosarcoma growth in murine models by 71–79% through angiogenesis inhibition (PMID: 16689662)
  • Anti-extracellular vimentin vaccine (iBoost): In canine HSA, median OS increased from 136 to 235 days when combined with doxorubicin (PMID: 41009669)
  • Toripalimab + gemcitabine/nab-paclitaxel: Achieved 9-month partial response in radiation-associated laryngeal AS (PMID: 41496010)

13. Prevention

Primary Prevention

  • Occupational safety: Elimination of vinyl chloride exposure through engineering controls and regulatory limits — largely achieved in developed countries
  • Arsenic exposure reduction: Clean water initiatives in endemic areas
  • UV protection: Sun-protective measures for head/neck AS prevention
  • Judicious use of radiotherapy: Appropriate patient selection and field design

Secondary Prevention

  • Surveillance after breast radiation: Clinical monitoring for skin changes in irradiated fields, given 3-fold increased incidence of secondary breast AS. Hemangiosarcoma SIR was 27.11 (95% CI 21.6–33.61) on breast/trunk skin after breast radiation (PMID: 38457179)
  • Monitoring chronic lymphedema patients: Regular examination for Stewart-Treves syndrome
  • Germline TP53 testing: In patients with early-onset or radiation-associated AS, to identify Li-Fraumeni syndrome for cancer surveillance in families

Tertiary Prevention

  • Close surveillance for local recurrence and metastatic disease after treatment
  • Multidisciplinary follow-up with sarcoma specialists
  • Prompt treatment of recurrences

14. Other Species / Natural Disease

Canine Hemangiosarcoma

Canine hemangiosarcoma (HSA) is the most important comparative model for human angiosarcoma. It is a common spontaneous malignancy in dogs, particularly in golden retrievers, German shepherds, and Labrador retrievers.

Taxonomy: Canis lupus familiaris (NCBI Taxon: 9615)

Genomic Similarities: Whole-exome sequencing of 47 golden retriever HSAs revealed striking parallels with human angiosarcoma: - PIK3CA mutations: 46% (vs. 70% in human primary mammary AS) - TP53 mutations: 66% - NRAS mutations: 24% (G61R hotspot) - PLCG1 mutations: 4% - PTEN mutations: 6%

"Overall, we identified potential driver mutations in over 90% of the cases, including well-documented (in human cancers) oncogenic mutations in PIK3CA (46%), PTEN (6%), PLCG1(4%), and TP53 (66%), as well as previously undetected recurrent activating mutations in NRAS (24%)" (PMID: 32210430).

"Canine tumors share mutational hotspots with human tumors in oncogenes including PIK3CA, KRAS, NRAS, BRAF, KIT and EGFR. Hotspot mutations with significant association to tumor type include NRAS G61R and PIK3CA H1047R in hemangiosarcoma" (PMID: 37414794).

Clinical Features: Splenic HSA is the most common form, characterized by rapid growth, splenic rupture, and hemoperitoneum. Median survival after splenectomy alone is 1–3 months; with adjuvant doxorubicin, 5–7 months (PMID: 41009669). Stage III disease and hepatic metastases are associated with significantly decreased survival (P < 0.001) (PMID: 41742582).

Gene expression profiling identified inflammation and angiogenesis as distinguishing features of canine HSA compared to non-malignant endothelial cells (PMID: 21062482).

Other Species

Angiosarcoma/hemangiosarcoma is recognized in multiple mammalian species but is particularly prevalent in dogs. The shared mutational landscape and biological behavior make canine HSA an invaluable One Health model for drug development.

15. Model Organisms

In Vivo Models

Canine Hemangiosarcoma (Spontaneous) - Model type: Large animal, spontaneous - Phenotype recapitulation: Excellent — shared driver mutations, aggressive behavior, vascular origin, metastatic patterns - Applications: Drug development, immunotherapy testing, biomarker discovery - Limitations: Heterogeneous genetic background; breed-specific predispositions may not fully reflect human disease - Key cell isolates: Used for tumorgraft models and in vitro drug screening

Murine Models - SVR cell line: Transformed murine endothelial cells expressing oncogenic H-ras; forms angiosarcomas in nude mice (PMID: 16689662) - MS1-VEGF cell line: Murine endothelial cells expressing VEGF; low-grade angiosarcoma model - HAMON xenograft: Human angiosarcoma cell line xenograft in immunodeficient mice; expresses CD31, VEGFR2 (PMID: 23522954) - Applications: Drug testing (MEK/mTOR inhibitors, anti-angiogenic agents, immunotherapy)

In Vitro Models

  • Human angiosarcoma cell lines (limited availability)
  • Canine HSA cell isolates — used for drug combination studies
  • Patient-derived xenografts (PDX) / tumorgrafts

Model Limitations

  • Murine xenograft models lack intact immune system
  • Cell line models may not capture tumor heterogeneity
  • Canine HSA, while closely related, is not identical to human AS (e.g., MYC amplification is not a feature of canine HSA)
  • Limited availability of human AS cell lines due to disease rarity

