Cystic pancreatic lesions, the endless dilemma

Table 1 Different parameters in different types of pancreatic cysts

Type of cyst	CEA	CA-19-9	Amylase	Mucin stain
Inflammatory pseudocyst	Normal	↑	↑	Negative
Lymphoepithelial cysts	Normal	Normal	Normal	Negative
Serous cystic neoplasms	Normal	Normal	Normal	Negative
Mucinous cystic neoplasm	↑	↑	Normal	Positive
Intraductal papillary mucinous neoplasm	↑/Normal	↑/Normal	↑/Normal	Positive
Solid papillary neoplasm	-	-	-	Negative

CEA: Carcinoembryonic antigen.

Table 2 The last randomized clinical studies in the radiological and imaging modalities of pancreatic cystic lesions

Ref.	Country	Sample size	Study period/design	Aim of study	Conclusion
Singhi et al[108], 2018	Pittsburgh	595	2014-2017/prospective	Evaluation of preoperative pancreatic cyst fluid (PCF) DNA testing	Preoperative next-generation sequencing of PCF for KRAS/GNAS mutations is highly sensitive for IPMNs and specific for mucinous PCLs. In addition, the combination of TP53/PIK3CA/PTEN alterations is a useful preoperative marker for advanced neoplasia
Basar et al[75], 2018	United States	42	2015-2016/retrospective	Comparison between the tissue acquisition and diagnostic tissue yield of microforceps biopsy (MFB) with cyst fluid cytology	The cyst tissue acquisition yield for MFBs was 90%. Although cytology of cyst fluid and MFB were comparable in distinguishing mucinous and nonmucinous cysts and detecting cysts at high risk for malignancy, MFB was far superior to cytology for providing a specific cyst diagnosis
Kovacevic et al[76], 2018	Multicenter	28	NR/retrospective	Evaluation of the use of EUS-guided MFB in diagnosing pancreatic cystic lesions in a multicenter clinical setting	The use of the microforceps is feasible with acceptable rates of technical and clinical success
Mittal et al[110], 2018	United States	27	2016-2017/retrospective	Assessment of the technical feasibility, diagnostic yield, and safety of EUS-guided MFB for PCLs	MFBs were associated with high technical success, and an excellent safety profile and may be a useful adjunctive tool, complementing existing EUS-FNA sampling protocols for PCLs
Zhang et al[111], 2018	United States	48	2016-2017/retrospective	Comparing the diagnostic performance of the MFB with the current conventional analysis of PCF	PCF analysis and MFB have comparable performance in distinguishing between mucinous and non-mucinous cysts and for detecting high-risk cysts. However, MFB was found to be superior for diagnosing specific cyst subtypes, thus adding a significant value to preoperative patient management
Cheesman et al[112], 2019	United States	41	NR/retrospective	Comparing the diagnostic outcomes and changes in clinical management resulting from MFB and nCLE use in PCL	The combination of cyst fluid cytology/chemistry along with MFB and/or nCLE results in a significantly higher rate of a specific PCL diagnosis and has a major impact on changing clinical management decisions including need for continued surveillance or surgery. MFB and/or nCLE should thus be utilized with standard cyst fluid cytology/chemistry when performing EUS-FNA of PCL
Crinò et al[73], 2019	Italy	61	2016-2018/prospective	Evaluation of the diagnostic yield of EUS-guided through-the-needle MFB sampling of pancreatic cystic lesions according to the number of macroscopically visible samples retrieved	Two TTNB macroscopically visible specimens reached 100% histologic adequacy and a specific diagnosis in 74% of patients. The collection of a third specimen did not add any additional information and should be avoided to possibly decrease the risk of adverse events
Robles-Medranda and Olmos[113], 2019	Ecuador	36	2013-2018/retrospective	Defining the role of through-the-needle technologies such as nCLE and EUS- through-the-needle MFB in the diagnosis of pancreatic cyst malignancy	EUS-through-the-needle direct intracystic MFB and nCLE improves malignancy detection in pancreatic cysts
Samarasena et al[114], 2019	United States	15	NR/retrospective	Reporting the technical success and safety of EUS-guided through the needle biopsy (TTNB) for pancreatic cystic lesions	This technique has the potential to improve the diagnostic yield of EUS-FNA for pancreatic cystic neoplasms
Vestrup Rift et al[115], 2019	Denmark	27	2016-2017/retrospective	Analysis of the results of next-generation sequencing of microbiopsies from pancreatic cysts	Next-generation sequencing of microbiopsies may have the potential to improve diagnostic decision-making
Yang et al[116], 2019	United States	114	2016-2018/prospective	Comparing the yield of tissue acquired with EUS-guided TTNB with that of samples collected by EUS-guided FNA, and the accuracy of analysis of each sample type in the diagnosis of mucinous PCLs	TTNB collection of tissues for histologic analysis is safe and feasible, with an acquisition yield of 83.3%. Histologic analysis of samples collected by TTNB identified a larger proportion of mucinous PCLs compared with cytologic analysis of samples collected by FNA-even among samples categorized as equivocal, based on the level of carcinoembryonic antigen (CEA)
Wilen et al[117], 2019	United States	30	2016-2018/retrospective	Evaluation of the feasibility and added value of cyst wall biopsy using micro forceps in the diagnosis of pancreatic cysts	Cyst wall biopsy was able to make the diagnosis in 44% of cases where cytology was non-diagnostic and in 64% of cases when composite fluid markers and cytology was non-diagnostic. The high rate of histologic and IHC evaluation suggests that it offers the potential to incorporate tissue-based biomarkers in the diagnosis and management of pancreatic cysts
Krishna et al[118], 2020	United States	144	2015-2018/ Prospective	Comparing the accuracy of EUS with nCLE in differentiating mucinous from non-mucinous PCLs with that of measurement of CEA and cytology analysis	Analysis of cysts by nCLE identified mucinous cysts with greater accuracy than measurement of CEA and cytology analysis. EUS with nCLE can be used to differentiate mucinous from non-mucinous PCLs
Keane et al[119], 2019	United Kingdom	56	2014-2016/prospective	Defining the safety and efficacy of nCLE in diagnosis of indeterminate PCL	EUS-nCLE under conscious sedation in the day case setting is safe and provides additional information to standard EUS-FNA for diagnosing indeterminate PCL
Napoleon et al[67], 2019	France	78	2013-2016/prospective	Evaluation of the diagnostic performance of nCLE for large single non-communicating PCLs using surgical histopathology or EUS-FNA cytohistopathology as a reference diagnosis	nCLE had excellent diagnostic performance that surpassed that of CEA and EUS for the diagnosis of large single non-communicating PCLs. The nCLE procedure should be considered in patients with indeterminate PCLs to ensure a more specific diagnosis
Cheesman et al[120], 2020	United States	44	2016-2018/retrospective study	Comparing the diagnostic outcomes and changes in clinical management resulting from MFB and nCLE use in PCLs	MFB and nCLE led to significant improvements in specific PCL diagnosis, which in turn has major impacts in clinical management

IPMN: Intraductal papillary mucinous neoplasm; PCL: Pancreatic cystic lesion; EUS: Endoscopic ultrasonography; FNA: Fine-needle aspiration; NR: Not reported; nCLE: Needle-based confocal laser endomicroscopy; IHC: Immunohistochemistry.