Case 2 -

Angiolymphoid Hyperplasia with Eosinophilia (Epithelioid Hemangioma) Omar Sangueza

Clinical History: The patient is a 36-year-old male with a skin/superficial soft tissue mass involving his anterior scalp. Diagnosis: Angiolymphoid Hyperplasia with Eosinophilia (Epithelioid Hemangioma) Most cases of angiolymphoid hyperplasia with eosinophilia (ALHE) affect mainly young to middle age adults with roughly equal sex incidence. The most common anatomic location is the head and neck region followed by the distal extremities.1, 2 Less commonly, ALHE have been described in the mouth, trunk, extremities, vulva, penis and inner canthus of the eye. The majority of patients complain of localized but painless, superficial soft tissue swelling. In approximately 10% of patients, a history of prior trauma is reported. Microscopically, ALHE consists of well-circumscribed nodules involving the dermis and/or the subcutaneous fat. At scanning magnification there are two distinct components, namely irregular blood vessels and dense inflammatory infiltrate. The vascular component comprises irregular thick walled blood vessels lined by plump endothelial cells, which protrude into the lumen. The walls of the vessels often have thickened bundles of smooth muscle and abundant mucin. The endothelial cells lining the vessels are plump with a large round to oval nuclei and abundant eosinophilic cytoplasm, which often contains prominent vacuoles as an expression of primitive vascular differentiation. The endothelial cells can form solid sheets and the angiomatous nature of the lesion becomes less evident. Occasionally the proliferation of the endothelial is so prominent, especially within the lumina of large vessels to the point that can be confused with malignant neoplasms. In some cases, the endothelial cells cluster together giving the appearance of multinucleated cells with immature vascular lumens. The stroma consists of fibrovascular tissue that invariably contains lymphocytes, eosinophils, mast cells, and sometimes mucin deposits. In some cases, lymphoid follicles with germinal centers are present, but usually they are not as prominent as in Kimura's disease. Subcutaneous lesions are sometimes organized around a centrally-located larger blood vessel, usually an artery. These findings suggest that at least some forms of ALHE represent reactive processes and not true neoplasms. [1] Complete excision is the recommended form of therapy. Local recurrence occurs in up to one-third of patients. [2] The differential diagnosis of ALHE includes benign and malignant neoplasms. The differential diagnosis with Kimura's disease can be established on the basis of both the clinical and histopathological features. Clinically, Kimura's disease consists of skin-colored subcutaneous masses that in extreme cases distort the outline of the face dramatically, as a consequence of the presence of large infiltrates of inflammatory cells within the dermis and subcutaneous tissues. Usually patients also show intense peripheral eosinophilia and lymphadenopathy. Histopathologically Kimura's disease is devoid of vascular abnormalities seen in AHE, and when plump endothelial cells are present in the blood vessels they are a focal finding. The main findings are represented by the presence of numerous, closely packed lymphoid follicles that extend throughout the dermis and subcutaneous fat, and sometimes into the lymph nodes and internal organs. Within these infiltrates there are numerous eosinophils. In brief, Kimura's disease is not a disorder of blood vessels, but an inflammatory systemic process of unknown etiology. Cutaneous epithelioid angiomatous nodule is a recently described benign neoplasm characterized histologically by the presence of fairly circumscribed, solid vascular proliferations of large epithelioid endothelial cells with vesicular nuclei and prominent nucleoli. [3] The abundant cytoplasm frequently contains intracytoplasmic vacuoles. Vascular spaces within the lesion are present in variable number, size and shape. Although mitosis may be found in this tumor, atypia is absent. Inflammatory infiltrates and deposits of hemosiderin may be seen, but there are not as abundant as ALHE. Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor that may arise within soft tissue, bone, liver, or lung. For the purposes of this discussion, we will focus on the soft tissue form. The majority of patients with soft tissue EHE are middle aged to older adults. Children are rarely affected. There appears to be no gender bias. The extremities, especially the lower limb, are most commonly involved followed by the head and neck and trunk regions. [4, 5] EHE may arise in deep soft tissues, subcutaneous adipose tissue, or dermis. Up to 50% of subcutaneous or deep soft tissue cases appear to originate from a blood vessel, usually a vein. Complaints of soft tissue swelling, sometime accompanied by pain, are typical. Histologically, epithelioid endothelial cells proliferate as cords, strands, and/or nests of mostly round to cuboidal, epithelioid-appearing tumor cells containing ovoid to