Postirradiation Cutaneous Angiosarcoma Mimicking a Cyst in a Heart Transplant Recipient

Angiosarcomas (AS) are rare malignancies developing from blood or lymphatic endothelial cells. They account for approximately 2% of skin sarcomas and present usually in elderly patients as red violaceous plaques or tumors developing over the scalp, trunk, or limbs. Their cause is unknown; in contrast to Kaposi sarcoma, they are not linked with human herpesvirus (HHV)-8 infection. Risk factors include radiation therapy, chronic lymphedema, toxins (e.g., vinyl chloride), and some cancer-prone syndromes (e.g., neurofibromatosis and mutated BRCA1 or BRCA2 syndromes) (1). Immunosuppression may favor AS development through decreased immunosurveillance and destruction of malignant cells (2). Some cases of AS have been reported in patients with acquired immunodeficiency syndrome, and 20 cases of AS have been reported in renal transplant recipients (RTRs). We present here the first case of AS with a misleading clinical appearance developing in a heart transplant recipient after radiotherapy for a preceding anal carcinoma. A 73-year-old French man sought advice for a lesion in the pubis, which had appeared some weeks before consultation. The patient had a history of melanoma of the buttock (malignant transformation of a congenital naevus – Breslow thickness 18 mm, Clark level IV, Stage T2b N0 M0) excised 12 years ago. Two years later, he received a heart transplant because of cardiomyopathy. Initially, he received tacrolimus (2.5 mg/d), steroids (2.5 mg/d), and azathioprine (150 mg/d). Six years after receiving the graft, he developed moderate acute cellular rejection. During the fifth year after receiving the graft, he developed an ulcerated, vegetating, microscopically moderately differentiated epidermoid anal carcinoma measuring 4.5 cm; it infiltrated the smooth and (focally) the striated muscle layers and invaded one inguinal lymph node with extracapsular spread. The tumor was treated with surgery and radiotherapy. The patient was progressively weaned off tacrolimus and switched to everolimus (4.25 mg/d; trough levels, 8.8 ng/mL). Physical examination revealed an asymptomatic, pinkish white firm nodule of 2 cm on the pubis (Fig. 1A). The clinical appearance was consistent with an epidermoid cyst or an adnexal tumor, although the history of anal carcinoma arose suspicion for a cutaneous metastasis. Microscopic examination of a skin biopsy taken from the nodule showed a diffuse dermal infiltration with atypical, large, pleomorphic polygonal cells with large basophilic nuclei. The cells occasionally lined optically empty slits (Fig. 1B). Areas of necrosis and some hemorrhage were seen in the dermis. Immunohistochemically, tumor cells expressed strongly the proliferation-associated antigen Ki-67 and the endothelial antigens thrombomodulin, CD31, podoplanin/D2-40 and ERG (Fig. 1C–E) but were negative for keratins (pan-keratin, K5, K6, K7, K19, K20), p63, HHV-8, S-100 protein, Melan-A/MART1, CD30, CD43, CD45, CD34, CDX-2, and von Willebrand factor. These findings were diagnostic of poorly differentiated AS. A positron emission tomography performed 6 weeks after the diagnosis showed metabolic hyperactivity at the site of the tumor and the anal border, scrotal edema and right necrotic lymph node enlargement, but no evidence of distant metastasis. Chemotherapy with paclitaxel (given once weekly for 8 weeks) had to be discontinued because of severe neuropathy. At a 6-month follow-up after the diagnosis, new cutaneous nodules had appeared on the pubis; further treatment with radiotherapy was envisaged.FIGURE 1: A, Clinical appearance of the lesion: a 2-cm firm, pinkish white nodule on the pubis. B, Microscopic examination of a skin biopsy showing monomorphous, polygonal tumor cells with large basophilic nuclei, occasionally lining slit-like spaces (hematoxylin-eosin stain). Tumor cells express the vascular markers CD31 (C), D2-40/podoplanin (D), and ERG (E) (streptavidin-biotin-immunoperoxidase revealed with diaminobenzidine counterstaining with Meyer hematoxylin).The incidence of AS seems to be increased in immunocompromised patients (2). Currently, 20 cases of cutaneous AS (other than Kaposi sarcoma) have been reported in RTRs (2–17). The mean age at diagnosis is 48 years (range, 31–74 years), and there is a male predominance (sex ratio, 1.85:1). Angiosarcomas appear, on average, 6.5 years after receiving graft (range, 0.7–15 years); they usually manifest as tender violaceous hemorrhagic masses arising within, or adjacent to, the arteriovenous fistula performed for hemodialysis before renal transplantation (5–7, 9, 14, 16, 17), even after arteriovenous fistula ligation and defunctionalization (16, 17). Other sites include the legs (8), the scalp (4), and the transplant wound on the abdomen (13). Pathologically, they show a wide morphological spectrum ranging from vasoformative to poorly differentiated tumors, occasionally with an epithelioid appearance (7, 9, 14, 15). Tumor cells variably express endothelial markers (CD31, CD34, von Willebrand factor, endothelin, and VEGF) (4–6, 8, 9, 11, 14), and epithelioid AS may additionally express keratin (7). Search for HHV-8 was performed in four cases, including the one presented here (8, 9, 11), and proved negative, contrasting with Kaposi sarcoma (which is invariably positive for HHV-8). An association of Kaposi sarcoma and a tumor diagnosed as (bullous) lymphangiosarcoma was described in an RTR (12). Despite aggressive multimodal treatment, the prognosis of AS is grim, with dissemination of the tumor and a fatal issue in half of the cases on an average of 7 months after diagnosis. This case report is original because the patient is the first reported case of AS observed after cardiac transplantation. Furthermore, its clinical appearance was misleading because the lesion did not have the typical appearance of a vascular tumor (red violaceous or hemorrhagic lesion) but was presented as a whitish nodule reminiscent of a cyst or an adnexal tumor. In fact, cutaneous AS may have a misleading clinical presentation, mimicking various benign skin lesions (Table 1). The localization of the tumor in our patient on the pubis is also unique, probably explained by the preceding radiotherapy that seems to have contributed to its development. Pathologically, it was undifferentiated because it did not contain obvious vasoformative areas but was made of solid sheets of malignant endothelial cells with few red blood cells; this microscopic aspect likely explains the misleading clinical appearance of the tumor as a whitish nodule. The diagnosis was established by immunohistochemistry showing expressions of vascular markers (CD31, podoplanin/D2-40, thrombomodulin, and ERG, a novel endothelial cell marker) (18).TABLE 1: Benign-looking clinical presentations of cutaneous angiosarcomaThe present case further highlights the misleading clinical aspect that skin tumors may present in organ transplant recipients and the difficulty in making a correct diagnosis. In these patients, skin biopsy should always be taken from even benign-looking lesions to avoid misdiagnoses with potentially ominous consequences. Jean Kanitakis 1,2 Brigitte Chouvet1,2 Ana Roussouliéres3 Sylvie Euvrard1 1Department of Dermatology, Ed. Herriot Hospital Group, Lyon, France 2Department of Pathology, Ed.