Beauchamp Léonie, Elias Roy, Toll Adam D, Li Huili, Pallavajjala Aparna, Zhu Jing, Zou Ying S, Eshleman James R, Argani Pedram, Epstein Jonathan I, Baraban Ezra G
Department of Pathology, Johns Hopkins Hospital, Baltimore Maryland.
Department of Oncology, Johns Hopkins Hospital, Baltimore, Maryland.
Mod Pathol. 2025 Jun 21;38(11):100829. doi: 10.1016/j.modpat.2025.100829.
Extragonadal yolk sac tumors are rare and can be difficult to distinguish from somatically derived, non-germ cell tumors such as carcinomas with yolk sac differentiation, and there are very limited data available on this phenomenon in the urinary tract. A cohort of 10 tumors primary to the urinary tract with pure or extensive yolk sac differentiation was assembled to clarify their relationship to germ cell tumors, and herein, we describe the clinical, histologic, and molecular features of these lesions. The predilection for older males (8:2 male:female ratio, mean age = 78 years), the epicenter of disease along the urinary tract mucosa, association with prior pelvic radiation (40%), and frequent previous or subsequent diagnosis of conventional urothelial carcinoma (40%) mirrored the typical clinical and demographic features of urothelial carcinoma. Pathologically, all tumors demonstrated typical morphologic and immunohistochemical features of glandular yolk sac tumors and were not associated with other germ cell tumor subtypes. A subset of cases harbored additional histologic elements including sarcomatoid or squamous features (20%) or conventional urothelial carcinoma (10%). Most tumors showed aggressive clinical behavior with 7/8 cases with available follow-up demonstrating recurrence, metastasis, or death from disease. Molecular analysis, including panel-based DNA sequencing (n = 8) and fluorescence in situ hybridization (n = 2) on a subset of cases, showed no evidence of isochromosome 12p but did reveal recurrent mutations in TP53 (8/8, 100%), the TERT promoter (3/8, 38%), and one of several genes involved in chromatin remodeling including KDM6A, CREBBP, and KMT2D (5/8, 63%), and recurrent deletions involving chromosome 9p, including homozygous deletion encompassing the CDKN2A/MTAP locus (3/8, 38%)-a constellation of findings strikingly similar to the established molecular landscape of urothelial carcinoma. These findings indicate that primary extragonadal tumors with yolk sac differentiation involving the urinary tract frequently represent a rare, diagnostically deceptive, and clinically aggressive form of urothelial carcinoma.
性腺外卵黄囊瘤罕见，且可能难以与体细胞来源的非生殖细胞肿瘤（如具有卵黄囊分化的癌）相区分，关于尿路中这一现象的可用数据非常有限。我们收集了一组10例原发性尿路肿瘤，这些肿瘤具有纯或广泛的卵黄囊分化，以阐明它们与生殖细胞肿瘤的关系，在此，我们描述了这些病变的临床、组织学和分子特征。这些肿瘤好发于老年男性（男女比例为8:2，平均年龄78岁），病变沿尿路黏膜的中心部位分布，与既往盆腔放疗有关（40%），且既往或随后经常诊断为传统尿路上皮癌（40%），这些情况反映了尿路上皮癌典型的临床和人口统计学特征。病理上，所有肿瘤均表现出腺性卵黄囊瘤典型的形态学和免疫组化特征，且与其他生殖细胞肿瘤亚型无关。一部分病例还具有其他组织学成分，包括肉瘤样或鳞状特征（20%）或传统尿路上皮癌（10%）。大多数肿瘤表现出侵袭性临床行为，8例中有7例有随访资料，显示有复发、转移或死于疾病。分子分析，包括对一部分病例进行的基于基因panel的DNA测序（n = 8）和荧光原位杂交（n = 2），未发现12号染色体短臂等臂染色体，但确实揭示了TP53（8/8，100%）、TERT启动子（3/8，38%）以及参与染色质重塑的几个基因之一（包括KDM6A、CREBBP和KMT2D，5/8，63%）的复发性突变，以及涉及9号染色体短臂的复发性缺失，包括包含CDKN2A/MTAP基因座的纯合缺失（3/8，38%）——这一系列发现与已确立的尿路上皮癌分子格局惊人地相似。这些发现表明，原发性性腺外具有卵黄囊分化且累及尿路的肿瘤通常代表一种罕见的、诊断上具有欺骗性且临床侵袭性强的尿路上皮癌形式。
