Maximizing the endosonography: The role of contrast harmonics, elastography and confocal endomicroscopy

Table 1 Descriptors used in harmonic contrast-enhanced endoscopic ultrasound examination

Descriptors	Enhancement	Pattern of distribution	Wash-out
	Hyper/iso/hypoenhancement	Homogenous/inhomogenous	Slow/Fast
Corresponding feature	Arteriolar density compared to the adjacent normal parenchyma	Vascularity architecture	Velocity of the venous blood flow
Phase	Arterial	Arterial	Venous

Arterial phase: 20 s to 30-45 s after injection; Venous phase: Later than 30-45 s after contrast injection.

Table 2 Description of solid and cystic pancreatic lesions during harmonic contrast-enhanced endoscopic ultrasound examination

		Enhancement	Pattern of distribution	Wash-out
Solid pancreatic lesion	Adenocarcinoma	Hypoenhanced	Homogenous/non-homogenous	Fast
	NET	Hyperenhanced > hypoenhanced	Homogenous/non-homogenous	Slow > Fast
	Chronic pancreatitis	Isoenhanced/hyperenhanced > hypoenhanced	Homogenous/non-homogenous	Fast
	Autoimmune pancreatitis	Isoenhanced/hyperenhanced	Homogenous/non-homogenous	Fast
Cystic pancreatic lesion	SCA	Hyperenhancement of the vascularized septae,	Homogenous	Slow
		honeycomb aspect highlighted
	MCN	Hyperenhanced thick walls, thick septa and nodules are predictive for malignancy		Fast
	Pseudocyst	Avascular wall +		-
		solid component without any contrast uptake
	IPMN	Hyperenhanced septae and vascularized neoplastic nodules		Fast
	NET cystic	Hyperenhanced wall and vascularized nodules		Slow

NET: Neuroendocrine tumor; SCA: Serous cystadenoma; MCN: Mucinous cystic neoplasm; IPMN: Intraductal papillary mucinous neoplasm.

Table 3 Results of contrast-enhanced harmonics-endoscopic ultrasound assessment for solid pancreatic masses in various studies

Ref.	Type of study	Contrast agent	No. of patients	MI	Hypoenhancement as a sign of adenocarcinoma	EUS diagnostic rate	EUS-FNA diagnostic rate
Napoleon et al[18] 2010	Endoscopy	Sonovue	35	0.4	Sn = 89%		Sn = 79%
			PC-18		Sp = 88%		Sp = 100%
			NET-9		PPV = 89%		PPV = 100%
			CP-7		NPV = 88%		NPV = 54%
					Acc = 88.5%		Acc = 83%
Fusaroli et al[12] 2010	Prospective	Sonovue	90	0.36 radial	Sn = 96%	Sn = 86%
			PC-51, NET-13, CP-13	0.28 linear	Sp = 64%	Sp = 18%
					Ac = 82%	Ac = 57%
Ang et al[19] 2011		Definity	29 (PC-16, CP-4, Other-9)	0.3	Better detection of vascular invasion and tumor margins		-
Matsubara et al[20] 2011	Retrospective	Sonazoid	91	0.2	Sn = 87.5%	-	-
					Sp = 77.8%
Hocke et al[13] 2012	Prospective	Sonovue	58	-	Sn = 84%	Sn = 73%	-
					Sp = 76%	Sp = 61%
Kitano et al[15] 2012	Prospective	Sonazoid	277 (PC-204, NET-19, CrP-46, Other-8)	0.3	Sn = 95%	-	Sn = 92%1
					Sp = 89%		Sp = 100%
Lee et al[16] 2013	Prospective	Sonovue	37 (PC-28, NET-5, CP-2)	-	Sn = 93%	-	-
					Sp = 86%
					PPV = 93%
					NPV = 75%
					Acc = 92%
Gincul et al[14] 2014	Prospective	Sonovue	100	0.4	Sn = 96%		Sn = 95%
			(PC-69,		Sp = 94%		Sp = 93%
			NET-10, CP-13,		PPV = 94%		PPV = 100%
			Other-8)		NPV = 97%		NPV = 100%
					Acc = 91%		Acc = 86%
Park et al[17] 2014	Retrospective	Sonovue	90	-	Sn = 91.9%	-	Sn = 90%
					Sp = 67.8%		Sp = 100%
Dietrich et al[21] 2016	Retrospective	Sonovue	394		Sn = 92%	-	-
			PC-146
			NET-156

¹91 patients with resected lesions. MI: Mechanical index; PC: Pancreatic cancer; Cp: Chronic pancreatitis; NET: Neuroendocrine tumors; PPV: Positive predictive value; NPV: Negative predictive value; Sn: Sensitivity; Sp: Specificity; EUS-FNA: Endoscopic ultrasound-fine needle aspiration.

