Eiber Matthias, van Oers Johanna M M, Zwarthoff Ellen C, van der Kwast Theo H, Ulrich Oehler, Helpap Burkhard, Stoerkel Stephan, Blaszyk Hagen, Cheville John, Sauter Guido, Wild Peter J, Stoehr Robert, Hofstaedter Ferdinand, Hartmann Arndt
Institute of Pathology, University of Regensburg, Regensburg, Germany.
Am J Surg Pathol. 2007 Jun;31(6):938-46. doi: 10.1097/01.pas.0000249448.13466.75.
Inverted papilloma (IP) of the urinary tract can be difficult to distinguish from noninvasive urothelial carcinoma with prominent inverted growth pattern (invNIUC). Ancillary markers may help to resolve such cases and clarify the reported malignant potential of some IPs.
Eighty-nine urothelial lesions initially diagnosed as IP were reviewed by 4 experienced urologic pathologists and studied immunohistochemically (Ki67, p53, CK20, MSH2, MLH1, and MSH6). Mutations of the FGFR3 gene, deletions (loss of heterozygosity) of 9p, 9q, and 17p, microsatellite instability, and elevated microsatellite instability at selected tetranucleotides were also analyzed.
Considerable interobserver variability in histopathologic diagnoses was noticed. Only 62 (69.7%) initial diagnoses were confirmed by the review pathologists whereas 23 tumors (25.8%) were redefined as invNIUC. Molecular analyses revealed infrequent alterations in IPs, including microsatellite instability (1.8%), elevated microsatellite instability at selected tetranucleotides (13.2%), FGFR3 mutations (9.8%), 9p deletions (3.9%), 9q deletions (13.2%), 17p deletions (5.1%), nuclear p53 accumulation (18.9%), and aberrant immunostaining for MSH2 (5.8%), MLH1 (11.8%), and MSH6 (3.8%). IP and invNIUC differed in FGFR3 mutations and Ki-67 labeling index (P<0.001 each), and 9q loss of heterozygosity (P=0.03). There were fewer recurrences in IP (5.4%) compared with invNIUC (40.9%; P<0.0001).
IP is a benign lesion that lacks specific genetic alterations found in exophytic noninvasive papillary urothelial tumors. These lesions could be reactive in nature, perhaps secondary to chronic inflammation or a neoplastic process that lack specific genetic alterations. Nevertheless given the clinical and molecular data of this study a conservative clinical approach is appropriate.
尿路内翻性乳头状瘤（IP）可能难以与具有显著内翻生长模式的非侵袭性尿路上皮癌（invNIUC）相区分。辅助标志物可能有助于解决此类病例，并阐明一些IP报道的恶性潜能。
4名经验丰富的泌尿外科病理学家对89例最初诊断为IP的尿路上皮病变进行了复查，并进行免疫组化研究（Ki67、p53、CK20、MSH2、MLH1和MSH6）。还分析了FGFR3基因的突变、9p、9q和17p的缺失（杂合性缺失）、微卫星不稳定性以及选定四核苷酸处的微卫星不稳定性升高情况。
注意到组织病理学诊断中观察者间存在相当大的差异。复查病理学家仅确认了62例（69.7%）最初诊断，而23例肿瘤（25.8%）被重新定义为invNIUC。分子分析显示IP中改变不常见，包括微卫星不稳定性（1.8%）、选定四核苷酸处微卫星不稳定性升高（13.2%）、FGFR3突变（9.8%）、9p缺失（3.9%）、9q缺失（13.2%）、17p缺失（5.1%）、核p53积累（18.9%）以及MSH2（5.8%）、MLH1（11.8%）和MSH6（- 3.8%）的异常免疫染色。IP和invNIUC在FGFR3突变和Ki-67标记指数方面存在差异（均P<0.001），以及9q杂合性缺失方面存在差异（P=0.03）。与invNIUC（40.9%；P<0.0001）相比，IP的复发较少（5.4%）。
IP是一种良性病变，缺乏外生性非侵袭性乳头状尿路上皮肿瘤中发现的特定基因改变。这些病变可能本质上是反应性的，可能继发于慢性炎症或缺乏特定基因改变的肿瘤形成过程。然而，鉴于本研究的临床和分子数据，采取保守的临床方法是合适的。
