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. 2014 Jan 15;7(2):699-708.
eCollection 2014.

HER2 protein overexpression and gene amplification in upper urinary tract urothelial carcinoma-an analysis of 171 patients

Yuka Sasaki  1 , Takeshi Sasaki  2 , Taketo Kawai  3 , Teppei Morikawa  2 , Keisuke Matsusaka  2 , Akiko Kunita  2 , Haruki Kume  3 , Ichiro Aoki  1 , Yukio Homma  3 , Masashi Fukayama  2
Affiliations

HER2 protein overexpression and gene amplification in upper urinary tract urothelial carcinoma-an analysis of 171 patients

Yuka Sasaki et al. Int J Clin Exp Pathol. .

Abstract

Upper urinary tract urothelial carcinomas (UUTUC) are infrequent and show an occurrence of about 5-10% of all urothelial carcinomas. In this study, we investigated the HER2 status of 171 UUTUC patients with nephroureterectomy. The number of patients is the largest of any HER2 study. All 171 cases were analyzed for both HER2 overexpression using immunohistochemistry and HER2 gene amplification using dual-color in situ hybridization. The scoring system proposed by the ASCO/CAP and ToGA trials was used. Out of 171 patients, 140 patients had a HER2 score-0 or score-1 (81.9%), 17 a score-2 (9.9%), and 14 a score-3 (8.2%) with immunohistochemistry. HER2 gene amplification was observed in 31 out of 171 cases (18.1%). A good correlation was observed between protein overexpression and gene amplification (p<0.0001). Twenty-three UUTUC (13.5%) were determined as HER2-positive cancer according to ASCO/CAP and ToGA criteria. HER2 positivity in patients over 70 years old was higher than that of patients under 70 years old (p=0.0132). HER2 expression correlated to a high histological grade (p=0.0003) and the coexistence of a high grade carcinoma in situ (p=0.0089). No HER2-positive cancer was observed in patients with renal pelvic UUTUC (0 out of 76, p<0.0001). HER2-positive UUTUC showed a shorter recurrence time in the residual urinary bladder after nephroureterectomy with Kaplan-Meier analysis (p=0.0284) and multivariate analysis (p=0.0034). The results suggest that HER2 positivity in UUTUC is an independent predictive marker for early recurrence of urothelial carcinoma in the residual urinary bladder after surgery.

Keywords: DISH; HER2; immunohistochemistry; tissue microarray; upper urinary tract; urothelial carcinoma.

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Figures

Figure 1
Figure 1
HER2 expression using immunohistochemistry in UUTUC. A: Negative for HER2 was score-0. B: Weakly positive for HER2 was score-1. Weak staining was categorized as negative. C: Moderately positive for HER2 was score-2. Gene examination using DISH or FISH is recommended for score-2 in UUTUC, and group was divided into HER2-positive or negative urothelial carcinomas. D: Strongly positive for HER2 was score-3. A-D: Magnification ×200.
Figure 2
Figure 2
HER2 amplification by DISH in UUTUC. Red dots indicate centromere (CEP17) and black dots represent HER2. A: HER2/CEP17=0.97 mean negative for amplification of HER2 gene. B: HER2/CEP17=6.72 mean amplification of HER2 gene. Magnification ×1,000 (oil emersion lens).
Figure 3
Figure 3
Time to recurrence in urinary bladder-comparison with HER2 positive and negative patients. Kaplan-Meier analysis revealed that HER2-positive patients showed significant association with a shorter bladder recurrence after nephroureterectomy (log-rank p=0.0284).
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