Diagnostic Dilemma: Ulcerated Kaposi’s Sarcoma

Presentation A 78-year-old Caucasian man of Italian descent previously diagnosed with Kaposi’s sarcoma (KS) presented with an ulcerated lesion on the third digit of his right foot. The patient was diagnosed with classic type KS 10 years ago and since then intermittently develops several violaceous papules on the hands and feet. He underwent multiple treatments with liquid nitrogen, and one year ago was started on topical five-percent imiquimod cream applied nightly on his lesions with good results. Lesions clear after several weeks of treatment; however, new ones evolve. One week prior to consult, the patient noted ulceration of a violaceous papule, which had been present on the distal portion of his toe for 4 to 6 weeks. The lesion was moderately painful and the toe was swollen and red. The patient did not recall any specific traumatic event to the affected area although the lesion was located at a site of frequent contact with the adjacent toe. He continued to apply imiquimod cream on the ulcerated area and cover it with a plaster dressing. The patient had no other systemic illnesses, and had a cousin also diagnosed with Kaposi’s sarcoma. Physical Examination Examination revealed a mildly emaciated man with essentially normal systemic findings and no presence of lymphadenopathy. Cutaneous examination revealed a 5mm ulcerated violaceous papule with a moist erythematous base and a small amount of seropurulent discharge on the medial aspect of the tip of the third toe on the right foot (Figure 1). Dried-up golden crusts were heaped up on the periphery of the ulcer. The entire toe was swollen and erythematous. Toe nails were yellow, thickened, and opacified. Several other lesions were noted: a 3mm hyperkeratotic violaceous papule on the dorsal aspect of the left foot; a 5mm violaceous papule on the left sole; a 3mm shiny, bluish-red papule topped by a pinpoint erosion on the lateral aspect of the right foot (Figure 2); and a 6mm scaly, hyperkeratotic brownish papule on the dorsum of the right hand (Figure 3). Investigations A wound culture revealed growth of Staphylococcus aureus. Excision biopsy of tissue from the ulcerated lesion showed KS and adjacent abundant crust with impetiginization. Diagnosis This patient presented with the typical appearance of classic KS lesions—hyperkeratotic violaceous papules on the distal lower and upper extremities, one of which was ulcerated. He was of Mediterranean ancestry with both his parents originating from Italy, and had a cousin affected with the disease. The familial occurrence of classic KS is considered rare;[1] nonetheless, recent evidence suggests that family members of KS patients have a three-fold higher chance of being afflicted with the disease compared to the general population.[2] The risk factors associated with the other types of KS, such as HIV-disease, immunosuppression, cancer, or African heritage, were not present. His profile typified that of a classic KS patient: male with age of disease onset over 50 (his onset occurred at 68), and a chronic disease course. Biopsy confirmed this diagnosis, and wound culture revealed infection of the ulcerated lesion. Treatment Clinical description. KS was first described in 1872 by Moritz Kaposi when he noted unusual multifocal cutaneous sarcomas in five Hungarian men.[3] It was initially thought to be a chronic protracted disease mainly affecting elderly men of Jewish and/or Mediterranean descent. At present, four clinical variants are recognized: classic KS, African endemic KS, KS in iatrogenically immunosuppressed patients, and AIDS-related epidemic KS (Table 1). Etiology. KS is a complex disease that has taken many years to even begin to understand. The identification of a specific causal agent has generated great interest and intense investigation from numerous laboratories.[4] Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8, is a recently discovered and characterized member of the herpesvirus family. It is one of the few viruses proven to be associated with tumorigenesis in humans.[5] It has been detected in all forms of KS (classic, endemic, epidemic, and immunosuppression-associated types), and is, therefore, regarded as a causative factor in the pathogenesis of KS.[6] It is now acknowledged that KSHV is necessary, but far from sufficient, for KS development. Aside from AIDS and immunodeficiency, other cofactors remain to be discovered.[4] Pathology. The histological appearance of KS does not vary significantly between clinical subtypes, but does vary with the stage of the lesion. Early lesions show a proliferation of spindle-shaped cells within the interstitium of the upper dermis in close proximity to the superficial vascular plexus. The spindle cells form intersecting fascicles and are separated by characteristic slit-like spaces containing erythrocytes, sporadically displaying features of lymphangioma. Tumor nodules are often rimmed by ectatic or crescentric vessels, hemosiderin deposits, lymphocytes, and plasma cells and may be compartmentalized by fibrous bands.