Endosonographic diagnosis of advanced neoplasia in intraductal papillary mucinous neoplasms

Table 1 Comparison of molecular analyses to resected specimen[23]

Ref.	Design	Sample	Specific cyst type (NGS/surgery)					Sensitivity/ specificity	Key findings
			IPMN-Ca	IPMN-HGD	IPMN-LGD	MCN-HGD	MCN-LGD
Springer et al[22], 2015	Retrospective, multi-center, whole genome sequencing algorithm	n = 130 patients with surgical pathology	NA/12	NA/22	NA/62	-	NA/12	NGS identified IPMNs with 76% sensitivity and 97% specificity from presence of mutation in GNAS, RNF43, LOH in chromosome 9, or aneuploidy in chromosome 1q or 8p	Use of this molecular algorithm can avoid unnecessary surgery and is relatively sensitive for high risk cysts, Adding clinical markers and radiologic features improved sensitivity to 94% but decreased specificity to 84%
Singhi et al[16], 2016	Retrospective, molecular testing of cyst fluid with novel algorithmic pathway	n = 225 patients; n = 41 patients with surgical pathology	9/9	1/2	12/12	-	12/1	Six cancer genes targeted KRAS/GNAS sensitivity 100%, specificity 100% for IPMN, TP53, PIK3CA, and/or PTEN sensitivity 91%, specificity 97% for IPMN with advanced neoplasia	Integrating molecular testing with clinical features and cytopathology into algorithm resulted in sensitivity and specificity for advanced neoplasm of 100% and 90%, respectively
Jones et al[49], 20161	Prospective, NGS	n = 79 patients (92 PCL samples), n = 14 with surgical pathology	1/4	0/2	4/4	-	-	Thirty-nine cancer genes targeted, specificity and sensitivity for NGS was 75% and 86%, specificity and sensitivity for CEA was 100% and 57%, NGS was more sensitive but CEA was more specific for identifying mutinous etiology	A KRAS mutation reclassified 19% of cysts as mucinous that were originally identified as nonneoplastic and nonmucinous from CEA, 20% of cysts identified as nonmucinous by imaging were identified as mucinous by NGS, A KRAS/GNAS mutation correlated with nonmuciouns CEA in 71% of IPMNs
Rosenbaum et al[50], 2016	Retrospective, NGS	n = 113 PCL samples (105 patients); n = 25 patients with surgical pathology	NA	NA	NA	NA	NA	Nine cancer genes targeted, Detection of a KRAS variant yielded 80% sensitivity and 88% specificity for IPMN or carcinoma. GNAS variant yielded 27% sensitivity and 100% specificity for IPMN or carcinoma	Combining cytology, CEA, and NGS yielded a 90% sensitivity and 88% specificity for IPMN or carcinoma
Singhi et al[18], 2018	Prospective, FNA of cyst fluid with NGS	n = 626 PCL samples from 595 patients; n = 102 patients with surgical pathology	13/13	4/4	39/39	0/2	2/8	Eleven cancer genes targeted, KRAS/GNAS sensitivity 100%, specificity 96% for detection of IPMN; and 89% sensitive and 100% specific for IPMN and MCNs combined, Combination KRAS/GNAS with TP53, PIK3CA, and PTEN testing showed 88% sensitivity, 97% specificity for IPMN with advanced neoplasia, Combination KRAS/GNAS with TP53, PIK3CA, and PTEN testing showed 79% sensitive, 96% specific for all mucinous pancreatic cysts with advanced neoplasia	Mutant allele frequencies over 55% for GNAS correlated with IPMNs with HGD, even if no TP53/PIK3CA/PTEN mutations were detected, Preoperative NGS could be used to classify PCs and detect IPMNs with advanced neoplasia

¹No reported mutant allele frequencies which may impact risk stratification for 2 high-grade dysplasia intraductal papillary mucinous neoplasm.

²Identified by alterations in TP53, PIK3CA and/or PTEN; not KRAS or GNAS. IPMN: Intraductal papillary mucinous neoplasm; IPMN-Ca: IPMN with adenocarcinoma; HGD: High-grade dysplasia; LGD: Low-grade dysplasia; NGS: Next-generation sequencing; CEA: Carcinoembryonic antigen; NA: Not available.

