Abstract：
Homozygous deletion of the chromosomal region 9p21.3 is common in urothelial carcinoma (UC) and leads to loss of several genes, including CDKN2A and MTAP, resulting in loss of MTAP protein expression. Here, we aimed to explore the diagnostic potential of MTAP immunohistochemistry (IHC) as a surrogate marker for homozygous 9p21.3 deletion (9p21 homozygous deletion [HD]) in UC. MTAP status was determined by IHC on 27 UC tissue specimens with known 9p21.3 status as defined by fluorescence in situ hybridization in matched cytological specimens, by IHC and fluorescence in situ hybridization on a tissue microarray (TMA) containing 359 UC at different stages, and by IHC on 729 consecutive UC from routine practice. Moreover, we analyzed a longitudinal series of matched specimens from 38 patients with MTAP-negative recurrent UC. MTAP loss by IHC was found in all 17 patients with 9p21 HD and in 2/8 cases without 9p21 HD. In the TMA, MTAP loss was more common in metastases (53%) than in muscle-invasive (33%) and non-muscle-invasive UC (29%) (P = .03). In the consecutive series, 164/729 (22%) cases showed loss of MTAP expression. In 41 of these 164 cases (25%), loss of MTAP expression was heterogenous. We also discovered loss of MTAP expression in flat urothelium adjacent to MTAP-negative low-grade UC, suggesting true flat low-grade neoplasia that could not be diagnosed by morphology alone. Longitudinal analysis of recurrences showed persistent negative MTAP status over time in 37/38 (97%) patients. MTAP IHC can serve as a surrogate marker for 9p21 HD in UC and as a diagnostic tool to differentiate reactive urothelium from urothelial neoplasia. It also provides a unique opportunity to study clinicopathological associations and the heterogeneity of 9p21 HD across the whole spectrum of UC manifestations.
摘要：
染色体区域9p21.3的纯合缺失在尿路上皮癌（UC）中很常见，并导致几个基因的丢失。包括CDKN2A和MTAP，导致MTAP蛋白表达的损失。这里,我们旨在探讨MTAP免疫组织化学(IHC)作为UC中纯合9p21.3缺失(9p21HD)的替代标记的诊断潜力.通过IHC在27个UC组织标本上确定MTAP状态，已知9p21.3状态通过荧光原位杂交（FISH）在匹配的细胞学标本中确定，通过IHC和FISH在含有359个不同阶段UC的组织微阵列（TMA）上，并通过IHC对常规练习的729个连续UC进行分析。此外，我们分析了38例MTAP阴性复发性UC患者的一系列纵向匹配标本.在所有17例9p21HD患者和2/8例无9p21HD患者中，通过IHC发现MTAP丢失。在TMA中，MTAP丢失在转移中（53％）比在肌肉浸润性（33％）和非肌肉浸润性UC（29％）中更常见（p=0.03）。在连续系列中，164/729例(22%)显示MTAP表达缺失。在这164例病例中，有41例（25%）MTAP表达的缺失是异质性的。我们还发现MTAP阴性低度UC附近的平坦尿路上皮中MTAP表达缺失，提示真正的扁平低度肿瘤，不能单独通过形态学诊断。复发的纵向分析显示，随着时间的推移，37/38（97％）患者的MTAP状态持续阴性。MTAPIHC可作为UC中9p21HD的替代标记物，并作为区分反应性尿路上皮与尿路上皮瘤形成的诊断工具。它还提供了一个独特的机会来研究临床病理关联和9p21HD在整个UC表现谱中的异质性。
