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EUS-guided confocal laser endomicroscopy: Can we use thick and wide for diagnosis of early cancer?

      Abbreviations:

      HGD-Ca (high-grade dysplasia or adenocarcinoma), ICG (International Consensus Guidelines), IPMN (intraductal papillary mucinous neoplasia), MCN (mucinous neoplasia), nCLE (needle-based confocal endomicroscopy), PC (pancreatic cancer), PCLs (pancreatic cystic lesions), SCA (serous cystic adenoma)
      In this issue of Gastrointestinal Endoscopy, Krishna et al
      • Krishna S.G.
      • Hart P.A.
      • DeWitt J.M.
      • et al.
      EUS-guided confocal laser endomicroscopy: prediction of dysplasia in intraductal papillary mucinous neoplasms (with video).
      report their investigation of the use of EUS–needle-based confocal laser endomicroscopy (EUS-nCLE) for differentiating intraductal papillary mucinous neoplasms (IPMNs) with high-grade dysplasia or adenocarcinoma (HGD-Ca) from those with low- to intermediate-grade dysplasia. They performed a post hoc analysis of a series of consecutive IPMNs with a definitive diagnosis. In their study, the authors performed 3 phases of evaluation of IPMNs for determining the EUS-nCLE criteria. The authors report that quantification of “papillary epithelial width” and “darkness” identified high-grade dysplasia and adenocarcinoma in IPMNs with high accuracy.
      • Krishna S.G.
      • Hart P.A.
      • DeWitt J.M.
      • et al.
      EUS-guided confocal laser endomicroscopy: prediction of dysplasia in intraductal papillary mucinous neoplasms (with video).
      Pancreatic cystic lesions (PCLs) are diagnosed more frequently because of the increasing use of cross-sectional imaging studies such as magnetic resonance imaging, CT, and US. In 1 study, prevalence of detection of PCLs was reported in up to 19.6% of cross-sectional abdominal scans.
      • Laffan T.A.
      • Horton K.M.
      • Klein A.P.
      • et al.
      Prevalence of unsuspected pancreatic cysts on MDCT.
      PCLs are a wide spectrum of tumors, which have varying malignant potential. Many different types of PCLs have been described, some of which have malignant potential, like IPMNs and mucinous cystic neoplasms (MCNs). However, serous cysts and pseudocysts are usually considered benign. Therefore, differentiation of PCLs with malignant potential from the others is crucial to achieve early management. The diagnosis of high-grade dysplasia is required to perform prophylactic pancreatectomy. Imaging modalities including MRI and CT are helpful for the precise diagnosis of PCLs, but their value is limited in differentiating types of PCLs. EUS has been an indispensable tool for the diagnosis and treatment of PCLs in the past decades. The recent improvements in EUS technology have enhanced the diagnostic capabilities of EUS. The EUS findings and EUS-FNA cyst fluid analyses may provide a definitive diagnosis in a majority of cases, but a significant proportion of premalignant PCLs still remain undiagnosed with current tests.
      Confocal laser endomicroscopy is a novel imaging modality for live in vivo histologic imaging; nCLE using a confocal probe through a 19-gauge FNA needle provides real-time visualization of the microscopic cellular features of the cyst wall. nCLE imaging appears immediately upon the intravenous injection of fluorescein. After a first assessment of nCLE in humans during EUS-FNA procedures of the pancreas by Konda et al,
      • Konda V.J.
      • Aslanian H.R.
      • Wallace M.B.
      • et al.
      First assessment of needle-based confocal laser endomicroscopy during EUS-FNA procedures of the pancreas (with videos).
      many researchers have assessed the diagnostic performance of EUS-guided nCLE.
      • Kadayifci A.
      • Atar M.
      • Basar O.
      • et al.
      Needle-Based Confocal Laser Endomicroscopy for Evaluation of Cystic Neoplasms of the Pancreas.
      ,
      • Tsujino T.
      • Yan-Lin Huang J.
      • Nakai Y.
      • et al.
      In vivo identification of pancreatic cystic neoplasms with needle-based confocal laser endomicroscopy.
