It is the invited review article.
The prevalence of pancreatic cystic lesions (PCLs) has increased recently due to the increased use of cross-sectional abdominal imaging and the ageing global population. Current diagnostic techniques are inadequate to distinguish between PCLs that require surgery, close surveillance, or expectant management. This has resulted in increased morbidity from both inappropriately aggressive and conservative management strategies. Needle-based confocal laser endomicroscopy (nCLE) has allowed microscopic examination and visual delineation of the surface epithelium of PCLs. Landmark studies in this decade have correlated nCLE and histological findings and identified characteristics differentiating various types of PCLs. Subsequent studies have confirmed the high diagnostic yield of nCLE and its diagnostic utility in PCLs with an equivocal diagnosis. Moreover, nCLE has been shown to improve the diagnostic yield of PCLs. This will help avoid unnecessary pancreatic surgery, which carries significant morbidity and mortality risks. The early detection of high-grade dysplasia in PCLs will provide early surgical treatment and improve outcomes for pancreatic cancer. Despite the high upfront cost of nCLE, the improved diagnostic accuracy and resultant appropriate management have resulted in improved cost effectiveness. Refining the procedure technique and limiting the procedure length have significantly improved the safety of nCLE. A structured training program and device improvements to allow more complete mapping of the pancreatic cyst epithelium will be crucial for the widespread adoption of this promising technology.
Cystic lesions of the pancreas are increasingly detected because of the increased use of cross-sectional abdominal imaging such as computed tomography and magnetic resonance imaging [
Prior to the introduction of clinical guidelines by the International Association of Pancreatology5 and American College of Gastroenterology [
Updated clinical practice guidelines by major societies have sought to optimize the diagnosis and management of PCLs [
Confocal laser endomicroscopy (CLE) involves the use of a low-power laser to scan and illuminate tissue within a pancreatic cyst in a single focal plane, allowing for microscopic detail of the surface epithelium to be examined. Light is focused and passed through a confocal aperture. This reduces light scatter above and below the plane. The microscopic details of the surface epithelium can be examined [
Due to its extraluminal location, the pancreas is difficult to assess using the probe-based CLE method; therefore, a needle-based CLE (nCLE) was designed to overcome these technical difficulties assessing cystic lesions of the pancreas [
Two authors individually reviewed the English language literature from inception to November 2019. PubMed and Google Scholar were used to identify peer-reviewed original articles using the following keywords: “needle‑based confocal laser endomicroscopy”, “endoscopic ultrasound”, and “pancreatic cystic lesion”. Among the identified results, we included original research papers and cases series (consisting of at least three cases) that reported the use of nCLE. We also manually searched the references lists of the pertinent studies to identify additional relevant studies. Only studies involving humans were selected. We excluded non‑English papers, reviews, and papers that were unrelated to the issue at hand or were published only as abstracts. Retrieved duplicates were excluded. Indications, procedural details, technical and clinical outcomes, and adverse events and their management were reviewed for each study.
The AQ-Flex 19 miniprobe model (
Three safety features have been integrated into this miniprobe (
Before the beginning of the procedure, the locking device is attached to the proximal end of a 19-G FNA needle after removal of the stylet. A list of FNA needles compatible with the nCLE miniprobe (AQ-Flex; Cellvizio, Mauna Kea Technologies) is shown in
The landmark clinical studies examining the role of nCLE in the diagnosis of pancreatic cysts are summarized in
In the Diagnosis of Pancreatic Cysts: Endoscopic Ultrasound, Through-the-Needle Confocal Laser Endomicroscopy and Cystoscopy Trial of Nakai et al. [
Napoléon et al. [
Subsequently, Napoleon et al. conducted another study (CONTACT 1) [
In the CONTACT 2 study [
A recent publication on the prospective CONfocal endomicroscopy in CYSTic lesions of the pancreas trial by Keane et al.24 showed that EUS-nCLE had an overall sensitivity of 79.6% for all pancreatic lesions. This ranged from 55.6% for SCA to 90% for IPMN and 100% for pancreatic ductal adenocarcinoma. The overall accuracy of nCLE was 76.8%. There was a low rate of adverse events (3.5%) with one case of transient pruritus attributed to a fluorescein allergy and one patient having an infected pseudocyst.
