Advanced diagnostics for pancreatic cysts: Confocal endomicroscopy and molecular analysis

Table 1 Classification of pancreatic cysts

(A) Mucinous Cysts

1 Intraductal Papillary Mucinous Neoplasm (IPMN)

Branch Duct IPMN

Mixed Duct IPMN

2 Mucinous Cystic Neoplasm (MCN)

(B) Non-mucinous Cysts

Serous Cystadenoma (SCA)

Solid Pseudopapillary Tumor (SPT)

Cystic Neuroendocrine Tumor (Cystic-NET)

Squamous-Lined Cysts

Epidermoid Cysts

Lymphoepithelial Cysts

Pseudocysts

(C) Other malignant Cysts

Ductal Adenocarcinoma with Cystic Degeneration

Acinar Cell Cystadenocarcinoma

Cystic Degeneration of Metastatic Lesions to the Pancreas

IPMN: Intraductal papillary mucinous neoplasm.

Table 2 Treatment and surveillance guidelines for pancreatic cysts

Guideline	Recommendations
Sendai 2006 [8]	Recommended surgical resection if any of the following lesions were suspected:
	MCNs
	Main duct IPMNs
	Mixed duct IPMNs
	Also recommended surgical resection also based on:
	Clinical symptoms
	Dilated pancreatic duct (≥6mm)
	Intracystic mural nodules
	Positive cytology [8]
Fukuoka 2012 [6]	Recommended surgical resection for high-risk criteria:
	Dilated pancreatic duct (≥10mm)
	Presence of an enhancing solid component
	Obstructive jaundice [6]
American Gastroenterological Association (AGA) 2015 [9]	Recommended EUS-FNA if 2 out of 3 of the following high-risk features were present:
	Size ≥ 3 cm
	Dilated main pancreatic duct
	Solid component
	Recommended surgical resection if a cyst had both of the following:
	Solid component
	Dilated pancreatic duct and/or concerning features on EUS-FNA [9]
Fukuoka 2017 [7]	Enhancing mural nodule is a high risk feature if measuring ≥ 5 mm
	Added surveillance guidelines for BD-IPMN, noting presence of lymphadenopathy, increased serum CA19-9 and cyst growth rate >5 mm in diameter over 2 years as “worrisome features” [7]

MCN: Mucinous cystic neoplasm; IPMN: Intraductal papillary mucinous neoplasm; BD-IPMN: Branched duct intraductal papillary mucinous neoplasm; EUS: Endoscopic ultrasound; FNA: Fine needle aspiration.

Table 3 A summary of molecular biomarkers for pancreatic cysts types

Pancreatic cyst type	Molecular biomarkers
Intraductal papillary mucinous neoplasm	KRAS, GNAS, RNF43 positive[22,24,29,34,37]
	Advanced neoplasia: TP53, SMAD4, PIK3CA, PTEN, CDKN2A, AKT1, p16, p53 positive[30-34,38,39]
Mucinous cystic neoplasm	KRAS, RNF3 positive[22,24,29,34,37]
	GNAS negative[24,28,29]
	Advanced neoplasia: TP53, SMAD4, PIK3CA, PTEN, CDKN2A, AKT1 positive[30-34]
Serious cystadenoma	VHL positive[22,24,28]
Solid papillary neoplasm	CTNNB1 positive[22,24]
Pseudocyst	Negative for DNA
Cystic neuroendocrine tumor	Not well described

Table 4 Benefits and drawbacks of molecular analysis of cyst fluid and confocal endomicroscopy[11,12,15,29,34]

Molecular analysis of PCL fluid	EUS-nCLE of PCLs
(DNA analysis)
High sensitivity and specificity for the diagnosis of mucinous PCLs	High sensitivity and specificity for the diagnosis of mucinous PCLs
Markers can detect advanced neoplasia in IPMNs; need validation in multicenter studies	Need further studies to address role of EUS-nCLE in the identification of advanced neoplasia in PCLs
Lower sensitivity for the detection of KRAS mutations in MCNs	Detection of flat epithelium in MCNs can be difficult for early adapters of EUS-nCLE
Need large multicenter prospective studies with confirmed histopathology to replicate single center results	Need large multicenter prospective studies with confirmed histopathology to replicate single center results
Lack of established markers for cystic-NET and squamous lined cysts	EUS-nCLE reveals specific image patterns for different PCL types. Unable to differentiate between cystic-NET and SPN
During EUS-FNA, 5%-10% of PCLs may not yield DNA for molecular analysis	There is a 2%-5% risk of technical and procedural issues with failure of image acquisition during EUS-nCLE
Low sensitivity for the detection of VHL mutations in SCAs	EUS-nCLE identifies characteristic ‘fern-pattern’ of vascularity for diagnosing SCAs

PCL: Pancreatic cystic lesions; MCN: Mucinous cystic neoplasm; EUS: Endoscopic ultrasound; nCLE: Needle based confocal laser endomicroscopy; FNA: Fine needle aspiration; Cystic-NET: Cystic neuroendocrine tumor; SPN: Solid pseudopapillary neoplasm.