      The studies have established nCLE as a feasible and safe imaging modality for differentiating mucinous from nonmucinous PCLs (Table 1). Most recently, Krishna et al
      • Krishna S.G.
      • Hart P.A.
      • Malli A.
      • et al.
      Endoscopic ultrasound-guided confocal laser endomicroscopy increases accuracy of differentiation of pancreatic cystic lesions.
      published the results of the INDEX study, which comprises the largest number of study participants who have undergone EUS-guided nCLE and surgical resection of PCLs so far. The authors compared the accuracy of nCLE in differentiating mucinous from nonmucinous lesions with that of measurement of CEA and cytologic analysis validated by surgery. They reported the highest sensitivity, specificity, and accuracy rates to date for identifying mucinous PCLs in the EUS-guided nCLE group (Table 1). The overall incidence of postprocedure acute pancreatitis was 3.5%, and all episodes were mild.
      • Krishna S.G.
      • Hart P.A.
      • Malli A.
      • et al.
      Endoscopic ultrasound-guided confocal laser endomicroscopy increases accuracy of differentiation of pancreatic cystic lesions.
      In another study comprising 78 PCLs published recently, Napoleon et al
      • Napoleon B.
      • Palazzo M.
      • Lemaistre A.I.
      • et al.
      Needle-based confocal laser endomicroscopy of pancreatic cystic lesions: a prospective multicenter validation study in patients with definite diagnosis.
      reported that the sensitivities and specificities of nCLE for the diagnosis of all PCL groups were higher than 0.95. They evaluated the diagnostic performance of nCLE using surgical histopathologic analysis or EUS-FNA cytohistopathologic analysis as reference diagnosis.
      Table 1Major studies investigating the role of EUS-guided nCLE in the diagnosis of pancreatic cystic lesions
      StudyStudy designType of PCLTotal number of patientsSurgery (%)SensitivitySpecificityNPVPPVAccuracyConclusion
      INSPECT
      • Konda V.J.
      • Meining A.
      • Jamil L.H.
      • et al.
      A pilot study of in vivo identification of pancreatic cystic neoplasms with needle-based confocal laser endomicroscopy under endosonographic guidance.
      ProspectiveNeoplastic6614 (21)591005010071Presence of a villous or fingerlike structure is suggestive of IPMN
      DETECT
      • Nakai Y.
      • Iwashita T.
      • Park D.H.
      • et al.
      Diagnosis of pancreatic cysts: EUS-guided, through-the-needle confocal laser-induced endomicroscopy and cystoscopy trial: DETECT study.
      ProspectiveMucinous302 (6)801008010089Mucin on cystoscopy and papillary projections and dark rings are suggestive of mucinous cysts
      CONTACT-1
      • Napoleon B.
      • Lemaistre A.I.
      • Pujol B.
      • et al.
      A novel approach to the diagnosis of pancreatic serous cystadenoma: needle-based confocal laser endomicroscopy.
      ProspectiveSerous317 (22.5)691008210087Superficial vascular network has been defined for SCA
      CONTACT-2
      • Napoleon B.
      • Lemaistre A.I.
      • Pujol B.
      • et al.
      In vivo characterization of pancreatic cystic lesions by needle-based confocal laser endomicroscopy (nCLE): proposition of a comprehensive nCLE classification confirmed by an external retrospective evaluation.
      RetrospectiveMucinous339 (27)9195959194Gray epithelial band with a thin dark line for MCN and field of bright, gray, and black particles for PC
      CONCYST-01
      • Keane M.G.
      • Wehnert N.
      • Perez-Machado M.
      • et al.
      A prospective trial of CONfocal endomicroscopy in CYSTic lesions of the pancreas: CONCYST-01.
      ProspectiveIPMN563 (5)89.6696.386.67Substantial differences were not observed between different IPMN types or level of dysplasia
      INDEX
      • Krishna S.G.
      • Hart P.A.
      • Malli A.
      • et al.
      Endoscopic ultrasound-guided confocal laser endomicroscopy increases accuracy of differentiation of pancreatic cystic lesions.
      ProspectiveMucinous14465 (45)9894949897EUS-nCLE has higher accuracy for diagnosing mucinous PCLs than for serous PCLs
