Impact of needle-based confocal laser endomicroscopy on the therapeutic management of single pancreatic cystic lesions
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Abstract
Background and aim
The diagnosis and therapeutic management of large single pancreatic cystic lesions (PCLs) represent major issues for clinicians and essentially rely on endoscopic ultrasound fine-needle aspiration (EUS-FNA) findings. Needle-based confocal laser endomicroscopy (nCLE) has high diagnostic performance for PCLs. This study aimed to evaluate the impact of nCLE on the therapeutic management of patients with single PCLs.
Methods
Retrospective and comparative study. Five independent pancreatic disease experts from tertiary hospitals independently reviewed data from a prospective database of 206 patients with single PCL, larger than 2 cm and who underwent EUS-FNA and nCLE. Two evaluations were performed. The first one included the sequential review of clinical information, EUS report and FNA results. The second one included the same data + nCLE report. Participants had to propose a therapeutic management for each case.
Results
The addition of nCLE to EUS-FNA led to significant changes in therapeutic management for 28% of the patients (p < 0.001). nCLE significantly increased the interobserver agreement of 0.28 (p < 0.0001), from 0.36 (CI 95% 0.33–0.49) to 0.64 (CI 95% 0.61–0.67). nCLE improved the rates of full agreement among the five experts of 24% (p < 0.0001), from 30 to 54%. With nCLE, the surveillance rate of benign SCAs fell by 35%, from 40 (28/70) to 5% (4/76).
Conclusion
The addition of nCLE to EUS-FNA significantly improves reliability of PCL diagnosis and could impact the therapeutic management of patients with single PCLs. ClinicalTrials.gov number, NCT01563133.
Keywords
EUS-FNA Pancreatic cysts Needle-based confocal laser endomicroscopyAbbreviations
- BD-IPMN
Branch duct-intraductal papillary mucinous neoplasm
- CT
Computed tomography
- CEA
Carcinoembryonic antigen
- EUS-FNA
Endoscopic ultrasound fine-needle aspiration
- IML
Indeterminate mucinous lesion
- MCN
Mucinous cystic neoplasm
- MRI
Magnetic resonance imaging
- nCLE
Needle-based confocal laser endomicroscopy
- NEN
Neuroendocrine neoplasm
- PC
Pseudocyst
- PCLs
Pancreatic cystic lesions
- SCA
Serous cystadenoma
The therapeutic management of pancreatic cystic lesions (PCL) depends on the cyst type. Surveillance or surgical resection is considered for premalignant lesions [mucinous cystic neoplasm (MCN), branch-duct intraductal papillary mucinous neoplasm (BD-IPMN), and neuroendocrine neoplasm (NEN)], while the absence of any surveillance is usually proposed for benign cysts [serous cystadenoma (SCA), pseudocyst (PC)] [1]. When the diagnosis of a single PCL larger than 2 cm remains uncertain after conventional imaging, endoscopic ultrasound fine-needle aspiration (EUS-FNA) with cyst fluid analysis is proposed. Despite the quality of the information provided by EUS, it is not possible to establish the nature of cysts in up to 30% of cases [2]. FNA cytohistology is inconclusive in more than 50% of the cases [3], and the carcinoembryonic antigen (CEA) level lacks specificity [4]. The overall diagnostic accuracy remains low at 61% for both EUS and EUS-FNA [2]. The selection of the most appropriate treatment regimen relies on an accurate characterization of cysts and, therefore, remains suboptimal [5, 6, 7, 8]. The consequences of inappropriate treatment for patients in terms of mortality and morbidity are non-negligible with the current standard of care [9, 10, 11].
Needle-based confocal laser endomicroscopy (nCLE) is a new imaging modality allowing in vivo real-time imaging at a microscopic level of the inner wall of pancreatic cyst during an EUS-FNA procedure. nCLE feasibility and safety for the assessment of PCLs were demonstrated in a pilot study [12] and were validated in an international multicenter study [13]. Subsequent clinical investigations described the correlation between nCLE images and histological features, and comprehensive nCLE criteria were established for the characterization of the most frequent types of PCL (NEN, MCN, BD-IPMN, SCA, and PC) [14, 15, 16]. A recent international study confirmed excellent interobserver and intraobserver agreement for the interpretation of nCLE images for the diagnosis of PCLs [17]. The CONTACT2 clinical trial prospectively validated the very high nCLE sensitivity and specificity for the diagnosis of PCL on a large multicentric series of 78 cases with definitive diagnoses (surgery or cytohistology) [18]. It demonstrated that nCLE diagnostic performance significantly surpassed that of EUS and CEA titration for differentiating mucinous from non-mucinous lesions and benign from premalignant PCLs [18]. Nevertheless, no study has yet evaluated the impact of nCLE on therapeutic management in clinical practice in patients with PCLs. This second phase of the CONTACT2 study aimed to evaluate nCLE impact on therapeutic management through a retrospective analysis of the 206 prospectively included patients with a single PCL.
