Prognostic Significance of Lymphocyte Infiltration and a Stromal Immunostaining of a Bladder Cancer Associated Diagnostic Panel in Urothelial Carcinoma.

Hideki Furuya,Charles J Rosser,Landon Kozai,Yutaro Tsukikawa,Owen T.M Chan,Regan S Wong,Yunfeng Dai,Keanu Chee,Keith S Chan,Kanani Hokutan

doi:10.3390/diagnostics10010014

Abstract

We set out to expand on our previous work in which we reported the epithelial expression pattern of a urine-based bladder cancer-associated diagnostic panel (A1AT, ANG, APOE, CA9, IL8, MMP9, MMP10, PAI1, SDC1, and VEGFA). Since many of the analytes in the bladder cancer-associated diagnostic signature were chemokines, cytokines, or secreted proteins, we set out to report the stromal staining pattern of the diagnostic signature as well as CD3+ (T-cell) cell and CD68+ (macrophage) cell staining in human bladder tumors as a snapshot of the tumor immune landscape. Immunohistochemical staining was performed on 213 tumor specimens and 74 benign controls. Images were digitally captured and quantitated using Aperio (Vista, CA). The expression patterns were correlated with tumor grade, tumor stage, and outcome measures. We noted a positive correlation of seven of the 10 proteins (excluding A1AT and IL8 which had a negative association and VEGFA had no association) in bladder cancer. The overexpression of MMP10 was associated with higher grade disease, while overexpression of MMP10, PAI1, SDC1 and ANG were associated with high stage bladder cancer and CA9 was associated with low stage bladder cancer. Increased tumor infiltration of CD68+ cells were associated with higher stage disease. Overall survival was significantly reduced in bladder cancer patients’ whose tumors expressed eight or more of the 10 proteins that comprise the bladder cancer diagnostic panel. These findings confirm that the chemokines, cytokines, and secreted proteins in a urine-based diagnostic panel are atypically expressed, not only in the epithelial component of bladder tumors, but also in the stromal component of bladder tumors and portends a worse overall survival. Thus, when assessing immunohistochemical staining, it is important to report staining patterns within the stroma as well as the entire stroma itself.

Highlights

Bladder cancer, the fifth most common malignancy in the US, will be diagnosed in approximately80,470 patients and will result in approximately 17,670 deaths in 2019 [1]
The majority of newly diagnosed bladder cancer (70%) are non-muscle invasive bladder cancer (NMIBC), which is disease confined to the mucosa and submucosal tissues
Are at high risk for the recurrence of tumors (70%), leading to high prevalence of bladder cancer in the US, second only to colorectal cancer [3,4]. In addition to this high rate of tumor recurrence, 30% of patients with NMIBC will progress to muscle invasive bladder cancer (MIBC), which is associated with a reduced overall survival (5-year survival < 50%) compared to NMIBC (5-year survival > 90%), whilst another 50% of these NMIBC patients will undergo removal of their bladders in an attempt to control their disease [5]

Summary

Introduction

The fifth most common malignancy in the US, will be diagnosed in approximately80,470 patients (with a preponderance of these patients being males over the age of 60 years) and will result in approximately 17,670 deaths in 2019 [1]. Chemotherapy are considered as the treatment of choice resulting in improved progression-free intervals after initial tumor resection [2]. Despite these therapies, patients with NMIBC are at high risk for the recurrence of tumors (70%), leading to high prevalence of bladder cancer in the US, second only to colorectal cancer [3,4]. In the US, radical cystectomy is the preferred treatment modality for these tumors, but up to 50% of patients experience disease relapse and eventual death [7,8,9]

Methods

Results

Conclusion