Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Pathology, Tokyo Medical University, Tokyo, Japan.
Mod Pathol. 2017 Dec;30(12):1760-1772. doi: 10.1038/modpathol.2017.60. Epub 2017 Aug 4.
Intraductal tubulopapillary neoplasm is a relatively recently described member of the pancreatic intraductal neoplasm family. The more common member of this family, intraductal papillary mucinous neoplasm, often carries genetic alterations typical of pancreatic infiltrating ductal adenocarcinoma (KRAS, TP53, and CDKN2A) but additionally has mutations in GNAS and RNF43 genes. However, the genetic characteristics of intraductal tubulopapillary neoplasm have not been well characterized. Twenty-two intraductal tubulopapillary neoplasms were analyzed by either targeted next-generation sequencing, which enabled the identification of sequence mutations, copy number alterations, and selected structural rearrangements involving all targeted (≥300) genes, or whole-exome sequencing. Three of these intraductal tubulopapillary neoplasms were also subjected to whole-genome sequencing. All intraductal tubulopapillary neoplasms revealed the characteristic histologic (cellular intraductal nodules of back-to-back tubular glands lined by predominantly cuboidal cells with atypical nuclei and no obvious intracellular mucin) and immunohistochemical (immunolabeled with MUC1 and MUC6 but were negative for MUC2 and MUC5AC) features. By genomic analyses, there was loss of CDKN2A in 5/20 (25%) of these cases. However, the majority of the previously reported intraductal papillary mucinous neoplasm-related alterations were absent. Moreover, in contrast to most ductal neoplasms of the pancreas, MAP-kinase pathway was not involved. In fact, 2/22 (9%) of intraductal tubulopapillary neoplasms did not reveal any mutations in the tested genes. However, certain chromatin remodeling genes (MLL1, MLL2, MLL3, BAP1, PBRM1, EED, and ATRX) were found to be mutated in 7/22 (32%) of intraductal tubulopapillary neoplasms and 27% harbored phosphatidylinositol 3-kinase (PI3K) pathway (PIK3CA, PIK3CB, INPP4A, and PTEN) mutations. In addition, 4/18 (18%) of intraductal tubulopapillary neoplasms had FGFR2 fusions (FGFR2-CEP55, FGFR2-SASS6, DISP1-FGFR2, FGFR2-TXLNA, and FGFR2-VCL) and 1/18 (5.5%) had STRN-ALK fusion. Intraductal tubulopapillary neoplasm is a distinct clinicopathologic entity in the pancreas. Although its intraductal nature and some clinicopathologic features resemble those of intraductal papillary mucinous neoplasm, our results suggest that intraductal tubulopapillary neoplasm has distinguishing genetic characteristics. Some of these mutated genes are potentially targetable. Future functional studies will be needed to determine the consequences of these gene alterations.
管状乳头肿瘤是胰腺管内肿瘤家族中相对较新描述的成员。该家族中更为常见的成员是胰腺导管内乳头状黏液性肿瘤，通常具有与胰腺浸润性导管腺癌相似的遗传改变（KRAS、TP53 和 CDKN2A），但还存在 GNAS 和 RNF43 基因突变。然而，管状乳头肿瘤的遗传特征尚未得到很好的描述。通过靶向下一代测序分析了 22 例管状乳头肿瘤，该方法能够识别序列突变、拷贝数改变和涉及所有靶向（≥300）基因的选择结构重排，或全外显子组测序。其中 3 例管状乳头肿瘤也进行了全基因组测序。所有管状乳头肿瘤均显示出特征性的组织学（背靠背管状腺体的细胞内管内结节，由主要为立方状细胞组成，细胞核异型，无明显细胞内粘蛋白）和免疫组织化学特征（免疫标记为 MUC1 和 MUC6，但为阴性 MUC2 和 MUC5AC）。通过基因组分析，在 5/20（25%）的病例中发现 CDKN2A 缺失。然而，大多数先前报道的胰腺导管内乳头状黏液性肿瘤相关改变并不存在。此外，与大多数胰腺导管肿瘤不同，MAP-激酶途径并未参与。事实上，在 22 例管状乳头肿瘤中，有 2/22（9%）未发现任何测试基因的突变。然而，某些染色质重塑基因（MLL1、MLL2、MLL3、BAP1、PBRM1、EED 和 ATRX）在 7/22（32%）例管状乳头肿瘤中发生突变，27%的肿瘤存在磷脂酰肌醇 3-激酶（PI3K）途径（PIK3CA、PIK3CB、INPP4A 和 PTEN）突变。此外，在 18%（4/18）的管状乳头肿瘤中发现 FGFR2 融合（FGFR2-CEP55、FGFR2-SASS6、DISP1-FGFR2、FGFR2-TXLNA 和 FGFR2-VCL），在 5.5%（1/18）的肿瘤中发现 STRN-ALK 融合。管状乳头肿瘤是胰腺中的一种独特的临床病理实体。尽管其管内性质和一些临床病理特征与胰腺导管内乳头状黏液性肿瘤相似，但我们的结果表明，管状乳头肿瘤具有独特的遗传特征。其中一些突变基因可能是潜在的靶点。未来的功能研究将需要确定这些基因改变的后果。