The IOA analyses showed heterogeneous results. In the CONTACT 1 study [
A study by Kadayifci et al. [
Palazzo et al. [
PCLs are commonly detected. Distinguishing benign lesions from those requiring intervention remains difficult, while the adequate management of pancreatic cysts is challenging. After nCLE was shown to be technically feasible in 2011, multiple prospective studies described the appearance of various PCNs under nCLE and correlated them against the histological findings. This was followed by larger multicenter studies that showed the improved diagnostic accuracy of nCLE, which is also useful for obtaining a diagnosis in patients with a previously inconclusive EUS-FNA result with an accuracy comparable to that of surgical histopathology. The presence of a SVN is exclusive to SCA. However, the sensitivity of SVN is limited by epithelium denudation. Oligocystic SCA may not display this characteristic vascular pattern [
Existing studies have reported several complications related to nCLE (
The use of nCLE is limited by the presence of a significant learning curve. The surmounting of this learning curve requires not only understanding the technical aspect of setting up the device but also the ability to interpret the image sequences. Krishna et al. [
Additionally, nCLE has been shown to improve the cost effectiveness of pancreatic cyst management. Although the use of nCLE incurs a significant upfront cost, a cost effectiveness analysis by Le Pen et al. [
PCL is increasingly detected due to the widespread use of advanced imaging technique. However, the challenge remains regarding how to ascertain the exact nature of the PCL and select high-risk lesions for surgical resection while preventing oversurveillance or unnecessary procedures in patients with benign lesions. Here we highlighted the increasing positive evidence for nCLE in the assessment of PCL since it provides valuable information in the diagnostic process for PCLs and is a useful supplement to EUS-FNA. The limitations of its high upfront operating cost and steep learning curve must be addressed before nCLE can be widely used and incorporated into future guidelines as a standard of care for the assessment of PCL.
None.
Conceptualization: Yung Ka Chin, Clement Chun Ho Wu and Damien Meng Yew Tan
Data curation: YKC, CCHW, DMYT
Formal analysis: YKC, CCHW, DMYT
Project administration: YKC, CCHW, DMYT
Supervision: DMYT
Writing-review&editing: YKC, CCHW, DMYT
The AQ-Flex (Cellvizio, Mauna Kea Technologies, Paris, France) 19 needle confocal laser endomicroscopy miniprobe.
(A) The ferule is a metallic tap at the distal end of the probe that protects the device from the beveled needle tip. (B) The sheath of the probe comprises a robust protective biocompatible coating. (C) A locking device is attached by a Luer lock to the fine needle aspiration needle’s proximal hub and secured onto the probe to maintain needle position and prevent migration.
Superficial vascular network visible on needle-based confocal laser endomicroscopy of serous cystadenoma.
Papillary projections characterized by a vascular core (white) surrounded by an epithelial border (gray) are visible on needle-based confocal laser endomicroscopy of intraductal papillary mucinous neoplasm.
A thick epithelial band is visible on needle-based confocal laser endomicroscopy of mucinous cystadenoma.
Bright uniform particles are visible against a dark background on needle-based confocal laser endomicroscopy of pseudocyst.
Compatibility of Endoscopic Ultrasound-Fine Needle Aspiration Needle with the Needle-Based Confocal Laser Endomicroscopy Probe
Needle type | Manufacturer | Compatibility |
---|---|---|
EchoTip® Ultra Endoscopic Ultrasound Needle | Cook Medical | Compatible |
EZShot 2 Aspiration Needle | Olympus | Compatible |
ExpectTM Needle 19 Flex | Boston Scientific | Compatible |
SonoTip® Pro Control | MediGlobe Gmbh | Compatible |
SonoTip® II | MediGlobe Gmbh | Compatible |
BNX Fine Needle Aspiration System | Beacon | Compatible |
EchoTip® Ultra Endoscopic Ultrasound Access Needle | Cook Medical | Not compatible |
EchoTip® ProCore | Cook Medical | Not compatible |
Quick-Core® Endoscopic Ultrasound Needle | Cook Medical | Not compatible |
19 G FlexNeedleTM Clearview | CONMED | Not compatible |
All needles are 19 G. Adapted from Mauna Kea Technologies, Paris, France.
