Leoni Zoe, Calina Teodor G, Janik Tobias, Grafenhorst Elena, Taube Eliane T, Neumann Christopher Cm, Chen BaoQing, Braicu Elena I, Sehouli Jalid, Malinka Thomas, Schöning Wenzel, Pratschke Johann, Calin George A, Klimstra David S, Benhamida Jamal K, Esposito Irene, Möbs Markus, Horst David, Schallenberg Simon, Capper David, Dragomir Mihnea P
Institute of Pathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
Faculty of Physics, Babeș-Bolyai University, Cluj-Napoca, Romania.
J Pathol. 2025 Sep;267(1):10-24. doi: 10.1002/path.6439. Epub 2025 Jun 25.
The origin of mucinous cystic neoplasms (MCNs) remains a major challenge in hepato-pancreato-biliary pathology. These cystic tumors are defined by their mucinous epithelium and ovarian-like stroma, with an estimated 10% risk of progression to invasive carcinoma. The origin of the ovarian-like stroma remains a subject of debate. In this study, we conducted immunohistochemical profiling, targeted DNA sequencing, and genome-wide DNA methylation analysis on a cohort of 15 pancreatic MCNs (MCN-P) and six hepatic MCNs (MCN-L). Using immunohistochemistry and targeted DNA sequencing, we unequivocally established the diagnosis of MCN. Unsupervised DNA methylation profile analysis of reference classes of pancreatic neoplasms (11 entities and normal pancreatic tissue from 224 unique samples) revealed that MCN-P predominantly forms a distinct group. In the DNA methylation landscape of liver tumors, encompassing five tumor types and normal bile duct tissue from 136 unique samples, MCN-L demonstrated a specific methylation profile when compared with all other entities. Furthermore, within the DNA methylation landscape of ovarian tumors - featuring five tumor types, normal Fallopian tube, and normal ovarian tissue from 90 unique samples - we found that both MCN-P and MCN-L grouped with mucinous ovarian carcinoma and mucinous borderline ovarian tumors (mBOTs). Notably, low-grade MCNs exhibited greater DNA methylation similarities to mBOTs, while high-grade or invasive MCNs were primarily associated with mucinous ovarian carcinomas. When analyzing all samples together (19 tumor types and four normal tissue types, n = 430), MCNs similarly grouped with mucinous ovarian tumors and normal ovarian tissue. Additionally, in a network analysis of differentially methylated probes, MCN-P and MCN-L share significant methylation traits, closely resembling mucinous ovarian tumors. In conclusion, our findings highlight that MCN-P and MCN-L are distinct entities in the landscape of pancreatic and hepatic tumors and show DNA methylation profile similarities with mucinous ovarian tumors, suggesting a potential common origin. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
黏液性囊性肿瘤（MCNs）的起源仍是肝胰胆病理学中的一个重大挑战。这些囊性肿瘤由其黏液上皮和卵巢样间质所定义，进展为浸润性癌的风险估计为10%。卵巢样间质的起源仍是一个有争议的话题。在本研究中，我们对15例胰腺MCN（MCN-P）和6例肝脏MCN（MCN-L）进行了免疫组织化学分析、靶向DNA测序和全基因组DNA甲基化分析。通过免疫组织化学和靶向DNA测序，我们明确诊断了MCN。对胰腺肿瘤参考类别（11种实体以及来自224个独特样本的正常胰腺组织）进行的无监督DNA甲基化谱分析显示，MCN-P主要形成一个独特的组。在肝脏肿瘤的DNA甲基化图谱中，涵盖了5种肿瘤类型以及来自136个独特样本的正常胆管组织，与所有其他实体相比，MCN-L表现出特定的甲基化谱。此外，在卵巢肿瘤的DNA甲基化图谱中——包括5种肿瘤类型以及来自90个独特样本的正常输卵管和正常卵巢组织——我们发现MCN-P和MCN-L均与黏液性卵巢癌和黏液性交界性卵巢肿瘤（mBOTs）归为一组。值得注意的是，低级别MCN与mBOTs表现出更大的DNA甲基化相似性，而高级别或浸润性MCN主要与黏液性卵巢癌相关。当对所有样本（19种肿瘤类型和4种正常组织类型，n = 430）进行综合分析时，MCN同样与黏液性卵巢肿瘤和正常卵巢组织归为一组。此外，在对差异甲基化探针的网络分析中，MCN-P和MCN-L具有显著的甲基化特征，与黏液性卵巢肿瘤极为相似。总之，我们的研究结果表明，MCN-P和MCN-L在胰腺和肝脏肿瘤领域是独特的实体，并且与黏液性卵巢肿瘤具有DNA甲基化谱相似性，提示可能存在共同起源。© 2025作者。《病理学杂志》由约翰·威利父子有限公司代表大不列颠及爱尔兰病理学会出版。