Materials and methods
Study population
The population has been described in the first phase of the CONTACT2 trial published by Napoleon et al. [18]. The inclusion criteria were as follows: diagnosis of large (≥ 20 mm) single PCL identified with CT and/or MRI with at least one cavity larger than 13 mm (to allow for CEA and cytohistopathological analyses) without evidence of communication with the main pancreatic duct, without chronic calcifying pancreatitis; no evidence of criteria for malignancy (cyst containing solid masses or mural nodules, presence of metastatic nodes, presence of distant metastases, ascites and vascular infiltration); and scheduled for a diagnostic EUS-FNA procedure. The CONTACT study protocol was approved by the Institutional Review Board of the Institut Paoli Calmettes (Marseille, France), by the French Health Authority (Agence Française de Sécurité Sanitaire des Produits de Santé) and was registered on ClinicalTrials.gov with the following identifier: NCT01563133. The study was performed in accordance with Good Clinical Practice guidelines. All the co-authors had access to the study data and reviewed and approved the final manuscript.
Consensus on therapeutic management
- (1)
Eight diagnostic options were retained: SCA, MCN, BD-IPMN, PC, NEN, indeterminate mucinous lesion, indeterminate lesion, and other cyst types (including cystic solid pseudopapillary neoplasm, congenital pancreatic cyst, and cystic lymphoma).
- (2)
Three therapeutic management options were retained: “neither surgery nor surveillance”, “surveillance”, or “surgery”. If the diagnosis was certain, “neither surgery nor surveillance” was recommended for SCAs and PCs; surgery was recommended for MCNs and NENs; either surgery or surveillance was recommended for BD-IPMNs depending on worrisome features observed in EUS; and either surgery or surveillance was recommended for indeterminate mucinous lesions and for indeterminate lesions. The therapeutic management of other rare types of cysts relied on cyst aetiology. Confidence level modified therapeutic management. For example, surveillance instead of “neither surveillance nor surgery” was recommended for SCAs associated with fair confidence level.
Expert training
Common patterns of nCLE in pancreatic cystic tumors. A Serous cystadenoma: superficial vascular network in white (arrow) filled with fluorescein; black particles inside the vessels correspond to red cells. B IPMN: multiple papillae (arrows) with epithelial border in dark gray. C cystic NEN irregular clusters of tumoral cells (arrows)
Expert evaluations (Fig. 2)
Flowcharts of evaluation 1 (EUS-FNA) and evaluation 2 (EUS-nCLE-FNA). EUS-FNA endoscopic ultrasound-guided fine-needle aspiration, nCLE needle-based confocal laser endomicroscopy, CEA carcinoembryogenic antigen
Statistical analyses
Baseline characteristics, including demographic and clinical data, were described as percentages and ranges or means and standard deviations, as appropriate. Diagnostic yields were defined as the ratio of conclusive tests (nCLE and FNA cytohistology) over the total number of patients.
To assess interobserver agreement (IOA) between the five experts, Fleiss’ kappas were calculated for the proposed diagnoses and therapeutic management for evaluations 1 and 2. The R package “raters” was used to determine Fleiss’ kappa with 95% CI. Fleiss’ Kappa was interpreted using Landis and Koch-Kappa’s benchmark scale.
For each patient, final consensus on diagnosis and therapeutic management were determined with a majority of at least 3/5 of the experts. The absence of a final consensus led to indeterminate answers. A consensus on the diagnosis of indeterminate mucinous lesions was determined when a majority of experts proposed a diagnosis belonging to the overall group of mucinous lesions (IPMN, MCN, indeterminate mucinous lesion) in the absence of a majority for a more specific diagnosis (IPMN, MCN). The impact on diagnosis was defined as the change in the final consensus diagnosis between evaluations 1 and 2. The impact on therapeutic management was defined as the change in the final therapeutic management consensus between evaluations 1 and 2.