Key Findings — Detailed Evidence

Finding 1: Angiosarcoma is a Rare, Aggressive Vascular Malignancy with Poor Prognosis

Analysis of 5,135 patients in the SEER database (1975–2016) demonstrated an age-adjusted incidence rate of approximately 1.4 per million, with the majority of patients presenting as non-Hispanic Caucasian (75.4%) with a median age of 69 years. Tumor grades were predominantly high at presentation (Grade III 17.2%, Grade IV 19%), and the overall 5-year survival was 26.7% (95% CI 25.4–28.1%). A single-institution cohort of 128 patients confirmed poor outcomes with median PFS of 7 months and median OS of 20 months. Importantly, non-cutaneous angiosarcoma had significantly worse median OS than cutaneous disease (9 vs 36 months, P = 0.04), highlighting the prognostic importance of anatomic site.

Finding 2: MYC Amplification Defines Radiation-Associated Angiosarcoma

MYC amplification at 8q24 (5- to 20-fold) is present in 100% of radiation-associated breast angiosarcomas but in only 0–7% of primary angiosarcomas, establishing it as both a diagnostic biomarker and a mechanistic driver. FLT4 (VEGFR3) coamplification occurs in 25% of secondary AS. Downstream, MYC amplification drives upregulation of the miR-17-92 cluster and suppression of the anti-angiogenic factor thrombospondin-1, providing a mechanistic link between MYC and the angiogenic phenotype.

Finding 3: Primary Angiosarcoma Has Distinct Angiogenic Driver Mutations

Primary mammary angiosarcomas harbor recurrent activating mutations in KDR (70%), PIK3CA/PIK3R1 (70%), and PTPRB (30%), all at higher frequencies than in angiosarcoma across all sites. The KDR T771R hotspot mutation shows evidence of biallelism, indicating strong selection for constitutive VEGFR2 activation. Head/neck UV-associated angiosarcomas have a distinct mutational profile dominated by CSMD3, LRP1B, MUC16, POT1, and TP53 mutations with high TMB.

Finding 4: Canine Hemangiosarcoma as a Comparative Model

Canine hemangiosarcoma shares driver mutations in PIK3CA (46%), TP53 (66%), and NRAS (24%) with human angiosarcoma, with identical hotspot mutations (PIK3CA H1047R, NRAS G61R). This genomic convergence, combined with similar clinical behavior, validates canine HSA as a One Health model for therapeutic development.

Finding 5: Immunotherapy Shows Emerging Activity

Immune checkpoint inhibitors demonstrate meaningful activity in angiosarcoma, particularly in UV- and radiation-associated subtypes. The CEMangio phase II trial showed an ORR of 27.8% with cemiplimab in secondary AS, with high intratumoral CD3+ and CD8+ density predicting response. The cabozantinib-nivolumab combination achieved a remarkable 59% ORR in second-line, suggesting synergy between anti-angiogenic and immune checkpoint blockade.

Finding 6: Environmental Carcinogens Cause Distinct Subtypes

Vinyl chloride, thorotrast, arsenic, ionizing radiation, and UV radiation each cause distinct angiosarcoma subtypes through different mutagenic mechanisms — from oxidative DNA damage (K-ras mutations in hepatic AS) to DNA adduct formation (aristolochic acid SBS22 signature) to direct chromosomal amplification events (MYC in radiation-associated AS).

Mechanistic Model: Integrated Pathogenesis of Angiosarcoma Subtypes

┌─────────────────────────────────────────────────────────────────┐
│                    ANGIOSARCOMA SUBTYPES                        │
├─────────────┬──────────────┬────────────┬──────────┬────────────┤
│  Primary/   │  Radiation-  │ UV-Head/   │ Chemical │ Lymphedema │
│  Sporadic   │  Associated  │   Neck     │ Hepatic  │ (Stewart-  │
│             │              │            │          │  Treves)   │
├─────────────┼──────────────┼────────────┼──────────┼────────────┤
│ KDR (70%)   │ MYC amp      │ UV sig     │ K-ras    │ Unknown    │
│ PIK3CA(70%) │ (100%)       │ (SBS7)     │ (29%)    │ drivers    │
│ PTPRB (30%) │ FLT4 (25%)   │ High TMB   │ SBS22    │            │
│             │ CDKN2A loss  │ CSMD3,POT1 │ (AA)     │            │
├─────────────┼──────────────┼────────────┼──────────┼────────────┤
│             │              │            │          │            │
│   VEGFR2 ←──→  MYC/miR ←──→  DNA       │  Oxid.  │ Chronic    │
│   PI3K/AKT  │  17-92      │  repair    │  damage  │ inflam.    │
│   mTOR      │  THBS1↓     │  defects   │          │            │
├─────────────┴──────────────┴────────────┴──────────┴────────────┤
│            CONVERGENT DOWNSTREAM PATHWAYS                       │
│  ┌─────────────────────────────────────────────────────┐       │
│  │ Angiogenesis ↑ │ Cell cycle ↑ │ Apoptosis ↓        │       │
│  │ VEGF/VEGFR    │ CDKN2A loss  │ TP53 loss           │       │
│  │ Tie2/Ang      │ MYC          │ PI3K/AKT            │       │
│  └─────────────────────────────────────────────────────┘       │
│                          ↓                                      │
│           Malignant Endothelial Proliferation                   │
│           Aberrant Vascular Channel Formation                   │
│           Local Invasion → Hemorrhage → Metastasis              │
└─────────────────────────────────────────────────────────────────┘

