Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy.
ARC-Net Research Center, University of Verona, Verona, Italy.
Mod Pathol. 2022 Dec;35(12):1929-1943. doi: 10.1038/s41379-022-01143-2. Epub 2022 Sep 2.
Pancreatic intraductal tubulopapillary neoplasm (ITPN) is a recently recognized intraductal neoplasm. This study aimed to clarify the clinicopathologic and molecular features of this entity, based on a multi-institutional cohort of 16 pancreatic ITPNs and associated adenocarcinomas. The genomic profiles were analyzed using histology-driven multi-regional sequencing to provide insight on tumor heterogeneity and evolution. Furthermore, an exploratory transcriptomic characterization was performed on eight invasive adenocarcinomas. The clinicopathologic parameters and molecular alterations were further analyzed based on survival indices. The main findings were as follows: 1) the concomitant adenocarcinomas, present in 75% of cases, were always molecularly associated with the intraductal components. These data definitively establish ITPN as origin of invasive pancreatic adenocarcinoma; 2) alterations restricted to infiltrative components included mutations in chromatin remodeling genes ARID2, ASXL1, and PBRM1, and ERBB2-P3H4 fusion; 3) pancreatic ITPN can arise in the context of genetic syndromes, such as BRCA-germline and Peutz-Jeghers syndrome; 4) mutational profile: mutations in the classical PDAC drivers are present, but less frequently, in pancreatic ITPN; 5) novel genomic alterations were observed, including amplification of the Cyclin and NOTCH family genes and ERBB2, fusions involving RET and ERBB2, and RB1 disruptive variation; 6) chromosomal alterations: the most common was 1q gain (75% of cases); 7) by transcriptome analysis, ITPN-associated adenocarcinomas clustered into three subtypes that correlate with the activation of signaling mechanism pathways and tumor microenvironment, displaying squamous features in their majority; and 8) TP53 mutational status is a marker for adverse prognosis. ITPNs are precursor lesions of pancreatic cancer with a high malignant transformation risk. A personalized approach for patients with ITPN should recognize that such neoplasms could arise in the context of genetic syndromes. BRCA alterations, ERBB2 and RET fusions, and ERBB2 amplification are novel targets in precision oncology. The TP53 mutation status can be used as a prognostic biomarker.
胰腺导管内管状乳头状肿瘤（ITPN）是一种最近才被认识的导管内肿瘤。本研究旨在基于多机构队列的 16 例胰腺 ITPN 和相关腺癌，阐明该实体的临床病理和分子特征。使用基于组织学的多区域测序分析基因组谱，以提供对肿瘤异质性和进化的深入了解。此外，对 8 例浸润性腺癌进行了探索性转录组特征分析。根据生存指标进一步分析临床病理参数和分子改变。主要发现如下：1）同时存在的腺癌，见于 75%的病例，在分子上始终与导管内成分相关。这些数据明确将 ITPN 确立为浸润性胰腺腺癌的起源；2）局限于浸润性成分的改变包括染色质重塑基因 ARID2、ASXL1 和 PBRM1 以及 ERBB2-P3H4 融合的突变；3）胰腺 ITPN 可发生在遗传综合征背景下，如 BRCA-胚系和 Peutz-Jeghers 综合征；4）突变谱：经典 PDAC 驱动基因的突变存在，但在胰腺 ITPN 中较少见；5）观察到新的基因组改变，包括细胞周期和 NOTCH 家族基因以及 ERBB2 的扩增、涉及 RET 和 ERBB2 的融合以及 RB1 破坏性变异；6）染色体改变：最常见的是 1q 增益（75%的病例）；7）通过转录组分析，ITPN 相关的腺癌聚类为三个亚型，与信号机制途径和肿瘤微环境的激活相关，大多数具有鳞状特征；8）TP53 突变状态是不良预后的标志物。ITPN 是胰腺癌的癌前病变，具有较高的恶性转化风险。对 ITPN 患者的个性化治疗方法应认识到，这些肿瘤可能发生在遗传综合征背景下。BRCA 改变、ERBB2 和 RET 融合以及 ERBB2 扩增是精准肿瘤学的新靶点。TP53 突变状态可用作预后生物标志物。
