Department of Urology, Skåne University Hospital, Malmö, Sweden; Department of Translational Medicine, Lund University, Malmö, Sweden.
Unilabs Pathology Department, Helsingborg, Sweden.
Urol Oncol. 2019 Oct;37(10):791-799. doi: 10.1016/j.urolonc.2019.04.010. Epub 2019 May 2.
To investigate the preoperative prognostic value of molecular subtypes in relation to clinical information, histopathological findings, and molecular markers for patients with bladder cancer treated with radical cystectomy.
After standard preoperative staging, a population-based cohort of 519 patients underwent radical cystectomy between 2006 and 2011. Following pathological review of all transurethral resection of bladder tumor specimens, tissue microarrays were constructed, and RNA was extracted from formalin-fixed tissue blocks. Immunohistochemistry (IHC) was performed using markers suggested to be relevant for prognosis (ZEB2, CCND1, CD3, CD68, CDH3, HER3, KRT14, CDKN2A(p16), TP63, FGFR3, EPCAM, GATA3, FOXA1, ERBB2, and EGFR). IHC- and gene-expression-based molecular classification was also conducted. Univariate and multivariate Cox proportional hazards regression were used for survival analyses.
Clinical T3 stage (Hazard Ratio [HR] 1.6, Confidence Interval [CI] 1.1-2.3), hydronephrosis (HR 1.7, CI 1.2-2.3), lymphovascular invasion (LVI) (HR 2.6, CI 1.9-3.6), extensive necrosis (HR 1.6, CI 1.1-2.5), and CD68/CD3-ratio >1 (HR 1.3, CI 1.1-1.5) in the transurethral resection of bladder tumor specimen was associated with worse cancer-specific survival (CSS) and progression-free survival (data not shown). In multivariate analysis, higher clinical T stage (HR 1.3, CI 1.1-1.7; P = 0.007) and presence of LVI (HR 2.4, CI 1.7-3.5; P = 1.8 × 10) were associated with worse CSS, whereas only LVI was associated with progression-free survival. Molecular subtypes (assessed by Lund taxonomy and the Consensus molecular subtypes of muscle-invasive bladder cancer) and published single IHC markers were not associated with survival.
In the present large population-based cystectomy series, LVI and clinical stage were independently associated with CSS. However, molecular subtypes determined by global gene expression showed no such association with CSS according to either the Consensus molecular subtypes of muscle-invasive bladder cancer or Lund taxonomy.
研究分子亚型与临床信息、组织病理学发现和膀胱癌根治性切除术患者的分子标志物之间的术前预后价值。
在标准术前分期后,对 2006 年至 2011 年间接受根治性膀胱切除术的 519 例患者进行了基于人群的队列研究。对所有经尿道膀胱肿瘤切除术标本进行病理复查后,构建组织微阵列,并从福尔马林固定组织块中提取 RNA。使用被认为与预后相关的标志物进行免疫组织化学(IHC)检测(ZEB2、CCND1、CD3、CD68、CDH3、HER3、KRT14、CDKN2A(p16)、TP63、FGFR3、EPCAM、GATA3、FOXA1、ERBB2 和 EGFR)。还进行了基于 IHC 和基因表达的分子分类。使用单变量和多变量 Cox 比例风险回归进行生存分析。
临床 T3 期(危险比 [HR] 1.6,置信区间 [CI] 1.1-2.3)、肾盂积水(HR 1.7,CI 1.2-2.3)、淋巴血管侵犯(LVI)(HR 2.6,CI 1.9-3.6)、广泛坏死(HR 1.6,CI 1.1-2.5)和膀胱肿瘤经尿道切除术标本中 CD68/CD3 比值>1(HR 1.3,CI 1.1-1.5)与癌症特异性生存(CSS)和无进展生存(未显示数据)不良相关。多变量分析显示,较高的临床 T 分期(HR 1.3,CI 1.1-1.7;P = 0.007)和 LVI 存在(HR 2.4,CI 1.7-3.5;P = 1.8×10)与 CSS 不良相关,而只有 LVI 与无进展生存相关。分子亚型(通过 Lund 分类法和肌肉浸润性膀胱癌的共识分子亚型评估)和已发表的单 IHC 标志物与生存无关。
在本大型基于人群的膀胱切除术系列中,LVI 和临床分期与 CSS 独立相关。然而,根据共识分子亚型的肌肉浸润性膀胱癌或 Lund 分类法,通过全局基因表达确定的分子亚型与 CSS 无关联。