Overall diagnostic and therapeutic management proportion changes between evaluations 1 and 2 were compared using the χ2 square test. Changes between evaluations 1 and 2 regarding the specific diagnostic and therapeutic management categories were compared using McNemar’s test. Fleiss’ kappas from evaluations 1 and 2 were compared using the Z test. p < 0.05 was considered statistically significant.
Endpoints
The main objective of the study was to evaluate the impact of nCLE on PCL therapeutic management: a significant proportion of final consensus changes between evaluations 1 and 2 for a given therapeutic management option was defined as the primary endpoint. The secondary objectives of the study were to evaluate the impact of nCLE on diagnosis and on IOAs for both diagnosis and therapeutic management: a significant proportion of final consensus changes for a given type of diagnosis, a significant increase of IOAs and an increased rate of full agreement between the five experts, between evaluations 1 and 2, for both diagnosis and therapeutic management, were also defined as secondary endpoints.
Results
Demographics and clinical data
Demographic and clinical data for all cysts
| Patients (n = 206) | |
| Age, mean (range), years | 57 (23–84) |
| Male [n (%)] | 69 (33) |
| Pre-existing conditions [n (%)] | |
| Previous EUS-FNA | 64 (33) |
| Symptoms [n (%)] | |
| No symptoms | 154 (75) |
| Acute pancreatitis | 16 (8) |
| Aspecific abdominal pain | 36 (17) |
| Cyst morphology | |
| Location [n (%)] | |
| Uncinate | 10 (49) |
| Head | 58 (28) |
| Neck | 27 (13) |
| Body | 67 (33) |
| Tail | 44 (21) |
| Lesion size, mean (range), mm | 38 (20–200) |
| Main pancreatic duct dilation [n (%)] | 19 (9) |
| Number of cavities [n (%)] | |
| 1 | 88 (43) |
| 2 | 22 (11) |
| > 2 and < 10 | 58 (28) |
| ≥ 10 | 38 (18) |
| Wall thickness ≥ 1 mm [n (%)] | 32 (16) |
| Presence of calcification [n (%)] | 18 (9) |
| Intracystic concentrations | |
| CEA > 192 ng/mL [n (%)] | 55 (27) |
| CEA < 5 ng/mL [n (%)] | 59 (29) |
| Amylase < 250 IU/L [n (%)] | 63 (31) |
Technical feasibility and safety for all cysts
| Cyst access [n (%)] | |
| Easy | 188 (91) |
| Moderate or difficult | 18 (9) |
| Needle type [n (%)] | |
| 19 G Echo Tip Ultra* | 21 (10) |
| 19 G Expect Flexible† | 185 (90) |
| Access route [n (%)] | |
| Transgastric | 140 (68) |
| Transduodenal | 66 (32) |
| Second part of the duodenum | 5 (2) |
| Miniprobe extraction from the needle [n (%)] | |
| Possible | 195 (95) |
| Not possible (extracted together with the needle) | 11 (5) |
| Cytohistology [n (%)] | |
| Contributive | 61 (30) |
| Non-contributive | 145 (70) |
| Biochemical dosage [n (%)] | |
| Successful | 157 (76) |
| Unsuccessful | 49 (24) |
| Insufficient fluid volume | 34 (17) |
| Intracystic bleeding (hematic fluid) | 8 (4) |
| High viscosity | 4 (1.9) |
| Fluid leak | 3 (1.4) |
| Safety [n (%)] | |
| Post-procedure pancreatitis | 3 (1.4) |
Impact of nCLE on PCL diagnoses
Diagnoses consensus in evaluations 1 (EUS-FNA) and 2 (EUS-nCLE-FNA). BD-IPMN branch duct-intraductal papillary mucinous neoplasm, IML indeterminate mucinous lesion, MCN mucinous cystadenoma, SCA serous cystadenoma, PC pseudocyst, NEN neuroendocrine neoplasm, EUS endoscopic ultrasonography, FNA fine-needle aspiration, nCLE needle-based confocal laser endomicroscopy. p values from McNemar test are indicated for each diagnostic option
Impact of nCLE on therapeutic management of patients with PCLs
Therapeutic management according to evaluations 1 (EUS-FNA) and 2 EUS-nCLE-FNA). EUS endoscopic ultrasonography, FNA fine-needle aspiration, nCLE needle-based confocal laser endomicroscopy. p values from McNemar test are indicated for each diagnostic option
Impact of nCLE on interobserver agreements
Agreement between the panel of five experts. A Agreement among the eight possible diagnosis options (NEN, BD-IPMN, MCN, indeterminate mucinous lesion, SCA, PC, indeterminate or other) according to evaluation 1 (EUS-FNA) and evaluation 2 (EUS-nCLE-FNA). B Agreement among the three possible therapeutic management options (“neither surgery nor surveillance”, “surveillance” or “surgery”) according to evaluation 1 and evaluation 2. EUS endoscopic ultrasonography, FNA fine-needle aspiration, nCLE needle-based confocal laser endomicroscopy, k Fleiss’ kappa. NEN neuroendocrine neoplasm, BD-IPMN branch duct-intraductal papillary mucinous neoplasm, MCN mucinous cystadenoma, SCA serous cystadenoma, PC pseudocyst
All authors had access to the study data and reviewed and approved the final version of the manuscript.
