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(American Journal of Pathology. 2000;156:1209-1215.)
© 2000 American Society for Investigative Pathology

Regular Articles

Proliferation in HHV-8-Positive Primary Effusion Lymphomas Is Associated with Expression of HHV-8 Cyclin but Independent of p27kip1

Antonino Carbone*, Annunziata Gloghini*, Daniela Bontempo*, Paolo Monini{dagger}, Umberto Tirelli{ddagger}, Rachele Volpe*, Philip J. Browning§ and Gianluca Gaidano

From the Divisions of Pathology*
and Medical Oncology A,{ddagger}
Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Aviano, Italy; the Laboratory of Virology,{dagger}
Istituto Superiore di Sanità, Roma, Italy; the Division of Medical Oncology,§
Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee; and the Division of Internal Medicine,
Department of Medical Sciences, "Amedeo Avogadro" University of Eastern Piedmont, Novara, Italy

Primary effusion lymphoma (PEL) develops in immunodeficient patients, selectively localizes to the serous body cavities, and harbors infection by human herpesvirus type-8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus. HHV-8 encodes a viral (v)-cyclin homologous to cellular D-type cyclins, a class of positive cell-cycle regulators that are physiologically modulated by the p27Kip1 cell cycle inhibitor. The aims of the present study were: 1) to establish the expression pattern of p27Kip1 in PEL; and 2) to address the relationship between p27Kip1 expression, proliferation index, and expression of cellular cyclin D1 and v-cyclin in PEL. Expression of p27Kip1 was detected in all (n = 18) PEL samples analyzed by both immunocytochemistry and Western blot. All PELs displayed a high proliferation index as assessed by Ki-67 staining. Expression of cellular cyclin D1 was absent in all PELs tested, which conversely expressed (14 out of 14 samples) v-cyclin by immunocytochemistry and/or Western blot. In contrast to PELs, HHV-8-negative lymphomatous effusions secondary to a tissue-based lymphoma generally failed to express p27Kip1. Overall, these data show that PELs consistently express p27Kip1 protein despite the high proliferative rate of the lymphoma clone, suggesting that p27Kip1 may be unable to drive cell-cycle arrest in PEL cells. The co-existence of p27Kip1 expression and high proliferative index is a selective feature of PEL among lymphomas involving the serous body cavities, because lymphomatous effusions secondary to a tissue-based lymphoma generally display the inverse relationship between p27Kip1 positivity and growth fraction observed in normal lymphoid tissues and in most other lymphomas. Expression of p27Kip1 in PEL associates with expression of HHV-8 v-cyclin, but not of cellular cyclin D1. The fact that HHV-8 v-cyclin is resistant to p27Kip1-modulated inhibition, whereas cellular cyclin D1 is sensitive, may explain, at least in part, the co-existence of p27Kip1 expression and high proliferative index observed in PEL.




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