Clinical Utility

Both pancreatic cysts and pancreatic solid lesions represent a broad and diverse group of benign and malignant entities. Among pancreatic cysts, distinguishing one pancreatic cyst from another can be challenging on the basis of standard clinical findings, imaging parameters and ancillary fluid studies, such as cytology and CEA analysis. DNA and RNA sequencing studies of pancreatic cysts have identified a number of genetic alterations that can be used diagnostically and prognostically to classify pancreatic cysts.(1-7,12) Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) represent mucinous pancreatic cystic neoplasms. Over 95% of IPMNs are characterized by mutations in the genes: KRAS (codons 12, 13 and/or 61), GNAS (codons 201 and 227), RNF43, BRAF, and CTNNB1.(1-4, 7-10) KRAS, RNF43 and CTNNB1 mutations can also be found in MCNs with a prevalence that ranges from 14% to 50%.(1-4, 7-10) In contrast to IPMNs, MCNs do not harbor GNAS and BRAF mutations, and, thus, genetic alterations in GNAS and BRAF are highly specific for IPMNs.(2-4, 7-10) Other neoplastic cysts include serous cystadenomas and solid pseudopapillary neoplasms. Serous cystadenomas (SCAs) have an extremely low malignant potential and approximately 89% to 100% harbor mutations and/or deletions in VHL, but lack mutations in KRAS, GNAS and BRAF.(3, 4, 7-10) Finally, solid-pseudopapillary neoplasms (SPNs) are characterized by the presence of CTNNB1 mutations (within exon 3), and an absence of alterations in KRAS, GNAS, RNF43, BRAF and VHL.(2-4, 7-10)

IPMNs and MCNs are precursor neoplasms to pancreatic ductal adenocarcinoma; however, only a subset harbor or progress to malignancy. Studies have shown that IPMNs and MCNs with genetic alterations in TP53, SMAD4 and the phosphatidyl-3 kinase (PI3K) pathway, which include PIK3CA, PTEN, and AKT1, are associated with high-grade dysplasia and early invasive pancreatic ductal adenocarcinoma (PDAC). (2, 3, 7, 8, 11, 12) Kameta et al demonstrated that NGS for KRAS, TP53 and SMAD4 alterations on EUS-FNA specimens is associated with a 96%, 44% and 11% sensitivity, respectively, and 100% specificity for PDAC.(14) Similarly, Young and colleagues found EUS-FNA specimens harboring mutations in KRAS, TP53 and/or SMAD4 were present in 95% of cases that correlated with PDAC.(15) Within a large cohort of EUS-FNA specimens, Gleeson et al. found KRAS, TP53 and SMAD4 alterations were present in 93%, 72% and 31% of PDACs.(16)

Cystic pancreatic neuroendocrine tumors (PanNETs) are typically diagnosed by standard cytology, but the diagnosis may be facilitated by the detection of specific molecular alterations. PanNETs do not have KRAS mutations, but harbor frequent alterations in MEN1, VHL, and/or TSC2.(2-4, 17) Further, recurrent genomic alterations in several chromatin remodeling genes leads to numerous chromosomal copy number alterations, which is associated with decreased disease-free survival and decreased disease-specific survival.(2,3) This is especially critical when evaluating small neuroendocrine tumors.(17)

Genetic alterations are absent in benign non-neoplastic cysts, such as pseudocysts, lymphoepithelial cysts, retention cysts, squamoid cysts or acinar cell cystadenomas.(2,3)

Utility of molecular markers have been discussed by the International Consensus Fukuoka Guidelines for the management of IPMNs and MCNs, and the European Evidence-Based Guidelines on pancreatic cystic neoplasms where their role in the diagnosis of pancreatic cysts was highlighted.(7, 8, 13, 19)

A pancreatic cyst fluid carcinoembryonic antigen (CEA) is a useful marker in identifying mucinous cysts. The CEACAM5 gene encodes a cell surface glycoprotein that plays a role in cell adhesion, intracellular signaling and tumor progression and is the founding member of the carcinoembryonic antigen (CEA) family of proteins.  Measuring mRNA expression of the CEACAM5 gene in pancreatic cyst fluid samples can be used to detect CEA upregulation. (18)


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