J Korean Med Sci.  2015 Aug;30(8):1068-1077. 10.3346/jkms.2015.30.8.1068.

Clinical Significance of Substaging and HER2 Expression in Papillary Nonmuscle Invasive Urothelial Cancers of the Urinary Bladder

• Lim SD
• Cho YM
• Choi GS
• Park HK
• Paick SH
• Kim WY
• Kim SN
• Yoon G

• KMID: 2164501
• DOI: http://doi.org/10.3346/jkms.2015.30.8.1068

Abstract

The study aimed to verify the prognostic utility, therapeutic application and clinical benefits of tumor substaging and HER2 status in papillary non-muscle invasive bladder cancer (NMIBC). Select NMIBC transurethral resection specimens from 141 patients were used to construct tissue microarrays for assessing the substaging, HER2 protein expression by immunohistochemistry (HER2-IHC) and gene amplification by dual-color silver in situ hybridization (HER2-SISH). Substages were identified by the differing depth of tumor invasion (pTa / pT1a / pT1b / pT1c). HER2 protein expression was semiquantitatively analyzed and grouped into negative (score 0, 1+) and positive (score 2+, 3+). Other clinicopathological variables were also investigated. For NMIBC, HER2-IHC and HER2-SISH showed positive results in 6/141 (4.3%) and 4/141 (2.8%) respectively, which correlated well with tumor substaging. In multivariate analysis, substaging, HER2-IHC, and HER2-SISH were found to be independent predictors of progression-free survival (P < 0.001, P < 0.001, P = 0.031). HER2-IHC was the sole independent predictor of recurrent free survival in NMIBC (P = 0.017). It is suggested that tumor substaging and HER2 status are independent predictive markers for tumor progression or recurrence, and thus could be included in diagnostic and therapeutic management for NMIBC.

Keyword

Bladder Cancer; Cancer Staging; HER2 Gene; Immunohistochemistry; In Situ Hybridization

MeSH Terms

Adult
Aged
Aged, 80 and over
Biomarkers, Tumor/*metabolism
Carcinoma, Papillary/*metabolism/*pathology
Carcinoma, Transitional Cell/metabolism/pathology
Female
Humans
Male
Middle Aged
Neoplasm Staging
Receptor, ErbB-2/*metabolism
Reproducibility of Results
Sensitivity and Specificity
Urinary Bladder Neoplasms/*metabolism/*pathology
Young Adult
Biomarkers, Tumor
Receptor, ErbB-2

Figure

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  Fig. 1 HER2 immunohistochemistry (HER2-IHC). (A) 3+, moderate-to-strong complete membrane staining in all tumor area. (B) 2+, variable weak-to-moderate complete membrane staining in ≥ 50% of tumor area. (C) 1+, faint/barely partial membrane staining less than 50% of tumor area. (D) 0, no staining. (magnification × 200).

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  Fig. 2 HER2 gene amplification by dual-color silver in situ hybridization (HER2-SISH). HER2-SISH positive case (A) matched with HER2-IHC 3+ (B). (magnification: (A) × 1,000; (B) × 400).

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  Fig. 3 Kaplan Meier analysis for recurrence free survival in NMIBC. Tumor size (A) and HER2-IHC positive (B) significantly correlated with recurrence-free survival.

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  Fig. 4 Kaplan Meier analysis for progression free survival in NMIBC. Pathologic substage (A), tumor grade (B), HER2-IHC (C) and HER2-SISH (D) correlated with progression-free survival.

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