Oncocytoma-like renal tumor with transformation toward high-grade oncocytic carcinoma: a unique case with morphologic, immunohistochemical, and genomic characterization

Abstract

Renal oncocytoma is a benign tumor with characteristic histologic findings. We describe an oncocytoma-like renal tumor with progression to high-grade oncocytic carcinoma and metastasis. A 74-year-old man with no family history of cancer presented with hematuria. Computed tomography showed an 11 cm heterogeneous multilobulated mass in the right kidney lower pole, enlarged aortocaval lymph nodes, and multiple lung nodules. In the nephrectomy specimen, approximately one third of the renal tumor histologically showed regions classic for benign oncocytoma transitioning to regions of high-grade carcinoma without sharp demarcation. With extensive genomic investigation using single nucleotide polymorphism-based array virtual karyotyping, multiregion sequencing, and expression array analysis, we were able to show a common lineage between the benign oncocytoma and high-grade oncocytic carcinoma regions in the tumor. We were also able to show karyotypic differences underlying this progression. The benign oncocytoma showed no chromosomal aberrations, whereas the high-grade oncocytic carcinoma showed loss of the 17p region housing FLCN (folliculin [Birt-Hogg-Dubé protein]), loss of 8p, and gain of 8q. Gene expression patterns supported dysregulation and activation of phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (Akt), mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK), and mechanistic target of rapamycin (serine/threonine kinase) (mTOR) pathways in the high-grade oncocytic carcinoma regions. This was partly attributable to FLCN underexpression but further accentuated by overexpression of numerous genes on 8q. In the high-grade oncocytic carcinoma region, vascular endothelial growth factor A along with metalloproteinases matrix metallopeptidase 9 and matrix metallopeptidase 12 were overexpressed, facilitating angiogenesis and invasiveness. Genetic molecular testing provided evidence for the development of an aggressive oncocytic carcinoma from an oncocytoma, leading to aggressive targeted treatment but eventual death 39 months after the diagnosis.

FIGURE 1

(A) FNA of the aortocaval lymph node (20× objective). (B) Benign oncocytoma-like region of the renal tumor (20× objective). (C) High-grade oncocytic carcinoma region of the renal tumor (20× objective). (D) Aortocaval lymph node with metastatic tumor (10× objective). FNA = fine needle aspirate.

FIGURE 2

(A) Virtual karyotype using SNP-based array analysis. (B) Magnification of the heterozygous deletion in 17p that houses FLCN at 17p11.2. FLCN = folliculin (Birt–Hogg–Dubé protein).

FIGURE 3

(A) and (B) Immunohistochemical FLCN protein expression. (A) High-grade oncocytic carcinoma. (B) Benign oncocytoma-like region with slightly higher protein expression of FLCN. FLCN = folliculin (Birt–Hogg–Dubé protein).

FIGURE 4

(A) Scatter plot of expression data for 29,378 probes. The colored sections represent the following: blue = high-grade downregulated, red = high-grade upregulated, green = benign downregulated, yellow = benign upregulated, grey = high-grade upregulated and benign downregulated, orange = high-grade downregulated and benign upregulated. (B) Hierarchical clustering and heat map of expression ratios for 748 transcripts relative to the normal kidney. The genes falling within the 6 colored sectors in (A) and the gene probes corresponding to the 6 colored bars beneath the dendrogram in (B) represent genes that showed 2-fold overexpression or underexpression in 1 region with the other region having the opposite 2-fold expression or similar expression relative to normal kidney. FLCN = folliculin (Birt–Hogg–Dubé protein).