A Summary of the Key Clinical Studies Examining the Use of Needle-Based Confocal Laser Endomicroscopy for Diagnosing Pancreatic Cystic Lesions
Study | Study design | Country | EUS-nCLE accuracy | Basis of final diagnosis | n | Sex (M/F) | Age (mean in years) | Size (mm) |
---|---|---|---|---|---|---|---|---|
Konda et al. (2011) [ |
Prospective | USA | Safety and feasibility study | • Surgical histology | 18 | 7/11 | 57.9 | 43 |
• EUS-FNA cytology | ||||||||
• EUS imaging | ||||||||
Nakai et al. (2015) [ |
Prospective | USA | 89% | • Surgical histology | 30 | 9/21 | 72 | 30 |
• Cross-sectional imaging | ||||||||
• EUS imaging | ||||||||
• Cyst fluid analysis | ||||||||
• EUS-FNA cytology | ||||||||
Napoléon et al. (2015) [ |
Prospective | France | 87% | • Surgical histology | 31 | 6/25 | 57 | 39 |
• EUS-FNA cytology | ||||||||
• Multi-disciplinary consensus | ||||||||
Karia et al. (2016) [ |
Retrospective | USA | 46% | • Surgical histology | 15 | 10/5 | 66.6 | 25 |
• Cross-sectional imaging | ||||||||
• EUS imaging | ||||||||
• Cyst fluid analysis | ||||||||
• EUS-FNA cytology | ||||||||
Krishna et al. (2016) [ |
Retrospective | USA | 95% | • Surgical histology | 26 | 10/16 | 54.8 | 32 |
• EUS-FNA cytology | ||||||||
• Multi-disciplinary consensus | ||||||||
Kadayifci et al. (2017) [ |
Retrospective | USA | 83% | • Surgical histology | 18 | 8/10 | 65.4 | 34 |
• EUS imaging | ||||||||
• Cyst fluid analysis | ||||||||
Krishna et al. (2017) [ |
Retrospective | USA | 95% | • Surgical histology | 29 | 13/16 | 53 | 32 |
• Multi-disciplinary consensus | ||||||||
Napoleon et al. (2019) [ |
Prospective | France | 91% | • Surgical histology | 78 | 26/52 | 57 | 40 |
• EUS imaging | ||||||||
• Cross-sectional imaging | ||||||||
• Cyst fluid analysis | ||||||||
• EUS-FNA cytology | ||||||||
Chin et al. (2018) [ |
Prospective | Singapore | 80% | • Surgical histology | 12 | 6/6 | 66.5 | 34 |
• EUS imaging | ||||||||
• Cross-sectional imaging | ||||||||
• Cyst fluid analysis | ||||||||
• EUS-FNA cytology | ||||||||
Keane et al. (2019) [ |
Prospective | United Kingdom | 77% | • EUS imaging | 56 | 35/21 | 68 | 25 |
• Cross-sectional imaging | ||||||||
• EUS-FNA cytology | ||||||||
• Multi-disciplinary consensus | ||||||||
Palazzo et al. (2019) [ |
Retrospective | France | 85% | • Clinical factors | 206 | 69/137 | 57 | 38 |
• Cross sectional imaging | ||||||||
• EUS imaging | ||||||||
• Cyst fluid analysis |
EUS-FNA, endoscopic ultrasound-fine needle aspiration; nCLE, needle-based confocal laser endomicroscopy.
