Evidence for a multiclonal origin of multicentric advanced lesions of Kaposi sarcoma.

BACKGROUND Kaposi sarcoma (KS) is a complex tumor of uncertain clonality. Studying the viral clonality of the human herpesvirus 8 (HHV-8) in KS to determine clonality of the tumors, a strategy that has been used previously with Epstein-Barr virus and its associated tumors, may elucidate whether multicentric (disseminated) KS lesions correspond to metastatic lesions or to expansions of independent clones. METHODS A series of 139 KS biopsies (from skin, lymph node, or tonsil) was obtained from 98 patients, with 59 biopsies from 18 patients with disseminated multicentric KS skin lesions. The degree of spindle cell infiltration in biopsies was established by direct observation of hematoxylin-eosin-stained sections, and HHV-8 viral load was quantified by real-time polymerase chain reaction. To determine cellular clonality, the size heterogeneity of the HHV-8-fused terminal repeat (TR) region was determined by probing of electrophoresed restricted genomic DNA from KS biopsies for the HHV-8 TR sequence. RESULTS HHV-8 clonality analysis was performed on the 62 samples for which sufficient DNA was obtained. Most samples corresponded to histologically nodular lesions with high spindle cell infiltration and high viral load. A clonal HHV-8 pattern was determined for 59 samples; 11 were found to be monoclonal and 48 to be oligoclonal. The informative samples that were from disseminated KS skin lesions (n = 26, from six patients) were either monoclonal or oligoclonal, and the size of HHV-8 episomes varied between these samples. CONCLUSION Although some tumor KS lesions were monoclonal expansions of HHV-8-infected spindle cells, most advanced lesions were oligoclonal proliferations. Furthermore, individual KS disseminated tumor skin lesions were found to represent distinct expansions of HHV-8-infected spindle cells. Thus, our results suggest that KS lesions, especially in patients with advanced skin tumors, are reactive proliferations rather than true malignancies with metastatic dissemination.