Journal of the National Cancer Institute Advance Access originally published online on July 10, 2007
JNCI Journal of the National Cancer Institute 2007 99(14):1086-1094; doi:10.1093/jnci/djm045
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© The Author 2007. Published by Oxford University Press.
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ARTICLES |
Evidence for a Multiclonal Origin of Multicentric Advanced Lesions of Kaposi Sarcoma
Affiliations of authors: Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, Département de Virologie, Institut Pasteur, Paris, France (RD, VL, PT, AG); Service d’Anatomie Pathologique (JB) and Service de Dermatologie (CL), Hôpital Saint-Louis, Paris, France; Service de Dermatologie, Hôpital de Cayenne, Cayenne, French Guiana (PC, DSM); Service de Dermatologie, Hôpital de la Pitié-Salpêtrière, Paris, France (CF); Institut Pasteur de Bangui, Bangui, Central African Republic (EKK); Service de Médecine et d’Anatomopathologie, CHU de Yaoundé, Cameroon (MJL, BN); Service d’Anatomopathologie, Centre Pasteur de Yaoundé, Cameroon (JLEO); Institut Pasteur du Maroc, Morocco (OH); Institut d’Hygiène Sociale, Dakar, Senegal (AM); Unité de Recherche et d’Expertise Histotechnologie et Pathologie, Institut Pasteur, Paris, France (MH)
Correspondence to present address: Renan Duprez, PhD, Laboratorio de Diagnóstico Virológico del CIENI, Instituto Nacional de Enfermedades Respiratorias, Calzada de Tlalpan 4502, Col. Sección XVI, CP 14080 Tlalpan, México DF (e-mail: renan.duprez{at}cieni.org.mx).
Correspondence to: Antoine Gessain, MD, PhD, Unité d’Epidémiologie et Physiopathologie des Virus Oncogènes, URA CRNS 3015, Département de Virologie, Bâtiment Lwoff, Institut Pasteur, 28 rue du Docteur Roux, 75724 Paris cedex 15, France (e-mail: agessain{at}pasteur.fr).
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.
| CONTEXT AND CAVEATS Prior knowledge Whether Kaposi sarcoma (KS) lesions arise from transformation and proliferation of a unique somatic cell that is infected with human herpesvirus 8 (HHV-8) or from a nonneoplastic expansion of infected cells has been debated. Study design Molecular diagnostic techniques were used to characterize HHV-8 DNA from KS tumor samples for heterogeneity. Contribution The study presented evidence that most advanced lesions are reactive proliferations of multiple cells after distinct infections rather than malignancies deriving from a single infected and transformed cell. Similarly, separate disseminated tumor skin lesions in the same patient were found to often represent distinct expansions of multiple cells after multiple infections. Implications The etiology of KS is different in kind from that of the majority of cancers, which arise from immortalization of a single cell. Limitations Much additional work will be needed to understand how human HHV-8 causes KS.
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Manuscript received November 28, 2006; revised May 15, 2007; accepted June 7, 2007.
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  P. S. Gill The Origin of Kaposi Sarcoma J Natl Cancer Inst, July 18, 2007; 99(14): 1063 - 1063. [Full Text] [PDF]
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