A Summary of Needle-Based Confocal Laser Endomicroscopy Diagnostic Features for each Cystic Pathology as well as Their Sensitivity, Specificity, and Accuracy in Key Clinical Studies
Serous cystadenoma |
|||||
---|---|---|---|---|---|
Pattern | Study | Sensitivity | Specificity | Accuracy | |
Fern pattern | Krishna et al. (2017) [ |
13 | 98% | 97% | 92% |
Krishna et al. (2020) [ |
113 | 87% | 100% | 97% | |
Superficial vascular network | Napoléon et al. (2015) [ |
31 | 69% | 100% | 87% |
Napoleon et al. (2019) [ |
71 | 95% | 100% | 99% | |
Keane et al. (2019) [ |
56 | 56% | - | 38% | |
Bright particles against dark background | Napoleon et al. (2016) [ |
31 | 43% | 100% | 87% |
Krishna et al. (2020) [ |
65 | 67% | 97% | 95% | |
Bright grey and black particles | Keane et al. (2019) [ |
56 | 67% | - | 67% |
Finger-like papilla | Nakai et al. (2015) [ |
30 | 77% | 100% | 87% |
Napoleon et al. (2016) [ |
31 | 80% | 92% | 90% | |
Krishna et al. (2020) [ |
65 | 98% | 94% | 97% | |
Keane et al. (2019) [ |
56 | 90% | - | 77% | |
Epithelial bands | Napoleon et al. (2016) [ |
31 | 67% | 96% | 90% |
Krishna et al. (2020) [ |
65 | 98% | 94% | 97% | |
Finger-like papilla or epithelial bands | Krishna et al. (2015) [ |
33 | 91% | 95% | 94% |
Krishna et al. (2016) [ |
26 | 94% | 82% | 89% | |
Napoleon et al. (2019) [ |
71 | 95% | 100% | 97% | |
Finger-like papilla or dark ring or gland-like structure or epithelial band | Kadayifci et al. (2017) [ |
18 | 66% | 100% | 83% |
Rope ladder or branch vascular pattern or finger-like papilla or epithelial bands | Krishna et al. (2017) [ |
16 | 93% | 89% | 91% |
Trabeculae of compact cells surrounded by grey tissue | Krishna et al. (2017) [ |
13 | 98% | 97% | 92% |
Krishna et al. (2020) [ |
65 | 100% | 96% | 96% | |
Napoleon et al. (2019) [ |
71 | 100% | 95% | 96% | |
Epithelial villous structures | Konda et al. (2013) [ |
66 | 59% | 100% | 71% |
• Finger-like papillary projections | |||||
• Dark ring with white core | |||||
• Gland-like or crypt-like structures |
Complications of Needle-Based Confocal Laser Endomicroscopy for Pancreatic Cystic Lesions
Study | Complications |
||||||
---|---|---|---|---|---|---|---|
Pancreatitis | Bleeding | Infection | Fluorescein- related | Death | Overall | ||
Konda et al. (2011) [ |
18 | 2 (12%) | 0 | 0 | 0 | 0 | 2 (12%) |
Konda et al. (2013) [ |
66 | 2 (3.0%) | 3 (4.5%) | 0 | 0 | 0 | 6 (9.1%) |
Nakai et al. (2015) [ |
30 | 2 (6.7%) | 0 | 0 | 0 | 0 | 2 (6.7%) |
Napoléon et al. (2015) [ |
31 | 1 (3.2%) | 4 (12.9%) | 0 | 0 | 0 | 5 (16.1%) |
Krishna et al. (2016) [ |
49 | 3 (6.1%) | 0 | 0 | 0 | 0 | 3 (6.1%) |
Chin et al. (2018) [ |
12 | 0 | 1 (8.3%) | 0 | 0 | 0 | 1 (8.3%) |
Napoleon et al. (2019) [ |
78 | 1 (1.3%) | 1 (1.3%) | 0 | 0 | 0 | 2 (2.6%) |
Keane et al. (2019) [ |
56 | 0 | 0 | 1 (1.8%) | 1 (1.8%) | 0 | 2 (3.6%) |
Palazzo et al. (2019) [ |
209 | 3 (1.4%) | 0 | 0 | 0 | 0 | 3 (1.4%) |
Overall | 549 | 14 (2.6%) | 9 (1.6%) | 1 (0.2%) | 1 (0.2%) | 0 (0.0%) | 27 (4.9%) |