Cancer Res Treat.  2024 Jul;56(3):856-870. 10.4143/crt.2023.1150.

Invasiveness of Upper Tract Urothelial Carcinoma: Clinical Significance and Integrative Diagnostic Strategy

• Ahn B
• Kim D
• Park KJ
• Park JM
• Yoon SY
• Hong B
• Cho YM
• Kim D

• KMID: 2557672
• DOI: http://doi.org/10.4143/crt.2023.1150

Abstract

Purpose
In this study, we aimed to determine the clinicopathologic, radiologic, and molecular significance of the tumor invasiveness to further stratify the patients with high-grade (HG) upper tract urothelial carcinoma (UTUC) who can be treated less aggressively.
Materials and Methods
Clinicopathologic and radiologic characteristics of 166 surgically resected HG UTUC (48 noninvasive, and 118 invasive) cases were evaluated. Six noninvasive UTUC cases with intratumoral tumor grade heterogeneity were selected for whole-exome sequencing (WES) to understand the underlying molecular pathophysiology. Barcode-tagging sequencing was done for validation of the target genes from WES data.
Results
Patients with noninvasive UTUC showed no cancer-specific death with better cancer-specific survival (p < 0.001) and recurrence-free survival (p < 0.001) compared to the patients with invasive UTUC. Compared to the invasive UTUC, noninvasive UTUC was correlated to a low grade (LG) on the preoperative abdominal computed tomography (CT) grading system (p < 0.001), histologic intratumoral tumor grade heterogeneity (p=0.018), discrepancy in preoperative urine cytology diagnosis (p=0.018), and absence of urothelial carcinoma in situ (p < 0.001). WES of the heterogeneous components showed mutually shared HRAS and FGFR3 mutations shared between the HG and LG components. HRAS mutation was associated with the lower grade on preoperative abdominal CT and intratumoral tumor grade heterogeneity (p=0.045 and p < 0.001, respectively), whereas FGFR3 mutation was correlated to the absence of carcinoma in situ (p < 0.001).
Conclusion
According to our comprehensive analysis, HG noninvasive UTUC can be preoperatively suspected based on distinct preoperative radiologic, cytologic, histologic, and molecular features. Noninvasive HG UTUC shows excellent prognosis and thus should be treated less aggressively.

Keyword

Noninvasive urothelial carcinoma; Invasive urothelial carcinoma; Upper tract urothelial carcinoma; Whole-exome sequencing; Barcode-tagged sequencing

Figure

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  Fig. 1. Representative abdominal computed tomographic (CT) images of high-grade upper tract urothelial carcinoma (UTUC). Axial (A) and coronal (B) views of the CT scan shows 2-cm tumor (arrows) without spiculation in the right distal ureter, causing hydroureterosis. This lesion was radiologically classified as grade A (pattern 3) and was pathologically confirmed as noninvasive high-grade UTUC. Axial (C) and coronal (D) reformatted CT scans reveal a 2.2-cm mass with irregular surface (arrows) in the left distal ureter and ureterovesical junction. This lesion was radiologically classified as grade B (pattern 6) and was pathologically confirmed as pT2.

• 

  Fig. 2. Representative microscopic images of a case of noninvasive upper tract urothelial carcinoma with intratumoral heterogeneity. (A) Papillary structure of neoplastic urothelium of variable thickness is noted with heterogenous components of both high grade and low grade (H&E, ×1.0). Low-grade component shows a relatively orderly appearance with only mild nuclear atypia (H&E, ×40, lower right inlet). High-grade component shows cellular disorder, nuclear size variation and pleomorphic nuclei with frequent mitosis (H&E, ×40, lower left inlet). (B) Preoperative biopsy shows a low-grade noninvasive urothelial carcinoma with delicate papillae of urothelial proliferation with mild nuclear irregularity.

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  Fig. 3. Cancer-specific survival (CSS) and recurrence-free survival (RFS) of patients with high-grade upper tract urothelial carcinoma (UTUC). (A) Patients with noninvasive UTUC showed a significantly better CSS than invasive UTUC (5-year survival rate, 100% vs. 52.9%; p < 0.001). (B) Patients with noninvasive UTUC showed a significantly better RFS than invasive UTUC (5-year survival rate, 95.5% vs. 54.8%; p < 0.001).

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  Fig. 4. Phylogenetic tree of four high-grade, noninvasive upper tract urothelial carcinoma cases. Whole-exome sequencing was done for four cases with intratumoral heterogeneity. Each of the low-grade (LG) and high-grade (HG) components was manually dissected for mutational analysis. Each branch of the phylogenetic tree designates each component. FGFR3 mutation and HRAS mutations were shared between the LG and HG components of case 1 and cases 2-4, respectively.

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  Fig. 5. Clinicopathologic significance and survival impact of HRAS and FGFR3 mutations. (A) Presence of HRAS mutation was significantly correlated with tumor located in the kidney (p=0.012), tumor with higher pathologic T category (p=0.034), higher American Joint Committee on Cancer (AJCC) stage (p=0.045), and intratumoral heterogeneity (p < 0.001). (B) Presence of FGFR3 mutation was significantly correlated with the absence of urothelial carcinoma in situ (p < 0.001). (C) Cancer-specific survival (CSS; 5-year survival rate, 66.7% vs. 70.4%; p=0.335) and recurrence-free survival (RFS; 5-year survival rate, 59.2% vs. 70.4%; p=0.160) were not significantly different between patients with HRAS mutation and those without HRAS mutation. (D) Patients with FGFR3 mutation showed a tendency of better survival but did not show any significant difference in CSS from those without FGFR3 mutation (95.0% vs. 65.2%, p=0.200). However, patients with FGFR3 mutation showed significantly better RFS than those without HRAS mutation (95.2% vs. 61.7%, p=0.044).

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  Fig. 6. Nomogram for predicting non-invasiveness in high grade (HG) upper tract urothelial carcinoma (UTUC). To estimate the probability of HG UTUC cases being noninvasive, each individual HG UTUC patients’ values were plotted on each variable axis. A vertical line shows the number of points that were assigned to the variable, and the points from each variable can be summed and projected to the bottom axis. According to the nomogram, preoperative computed tomography (CT) grading is the strongest predictive factor for noninvasive UTUC which is assigned with the highest points, followed by the presence of urothelial carcinoma in situ, the absence of discrepant urine cytology results, and absence of tumor grade heterogeneity.

Reference

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