Evidence Base

Landmark Papers

Paper PMID Key Contribution
SEER analysis (2022) 35478727 Comprehensive epidemiology: 5,135 patients, 26.7% 5-year OS
Manner et al. (2010) 20949568 MYC amplification in 100% of secondary AS, FLT4 in 25%
Italiano et al. (2020) 32123305 KDR/PIK3CA/PTPRB mutations in primary mammary AS
Wang et al. (2020) 32210430 Canine HSA genomic landscape — PIK3CA, TP53, NRAS drivers
CEMangio trial (2025) 40632032 Cemiplimab ORR 27.8% in secondary AS with biomarker correlates
US hepatic AS survey (1979) 7199426 Established VCM, thorotrast, arsenic as causes
Guo et al. (2012) 22383169 MYC → miR-17-92 → THBS1 mechanistic link
Angiosarcoma Project (2020) 32042194 Patient-partnered genomic and clinical discovery platform
Spatial transcriptomics (2023) 37106027 UV signature and immune topology in head/neck AS
Genomic comparison rad vs sporadic (2019) 31243333 CDKN2A/B losses, transcriptomic subtypes

Limitations and Knowledge Gaps

  1. Rarity precludes large randomized trials: Most treatment evidence comes from retrospective series, small phase II trials, and case reports. No phase III randomized trials exist for any angiosarcoma treatment.

  2. Molecular heterogeneity: The marked molecular diversity across subtypes makes unified treatment approaches challenging. Better subtype-specific trial designs are needed.

  3. Limited understanding of primary sporadic AS pathogenesis: While radiation-associated and chemical subtypes have clear initiating events, the triggers for primary sporadic AS remain largely unknown.

  4. Biomarker validation: Predictive biomarkers for immunotherapy response (TMB, PD-L1, TIL density) require prospective validation in larger cohorts.

  5. Incomplete genomic landscape: Whole-genome sequencing has been performed on limited cohorts; non-coding mutations, structural variants, and epigenomic alterations remain underexplored.

  6. Lack of standardized staging: The AJCC staging system for soft tissue sarcomas may not adequately capture the prognostic nuances of angiosarcoma across different anatomic sites.

  7. Limited cell line resources: Few authenticated human angiosarcoma cell lines exist, hampering preclinical drug development.

  8. Underrepresentation of non-Western populations: Most genomic and clinical data derive from Western populations; the role of aristolochic acid in Asian liver AS is only now being characterized.

Proposed Follow-up Experiments/Actions

  1. Prospective biomarker-stratified clinical trials: Design trials stratifying patients by molecular subtype (MYC-amplified, KDR-mutant, high-TMB) to match targeted therapies to specific driver alterations.

  2. Combinatorial immunotherapy-TKI trials: Given the 59% ORR with cabozantinib-nivolumab, expand this approach with additional anti-angiogenic/ICI combinations across subtypes.

  3. Comprehensive genomic profiling: Perform whole-genome sequencing on a large, multi-institutional angiosarcoma cohort to identify non-coding drivers, structural variants, and novel therapeutic targets.

  4. Canine comparative trials: Leverage canine HSA as a platform for rapid therapeutic testing — particularly for PIK3CA inhibitors, NRAS-targeted approaches, and immunotherapy combinations.

  5. Single-cell multi-omics: Expand scRNA-seq studies to characterize the tumor microenvironment across subtypes, with focus on identifying determinants of immunotherapy response.

  6. Liquid biopsy development: Develop ctDNA assays for MYC amplification, KDR mutations, and other actionable alterations to enable non-invasive diagnosis and monitoring.

  7. CDK4/6 inhibitor trials: Given frequent CDKN2A loss across subtypes, test CDK4/6 inhibitors (palbociclib, ribociclib) as single agents and in combinations.

  8. MEK + mTOR combination trials: Translate preclinical synergy data into clinical trials for patients with RAS/MAPK pathway-activated angiosarcomas.

  9. Epidemiological surveillance: Monitor aristolochic acid-associated liver angiosarcoma in Asian populations and implement public health interventions.

  10. Patient-partnered research: Expand the Angiosarcoma Project (ASCProject) to increase patient enrollment, diversity, and longitudinal follow-up for this rare disease.

Report generated: 2026-05-05 Sources: SEER database analyses, genomic profiling studies, clinical trials, systematic reviews, and comparative oncology studies spanning 93 reviewed publications.