Proliferation and Maturation Indices in Nephrogenic Rests and Wilms Tumor; The Emergence of Heterogeneity from Dormant Nodular Renal Blastema

Abstract

Independent nephrogenic rests (NRs) accompany many Wilms tumors (WTs), exhibit a range of qualities suggesting dormancy, maturation, regression, and hyperplasia, and may carry the WT-I mutation. We assessed nucleolar organizer regions, proliferating cell nuclear antigen (PCNA) activity, cytoplasmic filament expression, and nuclear morphology in 79 nephrogenic rests accompanying 20 WTs. We found a direct relationship between the size of a blastematous NR and the AgNOR number per nucleus and a close correlation with PCNA activity. The blastema of most NRs > I cm in diameter was indistinguishable from blastema of most WTs. The smallest NR usually had a low number of silver-reactive nucleolar organizing regions (AgNORs), low PCNA activity, and absent cytoplasmic filaments, all characteristics of a nascent dormant state in which both proliferation rate and protein synthetic activity are low. Intermediate filament expression was variable in blastema of larger NRs; cytoplasmic filaments correlated with emergence of epithelial maturation and absence of filaments with accumulation of immature cells; mature epithelial structures in NRs had low AgNOR number and PCNA activity representing a terminal dormant state. The majority of blastemal cells in most WTs and in one-third of large hyperplastic NRs lack cytoplasmic filaments. This, plus the occasional finding in large NRs of features more typical of WTs such as prevalence of apoptosis, patches of frank necrosis, multinodular architecture, and expanses of monomorphic, poorly vas-cularized blastema with low PCNA activity, suggest that it may be possible to distinguish NRs that are progressing toward WT from those that are merely hyperplastic. This study refines the concepts of dormancy and hyperplasia as expressed in NRs and provides a general framework for probing the relationship of molecular events to progression of a small proportion of NRs to WT. Criteria used herein to define dormancy and hyperplasia may be useful in assessing lesions other than typical WT, such as unusually large or extensive NRs or uncommon differentiated WTs where the potential for aggressive behavior may be lower than in usual WTs.

Key Words:

• AgNOR
• PCNA
• nephrogenic rests
• Wilms tumor