Variant morphology and random chromosomal integration of BK polyomavirus in posttransplant urothelial carcinomas.,Modern Pathology

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Variant morphology and random chromosomal integration of BK polyomavirus in posttransplant urothelial carcinomas.
Modern Pathology ( IF 7.1 ) Pub Date : 2020-02-11 , DOI: 10.1038/s41379-020-0489-0
Simone Bertz ₁ , Armin Ensser ₂ , Robert Stoehr ₁ , Markus Eckstein ₁ , Hendrik Apel ₃ , Doris Mayr ₄ , Maike Buettner-Herold ₅ , Nadine Therese Gaisa ₆ , Eva Compérat ₇ , Bernd Wullich ₃ , Arndt Hartmann ₁ , Antje Knöll ₂

Affiliation

BK polyomavirus (BKPyV) causes major complications in solid organ transplant recipients but little is known about its role in the development of urothelial carcinoma (UC) during immunosuppression. Immunohistochemistry (IHC) screening for polyomavirus large T antigen (LTag) was performed in 94 micropapillary UC (MPUC), 480 unselected UC, 199 muscle invasive UC (including 83 UC with variant differentiation), 76 cases of plasmocytoid, nested and large nested UC and 15 posttransplant UC. LTag expressing UC were reevaluated regarding their histomorphological features and characterized by IHC for p53 and HER2, chromogenic in situ hybridization for HER2 and SNaPshot analysis of the TERT promoter and HRAS. Real-time PCR and next generation sequencing (NGS) were performed to search for BKPyV-DNA and for variants in the tumor and viral genomes. We detected five LTag expressing UC which were diagnosed between 2 and 18 years after kidney (n = 4) or heart (n = 1) transplantation. 89 MPUC without history of organ transplantation and overall 755 UC (including cases with variant histology) were LTag negative. Of the five LTag expressing UC, three were MPUC, one showed extensive divergent differentiation with Mullerian type clear cell carcinoma, and one displayed focal villoglandular differentiation. All five tumors had aberrant nuclear p53 expression, 2/5 were HER2-amplified, and 3/5 had TERT promoter mutations. Within the 50 most common cancer related genes altered in UC we detected very few alterations and no TP53 mutations. BKPyV-DNA was present in 5/5 UC, chromosomal integration of the BKPyV genome was detectable in 4/5 UC. Two UC with BKPyV integration showed small deletions in the BKPyV noncoding control region (NCCR). The only UC without detectable BKPyV integration had a high viral load of human herpesvirus 6 (HHV-6). Our results suggest that LTag expression of integrated BKPyV genomes and resulting p53 inactivation lead to aggressive high-grade UC with unusual, often micropapillary morphology.

中文翻译：

BK 多瘤病毒在移植后尿路上皮癌中的变异形态和随机染色体整合。

BK 多瘤病毒 (BKPyV) 在实体器官移植受者中引起严重并发症，但对其在免疫抑制期间尿路上皮癌 (UC) 发展中的作用知之甚少。对 94 例微乳头状 UC (MPUC)、480 例未选择的 UC、199 例肌肉浸润性 UC（包括 83 例变异分化的 UC）、76 例浆细胞样、巢状和大巢状 UC 进行了多瘤病毒大 T 抗原（LTag）的免疫组织化学（IHC）筛查和 15 例移植后 UC。对表达 UC 的 LTag 的组织形态学特征进行了重新评估，并通过 p53 和 HER2 的 IHC、HER2 的显色原位杂交以及 TERT 启动子和 HRAS 的 SNaPshot 分析来表征。执行实时 PCR 和下一代测序 (NGS) 以搜索 BKPyV-DNA 以及肿瘤和病毒基因组中的变异。我们检测到 5 个表达 LTag 的 UC，这些 UC 在肾脏（n = 4）或心脏（n = 1）移植后 2 至 18 年之间被诊断出来。89 例无器官移植史的 MPUC 和 755 例 UC（包括具有变异组织学的病例）均为 LTag 阴性。在表达 UC 的 5 例 LTag 中，3 例为 MPUC，1 例显示与苗勒管型透明细胞癌广泛分化，1 例显示局灶性绒毛腺分化。所有五个肿瘤都有异常的核 p53 表达，2/5 是 HER2 扩增的，3/5 有 TERT 启动子突变。在 UC 中改变的 50 个最常见的癌症相关基因中，我们检测到很少的改变并且没有 TP53 突变。BKPyV-DNA 存在于 5/5 UC 中，在 4/5 UC 中可检测到 BKPyV 基因组的染色体整合。两个具有 BKPyV 集成的 UC 在 BKPyV 非编码控制区 (NCCR) 中显示出小的缺失。唯一没有检测到 BKPyV 集成的 UC 具有高病毒载量的人类疱疹病毒 6 (HHV-6)。我们的结果表明，整合的 BKPyV 基因组的 LTag 表达和由此产生的 p53 失活导致侵袭性高级 UC 具有异常的、通常是微毛细管形态。

更新日期：2020-02-11

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