Discussion
Increasing numbers of incidental PCLs have been identified due to increasing use of computed tomography (CT) scans and magnetic resonance imaging (MRI) [20, 21]. Single non-communicating PCL without chronic calcified pancreatitis represents the most challenging diagnostic issue and should be carefully considered because of the malignant potential of some types of PCLs. In current practice, the therapeutic management of PCLs usually relies on multidisciplinary review board decisions based on cyst imaging characteristics, CEA levels and cytohistopathological analyses. Using this approach for 206 patients extracted from a prospective database, the IOA Fleiss’ kappas between a panel of experts in pancreatic diseases were dramatically low for both PCL diagnosis (0.45) and therapeutic management (0.36). These results can be explained by the low rate of 30% of contributory FNA cytohistopathological analyses and by the lack of accuracy of CEA level. These data are consistent with those of the literature [22] and emphasize the necessity of a more reliable diagnostic method for the diagnosis of PCLs.
In our series, the overall diagnostic yield of nCLE (85%) was significantly higher than that of FNA cytohistopathology (30%). The addition of nCLE to EUS-FNA allowed significant changes of diagnoses and therapeutic managements in 27% and 28% of the cases, respectively (with p = 0.005 and p < 0.0001, respectively), while IOA Fleiss’ kappas among the experts significantly increased from 0.45 to 0.70 for diagnosis and from 0.36 to 0.64 for therapeutic management strategies. Strikingly, nCLE increased the rate of full agreement among the panel of experts from 29 to 61% for diagnoses and from 30 to 54% for therapeutic managements. This effect of nCLE increased the value of multidisciplinary review boards with less disagreement among participants.
The addition of nCLE significantly increased the number of BD-IPMNs diagnoses (p = 0.002) at the expense of a significant decrease of IML (p = 0.001). Indeed, EUS-nCLE-FNA refined 23 indeterminate mucinous lesions into 16 BD-IPMNs and 7 MCNs. These data emphasize that nCLE is useful to ascertain the diagnosis of BD-IPMN and should be recommended for a more specific diagnosis. nCLE also increased the number of SCA diagnoses (p = 0.034) and the number of “neither surgery nor surveillance” recommendations (p < 0.0001) while decreasing surveillance recommendations (p < 0.0001); the surveillance rate of SCAs fell from 40 (28/70) to 5% (4/76). These data show that nCLE is essential to ascertain the diagnosis and the therapeutic management of SCA by allowing the identification of its specific “superficial vascular network”. nCLE should be at least recommended to ascertain the presumptive diagnosis of SCA. Moreover, a recent French health economic model reported that nCLE may be cost-effective for the therapeutic management of SCA [23]. In this medico-economic analysis, the additional cost per patient for nCLE was estimated at 600€. This analysis showed that the addition of nCLE to EUS-FNA resulted in a reduction of 23% in the total rate of surgical intervention, which translated to a reduction in clinical costs of 13% (public sector) and 14% (private sector). Therefore, nCLE should be systematically considered when EUS-FNA is indicated for the evaluation of PCLs.”
