Eosinophilic Vacuolated Tumor of the Kidney: A Review of Evolving Concepts in This Novel Subtype With Additional Insights From a Case With MTOR Mutation and Concomitant Chromosome 1 Loss

Abstract

Recent advances in molecular genetics have expanded our knowledge of renal tumors and enabled a better classification. These studies have revealed that renal tumors with predominantly "eosinophilic/oncocytic" cytoplasm include several novel biological subtypes beyond the traditionally well-recognized renal oncocytoma and an eosinophilic variant of chromophobe renal cell carcinoma. Herein, we present a comprehensive review of the eosinophilic vacuolated tumor (EVT) building upon a case report including radiology, histopathology, electron microscopy, and next-generation sequencing. EVTs are characterized by mTORC1 activation. We speculate that loss of chromosome 1 in EVT with MTOR mutation may be driven in part by an advantage conferred by loss of the remaining MTOR wild-type allele. mTORC1 is best known for its role in promoting protein translation and it is interesting that dilated cisterns of rough endoplasmic reticulum (ER) likely account for the cytoplasmic vacuoles seen by light microscopy. We present an integrated view of EVT as well as cues that can assist in the differential diagnosis.

Figure 1.. Radiological and microscopic features of Eosinophilic Vacuolated Tumors (EVT).

(A) Axial reconstruction of a contrast-enhanced CT acquisition during the corticomedullary phase demonstrating a small renal mass peripherally located in the left kidney. Note disproportionate enhancement (long arrow) suggesting intense angiogenesis. Laterally the mass exhibits an area with decrease enhancement (short arrow). (B) Representative hematoxylin and eosin stained sections reveal a well circumscribed unencapsulated tumor with (C) prominent thick-walled abnormal vessels and (D) focal scarring (white arrow). (E) Tumor cells are arranged in tubular to nested architecture in a hyalinized hypovascular stroma. (F-G) The cells show round nuclei with smooth nuclear membranes, prominent nucleoli, multinucleation and abundant eosinophilic cytoplasmic with distinct cell borders. (H) Characteristic features included the presence of prominent large cytoplasmic vacuoles.

Figure 2.. Immunohistochemical features of EVT.

EVT characteristically have (A) positive membranous CD117; (B) negative cytokeratin 7; (C) focal positive cathepsin-K; and (D) diffuse phospho-S6 expression. (E-F) Ultramicrographs showing numerous mitochondria (arrow head) and dilated cisterns of rough endoplasmic reticulum (arrow).

Figure 3.. Sequencing analyses.

(A) Oncoplot of selected genes including those with somatic mutations based on COSMIC and (B) screenshot of MTOR c.7280A>T mutation viewed with Integrated Genome Viewer (IGV). (C) Sanger sequencing chromatogram validating the mutation. (D) Genome-wide plots showing copy number variation (CNV) analysis of whole exome sequencing with loss of chromosome 1.

Figure 4.. Schematic mapping of mTOR mutations in EVT.

(A) Schematic representation of the mTOR domains along the chain from N-terminus to C-terminus. The position of the L2427Q is indicated. (B) Model showing active (cyan)/inactive (green) kinase domains superimposed, with active site residues in black stick and ATP in ball and stick. The L2427Q mutation is positioned in a unique kα9b insertion (pink) that overlaps with a negative regulatory region whose deletion activates the kinase. The Leu2427 sidechain (magenta stick, with interacting residues within 4 Å in stick) anchors kα9b (pink) alongside the substrate binding groove, linking one end to the FAT helical network (orange).