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Item Histological Tracking into the Third Dimension: Evolution of Early Tumorigenesis in VHL Kidney(Codon, 2021-09-10) Mubarak, Mayyan; Al-Gharaibeh, Nayef; Sommaruga, Samuel; Li, Jie; Vortmeyer, Alexander Oliver; Pathology and Laboratory Medicine, School of MedicineUsing a novel three-dimensional (3D) approach, we tracked histological changes to elucidate the earliest stages of renal clear cell neoplasia in normal kidney tissue of patients with von Hippel-Lindau (VHL) disease. Tissue blocks of interest were procured, serially sectioned, and 3D reconstruction of the entirety of pathologic events was performed. The results reveal an abundance of foci with aberrant clear cell proliferation that initially develop along the tubular lining, but have the potential to aggregate within individual tubules. This stage is followed by the extension of clear cell aggregates beyond the tubular basement membrane, which allows for the recruitment of angiogenesis derived from interstitial vasculature. The results suggest that the most frequent pathologic event in VHL kidneys is the presence of isolated or aggregated clear cells within the tubular epithelium, potentially developing further into a protracted process of neoplasia. The abundance of independent pathologic events in VHL kidneys confirms developmental mechanisms to precede tumor initiation. To our knowledge, this is the first report demonstrating that tracking of histologic changes in the 3rd dimension enables the confirmation of the sequence of events from the earliest pathologic change in the VHL kidney to the neoplastic stage. This approach is not only useful for visualization and quantification of pathologic changes but also for targeted sampling allowing selective analysis of the earliest stages of clear cell carcinogenesis.Item Kidney in VHL disease: Early clear cell proliferation occurs in the distal tubular system(Spandidos Publications, 2022) Al-Gharaibeh, Nayef S.; Temm, Constance J.; Shively, Sharon B.; Vortmeyer, Alexander O.; Pathology and Laboratory Medicine, School of MedicineRenal clear cell carcinoma commonly occurs in patients with von Hippel-Lindau disease (VHL). Kidneys of VHL disease patients (VHL kidneys) contain an abundance of independent clear cell proliferation events that have been hypothesized to represent precursor structures of clear cell carcinoma. In the present study, it was tried to identify the site of origin of clear cell proliferation, and the immunophenotype of clear cells. Using 3D histological tracking, the topographic origin of microscopic clear cell proliferation was investigated by identification of informative structures of interest and immunohistochemical staining for cluster of differentiation 10 (CD10) and cytokeratin 7 (CK7) in consecutive serial sections. In addition, the CD10/CK7 immunophenotype of proliferating clear cells was evaluated. Clear cell proliferation uniformly occurred in the distal tubular system. Some clear cell proliferation, however, revealed proximal tubule immunophenotype. It was concluded that early proliferation of VHL-deficient clear cells occurs in the distal tubular system. Despite the association with the distal tubular system, the immunohistochemical profile of early clear cell proliferation may be inconsistent with its distal tubular origin.