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2009 — January Case of the Month

Updated February 13, 2009

CLINICAL SUMMARY: SKIN  

CAP Foundation January 2009 Online Case of the Month

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After reading the summary, try answering the three related multiple-choice questions below.

A 75-year-old woman developed ill-defined, red to violaceous patches and focally ulcerated nodules in the abdominal skin. One of the lesions was biopsied, and the area was excised. A 15.0 x 5.6 cm skin ellipse was excised to a depth of 2.5 cm with subcutaneous adipose tissue. The skin was indurated with focal areas of superficial hemorrhage, and there was thickening and expansion of the dermis by an ill-defined tumor.

Archive Case and Diagnosis: This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2006, Case 2 and is an Angiosarcoma.

Criteria for Diagnosis and Comments:
This is a malignant cutaneous endothelial tumor with histologic features typical of angiosarcoma (AS). It is multifocal, infiltrates the dermis and extends into subcutaneous fat. Varying degrees of differentiation are present, with distinctly angiomatous areas (grade 1) contrasting with a very poorly differentiated (grade 3) component composed of sheets of epithelioid tumor cells forming circumscribed nodules. In angiomatous areas, distinct individual or widely anastomosing, irregular, thin-walled vascular spaces dissect dermal collagen. The endothelium varies from a single attenuated layer with subtle cytologic atypia to multilayered epithelioid cells that focally fill vascular spaces and have more obvious cytologic atypia - enlarged, vesicular nuclei and macronucleoli with frequent mitoses. "Epithelioid" tumor cells have abundant acidophilic or amphophilic cytoplasm. In areas forming expansile solid nodules, lumen formation is only evident at the intracytoplasmic level.

Cutaneous AS is a rare entity that typically occurs on the face and scalp of elderly men and has a poor prognosis. It may also occur in the setting of chronic lymphedema, e.g., in the upper extremity as a late sequela of radical mastectomy (Stewart-Treves syndrome), or following ionizing irradiation, e.g., in the abdominal wall region after irradiation of pelvic tumors.

A substantial part of the broad, but distinctive spectrum of architectural patterns seen in AS may be sampled in a biopsy specimen and a correct diagnosis is often possible based on H&E stained sections. If one has a high index of suspicion and searches for vasoformative features, immunohistochemistry is generally not needed. Immunohistochemical analysis requires a broad panel of antibodies. AS may react with Ulex europaeus lectin 1, vimentin, laminin, factor VIII-related antigen, CD31 and CD34. Immunohistochemical patterns are variable and staining may be focal as well as vary within tumors, suggesting mixed differentiation of both vascular and lymphatic endothelium. Ultrastructurally, the neoplastic cells of angiosarcoma consistently exhibit one or more features of endothelial differentiation, such as Weibel-Palade bodies or numerous pinocytotic vesicles, and the preponderance of ultrastructural evidence indicates that AS often show differentiation toward blood vessels rather than lymph channels.

The differential diagnosis primarily includes the other malignancies in the Master List, particularly Kaposi sarcoma (KS), which may be biopsied in the patch stage, plaque stage or tumor stage. The histologic features are essentially identical for all the various clinical forms - classic (chronic or European), endemic (African), Mediterranean, and AIDS-associated (epidemic) KS. Important criteria of more evolved lesions include spindle cells, slit-like spaces containing erythrocytes, hyaline globules, apoptotic cells and hemosiderin deposition. Markers that react with KS are CD31, CD34 and CD40, as well as antibody to VEGFR-3. In addition, the detection of human herpes virus 8 (HHV-8) by PCR and the localization of the virus to specific cells by immunohistochemistry may assist in discriminating KS from its mimics. If the clinical setting is not kept in mind, particular confusion may arise between the lymphangiomatous pattern of AS and the lymphangiomatous variant of KS. In contrast to AS, which typically has endothelial layering with cytologic atypia, the endothelial lining of KS is usually inconspicuous and almost always one cell layer in thickness. In general, AS displays more intralesional variation than KS, and areas of more typical AS should be looked for in lymphedema-associated AS. HHV-8 does not appear to be closely linked to AS. AS with a predominant spindle cell pattern may mimic plaques and nodules of KS. Helpful diagnostic features include more angiomatous areas in AS and a degree of cytologic atypia exceeding that observed in even florid nodules of KS.

Some squamous cell carcinomas have an intense acantholytic pattern that mimics the histology of well-differentiated AS. Direct epidermal invasion or involvement of papillary dermis usually do not occur in AS. Presence of a squamous proliferative lesion with atypia in the intact epidermis and demonstration of keratins in the absence of endothelial markers is usually diagnostic of acantholytic squamous cell carcinoma.

