IATROGENIC KAPOSI???S SARCOMA HHV8 Positivity Persists But The Tumors Regress Almost Completely Without Immunosuppressive Therapy 1

Kaposi’s sarcoma (KS) is one of the most common neoplasms in human immunodeficiency virus (HIV)-negative organ transplant patients. Human herpes virus (HHV)8 has been detected in all forms of KS, but the presence of HHV8 DNA in regressed iatrogenic KS has not yet been investigated. Here we report the case of a kidney transplant patient who has developed HHV8 positive KS lesions during immunosuppressive therapy. After rejection of the transplanted kidney, immunosuppressive therapy was withdrawn and the patient’s tumors regressed almost completely. The small residual lesions still contained HHV8, as detected by polymerase chain reaction (PCR). This case suggests that (1) suppressed immune function has a primary role in the development of KS; and (2) with restored immune function HHV8 can be suppressed into latency. KS is a vascular neoplasm that appears in four different forms: classic, endemic, epidemic, or acquired immunodeficiency-associated and iatrogenic KS which arises after drug-induced immune suppression. HHV8 has been detected with almost 95% consistency in all forms of KS tumors, suggesting a causative role in its pathogenesis (12). Iatrogenic KS has been reported in patients treated with immunosuppressive drugs, such as corticosteroids, azathioprine, methotrexate, and cyclosporine A for distinct and severe clinical entities, most frequently, for immune suppression after solid organ transplantation (3–5). This type of KS sometimes shows a fulminant course, but it could also regress after discontinuation of the immunosuppressive medication. A 53-year-old Caucasian man had end-stage renal disease and underwent hemodialysis for 2 years before receiving a cadaver allograft kidney. After transplantation, he responded well to immunosuppressive therapy (prednisolone 30 mg/day and cyclosporine 400 mg/day) and had stable renal function. Three months later, multiple, irregular reddish-blue and reddish-brown macules, nodules, and plaques appeared mostly on the pretibial region on his legs, on his left arm, on the mucous membranes of the pharynx and on the right conjunctive. A clinical diagnosis of KS was made and confirmed by histologic method. A paraffin-embedded tissue section was also analyzed by PCR using primers specific for the HHV8(1). HHV8 sequences were detected in the lesion from the left pretibial region (Fig. 1Figure 1: Detection of HHV8 DNA sequences (KS330233) in active and regressed Kaposi’s sarcoma skin by PCR. Lane M: 1Kb molecular marker; lane 1: HHV8 positive control (BCBL-1 cell line); lane 2: HHV8 in active KS skin; lane 3: HHV8 in regressed KS skin; lane 4: negative control (water). To assess the integrity of genomic DNA extracted from the biopsy specimens, a region of the β-globin gene was amplified. The 268 bp-sized β-globin fragments could be detected in all of these samples, indicating the absence of possible inhibitors of PCR (data not shown).). Viral serologic finding were negative for HIV types 1 and 2, hepatitis B surface antibody, and human hepatitis C virus. Cytomegalovirus reactivity was found. There were no signs of systemic dissemination of KS. Cyclosporine was replaced by azathioprine (25 mg/day) and interferon α-2b (5 mU 3 ×/week) therapy was introduced. The tumors on the lower leg have been treated with radiotherapy (30 Gy in 10 fractions over 2 weeks), with a moderate effect. Six months later, the patient’s transplant was rejected and he underwent graftectomy and hemodialysis was introduced again. All his immunosuppressive medications were discontinued. Two months later, the KS lesions disappeared almost completely. A punch biopsy specimen was obtained from one of his regressed lesions on his left arm. A histological examination revealed regressed KS. The HHV8-specific DNA was still present in the regressed lesion (Fig. 1). In 1973, Dobozy et al. (6) described that dysfunction of the humoral and cellular immune system have a close correlation with the appearance of classic form of KS. In the literature, we have found 6 documented cases of HHV8-positive KS that appeared after introduction of immunosuppressive therapy in renal transplant patients and disappeared after discontinuation of the immunosuppressive therapy (47–10). In our case, KS appeared after kidney transplantation and the initiation of immunosuppressive therapy. The tumors underwent almost complete regression after the allograft kidney rejection when the immunosuppressive drugs were discontinued, but the HHV8 viral DNA could be still detected. To our knowledge this is the first report presenting the persistence of HHV8 viral DNA in regressed iatrogenic Kaposi’s sarcoma specimens. This case demonstrates the primary role of immunosuppressive therapy in the development of KS. The compromised immune host may not be able to control the lymphotropic virus. Supposedly, the virus activates certain cytokine pathways, which leads to inflammation and angiogenesis, but not necessarily malignant transformation. When the immune system is restored, the virus becomes suppressed, the angiogenic inflammation stops, and the tumors regress. The latent virus remains detectable, and, with the forthcoming immunosuppressive medication, it can be activated again. Acknowledgments. The authors are grateful to Dr. Irma Korom for the histopathological evaluation and Dr. Zsuzsanna Bata-Csorgo for critical reading of the manuscript. Szilvia Nagy Rolland Gyulai Lajos Kemény2 Pál Szenohradszky Attila Dobozy