Definition

Angiosarcoma (AS) is a malignant tumor of vascular origin. It is also known as hemangiosarcoma, malignant hemangioendothelioma, malignant angioendothelioma, lymphedema-associated angiosarcoma, and lymphangiosarcoma.

Epidemiology and Presentation

AS accounts for 1–3% of all soft tissue sarcomas and can affect patients of all ages although the incidence peak in the seventh decade of life, with a male predominance. Its annual incidence has been estimated to be one case for every million people.

The primary sites of angiosarcoma include the skin (the most frequent site, the head and neck being the most common cutaneous site), breast (→ see section entitled “Breast Angiosarcoma”), soft tissue, viscera (especially liver and spleen; → see section entitled “Hepatic Angiosarcoma”), and bone. Clinical presentation varies considerably depending on the primary site: cutaneous AS presents as bruise-like patches, violaceous nodules, or plaques, whereas AS of soft tissue presents as an enlarged painful mass of deep muscles of the lower extremities (approximately 40% of cases) or as a mass of retroperitoneum, mediastinum, or mesentery; the clinical presentation of visceral AS is variable depending on the organ involved. Since extensive hemorrhage is commonly present, the lesion can be confused with a hematoma.

Etiology and Predisposition

Although its etiology is unknown in most cases (primary angiosarcoma), a subset of AS is associated with specific risk factors (secondary angiosarcoma). In particular, secondary AS is associated with exposure to ionizing radiation (mainly breast AS after radiotherapy for breast carcinoma, which has been reported to occur in approximately 1 out of 1000 cases even 20 years after exposure), ultraviolet radiation (occurs mainly on the scalp of elderly men), chronic lymphedema (due to lymphadenectomy or lymphatic diseases such as filariasis; the AS lymphedema association is known as Stewart-Treves syndrome), and chemicals such as vinyl chloride (utilized in the production of PVC; it has been associated with the development of hepatic AS) and thorotrast (utilized as contrast agent in radiology, it has been associated with hepatic AS).

Li-Fraumeni syndrome (LFS) has been associated with an increased risk of angiosarcoma in multiple locations such as the liver, spleen, breast, head and neck, and (rarely) heart. In most cases (80%), LFS is triggered by the germline mutations in the TP53 tumor suppressor gene (encoding the p53 protein). The estimated prevalence of causal deleterious germline TP53 mutations is approximately 1/20,000. The lifetime risk of cancer in LFS is about 70% for men and close to 100% for women. Typical cancers observed in LFS include early-onset breast cancer, adrenal cortical carcinoma, soft tissue and bone sarcomas (especially rhabdomyosarcoma and osteosarcoma), and brain tumors (choroid plexus carcinoma, astrocytoma, medulloblastoma, and glioblastoma). LFS is inherited in an autosomal dominant pattern; most patients with LFS inherit an altered copy of the gene from an affected parent: In 7–20% of cases, however, the altered gene is the result of a new mutation in the gene that occurred during the formation of reproductive cells or very early in development. For a cancer to develop in LFS, a somatic mutation involving the other copy of the TP53 gene must occur, according to the classical Knudson two-hit hypothesis.

Recently, a germline missense variant (p.R117C) in the POT1 gene (encoding protection of telomeres 1, a protein involved in telomere maintenance) has been proven to be responsible for cardiac angiosarcoma, a very rare malignant tumor that represents <10% of cardiac malignancies.

Pathology

Macroscopically it usually presents as multinodular hemorrhagic and necrotic nodules. Microscopically AS shows a variety morphological appearances ranging from areas of well-formed anastomosing vessels with limited cell atypia to solid sheets of high-grade epithelioid or spindled cells without clear formation of vessels composed of high-grade spindled and epithelioid cells (multiple patterns may be present in the same lesion, which calls for accurate tumor sampling). An AS with predominant epithelioid cells is called epithelioid angiosarcoma, which can be misdiagnosed as a carcinoma because of morphological and immunophenotypical commonalities. Most AS are high-grade tumors with brisk mitotic activity, coagulative necrosis, and marked nuclear atypia.

Differential diagnosis may be needed with other vascular lesions such as atypical post-radiation vascular proliferations (relatively common in radiated skin, can form an erythematous lesion, consists of dilated round or angulated vessels in the dermis lined by a single layer of endothelium that shows mild/absent cytological atypia without mitoses), Kaposi sarcoma (HHV8 positive), and papillary endothelial hyperplasia (also known as Masson tumor, a non-neoplastic benign intravascular lesion only, with papillary formations with hyaline or fibrous stalks, anastomosing vascular channels, plump endothelial cells; no necrosis, no atypia, no atypical mitotic figures).

Biomarkers

AS expresses typical vascular biomarkers (e.g., CD34, CD31, ERG, FLI1) and occasionally lymphatic biomarkers (e.g., podoplanin). Epithelioid AS can coexpress epithelial antigens (e.g., cytokeratins, EMA), which should be kept in mind for differential diagnosis with carcinomas. Immunostaining for HHV8 is negative (which is helpful to differentiate AS from Kaposi sarcoma).

AS has not been associated with specific genetic alterations except for high-level MYC gene amplification (chromosome 8q24),Footnote 1 which is a consistent hallmark of radiation-induced and lymphedema-associated AS.

Prognosis

AS is a high-grade malignancy associated with high rates of disease recurrence (70%) and mortality (50%), representing the most aggressive type of all vascular malignancies (once metastasized the median survival is 4–12 months). Negative prognostic factors are the following: older age, retroperitoneal location, large size, high mitotic rate, necrosis, and epithelioid subtype. In the light of the high metastatic potential, thoraco-abdominal computed tomography scan coupled with central nervous system magnetic resonance imaging is suggested for staging purposes.

Therapy

Surgery (wide excision) is the mainstay of treatment for localized primary AS, although ill-defined margins can make radical surgery a challenging task; in order to maximize the curative intent, large skin removal may be needed, which may require plastic surgery techniques to repair cutaneous defects. In order to improve local disease control, adjuvant radiotherapy is often delivered. Definitive radiotherapy has been also utilized as the only treatment for patients unsuitable for surgery; the combination of radiotherapy plus chemotherapy has been proposed as an alternative to surgery. Other locoregional treatments such as electrochemotherapy and isolated limb perfusion are available for the control of localized disease not amenable to surgery.

Patients with locally advanced or metastatic disease are treated with systemic chemotherapy; beside the “pan-sarcoma” doxorubicin (which—however—has not been evaluated in prospective studies dedicated to AS), there is prospective non-randomized evidence supporting the use of paclitaxel (often considered as first-line treatment). Targeted therapy with multikinase small molecule inhibitors such as sunitinibFootnote 2 and sorafenibFootnote 3 has been tested in the clinical setting with some benefit. Despite some promising results in non-randomized studies of bevacizumabFootnote 4 as a single agent, a randomized trial of paclitaxel with or without bevacizumab showed no difference between the study arms. PazopanibFootnote 5 is approved for the second-line treatment of metastatic soft tissue sarcomas based on the results of the PALETTE randomized controlled trial that included patients with AS. Attempts to identify biomarkers predictive of response to target therapy are underway. PIK3CA-activating mutationsFootnote 6 have been recently reported in AS, which suggests a therapeutic rationale for the use of PI3K inhibitors already available in the clinical setting (e.g., alpelisib, currently approved for breast cancer treatment). Also in the light of the high tumor mutation burden that can be found in this tumor, immunotherapy with anti-PD1 checkpoint inhibitors is being tested in patients with AS, with some encouraging results.