      IPMN, Intraductal papillary mucinous neoplasia; MCN, mucinous neoplasia; nCLE, needle-based confocal endomicroscopy; NPV, negative predictive value; PC, pancreatic cancer; PCL, pancreatic cystic lesion; PPV, positive predictive value; SCA, serous cystic adenoma.
      EUS-guided nCLE reproducibility has also been confirmed in several inter- and intraobserver studies over the past few years. IPMNs consist of nearly 50% of all PCLs and can be divided into 3 subtypes: main duct, branch duct, and mixed IPMNs. Branch-duct IPMNs are the most common subtype, covering almost half of the diagnosed IPMNs. Despite revision of the International Consensus Guidelines (ICG) 2012 criteria (Fukuoka) in 2017,
      • Tanaka M.
      • Fernandez Del-Castillo C.
      • Kamisawa T.
      • et al.
      Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas.
      detection of advanced neoplasia in IPMNs remains challenging with current diagnostic techniques. Therefore, further studies are still needed to achieve more accurate detection of HGD-Ca in IPMNs.
      In the innovative study reported in their current article, Krishna et al.
      • Krishna S.G.
      • Hart P.A.
      • DeWitt J.M.
      • et al.
      EUS-guided confocal laser endomicroscopy: prediction of dysplasia in intraductal papillary mucinous neoplasms (with video).
      performed 3 phases of evaluation of the EUS-guided nCLE images of IPMNs. They used a powerful method to identify the most predictive criteria for HGD-Ca. They describe some variations in endomicroscopic images of papillary structures in IPMNs and reveal that correlating endomicroscopy markers of histopathologic progression of IPMNs could be qualitatively evaluated and quantitatively measured by the use of EUS-nCLE. The authors assessed qualitative derivation and interobserver variation in phase 1 and phase 2, and quantitative derivation in phase 3 (Table 2). Finally, they report that EUS-nCLE characteristics of increased papillary epithelial “width” and “darkness” were the most sensitive and accurate variables, with substantial κ in phase 2. They also reported high rates of sensitivity, specificity, and accuracy in phase 3. For papillary width (cutoff ≥50 μm), the sensitivity, specificity, and accuracy for the detection of HGD-Ca were 87.5%, 100%, and 95%, respectively. For papillary darkness (cutoff ≤90 μm), the sensitivity, specificity, and accuracy for the detection of HGD-Ca were 87.5%, 100%, and 90%, respectively. Both of these variables (thickness and darkness of the papillary epithelium) have higher diagnostic accuracy to detect HGD-Ca than the maximum reported accuracies of the ICG 2012 high-risk criteria for detection of HGD-Ca in the current study. Furthermore, Krishna et al
      • Krishna S.G.
      • Hart P.A.
      • DeWitt J.M.
      • et al.
      EUS-guided confocal laser endomicroscopy: prediction of dysplasia in intraductal papillary mucinous neoplasms (with video).
      demonstrate that the quantification of papillary thickness and darkness reduces interobserver variability. Although this study’s method is powerful, there are also some limitations. The study comprised a statistically small group of patients, so the predictive values need further validation to be more generalizable. Furthermore, the use of shortened high-yield generated nCLE video sequences would not be feasible in practical life. Therefore, it is important to discover innovations to shorten the observation time.
      Table 2Selected studies performed as interobservation and intraobservation of mucinous pancreatic cystic lesions
      StudyNo. of patientsType of PCLOutcomePhases of studyVariableκSensitivity (95% CI)Specificity (95% CI)Accuracy (95% CI)
      Napoleon et al
      • Napoleon B.
      • Lemaistre A.I.
      • Pujol B.
      • et al.
      In vivo characterization of pancreatic cystic lesions by needle-based confocal laser endomicroscopy (nCLE): proposition of a comprehensive nCLE classification confirmed by an external retrospective evaluation.
      11MCN, IPMNsDescribing diagnostic nCLE criteriaStep 1:

