Aberrant expression of cell cycle regulators in Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma.
The characteristic Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma, although highly positive for proliferation markers, do not accumulate to excessive cell numbers. These cells are characterized by abortive mitotic cycles, leading to multinucleation or cell death in mitosis. We have previously described high expression of G1-phase cyclins in classical Hodgkin's lymphoma, which could explain the high percentage of cells staining for proliferation markers. To further our understanding of proliferation control in classical Hodgkin's lymphoma, we extended our immunohistochemical analysis to the main S-phase cyclin, cyclin A, and its regulators p21CIP1 and p27KIP1. Expression of proliferating cell nuclear antigen (PCNA) was used as an additional marker for cells being in either S- or G2-phase. In 47% (112/239) of classical Hodgkin's lymphoma cases p21CIP1 was detected within a mean frequency of 15% positive Hodgkin's and Reed-Sternberg cells per case. Similarly, 47% (116/249) of the cases stained positively for p27KIP1 with a mean frequency of expression in Hodgkin's and Reed-Sternberg cells of 12%. In contrast, 90% of the cells in all 246 evaluable classical Hodgkin's lymphoma cases were positive for PCNA. In addition, 98% of Hodgkin's and Reed-Sternberg cells in 99% (250/253) of the cases stained strongly positive for cyclin A. These findings further corroborate the hypothesis that Hodgkin and Reed-Sternberg cells exhibit a disturbed cell cycle with an abnormally short or even absent G1-phase. In contrast to other tumors, expression of PCNA or cyclin A had no prognostic value for patient survival.
Tzankov
Alexandar
A
Institute of Pathology, Medical University of Innsbruck, Austria.
Zimpfer
Annette
A
Went
Philip
P
Maurer
Robert
R
Pileri
Stefano A
SA
Geley
Stephan
S
Dirnhofer
Stephan
S
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins / Q000032:analysis; D018797:Cell Cycle Proteins / Q000032:analysis*; D002648:Child; D019925:Cyclin A / Q000032:analysis; D019938:Cyclin D1 / Q000032:analysis; D056743:Cyclin D3; D019927:Cyclin E / Q000032:analysis; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000032:analysis; D005260:Female; D006689:Hodgkin Disease / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis; D008297:Male; D008875:Middle Aged; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D016539:Reed-Sternberg Cells / Q000737:chemistry / Q000473:pathology*
C534696:CCND3 protein, human; C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D019925:Cyclin A; D056743:Cyclin D3; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D047908:Intracellular Signaling Peptides and Proteins; D018809:Proliferating Cell Nuclear Antigen; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27