Angiosarcoma

Synonyms:

Hemangiosarcoma, lymphangiosarcoma, malignant

hemangioendothelioma

Etiology:

Ultraviolet light, radiotherapy, lymphedema (Treves-

Stewart syndrome), preexisting vascular malformations

(Mafucci's syndrome)

Associations:

Mafucci's syndrome

Clinical:

Rapidly expanding bruise-like patch, erythematous

papules, violaceous nodules

Histology:

Ill-defined anastomosing dermal network of atypical

endothelial-lined spaces (most common) or defined

diffusely arranged aggregates of epithelioid or spindled

cells

IHC repertoire:

CD-31 (most sensitive and specific), CD-34, Ulex

europaeus, Factor VIII

Staging:

None for cutaneous disease

Prognosis:

Overall 5-year ~10%

Adverse variables:

Size > 5 cm, depth of invasion > 3.0 mm, mitotic rate >

3 HPF, positive surgical margins, recurrence, and

metastases

Treatment:

WLE/XRT for localized disease, XRT for systemic disease,

limited role for CTX

Angiosarcoma (AS), otherwise known as hemangiosar-coma, lymphangiosarcoma, or malignant hemangioendothelioma, is a malignant tumor derived from endothelium that occurs in a variety of anatomic sites including the skin (1-3). Sixty percent of cases arise within the skin or superficial soft tissues. Although these tumors derive from the vascular endothelium, the exact vascular origin is unknown and likely derives from both the blood vessels and lymphatics.

AS is an extremely uncommon tumor, accounting for less than 1% of all sarcomas (4). With the exception of tumors that may arise in preexisting vascular lesions, AS predominantly afflicts the elderly and is seen more commonly in men. Males outnumber females by a ratio of approximately 2 : 1. Most patients described have been Caucasian. The etiology of AS is multifactorial and is influenced by the clinical setting. Fifty percent of cases occur on the head and neck and in particular the scalp of elderly men where ultraviolet light is thought to constitute an important risk factor. While tenable, investigators have argued that CA remains an extremely uncommon tumor among individuals with excessive ultraviolet light exposure and that other sun-prone anatomic sites are rarely afflicted by AS (5). In reconciling these contradictions, it has been recently hypothesized that factors unique to these anatomic locations might exist that predispose to its development. These factors might include the vascular density of the scalp or the anastomotic arrangement of the vessels in these areas. Unusual vascular arrangements or density might also combine with ultraviolet light or thermal (heat) effect potentiating oncogenesis. Ionizing radiation in the form of radiotherapy is a recognized risk factor for these tumors particularly involving the anterior chest wall of women who have undergone treatment for breast cancer (6). Lymphedematous extremities, particularly resulting from radical mastectomy for breast cancer, predispose to AS. Known as the Treves-Stewart syndrome, named after the surgeons who described this association among six patients in 1948, this condition has been reported in over 300 patients to date. Other causes of chronic lymphedema, including congenital lymphedema, and complications resulting from long-standing filariasis infection may eventuate in this tumor as well. Preexisting vascular lesions, including arteriovenous malformations, and hemangiomas including the Mafucci syndrome have been described in conjunction with this neoplasm. Interestingly, most of these cases have been described in children. AS has also been rarely described following foreign body implantation and in sites of recurring herpes zoster infection. Unlike identical tumors occurring in the viscera, there is no known association of cutaneous lesions with toxin exposure including Thoratrast, arsenic, polyvinyl chloride, or anabolic steroids.

The clinical presentation is varied and dependent upon the various risk factor(s). The classic presentation associated with ultraviolet exposure is of a rapidly centripetally expanding brown-to-erythematous patch situated on the forehead or scalp (Figure 1.1) (7). In time, the lesion is capable of producing an ulcerated erythematous-to-violaceous plaque or nodule. Later, there is a tendency to develop a centrifugal pattern of tumor satellites (8,9). Among the most common entities cited in the differential diagnosis are lymphoma and metastatic carcinoma. Although the scalp and face are most commonly afflicted,

Angiosarcoma The Face
Figure 1.1. Violaceous plaque of angiosarcoma.

the ears, neck, and upper trunk may be involved as well. Lesions attributed to antecedent radiotherapy consist of rapidly growing papules and nodules classically located on the chest wall of women with a history of irradiated breast carcinoma. Radiotherapy-associated tumors may, however, arise in either sex and within the radiation field of a variety of anatomic sites. Most tumors arise following a 10-year or greater latent period. AS arising within a lymphedematous extremity is generally heralded by the development of a rapidly enlarging papule/nodule superimposed upon the brawny induration typical of longstanding lymphedema. Most lesions develop an average of 10 years following surgery. Lesions associated with congenital lymphedema generally occur in younger patients who have experienced lymphedema for greater than 20 years. AS associated with preexisting vascular lesion(s) is characterized by rapid eccentric growth and epidermal ulceration.

The histologic attributes of this lesion are varied. The most common pathologic alteration consists of a subtle increase in vascularity detected in the superficial and mid-dermis (5). The vascular channels diffusely ramify throughout the dermis, forming an anastomosing network of endothelial lined vascular spaces (Figures 1.2 and 1.3). The vascular channels may consist of sinusoids with parallel sides or gaping cavernous spaces. The vascular spaces are lined by a population of cuboidal to hobnailed cells possessing enlarged and hyperchromatic nuclei (Figures 1.4 and 1.5). The endothelial may stratify forming papil-lations. The intervening stroma often contains plasma cells and neutrophils as well as hemosiderin pigment. The tumor periphery is often bounded by a fringe of dilated and otherwise normal-appearing vascular spaces. Less common histologic presentations include a nested or diffusely arranged population of either spindled or enlarged epithelioid cells. In the latter setting, striking cellular pleomorphism may rarely be encountered. Although early lesions are confined to the dermis, well-developed lesions may extend laterally over a large expanse of dermis as well as deep into the subcutaneous fat and soft tissues. Microscopic extension of tumor is commonly seen well beyond what is deemed to be the clinical boundary of tumor.

