Histological Tracking into the Third Dimension: Evolution of Early Tumorigenesis in VHL Kidney.

Mayyan Mubarak,Alexander Vortmeyer,Nayef Al Gharaibeh,Jie Li,Samuel Sommaruga

doi:10.15586/jkcvhl.v8i3.189

Abstract

Using 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.

Highlights

Patients with VHL disease develop tumors in the nervous system, kidneys, endolymphatic sac, epididymis or broad ligament, neuroendocrine tumors, and pheochromocytomas [1].The presence of abundant microscopic tumor precursor structures in the nervous system of patients with von Hippel- Lindau (VHL) disease has been previously demonstrated [2, 3]
Upon analysis in 3D tracking, we identified occasional and focal destruction of tubular epithelium and basement membrane indicative of amplification, proliferation, and invasion of clear cells beyond the basal membrane into the renal interstitium separately categorized as Type E, invasive clear cell clusters (Figure 3)
Renal tubular clear cell change resembling VHL-deficient clear cells can occur secondary to metabolic/toxic etiologies

Summary

Introduction

The presence of abundant microscopic tumor precursor structures in the nervous system of patients with von Hippel- Lindau (VHL) disease has been previously demonstrated [2, 3]. The cells of these precursor structures were shown to be immature [3, 4], and several lines of evidence suggest that. The growth pattern of precursor structures appears highly protracted, with only a subset of them developing into frank tumors [3]. Precursor structures defy categorization as teratomatous, tumorous, or dysplastic, and the designation of a developmentally arrested structural element (DASE) has been previously suggested [4]. A key question remains the nature of the “third hit” that would transform DASEs into frank tumors

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