Three-dimensional imaging of upper tract urothelial carcinoma improves diagnostic yield and accuracy
Keishiro Fukumoto, Shigeaki Kanatani, Georg Jaremko, Zoe West, Yue Li, Kimiharu Takamatsu, Ibrahim Al Rayyes, Shuji Mikami, Naoya Niwa, Tomas Andri Axelsson, Nobuyuki Tanaka, Mototsugu Oya, Ayako Miyakawa, Marianne Brehmer, Per Uhlén
Keishiro Fukumoto, Shigeaki Kanatani, Georg Jaremko, Zoe West, Yue Li, Kimiharu Takamatsu, Ibrahim Al Rayyes, Shuji Mikami, Naoya Niwa, Tomas Andri Axelsson, Nobuyuki Tanaka, Mototsugu Oya, Ayako Miyakawa, Marianne Brehmer, Per Uhlén
View: Text | PDF
Research Article Oncology

Three-dimensional imaging of upper tract urothelial carcinoma improves diagnostic yield and accuracy

Abstract

Upper tract urothelial carcinoma (UTUC) is a rare form of urothelial cancer with a high incidence of recurrence and a low survival rate. Almost two-thirds of UTUCs are invasive at the time of diagnosis; therefore, improving diagnostic methods is key to increasing survival rates. Histopathological analysis of UTUC is essential for diagnosis and typically requires endoscopy biopsy, tissue sectioning, and labeling. However, endoscopy biopsies are minute, and it is challenging to cut into thin sections for conventional histopathology; this complicates diagnosis. Here, we used volumetric 3-dimensional (3D) imaging to explore the inner landscape of clinical UTUC biopsies, without sectioning, revealing that 3D analysis of phosphorylated ribosomal protein S6 (pS6) could predict tumor grade and prognosis with improved accuracy. By visualizing the tumor vasculature, we discovered that pS6+ cells were localized near blood vessels at significantly higher levels in high-grade tumors than in low-grade tumors. Furthermore, the clustering of pS6+ cells was associated with shorter relapse-free survival. Our results demonstrate that 3D volume imaging of the structural niches of pS6 cells deep inside the UTUC samples improved diagnostic yield, grading, and prognosis prediction.

Authors

Keishiro Fukumoto, Shigeaki Kanatani, Georg Jaremko, Zoe West, Yue Li, Kimiharu Takamatsu, Ibrahim Al Rayyes, Shuji Mikami, Naoya Niwa, Tomas Andri Axelsson, Nobuyuki Tanaka, Mototsugu Oya, Ayako Miyakawa, Marianne Brehmer, Per Uhlén

×

Figure 3

Cluster analysis of pS6+ cells in UTUC samples.

Options: View larger image (or click on image) Download as PowerPoint
Cluster analysis of pS6+ cells in UTUC samples. (A) Cross sections of UT...
(A) Cross sections of UTUC sample #14HG with clustered pS6+ cells at depth z = 620 μm (upper) and sparse pS6+ cells at depth z = 594 μm (lower). Nuclei stained with histone. (B) Volume rendering and cell-by-cell analysis of pS6+ cells in UTUC samples #3HG (upper) and #6LG (lower). Bounding boxes, 1,548 × 1,500 × 708 μm (#3HG) and 1,600 × 1,260 × 1,100 μm (#6LG). (C–I) Violin plots of pS6+ cells in low-grade (LG, n = 8) and high-grade (HG, n = 11) UTUC samples analyzed for nearest distance (C, P = 0.008), number of cells within a 100 μm radius (D, P = 0.003), nearest neighbor index (E, P = 0.004), cluster density (F, P = 0.002), clustered pS6+ cell density (G, P < 0.001), cells per cluster (H, P = 0.026), and clustered pS6+ cell ratio (I, P = 0.048). For the violin and box plots, the violin indicates the distribution, the box center line indicates the median, the upper and lower boundaries of the box indicate the upper and lower quartiles, and the whiskers indicate the minimum and maximum values. au, arbitrary unit. Scale bars: 50 μm (yellow), and x, y, z indicators 250 μm (white). *P < 0.05, **P < 0.01, ***P < 0.005, ****P < 0.001 by Mann-Whitney U tests.