Table 2 Comparison of endoscopic ultrasound-guided microforceps biopsy to resected specimen[23]

Ref.	Design	Sample	Specific cyst type (MFB/surgery)					Results	Additional key findings
			IPMN-Ca	IPMN-HGD	IPMN-LGD	MCN-HG	MCN-LG
Basar et al[51], 2018	Retrospective, open label, multicenter; MFB	n = 42 patients; n = 7 surgical pathology	2/2	0/0	1/1	-	0/1	Cystic tissue acquisition yield 90% MFB vs 88.1% FNA. Diagnostic yield was 61.9% MFB vs 47.6% CFC	Specific cyst type diagnosis provided by MFB 35.7% vs CFC 4.8%
Kovacevic et al[31], 2018	Retrospective, MFB	n = 31 patients; n = 18 FNA cytology; n = 4 surgical pathology	0/1	0/0	31/2	-	-	Technical success for MFB 87.1% vs 58.1% FNA. Diagnostic yield 71% MFB vs 35.5% CFC	MFB yielded change in clinical management in 19.4% of cases
Mittal et al[52], 2018	Retrospective, EUS-MFB	n = 27 patients	0/0	0/0	12/3	NA	NA	Technical success 100% EUS-MFB; Diagnostic yield 88.9% EUS-MFB	MFB altered diagnosis in 26% of cases. However, cytology diagnosed 4 mucinous cysts (14.8%) that MFB missed
Yang et al[53], 2018	Retrospective, EUS-MFB	n = 47 patients; n = 8 surgical pathology	0/0	2/2	43/5	-	-	Technical success EUS-MFB 85.1% vs 48.9% FNA	Mucinous cysts were diagnosed more often by EUS-MFB (34.3%) compared to FNA + CEA analysis combined (9.4%); FNA diagnosed adenocarcinoma for 1 patient, but was benign via EUS-MFB and surgical resection
Zhang et al[54], 2018	Retrospective, MFB	n = 48 patients	14/3	11/0	4/4	-	0/1	Diagnostic yield MFB 75.0% vs 72.9% CFC	Specific cyst type diagnosis was successful 50.0% MFB vs 18.8% for FNA cytology; Three times as many IPMNs were diagnosed by MFB alone compared to CFC
Crinò et al[55], 2019	Retrospective, EUS-MFB	n = 61 patients	-	-	-	0/1	11/12	Diagnostic reliability of EUS-MFB compared to surgery was 90% vs 20% CFC	Two EUS-MFB histologic samples resulted in a specific cyst diagnosis in 74% of cases; 100% histological adequacy reached with two EUS-MFB samples
Yang et al[24], 2019	Prospective, Open Label, EUS-MFB	n = 114 patients; n = 23 surgical pathology	2/2	2/2	5/5	3/3	1/1	Specificity for EUS-MFB was 100% vs 21.4% CFC; EUS-MFB was diagnostic to the degree of dysplasia by 80% vs 0% CFC	Tissue acquisition reached 83.3% with EUS-MFB vs 37.7% with FNA; Findings from EUS-MFB were 100% concordant with analysis from resection vs 21.4% with CFC alone

¹False negative by micro-forceps biopsy, surgery identified as adenocarcinoma.

²Cysts classified as mucinous, but not differentiated into intraductal papillary mucinous neoplasm or mucinous neoplasm.

³Intraductal papillary mucinous neoplasms with no dysplasia subtype were grouped as intraductal papillary mucinous neoplasm low-grade dysplasia.

⁴Undiagnostic on micro-forceps biopsy. IPMNs: Intraductal papillary mucinous neoplasms; IPMN-Ca: IPMN with adenocarcinoma; HGD: High-grade dysplasia; LGD: Low-grade dysplasia; MFB: Micro-forceps biopsy; CFC: Cystic fluid cytology; FNA: Fine needle aspiration; MCN: Mucinous neoplasm; NA: Not available.