Special techniques that may be employed in confirmation of the diagnosis include electron microscopy, and increasingly, immunohistochemistry (6). Ultrastructural features of endothelial derivation include the presence of prominent external laminae, pinocytotic vesicles, and specialized endothelial organelles termed Weibel-Palade bodies. These attributes are more commonly observed in well-differentiated and epithelioid tumors. Immunohis-tochemistry has become an indispensable diagnostic adjunct, particularly in the evaluation of poorly differentiated tumors and in the epithelioid variant. Among the

Thoratrast

various markers that include CD-31, CD-34, Ulex euro-paeus, Factor VIII, CD-31 is regarded as the most specific marker for endothelial derivation with Ulex europaeus as the most sensitive (4). An important pitfall to consider is that approximately one-third of cases stain with keratin antibodies, prompting consideration for carcinoma.

Important entities to consider in the histologic differential diagnosis include benign entities such as the tufted angioma (TA) and targetoid hemosiderotic hemangioma (THH), low-grade vascular tumors of intermediate prognosis such as epithelioid hemangioendothelioma (EHA) and Kaposi's sarcoma (KS), as well as malignant entities

Figure 1.3. Medium power photomicrograph depicting subtle proliferation of endothelial-lined dermal vascular channels.

Figure 1.3. Medium power photomicrograph depicting subtle proliferation of endothelial-lined dermal vascular channels.

Targetoid Hemosiderotic HemangiomaFondo Brillantes Dorado
Figure 1.4. Medium power photomicrograph depicting deeper dermis with gaping vascular channels lined by atypical hyperchro-matic endothelial cells.

such as poorly differentiated carcinoma. THH consists of a superficial papillary dermal central focus of hobnail-lined vascular spaces and surrounding progressively inconspicuous and attenuated vascular channels. TA consists of discrete nests or tufts of epithelioid endothelia situated throughout the dermis. Endothelial atypia and/or extensive dermal or subcutaneous fat extension are not seen in these lesions. EHA is an uncommon tumor comprised of dermal and subcutaneous nests, strands, and diffusely arranged epithelioid cells often possessing intracytoplasmic lumina that contain erythrocytes. KS consists of a diffusely spindled cell population that char

Angiosarcoma Intracytoplasmic Globules
Figure 1.5. High power photomicrograph depicting cytologic detail of vascular channels lined by atypical endothelial cells.

acteristically forms slit-like vascular spaces and is punctuated by plasma cells and extracellular hyaline globules. Metastatic and poorly differentiated carcinoma may closely simulate AS. Epithelial connection, intercellular bridges, and glandular formation favor carcinoma. Difficult cases may require immunohistochemical characterization. Carcinomas should not stain with antibodies to CD-31.

AS is an aggressive tumor. It tends to recur locally, later metastasizing despite aggressive multimodal therapy. Because of its predilection for multifocality and inapparent spread, complete surgical resection is often unattainable. Overall prognosis is poor, with reported 5-year survival rates of 10%-35%. Usual metastatic sites are the skin, lung, lymph nodes, spleen, liver, and bone. The development of metastases is ominous, as most patients eventually succumb to their disease. Metastases and recurrences usually develop within 2 years of diagnosis. Histologic appearance, tumor grade, demographic factors such as age and gender, anatomic location, and clinical setting, do not influence prognosis (10). The diameter of the lesion at the time of initial diagnosis is the most important factor in influencing survival. Lesions of less than 5 centimeters have a better prognosis (5). Generally, smaller tumors are more accessible to treatment with surgery. Other potential factors responsible for this observation include shorter clinical duration and limited vascular access with the attendant risk of metastases. Other favorable attributes recently shown to influence survival include average tumor mitotic rate of less than 3 per microscopic high power field, a tumor depth of less than 3 millimeters, and absence of recurrence and metastases.

Patients need clinical examination every 3 months for the first year following diagnosis to detect early recurrence. Lymph node survey and imaging studies including CT or MRI of the head and neck should be considered at these time intervals as well (11). Due to the rarity of this tumor, there are no widely adopted standard protocols for therapy (11). Localized disease is generally treated with wide local excision or in combination with radiotherapy if the anatomic site and health status of the patient permits.

Those who cannot tolerate surgery can be palliated with radiotherapy. Most radiation protocols employ fractional-ized megavoltage dosing of between 180 and 300 centigray per day for a total of between 3000 and 7000 centigray. Systemic disease can also be palliated with radiotherapy. The use of various chemotherapeutic agents, including methotrexate, doxorubixin, cyclophosphamide, and vincristine, has been reported with varying success. The role of chemotherapy is not well defined and requires further investigation. Future developments include the use of anti-angiogenic drugs, anti-endothelial antibodies conjugated with cytotoxins, and XRT radiosensitizers.

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Responses

  • autumn
    When you get angiosarcoma in the sinus what happens in the future?
    8 years ago
  • kibra eyob
    What does secondary angiosarcoma of the chest wall look like?
    7 years ago

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