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Develop a nose for suspecting angiosarcoma

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Angiosarcoma histopathology. Anastomosing dilated vessels, lined by crowded endothelial cells, extend between pre-existing collagen bundles. (Hematoxylin-eosin-saffron stain; original magnification: ×40.)
Credit: JAAD

By Warren R. Heymann, MD
Nov. 12, 2018

Occasionally I read an article that disturbs me, because I know that I would miss the diagnosis, with resultant tragic consequences. Such possibilities wake dermatopathologists up at 3 AM — could that dermatofibroma have been a desmoplatic melanoma? Add a new reason for histopathologic insomnia — “deceptively bland” angiosarcomas (AS) mimicking hemangiomas.

Mitteldorf et al presented 2 cases of histologically deceptively bland cutaneous AS, which showed a uniform clinical presentation with rapidly growing tumors on the nose, in 67 and 59-year-old men, respectively. It was unclear whether these were primary cutaneous tumors or metastases. Both tumors initially presented with a high histologic overlap with a benign vascular tumor, notably a lobular capillary hemangioma-like vascular tumor. The diagnosis was ultimately based on the rapidly progressing clinical course, subsequent biopsies demonstrating atypia, and the results of the staging procedures. Both patients died; the first after 7 months, and the second at 18 months. (If you have access to the article, please look. The clinical progression is dramatic — any dermatologist would have been alarmed and questioned the validity of the initial biopsy reports). The authors appropriately concluded: “rapidly proliferating lobular capillary hemagioma-like vascular lesions, especially in elderly patients, should always be scrutinized with care.” (1)

Although I am a firm advocate of clinical-pathologic correlation, when it comes to choosing between discrepant findings, believe your clinical impression first (and repeat the biopsy).

Cutaneous AS is a rare and highly aggressive malignancy derived from vascular endothelium, with a predilection for skin and soft tissues. AS can be sporadic, usually presenting on the head and neck of elderly patients. AS may also appear secondary to radiation or in association with chronic lymphedema. Securing the diagnosis as early as possible is crucial, as the prognosis is poor, with high rates of local recurrence, and a tendency to metastasize despite aggressive therapy. (2)

Lesions may initially appear as subtle ecchymoses before presenting as plaques or nodules. With progression, tumors develop and may ulcerate. (3) AS can deceive experienced dermatologists, and biopsies are mandatory. (Recently, I saw a nonagenarian with a light purple patch in his scalp. I was convinced he had AS and expressed my concern. I was never happier to inform a patient that his diagnosis was “only” a follicular B-cell lymphoma!) Histologically, features of AS are variable; low grade AS is a well-differentiated tumor that retains some of the morphological features of normal vascular endothelium, whereas poorly differentiated AS demonstrates sheets of pleomorphic cells with distorted architecture, markedly pleomorphic nuclei, and brisk mitoses, making it difficult to distinguish from melanoma or carcinomas. On immunohistochemistry, AS are positive for CD31, CD34, and factor VIII antigen, and lack expression of pancytokeratin and HMB45. Both low grade and poorly-differentiated AS show rapid and invasive growth involving the dermis and deep structures. (4)

Molecular advances have enabled elucidation of signaling pathways that may be used to therapeutic advantage. Notably the expression of VEGF, tyrosine kinases, and beta-adrenergic receptors in AS, have allowed introduction of drugs such as bevacizumab, pazopanib, and propranolol to be used with some efficacy, either as monotherapy or combined with standard treatment regimens. (3,5)

Hopefully, with such advances, the prognosis for AS will not be as abysmal as it is today. Currently wide local excision of the lesion with histologically negative margins is desirable. Radiation therapy is usually indicated post-surgery to improve survival rates. (4) The conclusion in the outstanding article by Ishida et al (6) summarizes the therapeutic horizon for AS:

Advances in basic research have unveiled genomic alterations characteristic of angiosarcoma. This knowledge has not yet transferred to clinical practice. Paclitaxel is the mainstay of the systemic treatment for unresectable or metastatic cAS [cutaneous AS]. Studies have shown the activity of eribulin mesylate [a microtubule-targeting agent] and, to a lesser extent, trabectedin [a histone deacetylase inhibitor]. Propranolol is an emerging treatment modality with a favorable safety profile. Studies have shed light on the role of the immune system in patients with cAS. Preliminary reports show that patients with angiosarcoma may benefit from anti-PD-1 therapy. Larger research efforts to clarify the role of immune checkpoint therapy in angiosarcoma are urgently needed.

Point to remember: Highly aggressive angiosarcoma may have a deceptively bland histology. If your clinical concern is for AS, stay vigilant and repeat biopsies as often as necessary.

1. Mitteldorf C, et al. Deceptively bland cutaneous angiosarcoma on the nose mimicking hemangioma – a clinicopathologic and immunohistochemical analysis. J 2. Cutan Pathol 2018; 45: 652-8.
3. Shustef E, et al. Cutaneous angiosarcoma: A current update. J Clin Pathol 2017; 70: 917-25.
4. Fujisawa Y, et al. Cutaneous angiosarcoma: The possibility of new treatment options especially for patients with large primary tumor. Front Oncol 2018; 8: 46.
5. Kumar S, et al. Cutaneous angiosarcoma of the scalp. Indian Dermatol Online J 2017; 8: 492-3.
6. Amaya CN, et al. Non-selective beta blockers inhibit angiosarcoma cell viability and increase progression-free and overall-survival in patients diagnosed with metastatic angisarcoma. Oncoscience 2018; 3-4: 109-19.

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