New horizons in the endoscopic ultrasonography-based diagnosis of pancreatic cystic lesions

Table 1 Contrast harmonic enhanced endoscopic ultrasound in pancreatic cystic lesions

Authors	Study	n	Main outcomes	Complications
Yamashita et al[39], 2013	P	17	Differential diagnosis between mural nodules and mucus clots: CH-EUS: Sen 100%, Spe 80%, PPV 92%, NPV 100%, A 94% CT and Doppler-EUS: Sen 41% and 0% respectively	0
Hocke et al[36], 2014	R	125	Differential diagnosis between non-neoplastic cysts and PCNs. Hyperenhancement: 100% PCNs Hypoenhancement: 94% non-neoplastic cysts (PCs and dysontogenic cysts) CH-EUS superior to EUS in differential diagnosis between PCNs and non-neoplastic cysts (aP < 0.001)	0
Harima et al[41], 2015	R	30	Performance for diagnosing mural nodules CT: Sen 71%, Spe 100%, PPV 100%, NPV 90%, A 92% EUS: Sen 72%, Spe 61%, PPV 50%, NPV 100%, A 72% CH-EUS: Sen 100%, Spe 97%, PPV 93%, NPV 100%, A 98%	0
Fujita et al[40], 2016	R	50	Sensitivity for diagnosing mural nodules: CT: 86% vs MRI 71% vs EUS 100% EUS was not able to distinguish mural nodules from mucus clots CH-EUS correctly differentiated mural nodules from mucus clots in all cases	0
Fusaroli et al[37], 2016	R	76	Differential diagnosis between non-neoplastic cysts and PCNs and between benign and malignant cysts. Hyperenhancement: 86% SCAs and 89% mucinous cysts (P = ns) Hypoenhancement: 90% PCs (bP < 0.000004 vs SCAs and cP < 0.000005 vs mucinous cysts) Hyperenhanced solid components : 100% malignant cysts Non- hype-enhanced solid components: 100% benign cysts	0
Kamata et al[38], 2016	R	70	Mural nodule as a sign of mucinous cyst EUS vs CH-EUS: Sen 85% vs 79%, Spe 46% vs 96%, A 73% vs 84% (P = 0.057) Mural nodule as a sign of malignancy EUS vs CH-EUS: Sen 97% vs 97%, Spe 40% vs 75%, A 64% vs 84% (dP = 0.0001)	0
Yamamoto et al[42], 2016	R	30	Quantitative CH-EUS in IPMNs Echo intensity change and echo intensity reduction rate, and nodule/parenchyma contrast ratio significantly higher in HGD/invasive carcinoma (eP < 0.05) Microvessel density in mural nodule Significantly higher in HGD/invasive carcinoma (fP < 0.002) Significant correlation between echo intensity change and microvessel density (gP < 0.001)	0

P: Prospective; R: Retrospective; CT: Computed tomography; MRI: Magnetic resonance imaging; EUS: Endoscopic ultrasonography; CH-EUS: Contrast harmonic endoscopic ultrasonography; Sen: Sensitivity; Spe: Specificity; PPV: Positive predictive value; NPV: Negative predictive value; A: Accuracy; PCNs: Pancreatic cystic neoplasms; IPMN: Intraductal papillary mucinous neoplasm; HGD: High grade dysplasia.

Table 2 Needle-based confocal laser endomicroscopy in pancreatic cystic lesions

Authors	Study	n	Main outcomes	Complications
Konda et al[48], 2011	P	16	94% Technical success (feasibility study)	12% post-procedure pancreatitis
Konda et al[49], 2013	P	66	Stage 1: Description of visualized structures (n = 26) with histological correlation Stage 2: Performance assessment of defined criteria (n = 31): Villous pattern: Sen 59%, Spe 100%, PPV 100%, NPV 50%, A 71% for PCNs Significant association with PCNs (aP = 0.004)	3% post-procedure pancreatitis 4.5% intracystic self-limited bleeding
Nakai et al[50], 2015	P	30	Villous pattern in 18 patients with highly certain diagnosis: Sen 80%, Spe 100%, PPV 100%, NPV 80%, A 89% for mucinous cysts Significant association with mucinous cysts (bP = 0.001)	7% post-procedure (cystoscopy followed by nCLE) pancreatitis
Napoléon et al[51], 2015	P	31	Superficial vascular network: Sen 69%, Spe 100%, PPV 100%, NPV 82%, A 87% for SCAs	3% post-procedure pancreatitis
Napoléon et al[52], 2016	R	31	Step 1: Description of nCLE patterns for mucinous cysts, PCs and cystic NENs with histological correlation Step 2: Retrospective external validation of nCLE criteria Accuracy 94% for mucinous cysts (90% IPMN - 90% MCA) - 87% SCA - 87% PCs Substantial global IOA: Perfect PC, almost perfect SCA, moderate IPMN, fair MCA
Kadayifci et al[53], 2017	P	20	nCLE performance for mucinous cysts: Sen 66% -Spe 100% -A 80%	0 complications
Krishna et al[54], 2017	P	10	Reproducibility of the in vivo nCLE criteria in ex vivo specimens
Napoléon et al[55], in press	P	209	Diagnostic yield 91% in 78 patients with non-communicating cysts and pathological diagnosis: Sen 95%, Spe 100% - PPV 100% - NPV 98% - A 99% for SCAs Sen 95%, Spe 100% - PPV 100% - NPV 94% - A 97% for mucinous cysts Sen 100%, Spe 95% - PPV 70% - NPV 100% - A 96% for NENs Sen 96%, Spe 95% - PPV 98% - NPV 91% - A R96% for premalignant cysts	1.3% post-procedure pancreatitis
Karia et al[56], 2016	R	15	IOA poor to fair for all nCLE variables
Krishna et al[57], 2016	R	49	nCLE performance on 26 patients with definitive diagnosis (23 with pathological diagnosis): Sen 94%, Spe 82% - PPV 88% - NPV 92% - A 89% for mucinous cysts IOA and IOR: Substantial for all nCLE criteria	6.1% post-procedure pancreatitis
Krishna et al[58], 2017	R	29	nCLE performance on 29 patients with definitive diagnosis (23 with pathological diagnosis): Sen 95%, Spe 94% - A 95% for mucinous cysts Sen 99%, Spe 98% - A 98% for SCAs Sen 99%, Spe 98% - A 98% for NENs IOA and IOR: Almost perfect for mucinous cysts and SCAs

P: Prospective; R: Retrospective; Sen: Sensitivity; Spe: Specificity; PPV: Positive predictive value; NPV: Negative predictive value; A: Accuracy; PCNs: Pancreatic cystic neoplasms; PC: Pseudocyst; MCA: Mucinous cystadenoma; SCA: Serous cystadenoma; IPMN: Intraductal papillary mucinous neoplasm; NENs: Neuroendocrine neoplasm; IOA: Interobserver agreement; IOR: Intraobserver reliability.