Purpose: Two clinical characteristics of the metastatic cancer phenotype are virulence-which reflects the pace of disease growth, clinical manifestation, and dissemination-and metastagenicity, the ultimate likelihood of distant metastasis. Molecular markers may allow distinguishing between these two cancer phenotypes. The purpose of this study is to determine whether proliferating cell nuclear antigen (PCNA) and tumor nuclear grade are markers of virulence or metastagenicity.
Patients and methods: PCNA and tumor nuclear grade were determined in patients with extensive follow-up, treated only with mastectomy, for whom archival paraffin-embedded tissue was available.
Results: There is no significant difference in long-term disease-free survival (DFS) as a function of PCNA, but after only 5 years of analysis there are significant differences that gradually disappear with further follow-up, reflecting differences in virulence. While the likelihood of recurrence is the same, in patients with high PCNA 80% of disease recurrences become evident in the first 2 to 3 years, whereas in patients with low PCNA it takes more than 10 years for 80% of metastases to become clinically detectable. There was a significant difference in 20-year DFS for nuclear grade 1 compared with nuclear grade 2 and 3 tumors, indicating a difference in metastagenicity. The differences in DFS between nuclear grade 2 and 3 tumors decrease as the length of follow-up increases; thus, like PCNA, these grade differences are also a marker of virulence. Eighty percent of the metastasis became evident within 4 years in grade 3 tumors and within 12 years in grade 2 tumors.
Discussion: PCNA and nuclear grade (2 vs 3) are markers of virulence. We have previously shown angiogenesis to be a marker of metastagenicity as is, in this study, the difference between nuclear grade 1 and nuclear grades 2 and 3. Both phenotypic characteristics, virulence and metastagenicity, are important to understanding the natural history of the tumors and may influence the nature of the therapy.