Our data confirmed the safety of nCLE in the largest multicentric cohort of 206 patients who underwent EUS-FNA+nCLE procedures. Indeed, the rate of post-procedure acute pancreatitis in the trial was 1.4% (3/206). This incidence is similar to the previously reported risk levels following standard EUS-FNA procedures [24] and is lower than those of nCLE pilot studies [12]. The necessity of using a 19G needle to perform nCLE procedure represents the main technical limitation. Two technical failures of cyst puncture were observed in lesions only accessible from the second part of the duodenum, which is consistent with previously reported experience [15].
Our study had several limitations: (1) only a few of the PCLs included in the study had a surgical gold standard-based diagnosis. This is inherent to the therapeutic management of the studied disease, especially when dealing with presumptive benign PCLs for which ethical considerations obviously prevent systematic resections. For the other PCLs, the follow-up was not very long term. Therefore, the diagnoses proposed by the experts are tentative. Thus, the only certain finding is that the use of nCLE increases interobserver agreement between specialists. The comparison of retrospective data analyses with a prospectively obtained gold standard diagnosis would have introduced a major methodological bias. Nevertheless, two large prospective studies have already validated the very high diagnostic performance of nCLE for all types of cysts [17, 18] and have demonstrated the almost perfect interobserver reliability of nCLE criteria [17]. (2) The contribution of CT and MRI outcomes was not evaluated in our study due to the heterogeneity of data collection. Nevertheless, this would probably not have affected the results because the patients included in our cohort were sent for EUS-FNA after inconclusive CT and MRI. (3) We did not include in our study new PCLs diagnostic tools for which the potential interests have been published during the conduct of the study, including DNA mutations [25, 26], string sign tests [27], and EUS-guided microforceps biopsies [28]. (4) For the sake of simplification, therapeutic management was based on a consensus of a panel of five experts. Systematic resection was recommended for all patients diagnosed with MCN, whereas surveillance was recommended for BD-IPMN without worrisome features [1]. This can be discussed as the most recent guidelines propose observation as an option for asymptomatic MCNs < 4 cm without mural nodules [22, 29]. Nevertheless, MCNs are predominantly present in the body or tail of the pancreas of middle-age women and are definitely cured without the need for follow-up in the absence of cancer. The natural history of MCN remains unknown and non-operative management would require years of follow-up based on high-resolution imaging associated with high costs [1]. Therefore, in most centers, resection remains proposed for MCN.
Conclusion
The diagnosis of large single pancreatic cysts represents a major issue for clinicians. The addition of nCLE information to EUS-FNA significantly improves the reliability both in diagnosis and therapeutic management among experts in pancreatic cystic lesions. These results support the recognition of nCLE as a key tool of the standard of care for such clinical situations.
Notes
Acknowledgements
We would like to thank all the procedural nurses and staff for their assistance during procedures. We would like to thank Leslie Assouline and Guillaume Trébuchet from Mauna Kea Technologies for additional logistical support during the trial.
Author contributions
Conception or design of the work (Dr. M. Palazzo, Dr. B. Napoleon, Dr. S. Marque); data collection (all authors); data analysis and interpretation (Dr. B. Napoleon, Dr. AI. Lemaistre, Dr. M. Morellon); drafting the article (Dr. B. Napoleon, Dr. M. Palazzo); critical revision of the article (all authors); final approval of the version to be published (all authors).
Funding
This study has been funded by Mauna Kea Technologies. Mauna Kea Technologies provided logistical support during the trial.
Compliance with ethical standards
Disclosure
Drs. B. Napoléon, Dr M. Palazzo is on the speakers’ bureau of Mauna Kea Technologies. Drs. B. Napoléon, M. Palazzo, A. Sauvanet, R. Gincul, I. Borbath, G. Vanbiervliet, R. Bourdariat, A.-I. Lemaistre, B. Pujol, F. Caillol, L. Palazzo, A. Aubert, F. Maire, L. Buscail, and M. Giovannini have received financial support from Mauna Kea Technologies. Dr. B. Napoléon has also received financial support from Cook Medical Corporation, Ipsen, Boston Scientific Corporation, Olympus Corporation and Cousin Corporation. R. Gincul has also received financial support from Ipsen. Dr. G. Vanbiervliet has also received financial support from Cook Medical Corporation and Boston Scientific Corporation. Dr. S. Marque has no conflicts of interest or financial ties to disclose.
Supplementary material
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