Table 4 Quantitative assessment studies for differentiating pancreatic masses

Ref.	Type of study	Type of mass	Contrast agent	Type of echoendoscope	MI	Quantitative assessment	Features useful for differentiation	Diagnostic rate
Seicean et al[31], 2010	Prospective	PC-15	Sonovue	Radial	0.36	Hue histogram	Uptake index ratio	Sn = 80%
		CP-12						Sp = 91%
								PPV = 92.8%
								NPV = 78%
Matsubara et al[20], 2011	Retrospective	PC-48	Sonazoid	Linear	0.20	TIC	Echo intensity reduction rate relative to the peak at 1 min	Sn = 87.5%
		AIP-14						Sp = 88.9%
		CP-13						EUS + TIC
		NET-16						Sn = 95.8%
								Sp = 92.6%
Gheonea et al[25], 2012	Prospective	CP-19	Sonovue	Linear	0.20	Postprocessing TIC	Peak intensity intensity	Sn = 93.7%
		PC-32					TTP	Sp = 89.4%
							AUC
Imazu et al[32], 2014	Prospective	AIP-8	Sonazoid	Radial	0.25-0.3	TIC	Peak intensity	Sn = 100%
		PC-22					Maximum intensity gain	Sp = 100%
Săftoiu et al[33], 2015	Prospective	PC-112	Sonovue	Linear	0.1-0.3	TIC	Peak intensity	Sn = 87.5%
		CP-55		Radial			Wash-in AUC	Sp = 92.72%
							Wash-in rate
							Wash-in perfusion index

MI: Mechanical index; PC: Pancreatic cancer; CP: Chronic pancreatitis; NET: Neuroendocrine tumors; AIP: Autoimmune pancreatitis; PPV: Positive predictive value; NPV: Negative predictive value; Sn: Sensitivity; Sp: Specificity.

Table 5 Contrast-enhanced endoscopic ultrasound for use in characterizing mural nodules in cystic pancreatic lesions

Ref.	Type of study	MI	No. of patients	Type of cystic lesions	Contrast substance	Detection of mural nodules accuracy	Diagnosis of malignancy	Cut-off height for malignancy diagnosis(mm)
Yamashita et al[40] 2013	Retrospective	0.36	17	IPMN	Sonazoid	EUS-0
						CT-71%
						CH-EUS-94%
Hocke et al[37] 2014	Retrospective	0.02-0.18	125	1 MCN	Sonovue	Not defined	Not defined	-
				6 MD-IPMN
				16 BD-IPMN
				103 others
Harima et al[41] 2015	Retrospective	-	50	IPMN BD	Sonazoid	CT-92%		8.8 (AUROC = 0.93)
						EUS-72%
						CH-EUS-98%
Kamata et al[42] 2016	Retrospective	0.30	70	6 MCN 42 BD-IPMNs	Sonazoid	EUS-73%	EUS-64	EUS-8 mm (AUROC = 0.84)
				4 SCN		CH-EUS-84%	CH-EUS-84	CH-EUS-4 mm (AUROC = 0.93)
				18 other
Yamamoto et al[43] 2016	Retrospective	0.20	30	6/18/2006	Sonazoid		Echo intensity change-0.8	No effect on malignancy rate
				MD/BD/Mixt IPMN			Echo intensity reduction
							rate-0.9
							Nodule/pancreatic parenchyma contrast ratio-0.89

IPMNs: Intraductal papillary mucinous neoplasms; CH-EUS: Contrast-enhanced harmonics-endoscopic ultrasound; MCN: Mucinous cystic neoplasm.

Table 6 Efficiency of E-endoscopic ultrasound for solid pancreatic mass assessment

