Epstein-Barr virus (EBV) infection probably has a role in this transforming event, which renders RS precursors resistance to apoptosis, as clonal EBV genomes can be detected in RS cells of classical HL in 30 -50% of cases. 3,4 EBV-encoded LMP-1 protein, known to be expressed in RS cells, is known for its immortalizing activity. 1,4 -6 EBV encoded EBNA-1 protein is also thought to have transforming capacity. 7,8 Moreover EBV is involved in immune suppression. 9,10 The major subset of HL of the nodular sclerosis subtype among the Western population is, however, frequently EBV negative. The distinct epidemiology of these cases has led to various speculations about their pathogenesis, but no other viruses have been identified to date. However, other transforming events such I B␣ gene mutations resulting in over-expression of NF-B as possible explanation of the rescue of these cells from apoptosis have been demonstrated. 11,12 The frequent finding of immunohistochemically detectable p53 protein expression in the nuclei of RS cells 4,13,14 suggests a possible role for p53 protein in the rescue of RS precursors from apoptosis. Wild-type p53 protein has the ability to intervene in cell proliferation and is necessary to maintain the integrity of the DNA.An aberrant p53 protein with lack of transcriptional activity can result in the survival of genetically unstable cells susceptible to malignant transformation. 15 A mutation in the TP53 gene is often associated with detectable p53 protein expression, because it stabilizes the protein as a consequence of conformational change. Several studies have demonstrated that a TP53 gene mutation causes impairment of p53 protein-mediated trans-activation. For HL a few studies have reported the presence of TP53 gene mutations in RS cells in only a minority of cases. 14,16,17 The low percentages of TP53 gene mutations (Ͻ10%) detected could be the result of the paucity of RS cells in the specimens, which may lead to false-negative findings. In general, higher TP53 gene mutation percentages were reported in studies with enrichment for RS cells. 13,18 -20 One exception was reported in a recent study in which even with enrichment no mutations were found. 21 Because TP53 gene mutations and EBV both can play a role in the resistance of RS precursors to apoptosis, the question arises whether these 2 potentially transforming events exclude each other. Chen et al. 13 found TP53 gene mutations in 6 of 16 EBVnegative cases and no mutations in 7 EBV-positive cases. This finding suggests that in some of the EBV-negative cases a TP53 gene mutation may be fundamental for the inhibition of apoptosis.To gain more insight in the frequency of TP53 gene mutations in HL and to test the hypothesis of an inverse correlation between the presence of TP53 gene mutations and EBV, we analyzed 67 cases of HL-involved tissues. All HL-involved tissues were analyzed for the presence of immunohistochemically detectable p53 protein and the presence of EBV. We enriched 15 EBV-positive and 11 EBV-negative HL-involved ti...