Mucinous cystic neoplasms and simple mucinous cysts are two distinct precursors of pancreatic cancer: clinicopathological, genomic, and transcriptomic characterization

Abstract

Mucinous cystic neoplasms (MCNs) of the pancreas are macroscopic precursors of pancreatic cancer. A similar cystic lesion but lacking the ovarian-type subepithelial stroma has been recently defined as a simple mucinous cyst (SMC); however, its nature remains unclear. This study aims to define the clinicopathological and molecular profiles of a cohort of MCNs and SMCs of the pancreas and their associated invasive carcinoma. Overall, 23 cases were identified, comprising 19 MCNs and 4 SMCs with co-occurring invasive carcinoma. A multiregional (two samples from each cystic lesion and one from the adenocarcinoma) DNA and RNA sequencing approach was used. The key findings can be summarized as follows: (1) Molecular association: In 22/23 cases (95.7%), the concomitant mucinous cyst and invasive carcinoma shared specific genomic alterations, establishing for the first time that SMC is a true precursor of pancreatic cancer. (2) Clinical behavior: carcinomas arising from SMC appeared to be more aggressive than those arising from MCN. (3) Mutational profile: both cyst types showed significant similarities to conventional pancreatic ductal adenocarcinoma (PDAC), with KRAS and TP53 the most commonly altered genes. (4) Intracystic heterogeneity: while most molecular alterations were present in both analyzed cystic areas, RNF43 showed the highest heterogeneity. (5) CDKN2A: its alterations were predominantly restricted to the invasive component, suggesting a role in driving the invasion in a subset of cases. CNKN2A may also serve as a potential biomarker for identifying high-risk cysts. (6) RNAseq: most cases showed a switch from the classical to the basal transcriptome subtype during the progression from cystic neoplasms to invasive cancers. These findings establish SMCs as new precursors of pancreatic cancer and provide critical insights into the tumorigenesis of MCNs, with potential immediate implications for tumor taxonomy and clinical management. © 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.

Keywords: CDKN2A; MCN; Mucinous cystic neoplasm; PDAC; RNF43; pancreatic precursors; simple mucinous cyst; transcriptome.

Figure 1

Macroscopic and microscopic features of simple mucinous cyst of the pancreas with associated invasive carcinoma. (A) CT scan showing a biloculated cyst in the pancreatic body (patient no. 21). (B) Magnetic resonance cholangiopancreatography revealed a multiloculated cyst in the tail of the pancreas, with no evidence of connection to the pancreatic ducts (patient no. 22). (C) Macroscopic features of a simple mucinous cyst located in the tail of the pancreas (patient no. 22). A multilocular cyst is visible, with the whitish and firm tissue representing the invasive carcinoma. A small fragment of spleen is also included in the image. (D–F) Histological features of simple mucinous cyst of the pancreas. Notably, the characteristic ovarian‐type stroma, typical of mucinous cystic neoplasms, is absent (hematoxylin–eosin staining). (D) Area showing low‐grade dysplasia (original magnification, 10×); (E) Another area, distant from the area in panel (D), demonstrating high‐grade dysplasia (10×); (F). Simple mucinous cyst with associated invasive carcinoma, indicated by an asterisk (10×).

Figure 2

Oncoprint of the genomic alterations detected by next‐generation sequencing in all cases. AC, associated carcinoma; F, female; Hom Del, homozygous deletion; IPMN, intraductal papillary mucinous neoplasm; LOH, loss of heterozygosity; M, male; MCN, mucinous cystic neoplasm; Simple MC, simple mucinous cyst.

Figure 3

Summarizing figures related to transcriptome analyses. (A, B) Volcano plot showing the differentially expressed genes between (A) mucinous cystic neoplasms (MCNs) and associated carcinomas (ACs), and (B) between simple mucinous cysts (SMCs) and associated carcinomas (ACs). Red dots represent genes whose differential expression reached statistical significance (NS, not statistically significant). (C) Alluvial plot showing the subtype transcriptome classification and highlighting, in most cases, the transition from classical to basal phenotype during the progression to invasive adenocarcinoma.