      IOR (n = 6)

      Step 2:

      IOA (n = 4)
      Thick gray line0.35 for MCN

      0.56 for IPMN
      919591
      Krishna et al
      • Krishna S.G.
      • Brugge W.R.
      • Dewitt J.M.
      • et al.
      Needle-based confocal laser endomicroscopy for the diagnosis of pancreatic cystic lesions: an international external interobserver and intraobserver study (with videos).
      16MCN, IPMNsIdentification of nCLE image patterns for diagnostic accuracyIOA (n = 6)

      IOR (n = 3)
      Papillae (fingerlike projection), epithelial bands, branched vascular pattern, rope-ladder pattern0.81 for IOA

      0.86 for IOR
      959495
      Palazzo et al

      Palazzo M, Sauvanet A, Gincul R, et al. Impact of needle-based confocal laser endomicroscopy on the therapeutic management of single pancreatic cystic lesions. Surg Endosc. Epub 2019 Aug 13.

      48 IPMN, 35 IML, 16 MCNMCN, IPMNs, IMLImpact of nCLE on PCL therapeutic managementStep 1:

      EUS-FNA,

      IOA (n = 5)

      Step 2:

      EUS-nCLE-FNA, IOA (n = 5)
      From 0.45 to 0.70 (agreement on diagnosis)

      From 0.36 to 0.64 (agreement on therapeutic management options)
      Current study by Krishna et al
      • Krishna S.G.
      • Hart P.A.
      • DeWitt J.M.
      • et al.
      EUS-guided confocal laser endomicroscopy: prediction of dysplasia in intraductal papillary mucinous neoplasms (with video).
      26IPMNsHigh-grade dysplasia-adenocarcinomaPhase 1, IOR (n = 3)

      Phase 2, IOA (n = 6)

      Phase 3, naïve observers (n = 7)
      Thickness of papillary epithelium, darkness of epithelium,

      size of papillae, intracystic cellularity, density of papillae
      0.54 (in phase 2-2)907383
      CI, Confidence interval; IML, indeterminate mucinous lesion; IOA, interobserver agreement; IOR, intraobserver reliability; IPMN, intraductal papillary mucinous neoplasia; κ, Landis and Koch interpretation of Cohen’s κ values: <0, no agreement; 0-0.20, slight; 0.21-0.40, fair; 0.41-0.60, moderate; 0.61-0.80, substantial; 0.81-1, almost perfect agreement; MCN, mucinous neoplasia.
      Interobserver agreement is also very important in the treatment of patients with PCLs. In a recent published study, Palazzo et al

      Palazzo M, Sauvanet A, Gincul R, et al. Impact of needle-based confocal laser endomicroscopy on the therapeutic management of single pancreatic cystic lesions. Surg Endosc. Epub 2019 Aug 13.

      reported that nCLE significantly increased the interobserver agreement not only on the diagnosis of PCLs (κ, 0.36 to 0.64) but also on treatment options. They revealed that the addition of nCLE to EUS-FNA significantly improves the reliability of PCL diagnosis, and it might have an impact on decisions about the treatment of patients with PCLs. They also reported that with nCLE, the surveillance rate of benign serous cystic adenomas fell by 35%, from 40%.

      Palazzo M, Sauvanet A, Gincul R, et al. Impact of needle-based confocal laser endomicroscopy on the therapeutic management of single pancreatic cystic lesions. Surg Endosc. Epub 2019 Aug 13.

      Further studies using a larger cohort of patients with PCLs to validate these findings are needed. Research and technologic developments involving nCLE probes compatible with a 22-gauge needle would provide a larger area of in vivo sampling and effectively permit an increase of the total PCL surface area visualized during the procedure. Another example for novel technology products could be EUS-guided microforceps biopsy. The utility of EUS-guided microforceps biopsy has been studied, and its feasibility, diagnostic yield, technical success, and associated adverse effects have been reported in recent years.
      • Mittal C.
      • Obuch J.C.
      • Hammad H.
      • et al.
      Technical feasibility, diagnostic yield, and safety of microforceps biopsies during EUS evaluation of pancreatic cystic lesions (with video).
      ,
      • Basar O.
      • Yuksel O.
      • Yang D.J.
      • et al.
      Feasibility and safety of microforceps biopsy in the diagnosis of pancreatic cysts.
      Such devices could provide tissue sampling and histopathologic analysis of the PCL epithelium. Combining both EUS-guided nCLE and microforceps biopsy might increase diagnostic yield and accuracy. Comparative large prospective studies assessing the utility of novel devices and techniques are needed.

      Disclosure

      All authors disclosed no financial relationships.

