Koebner phenomenon on skin graft donor site in cutaneous angiosarcoma

ARTICLE

Angiosarcoma is a malignant vascular tumor of endothelial origin. It can occur in any region of the body, but 60% of the cases arise in skin or superficial soft tissue [1]. Angiosarcoma of the skin occurs in four clinical settings [2]: 1) cutaneous angiosarcoma associated with lymphedema, 2) cutaneous angiosarcoma of the face and scalp, 3) postirradiation angiosarcoma, and 4) primary angiosarcoma of the breast. Cutaneous angiosarcoma of the face and scalp is a distinctive neoplasm with characteristic clinicopathologic features that differ from other types of angiosarcoma.

We describe a case of a patient with a secondary tumor of angiosarcoma on a distant skin graft donor site.

Case report

In December 1997, an 81-year-old woman presented at our hospital with a crusted lesion on her scalp with a 2-month history. A dermatological examination revealed an elevated, dark-purple necrotic plaque, measuring 42 x 27 mm, and a surrounding palm-sized ill-defined purple-red macule on the temporal scalp (Fig. 1). There was no cervical lymphadenopathy and no prior trauma to the scalp. Laboratory data revealed no unusual findings. The chest X-ray; CT scan of the head, chest and abdomen; and whole-body gallium scintigraphy showed no evidence of metastases. She had undergone a Mile's operation for a colon cancer in 1987 but had no history of radiotherapy.

A biopsy specimen of the tumor on the scalp showed many atypical cells and irregular vascular channels filled with erythrocytes in the dermis. Epithelioid tumor cells lined numerous vascular spaces. The tumor cells were large, hyperchromatic, and pleomorphic. Immunohistochemistry showed focally weak positivity for factor VIII-related antigen and Ulex europaeus lectin type I.

She was initially treated with, and partially responded to, one cycle of ifosfamide at a daily dose of 2 g and cisplatin at a daily dose of 30 mg for 4 days. In February 1998 she received a wide surgical excision of the lesion on the scalp and the skin defect was autografted using a split-thickness skin graft (STSG) from the right buttock. After the operation, she was treated with intralesional injections and intravenous infusions of recombinant interleukin 2 (r-IL-2). She was discharged in April 1998 and was treated on an outpatient basis with intralesional injections of r-IL-2 at a daily dose of 4 x 10⁵ JRU once a week.

Five months after discharge, a local recurrence and cervical lymphadenopathy were noticed. In September 1998, she was readmitted and extensive electron-beam therapy (60 Gy in total) was initiated. After a partial response, the disease recurred at the margin of the radiation field and spread centrifugally. In October 1998, she developed a dark, purple-red, decubitus-like lesion on the STSG donor site. This lesion rapidly enlarged and became a blackish, hemorrhagic, ulcerative, plateau-like mass on the STSG donor site (Fig. 2). A biopsy specimen showed irregular clefts and vascular channels lined by atypical endothelial cells (Fig. 3) and confirmed the diagnosis of angiosarcoma. Immunohistochemistry yielded the same findings as in the primary lesions. Polymerase chain reaction (PCR) analysis for human herpes virus 8 (HHV-8) as described previously [3], was negative in DNA samples extracted from paraffin embedded tissue of the buttock lesion and primary lesions. Another STSG donor scar on the right buttock was intact. Eventually she developed multiple lung metastases and bilateral pneumothorax. Two months later she died of respiratory failure and cachexia. Postmortem examination showed extensive local and regional disease and metastases to the pharynx, lung, and liver.

Discussion

Cutaneous angiosarcoma of the face and scalp is the most common subtype of this disease, which affects predominantly elderly patients and is usually found on the scalp and upper forehead [4]. The neoplasm tends to recur locally, spreads centrifugally in a relatively short period, and is associated with a high rate of lymph node and systemic metastases. Most of the recorded metastases were disseminated to distant sites as a result of hematogenous dissemination [5]. The etiology of cutaneous angiosarcoma of the face and scalp is unknown. A history of prior trauma and surgery has been noted in some studies [6, 7]. However, Holden et al. [5] found no definitive predisposing factors in any of the 72 patients reviewed.

Cutaneous angiosarcoma is also reported to occur on sites of previous radiation or persistent chronic lymphedema. In the present case, there was no prior radiation therapy or lymphedema in the skin graft donor site. To our knowledge, development of a cutaneous angiosarcoma on the area of the skin graft donor site has not been reported. STSG donor sites may also be a source of neoplastic transformation including carcinoma and melanoma [8-11]. McLean et al. reported melanomas arising on the contralateral limb STSG donor site after excision of the primary lesion [9] and speculated that a hematogenous spread had occurred. Intraoperative seeding and lymphatic spread were excluded, because the skin graft was taken 1 week after the excision and the donor site was outside the catchment area of the lymphatic draining of the primary lesion. Studies with normal rats have shown that an increased number of tumor cells (Walker tumor) lodge at a site of trauma [12]. Vascular damage and vascular flow create a predisposition to metastasis [12]. In the present case, the donor site deposit may be simply a result of hematogenous spread. However, distant skin metastasis of cutaneous angiosarcoma is rare and it is noteworthy that metastatic angiosarcoma has been reported only in a STSG donor site.

We propose that the appearance of metastatic angiosarcoma on the skin graft donor site in the present case represents a kind of Koebner phenomenon in which a given skin disease localizes to a site of trauma in an individual who is susceptible to that disease [13]. There have been several reports of the Koebner phenomenon in Kaposi's sarcoma [14-17]. Boyd et al. classified Kaposi's sarcoma into a group defined by "occasional traumatic localization of lesions", in which production of a lesion or lesions following trauma occurs, albeit infrequently, and has been well described in the literature [13]. It has been speculated that basic fibroblast growth factor (b-FGF), released from traumatized keratinocytes, plays a key role in the development of the Koebner phenomenon [18]. In Kaposi's sarcoma, b-FGF stimulates proliferation of endothelial cells, which may lead to the development of a tumor [16]. We propose that a similar mechanism may be involved in the present case. In addition, Yamamoto et al. documented an overexpression of b-FGF and its receptor in angiosarcoma [19]. These results suggested that b-FGF synthesized in the tumor endothelial cells plays an important role in the growth and progression of angiosarcoma.

Chang et al. identified human herpes virus 8 (HHV-8) in AIDS-associated and non-AIDS-associated Kaposi's sarcoma [3, 20]. Therefore, the possibility that seeding of the surrounding skin with this virus may occur via increased vascular flow following a trauma was mentioned [15]. However, there is no agreement about the association of HHV-8 and angiosarcoma [21, 22].

CONCLUSION

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