Ref.	Type of study	Final diagnosis	No. of patients	E-EUS assessment	Main results
Giovannini et al[58] 2006	Prospective	Surgery	24	Color pattern	Sn = 100%
	Single center	EUS-FNA			Sp = 67%
Janssen et al[75] 2007	Prospective	Surgery	73	Color pattern	-
	Single center	EUS-FNA
Săftoiu et al[60] 2008	Prospective	Surgery	43	Hue histogram cut-off value=175	Sn = 91%, Sp = 87%, PPV = 88%. NPV = 90%, Acc = 89%
	Single center	EUS-FNA
Iglesias-Garcia et al[72] 2009	Prospective	Surgery	130	Color pattern	Sn = 100%, Sp = 85%, PPV = 90%, NPV= 100%, Acc = 94%
	Single center	EUS-FNA
Giovannini et al[79] 2009	Prospective	Surgery	121	Color pattern	Sn = 92%
	Multicenter	EUS-FNA			Sp = 80%
Iglesias-Garcia et al[57] 2010	Prospective	Surgical	86	SR = 4.62	Sn = 100%, Sp = 92%
	Single center	FNA
Săftoiu et al[59] 2011	Prospective	Surgery	258	Hue histogram cut-off value = 175	Sn = 93%, Sp = 66%, PPV = 92%, NPV = 68%, Acc = 85%
	Multicenter	EUS-FNA
Itokawa et al[73] 2011	Retrospective		109	SR=39.08	-
Hocke et al[13] 2012	Prospective	Surgical	58	Color pattern	Sn = 94.7%
	Single center	EUS-FNA			Sp = 33.4%
		Follow up
Figueiredo et al[71] 2012	Prospective	Surgical	47	SR = 8	Sn = 90% Sp = 75%
	Single center	EUS-FNA
		Follow up
Dawwas et al[70] 2012	Prospective	Surgical	111	SR = 4.69 (AUC = 0.69)	Sn = 100%, Sp = 16.7%, PPV = 86%, NPV = 100%, Acc = 86%
	Single center	EUS-FNA		Masks elasticity (AUC= 0.72)	Sn = 95%, Sp = 22%, PPV = 86%, NPV = 50%, Acc = 83%
Lee et al[74] 2013	Retrospective	-	15	Color pattern	-
				SR = 0.02%
Havre et al[54] 2014	Prospective	Surgery	48	SR = 4.4	Sn = 67%, Sp = 71%
		EUS-FNA
		Follow-up
Rustemovic et al[93] 2014	Prospective	Surgery	149	SR = 7.59	Sn = 100%
	Single center	EUS-FNA			Sp = 45%
Kongkam et al[69] 2015	Prospective	Surgery	38	SR=3.17	Sn = 86%, Sp = 66%
	Single center	EUS-FNA
Opačić et al[94] 2015	Prospective	Surgery	105 pancreatic mass	Hue histogram	Sn = 98%, Sp = 50%, PPV = 92%, NPV = 100%, Ac = 69%
	Single center	EUS-FNA	44 controls
Mayerle et al[68] 2016	Prospective	Surgery	85	SR = 24.82 or 10	Sn = 77%, Sp = 65%
	Single center	EUS-FNA			Sn = 96%, Sp = 43%
		Follow-up

E-EUS: Elastography endosonography; SR: Cut-off value of strain ratio; Sn: Sensitivity; Sp: Specificity; PPV: Positive predictive value; NPV: Negative predictive value; Acc: Accuracy; EUS-FNA: Endoscopic ultrasound-fine needle aspiration.

Table 7 Efficiency of E-endoscopic ultrasound for LN assessment

Ref.	Type of study	Final diagnosis	No. of patients	E-EUS assessment	Main results
Giovannini et al[58] 2006	Prospective	EUS-FNA	31	Color pattern	Sn = 100%
	Single center				Sp = 50%
Janssen et al[75] 2007	Prospective	EUS-FNA	66	Color pattern	Hard - Acc = 81%-86%
	Single center				Soft - Acc = 84%-86%
Săftoiu et al[95] 2007	Prospective Single center	Surgery	78	Hue histogram	Sn = 85%
		EUS-FNA			Sp = 91%
Giovannini et al[79] 2009	Prospective	Surgery	101	Color pattern	Sn = 91.8%
	Multicenter	EUS-FNA			Sp = 82.5%
Larsen et al[81] 2012	Prospective Single center	Surgery	56	Color pattern	Sn = 55%-59%
					Sp = 82%-85%
Paterson et al[78] 2012	Prospective	EUS-FNA	53	Strain ratio for malignancy = 7.5	Sn = 83%, Sp = 96%, PPV = 95%, NPV = 86%, Acc = 90%
	Single center
Knabe et al[83] 2013	Prospective	EUS-FNA	40	Color pattern	Sn = 100%
				Computed analysis	Sp = 64%
					Computed analysis
					Sn = 88.9%
					Sp = 86.7%

E-EUS: Elastographic endosonography; SR: Cut-off value of the strain ratio; Sn: Sensitivity; Sp: Specificity; PPV: Positive predictive value; NPV: Negative predictive value.

Table 8 Needle confocal laser endosonography features of different cystic lesions of the pancreas

Type of lesion	nCLE features	Diagnostic rate, references
SCA	A vascular network of the cystic wall	Sn = 69%, Sp = 100%, PPV = 100%, NPV = 82%[100]
MCN	A gray band delineated by a thin dark line	Sn = 80%, Sp = 100%[103]
		Sn = 67%, Sp = 96%[100]
IPMN	Papillary projections: characterized by the alternation of vascular cores (white) and epithelial borders	Sn = 59%, Sp = 100%[102]
		Sn = 80%, Sp = 92%[100]
Pseudocyst	Inflammatory cells bright, gray and black particles	Sn = 43%, Sp = 100%, Acc = 87%[100]
Cystic NET	Dark irregular clusters of compact cells + gray tissue of fibrovascular stroma	Sn = 67%, Sp = 96%, Acc = 90%[100]

nCLE: Needle confocal laser endosonography; SCA: Serous cystadenoma; MCN: Mucinous cystic neoplasm; IPMN: Intraductal papillary mucinous neoplasm; NET: Neuroendocrine tumor; Sn: Sensitivity; Sp: Specificity; PPV: Positive predictive value; NPV: Negative predictive value; Acc: Accuracy.