Malignant vascular tumor with tumor cells showing endothelial differentiation with morphological and immunohistochemical features of endothelial cells
Incidence – 2%-4% of soft tissue sarcomas
Etiology
Predisposing factors – chronic lymphedema and radiation
Molecular and genetic factors-
Angiosarcoma over express genes which are implicated in angiogenesis, including genes for
vascular specific receptor kinases
TLE 1 (transducin-like enhancer of split 1)
KDR (VEGFR2) [Kinase insert Domain Receptor]
SNRK (SNF related kinase)
TEK
FLT4 (VEGFR3)
Angiosarcomas are further subdivided into two genomic subgroups
Radiation induced lesions – overexpression of LYN and PRKCO
Non-radiation induced lesions – overexpression of FLT1 and AKT3
high levels of MYC amplification is seen in lymphedema and post irradiation associated angiosarcoma
Other gene abnormalities in angiosarcomas are
activating mutations of KDR
PTRB mutations with or without concurrent PLCG1 mutations
CIC gene abnormalities
clinical subtypes of Angiosarcomas are-
Primary cutaneous angiosarcoma
Angiosarcoma associated with lymphedema
Angiosarcoma of breast
Angiosarcoma of soft tissue
Radiation induced angiosarcoma
PRIMARY CUTANOUS ANGIOSARCOMA
accounts for 1.5% of all cases
Age – usually elderly, after 7th decades
Gender – No gender predilection
Site – half of them occur in head and neck, scalp, face and upper forehead
Clinical presentation
Poorly defined, rapidly growing painful masses
presentation is variable with bruise like areas having irregular indurated borders to advanced lesions presenting as elevated, nodular and occasionally ulcerated lesion
Gross – poorly defined hemorrhagic areas that ulcerate or flatten the overlying skin
Cut section – microcystic or spongelike with blood filled spaces
Tumor extends beyond apparent gross confines and extensively involves dermis
Microscopy
Well differentiated angiosarcomas resemble hemangioma, but in contrast to hemangiomas, vascular channels in angiosarcoma are imperfectly formed and are interconnected with another forming a network of sinuses
Vascular channels in angiosarcoma dissect through dermal collagen and fascia, splitting apart subcutaneous fat cells and isolating adnexal structures
Periphery of the tumor shows dilated lymphatic channels, chronic inflammatory cells, small capillaries in which piling up and tufting of endothelium occurs suggesting malignant change
Poorly differentiated angiosarcomas are composed of cells with high nuclear grade showing prominent nucleoli and may be spindled to rounded
solid areas typically show sheets of spindled to epithelioid cells with abundant eosinophilic to amphophilic cytoplasm, large vesicular nuclei and may be associated with blood lakes, hemorrhages and organizing hematoma
intraluminal budding, hobnail cells can also be seen
Immunohistochemistry
Tumor cells re positive for
CD31- membranous
ERG
CD34
factor VIII
rarely they express neuroendocrine tumor markers like CD56
outer layer of pericytes 9SMA +) is usually absent
Keratin and EMA expression is seen in epitelioid subtypes
Strong MYC expression is seen in Irradiation associated and lymphedema associated angiosarcoma
ANGIOSARCOMA ASSOCIATED WITH LYMPHEDEMA
Mostly seen in patients after mastectomy and axillary lymph node dissection, on abdominal wall after Lymph node dissection for carcinoma penis and arms or legs are affected by congenital causes
Develops after 4 to 10 years of lymphedema due to surgery, idiopathic, traumatic and filarial lymphedema
Recent association with obesity has also been documented
Age – usually above 70 years. Tumors occur in younger individuals (4th and 5th decades) if it occurs in congenital or idiopathic lymphedema
Clinical findings –
occurs in 1% of women who has undergone mastectomy
presents as deep dermal lesions appearing as mottled purple – red hue to the overlying skin
superficial lesions – presents as nodule that coalesce to form large, polypoidal growth or may ulcerate
Microscopy
Characteristic finding in lymphedema associated angiosarcoma is – capillary sized vessels lined by malignant cells that infiltrate skin and soft tissue
Lumens may be filled with clear fluid or empty or engorged with erythrocytes
Lymphocytes are occasionally found around the neoplastic vessels
These lesions are associated with lymphangiomatosis which represents premalignant changes of lymphatic vessels
Vessels are dilated and form diffuse network throughout the soft tissue which are lined by plump endothelial cells having hyperchromatic nuclei
MYC amplification is seen in most of the cases
ANGIOSARCOMA OF BREAST
Arise in mammary parenchyma and may also extend secondary to the skin
True parenchymal angiosarcoma account for approximately 1 in 1700 to 2000 primary malignant tumors of the breast
Occurs in women usually in 3rd and 4th decade
Clinical presentation – intramammary mass averaging about 5 to 7cms associated with discolouration of overlying skin
Metastasis can occur to regional lymph nodes and contralateral breast
Gross – poorly defined, hemorrhagic, spongy mass surrounded by a rim of engorged vessels
Microscopy
Breast angiosarcoma are graded as
Grade I: well-formed anastomotic vascular channels that permeate fat and breast. vessels are lined by single layer of endothelail cells with minimal atypia
Grade II: more cellular. vessels are lined by cells with distinct nuclear atypia and multilayering, but solid areas are not present
Grade III: compose of sheets of cells of high nuclear grade interrupted by intralesional blood lakes
post-irradiation cutaneous angiosarcoma involving the breast show MYC amplification which is not seen in primary mammary angiosarcoma
ANGIOSARCOMA OF SOFT TISSUE
Angiosarcoma arising from deep soft tissue account for about 10% of all angiosarcomas
Age – can occur at any age
Are associated with inherited diseases like Neurofibromatosis, Klippel-Trenaunay syndrome, Maffuci syndrome, synthetic vascular grafts and other neoplasms
In adults may develop in extremities or abdominal cavity
Microscopy
These tumor cells often have epithelioid appearance
Consists of sheets of high-grade rounded endothelial cells with prominent nucleoli
some cells show intracytoplasmic lumens
Immunohistochemistry – tumor cells are positive for keratin, CD31, FLI1, ERG
RADIATION INDUCED ANGIOSARCOMA
About 1/4th of angiosarcoma occur after radiation therapy
Incidence is 0.05% to 0.14% of all the patients
Develops with in 5 years of high doses of radiation (median: 50Gy)
Typically the lesion is multifocal
Size – varies from 0.4cms to 20cms
Histologically similar to cutaneous angiosarcoma except that MYC expression is present in these lesions
50% of cases show recurrence and 40% show distant metastasis