Epithelioid AS may be mistaken for poorly differentiated carcinoma, and the coexpression of cytokeratin and endothelial markers by epithelioid AS may cause further diagnostic confusion. Epithelioid hemangioendothelioma (EH) rarely presents in the skin; and cutaneous EH is usually associated with involvement of underlying bone. Cutaneous lesions may be solitary or multiple. EH contains "histiocytoid" or epithelioid-appearing endothelial cells that may be angiocentric. The endothelial cells appear as cords or solid nests of rounded or slightly spindled epithelioid cells. Small intracytoplasmic lumina appear as vacuoles and may contain red blood cells. The vascularity in cutaneous EH is relatively inconspicuous and, when present, generally consists of small vascular channels that may be lined by cuboidal endothelial cells. A hyaline to myxoid or myxochondroid-appearing stroma is common. "Benign"-appearing EH is cytologically bland without appreciable mitotic activity. The "malignant"-appearing tumors, which are clinically more aggressive, may be confused with epithelioid AS since they have significant cytologic atypia, more than 1 mitotic figure per 10 high-power fields, necrosis, and focal spindling of cells. EH usually marks with CD31, CD34 and factor VIII-related antigen.

Remaining benign entities in the Master List lack the cytologic atypia and mitotic activity seen in AS. Epithelioid hemangioma, which is synonymous with angiolymphoid hyperplasia with eosinophilia, presents as single or multiple, pink to red-brown papules or plaques in the head and neck region of young to middle-aged adults. Proliferating blood vessels have a characteristic epithelioid endothelium that may be multilayered, and there is a zonal inflammatory infiltrate of lymphocytes, with or without lymphoid follicles and germinal centers, and variable numbers of eosinophils.

Microvenular hemangiomas typically occur as solitary, asymptomatic, small, enlarging, purple to red, plaques and nodules that favor the extremities of young to middle-aged adults. It is characterized by a transdermal proliferation of irregular, branching venules with generally inconspicuous lumina and no cellular atypia. The vascular proliferation may insinuate collagenous septa of the subcutaneous tissue, but does not invade the fat.

Sclerosing hemangioma, a subtype of dermatofibroma, is of fibrohistiocytic origin (cutaneous benign fibrous histiocytoma). In all variants of dermatofibroma, a prominent capillary network can be seen, giving the lesion an angiomatous component. Those with prominent stromal sclerosis and vascular hyalinization have been referred to as sclerosing hemangioma.

Supplementary Questions For each of the following, select the most likely diagnosis from the diagnostic set (an answer may be used once, more than once, or not at all).

Question Diagnostic Set
1. Which lesion most commonly arises in the scalp and face of elderly men but may also occur in the abdominal region after irradiation of pelvic tumors? A. Angiosarcoma
B. Epithelioid hemangioendothelioma
C. Epithelioid hemangioma
D. Kaposi sarcoma
E. Microvenular hemangioma
F. Sclerosing hemangioma (dermatofibroma)
G. Squamous cell carcinoma, acantholytic type
2. In which lesion does human herpesvirus 8 (HHV-8) appear to have a pathogenetic role? A. Angiosarcoma
B. Epithelioid hemangioendothelioma
C. Epithelioid hemangioma
D. Kaposi sarcoma
E. Microvenular hemangioma
F. Sclerosing hemangioma (dermatofibroma)
G. Squamous cell carcinoma, acantholytic type
3. Which cutaneous lesion is usually associated with involvement of underlying bone? A. Angiosarcoma
B. Epithelioid hemangioendothelioma
C. Epithelioid hemangioma
D. Kaposi sarcoma
E. Microvenular hemangioma
F. Sclerosing hemangioma (dermatofibroma)
G. Squamous cell carcinoma, acantholytic type

References

  1. Cooper PH. Vascular tumors In: Pathology of the Skin: Farmer ER and Hood AF (eds), Norwalk, CT: Appleton & Lange; 1990:804-846.
  2. Elder D, Elenitsas R, Johnson B, et al. (eds) Tumors and cysts of the dermis and subcutis. In: Synopsis and Atlas Lever's Histopathology of the Skin. Philadelphia, PA: Lippincott Williams and Wilkins; 1999:255-366.
  3. Holden C, Spittle M, Wilson Jones E. Angiosarcoma of the face and scalp, prognosis and treatment. Cancer 1987;59:1046-1057.
  4. Hunt SJ, Santa Cruz DJ. Vascular tumors of the skin. Semin Diagn Pathol 2004; 21:166-218.
  5. MarrogiAJ, Hunt SJ, Santa Cruz DJ. Cutaneous epithelioid angiosarcoma. Am J Dermatopathol. 1990;12:350-356.
  6. Rosai J, Sumner H, Kostianovsky M, et al. Angiosarcoma of the skin: A clinicopathologic and fine structural study. Hum Pathol. 1976;7:83-109.
  7. Santa Cruz DJ. Hurt MA. Nonmelanocytic cutaneous tumors. In: Sternberg's Diagnostic Surgical Pathology (4th Edition). Mills SE (Sr. Ed). Philadelphia, PA: Lippincott Williams and Wilkins; 2004:49-88.
  8. Weiss S, Enzinger F. Epithelioid hemangioendothelioma: a vascular tumor often mistaken for a carcinoma. Cancer. 1982;50:970-981.
  9. Weiss S, Ishak K, Dail D, et al. Epithelioid hemangioendothelioma and related lesions. Semin Diagn Pathol. 1986;3:259-287.
Author:
2006
Mark A. Weiss, M.D.
Surgical Pathology Committee
TriHealth Laboratories, Good Samaritan Hospital
Cincinnati, OH