round, mostly uniform nuclei and abundant eosinophilic cytoplasm. Although easily overlooked, cytoplasmic vacuolation, indicative of primitive vascular differentiation, is present in all cases. Some of the cytoplasmic vacuoles contain a single erythrocyte. In other cells, the cytoplasmic vacuoles may be sufficiently large so as to displace the nucleus peripherally, creating a signet-ring cell appearance. The background stroma is typically loose and appears lightly basophilic myxoid to myxochondroid. Well-formed vascular channels, as observed in epithelioid hemangioma, are rarely seen and always focal in EHE. Significant nuclear pleomorphism may be present in small foci in EHE, but, if prominent and seen as solid sheets, the diagnosis of epithelioid angiosarcoma is more appropriately rendered. [5 ] Mitotic figures are usually less than 2 per 10 high power fields. Metaplastic bone may be observed. The neoplastic cells of EHE generally express CD31, CD34, and/or factor 8. At least focal cytokeratin positivity may be observed in 20-30% of cases. [5, 6] Alpha smooth muscle actin is expressed in up to 50% of cases. S-100 protein and desmin are negative. Although data are limited to two cases, cytogenetic analysis has revealed an unique chromosomal translocation, t(1;3)(p36.3;q25) in EHE. [7] There is no relationship between histologic features and clinical outcome. Local recurrence occurs in approximately 10-15% of patients; distant metastases have been reported in approximately 20-25% of patients. Death occurs in 15-20% of patients, regardless of anatomic site (e.g. bone vs. soft tissue). [4, 5, 6] Wide surgical resection is the therapy of choice. Epithelioid angiosarcomas are more common in the deep soft tissues of the lower extremities, although cutaneous lesions on the scalp and face have also been described. [8] Radiation exposure, a reaction to a foreign body, and chronic immunosuppression in the setting of renal transplantation have been implicated as possible causes of this neoplasm. [9] Histopathologically, epithelioid angiosarcoma mimics an epithelioid neoplasm. The tumor is composed of sheets of rounded epithelioid cells with large cytoplasm, vesicular nuclei and prominent nucleoli. Areas of irregular vascular channels lined by atypical endothelial cells that dissect the collagen bundles are not prominent, but the finding of such areas has high diagnostic value. In some areas, epithelioid cells exhibit cytoplasmic vacuoles as an expression of primitive luminal differentiation. Immunohistochemistry corroborates the vascular nature of this epithelioid neoplasm because expression of factor VIII related antigen, Ulex europaeus I lectin, CD31 and CD34 have been documented in examples of epithelioid angiosarcoma. However, these tumors also commonly express cytokeratins, attributable to the abundance of intracytoplasmic intermediate filaments in neoplastic cells, and this phenomenon may result in the misinterpretation of this type of angiosarcoma as carcinoma. [8] Ultrastructural studies have documented prominent cytoskeleton of intermediate filaments, numerous pinocytotic vesicles, and scarce or no Weibel-Palade bodies in neoplastic cells of cutaneous epithelioid angiosarcoma. A subset of AS show CD117 (c-kit) immunoexpression but are not associated with mutations of the tyrosine kinase domains of the c-kit gene. [10] No reproducible cytogenetic abnormalities have been identified in AS with most studies revealing nonspecific complex karyotypes. [11] Fetsch JF, Weiss SW. Observations concerning the pathogenesis of epithelioid hemangiomas (angiolymphoid hyperplasia). Mod Pathol 1991;4:449-455. Olsen TG, Helwig EB. Angiolymphoid hyperplasia with eosinophilia: a clinicopathologic study of 116 patients. J Am Acad Dermatol 1985;12:781-796. Brenn T, Fletcher CDM. Cutaneous epithelioid angiomatous nodule: a distinct lesion in the morphologic spectrum of epithelioid vascular tumors. Am J Dermatopathol 2004: 26(1):14-21. Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma: a vascular tumor often mistaken for a carcinoma. Cancer 1982;50:970-981.. Mentzel T, Beham A, Calonje E, et al. Epithelioid hemangioendothelioma of skin and soft tissues: clinicopathologic and immunohistochemical study of 30 cases. Am J Surg Pathol 1997;21:363-374. Kleer CG, Unni KK, McLeod RA. Epithelioid hemangioendothelioma of bone. Am J Surg Pathol 1996;20:1301-1311. Mendlick MR, Nelson M, Pickering D, et al. Translocation t(1;3)(p36.3;q25) is a nonrandom aberration in epithelioid hemangioendothelioma. Am J Surg Pathol 2001;25:684-687. Meis-Kindblom JM, Kindblom LG. Angiosarcoma of soft tissue: a study of 80 cases. Am J Surg Pathol 1998;22:683-697. Mark RJ, Poen JC, Tran LM, et al. Angiosarcoma: a report of 67 patients. Cancer 1996;77:2400-2406. Miettinen M, Sarlomo-Rikala M, Lasota J. KIT expression in angiosarcomas and fetal endothelial cells: lack of mutations of exon 11 and exon 17 of C-kit. Mod Pathol 2000;13:536-541. Schuborg C, Mertens F, Rydholm A, et al. Cytogenetic analysis of four angiosarcomas from deep and superficial soft tissue. Cancer Genet Cytogenet 1998;100:52-56.