[7] Figure 4 shows typical spindle cells arranged in short fascicles and numerous erythrocytes consistent with nodular stage KS. Treatment. Although KS is the most common neoplasm associated with AIDS, classic KS is still considered rare, and the best treatment modality is still unclear.[8] Typically, the disease is multifocal and recurs despite treatment. Several therapies of KS currently exist, depending on the extent and localization of the disease. Local therapies are easy to perform, relatively safe, and are often adequate for patients with a limited number of lesions. These therapies include cryotherapy, surgical excision, laser, and intralesional therapy.[9] In patients with solitary lesions, excision often provides sufficient treatment. Simple excision is also appropriate for resectable recurrences. Among 52 patients who underwent surgery as the primary treatment of single lesions, 56 percent had no recurrences for 1 to 162 months (median, 15).[10] Cryotherapy generally has good cosmetic results, but may occasionally produce hypopigmentation, and can be used only for small lesions. Lasers that may be used to treat KS include the carbon dioxide laser, pulsed-dye laser, and argon laser.[9] Due to associated side effects of pain, skin irritation, ulceration, and post-inflammatory hyper- or hypopigmentation, intralesional therapies are only recommended for isolated KS lesions. Successful agents used to treat classic KS include interferon,[11,12] vinblastine,[13] vincristine, and bleomycin.[14,15] Radiotherapy is an important treatment that has been used for many years in classic KS since KS lesions are radiosensitive. The treatment temporarily controls large localized lesions, and is well-tolerated. At present, extended field-radiation is preferred over local-field treatment. Flat lesions are usually irradiated with superficial x-ray; while large tumors are subjected to high-energy beams, including cobalt therapy.[1] Patients with a few lesions in a limited area are often best treated with single doses of radiation (8 to 12 Gy) delivered to an extended field.[10] Four Gy of total-skin-electron-beam therapy can also be used once a week for 6 to 8 consecutive weeks.[16] Systemic treatment is used in patients with recurrent, extensive, or rapidly progressive classic KS. Low-dose interferon alpha has been shown to have efficacy in the treatment of cutaneous and visceral lesions of uncomplicated classic KS.[17,18] Other effective chemotherapeutic agents include vinca alkaloids, bleomycin, doxorubicin, etoposide, actinomycin, and daunorubicin, and these may be used as monotherapy, or in combination. Systemic therapy may be used in conjunction with other treatment modalities such as radiotherapy or surgery. The treatment options for the other three types of KS are shown in Table 2. Patient Management In this patient’s case, lesions are relatively few and well-localized. This makes the patient ideal for conservative local therapies. The only FDA-approved (1999) topical medication for KS is the retinoid alitretinoin gel, which has been shown to be well-tolerated and effective for AIDS-related KS29–31 and in a case report for classic KS.[32] However, others topicals are emerging and showing promise. Among these are the antivirals cidofovir and docosanol and the immune response modifier imiquimod. In 1997, the US Food and Drug Administration indicated imiquimod five-percent cream for the treatment of genital and perianal warts in immunocompetent patients. Drug activity results primarily from induction of interferon alpha and other cytokines in the skin, which stimulate several other aspects of the innate immune response. It also stimulates acquired immunity, in particular the cellular arm.[33] This immune modification mediates the indirect antiviral, antiproliferative, and antitumor activity of imiquimod in vivo. These properties highlight the potential of imiquimod not only as an effective treatment for genital warts, but also as a treatment for other cutaneous viral infections and cutaneous neoplasms.[34] Imiquimod has proven to be effective for treatment of superficial basal cell carcinomas,[35] actinic keratosis,[36] and molluscum contagiosum.[37] Imiquimod currently is used to treat KS lesions; however, no clinical trials have been undertaken, and there is a dearth of case reports in literature. The patient in this case report was sent home on a two-week course of oral antibiotics (cephalexin 1g four times a day and mupirocin cream two times a day on the ulcerated lesion). He was advised to keep the ulcer covered and to continue imiquimod treatment for the other lesions. On follow-up two weeks later, the infection had resolved and the lesion was no longer ulcerated. Our patient’s case is of interest because it documents a positive response to imiquimod use in classic KS with clearing of treated lesions in 3 to 16 weeks. Our case also emphasizes the inclusion of KS in the differential diagnosis of ulcerated lesions occurring on the feet.