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A 67-year-old man presented with multiple hemorrhagic plaques and nodules on the right leg.
Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2008, Case 34, and is angiosarcoma.
Criteria for Diagnosis and Comments:
Histologic examination showed a highly infiltrative proliferation of hyperchromatic, mitotically active spindled to epithelioid cells, partially growing in solid nodules, and partially forming primitive vascular channels. These primitive vascular channels diffusely infiltrated the dermal collagen and subcutaneous fat and trapped dermal adnexal units. By immunohistochemistry the neoplastic cells were diffusely positive for CD31, CD34 and FLI-1 protein and focally positive for low-molecular weight cytokeratins (Cam 5.2). The histologic and immunohistochemical findings were those of a high-grade angiosarcoma.
Angiosarcomas may be broadly divided into cutaneous and deeply situated tumors. The skin and soft tissues of the head and neck are the most common location for cutaneous angiosarcoma, accounting for over 50% of 366 angiosarcomas accrued at the Armed Forces Institute of Pathology between 1966-1976. These tumors usually occur on the scalp and forehead of elderly individuals, typically with a long history of sun exposure. A second important group of cutaneous angiosarcomas occurs in the skin of the breast, in patients who have received wide local excision and adjuvant radiotherapy for breast carcinoma. Unlike other types of post-irradiation sarcomas, the latency period for cutaneous angiosarcomas following breast conserving therapy and irradiation may be quite short, often less than 2 years. Angiosarcomas occurring in the setting of chronic lymphedema (Stewart-Treves Syndrome) may be either cutaneous or deeply situated, but typically have cutaneous involvement at the time of presentation. The incidence of this rare type of angiosarcoma is decreasing as fewer radical and modified radical mastectomies are being performed for breast carcinoma. Angiosarcomas of deep soft tissue are very uncommon as compared with cutaneous tumors. They are frequently of uncertain etiology, but have been linked to implanted foreign material, such as shrapnel, Dacron-containing vascular grafts, arteriovenous shunts, or Thorotrast.
In cutaneous locations, angiosarcomas present as large, ill-defined plaques or nodules, which typically extend for some distance beyond the clinical impression of their extent, and are seldom excised with negative margins. Angiosarcomas display tremendous variability in their histologic appearances, from well-differentiated tumors with only subtle nuclear atypia to markedly anaplastic tumors that may require immunohistochemistry for diagnosis. The hallmark of angiosarcoma is an infiltrative proliferation of variably well-formed vascular channels, which grow in and around pre-existing structures, often trapping and isolating them. These vascular channels interlace and anastomose, and are lined by hyperchromatic endothelial cells, with intraluminal endothelial stratification and mitotic activity. A small number of angiosarcomas show almost exclusively spindled or epithelioid growth patterns. CD31, CD34 and FLI1 protein appear to be the best IHC markers of angiosarcoma; vWF (FVIIIRAg) is the least sensitive. Angiosarcomas of all types, especially those with epithelioid features, may express low molecular weight cytokeratins in approximately 50% of cases.
Local recurrence occurs in over two-thirds of patients, and the overall 5 year survival rate is approximately 20%. Tumor size > 5cm appears to be the only reliable prognostic factor for angiosarcoma, although other features such as older patient age, mitotic activity and epithelioid morphology have been of limited prognostic value in some studies.
Spindle cell hemangiomas are benign vascular tumors or possibly reactive vascular proliferations, which frequently occur in patients with Maffucci syndrome (multiple enchondromas and spindle cell hemangiomas). Spindle cell hemangiomas are non-infiltrative, circumscribed lesions which show a distinctive admixture of thick walled blood vessels, frequently with thrombosis and phleboliths, cavernous hemangioma-like zones, and spindled zones, containing and admixture of spindled pericytic cells (smooth muscle actin positive) and vacuolated, epithelioid endothelial cells (CD31 positive). Cytological atypia, mitotic activity and infiltrative growth are absent.
Kaposi sarcoma consists of short fascicles of eosinophilic, vaguely myoid-appearing spindle cells, which form slit like vascular channels, containing red blood cells. PAS-positive globules may be found within the spindled cells or in the slit-like spaces. A chronic inflammatory cell infiltrate is usually present, as are thick-walled, peripheral blood vessels. Very early KS lesions may show only these thick-walled vessels, with a subtle cuff of proliferating spindled cells. Nearly 100% of KS express the HHV-8 latency-associated nuclear antigen (LANA), a marker not expressed by other vascular tumors and pseudotumors, including angiosarcoma. Kaposi sarcoma lacks the hyperchromatism, pleomorphism, mitotic activity, necrosis, and epithelioid morphology frequently seen in angiosarcoma.
Squamous cell carcinoma with prominent acantholysis may mimic angiosarcoma, by virtue of the formation of pseudovascular spaces. Important clues to this diagnosis include the presence of associated epithelial dysplasia, individual keratinizing cells, and “dense” eosinophilic cytoplasm. By immunohistochemistry, pseudovascular squamous cell carcinomas show expression of both low and high molecular weight cytokeratins and p63, and are negative for endothelial markers, such as CD31 and FLI-1 protein.
Epithelioid sarcoma most frequently arises on the distal extremities of young patients, without associated sun damage. The cells of epithelioid sarcoma may be deceptively bland, unlike the cells of epithelioid angiosarcoma, which are clearly malignant appearing. A “garland-like” growth pattern and foci of central necrosis, mimicking necrobiotic change, are commonly seen in epithelioid sarcoma. Unlike epithelioid angiosarcoma, epithelioid sarcomas express both low and high molecular weight cytokeratins. Although approximately 50% of epithelioid sarcomas express CD34, they are CD31-negative. It has been very recently shown that >90% of epithelioid sarcomas show loss of expression of INI-1 protein, a tumor suppressor protein which is expressed in all normal cells and in almost all neoplasms, including angiosarcomas.