      References

        • Krishna S.G.
        • Hart P.A.
        • DeWitt J.M.
        • et al.
        EUS-guided confocal laser endomicroscopy: prediction of dysplasia in intraductal papillary mucinous neoplasms (with video).
        Gastrointest Endosc. 2020; 91: 551-563
        • Laffan T.A.
        • Horton K.M.
        • Klein A.P.
        • et al.
        Prevalence of unsuspected pancreatic cysts on MDCT.
        AJR Am J Roentgenol. 2008; 191: 802-807
        • Konda V.J.
        • Aslanian H.R.
        • Wallace M.B.
        • et al.
        First assessment of needle-based confocal laser endomicroscopy during EUS-FNA procedures of the pancreas (with videos).
        Gastrointest Endosc. 2011; 74: 1049-1060
        • Kadayifci A.
        • Atar M.
        • Basar O.
        • et al.
        Needle-Based Confocal Laser Endomicroscopy for Evaluation of Cystic Neoplasms of the Pancreas.
        Dig Dis Sci. 2017; 62: 1346-1353
        • Tsujino T.
        • Yan-Lin Huang J.
        • Nakai Y.
        • et al.
        In vivo identification of pancreatic cystic neoplasms with needle-based confocal laser endomicroscopy.
        Best Pract Res Clin Gastroenterol. 2015; 29: 601-610
        • Krishna S.G.
        • Hart P.A.
        • Malli A.
        • et al.
        Endoscopic ultrasound-guided confocal laser endomicroscopy increases accuracy of differentiation of pancreatic cystic lesions.
        Clin Gastroenterol Hepatol. 2019;
        • Napoleon B.
        • Palazzo M.
        • Lemaistre A.I.
        • et al.
        Needle-based confocal laser endomicroscopy of pancreatic cystic lesions: a prospective multicenter validation study in patients with definite diagnosis.
        Endoscopy. 2019; 51: 825-835
      1. Palazzo M, Sauvanet A, Gincul R, et al. Impact of needle-based confocal laser endomicroscopy on the therapeutic management of single pancreatic cystic lesions. Surg Endosc. Epub 2019 Aug 13.

        • Mittal C.
        • Obuch J.C.
        • Hammad H.
        • et al.
        Technical feasibility, diagnostic yield, and safety of microforceps biopsies during EUS evaluation of pancreatic cystic lesions (with video).
        Gastrointest Endosc. 2018; 87: 1263-1269
        • Basar O.
        • Yuksel O.
        • Yang D.J.
        • et al.
        Feasibility and safety of microforceps biopsy in the diagnosis of pancreatic cysts.
        Gastrointest Endosc. 2018; 88: 79-86
        • Konda V.J.
        • Meining A.
        • Jamil L.H.
        • et al.
        A pilot study of in vivo identification of pancreatic cystic neoplasms with needle-based confocal laser endomicroscopy under endosonographic guidance.
        Endoscopy. 2013; 45: 1006-1013
        • Nakai Y.
        • Iwashita T.
        • Park D.H.
        • et al.
        Diagnosis of pancreatic cysts: EUS-guided, through-the-needle confocal laser-induced endomicroscopy and cystoscopy trial: DETECT study.
        Gastrointest Endosc. 2015; 81: 1204-1214
        • Napoleon B.
        • Lemaistre A.I.
        • Pujol B.
        • et al.
        A novel approach to the diagnosis of pancreatic serous cystadenoma: needle-based confocal laser endomicroscopy.
        Endoscopy. 2015; 47: 26-32
        • Napoleon B.
        • Lemaistre A.I.
        • Pujol B.
        • et al.
        In vivo characterization of pancreatic cystic lesions by needle-based confocal laser endomicroscopy (nCLE): proposition of a comprehensive nCLE classification confirmed by an external retrospective evaluation.
        Surg Endosc. 2016; 30: 2603-2612
        • Keane M.G.
        • Wehnert N.
        • Perez-Machado M.
        • et al.
        A prospective trial of CONfocal endomicroscopy in CYSTic lesions of the pancreas: CONCYST-01.
        Endosc Int Open. 2019; 7: E1117-E1122
        • Tanaka M.
        • Fernandez Del-Castillo C.
        • Kamisawa T.
        • et al.
        Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas.
        Pancreatology. 2017; 17: 738-753
        • Krishna S.G.
        • Brugge W.R.
        • Dewitt J.M.
        • et al.
        Needle-based confocal laser endomicroscopy for the diagnosis of pancreatic cystic lesions: an international external interobserver and intraobserver study (with videos).
        Gastrointest Endosc. 2017; 86: 644-654 e2

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