Pancreatic cystic lesions (PCLs) represent an increasingly common diagnostic and therapeutic challenge. A significant number of pancreatic cysts are detected incidentally when noninvasive abdominal imaging is performed for an unrelated diagnosis Citation[1]. The vast majority of PCLs are cystic neoplasms (∼60%), while injury or inflammation-related cysts (e.g., pseudocysts) account for approximately 30% of PCLs. The remaining PCLs are congenital or miscellaneous cysts Citation[2]. Neoplastic cysts include intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs), serous cystic neoplasms (SCNs), solid pseudopapillary neoplasms (SPNs), cystic endocrine neoplasms, ductal adenocarcinomas with cystic degeneration and acinar-cell cystic neoplasms Citation[3]. Since the management of PCLs is a function of cyst type, reliable differentiation between the five most common diagnoses – pseudocyst, IPMN, MCN, SCN and SPN – is of vital importance Citation[4].
Differentiation of PCLs
Although a number of characteristic imaging features have been reported, many PCLs, especially those with diameter <2 cm, are extremely difficult to differentiate by imaging Citation[5]. Differentiation of low-risk lesions and high-risk lesions is also difficult. Low-risk lesions (pseudocysts, SCNs, congenital cysts and lymphoepithelial cysts) are generally not resected because they have no risk or an extremely low risk of malignant transformation Citation[2]. High-risk lesions are mucin-producing tumors (MCNs and IPMNs) and some cystic variants of solid tumors (e.g., ductal adenocarcinomas with cystic degeneration) Citation[2,4]. Depending on the degree of dysplasia, MCNs and IPMNs are classified as MCN/IPMN with low- or intermediate-grade dysplasia, MCN/IPMN with high-grade dysplasia and MCN/IPMN with an associated invasive carcinoma Citation[6].
More recently, endoscopic ultrasound (EUS) has been used to image the pancreas with improved resolution Citation[7]. Owing to the pancreas lying directly adjacent to the stomach, an EUS transducer can be placed in close proximity to the pancreas, and the entire gland can be readily imaged. However, the accuracy of EUS morphology in the differentiation of PCLs is not satisfactory Citation[8,9]. In differentiating mucinous from nonmucinous lesions, the accuracy of EUS morphology was 51% Citation[8]. In another study, the level of accuracy of EUS morphology to differentiate between all types of PCLs was 73% Citation[9].
The use of EUS-guided fine-needle aspiration (EUS-FNA) for fluid collection has enabled endoscopists to use tumor marker levels and cytology to supplement EUS imaging Citation[7]. The carcinoembryonic antigen has been reported to be the most accurate marker to distinguish nonmucinous from mucinous PCLs Citation[10]. Despite these advances, the accuracy of EUS and cyst fluid analysis for differentiation between mucinous and nonmucinous PCLs, and between benign and malignant PCLs, still remains modest Citation[4,10]. Challenges in EUS-FNA include sampling error, nondiagnostic cytology and limited on-site cytological evaluation Citation[11].
The potential of high-resolution optical imaging for improving diagnosis
High-resolution optical imaging has recently been investigated for differentiating between morphologic features of pancreatic tissue. This includes both confocal endomicroscopy (CEM) and optical coherence tomography (OCT) Citation[11–15].
CEM is a micron-scale optical imaging technique that provides powerful imaging features with subcellular resolution that complement, rather than replace, the use of conventional white-light endoscopy. Previously, in vivo use of CEM was limited owing to the inability to reduce the optics and the scanning mechanism to an endoscope-compatible size. As confocal instrumentation technology advances, submillimeter CEM probes will become available and new advancements in gastrointestinal imaging are being made. CEM use for imaging pancreatic cysts has recently been reported in a small pilot study Citation[11]. Pancreatic cysts and solid masses were investigated in this study. Although some technical challenges related to high-specular reflections degrading image quality were encountered, this study was quite successful and technical feasibility for performing micron-scale imaging with CEM during a pancreatic EUS-FNA procedure was achieved for the first time. However, although very promising, the main drawbacks of CEM are the reduced imaging depth and field of view, both being limited to several hundred microns. Therefore, CEM might not be able to reliably identify morphologic differences between the microcystic walls of the serous and mucinous cysts. Nevertheless, its capability for visualizing tissue morphology at the subcellular level can be further exploited for differentiating between various cystic lesions of the pancreas, as well as between autoimmune pancreatitis (AIP) and SPNs. The differentiation between AIP and SPNs is particularly important because AIP can produce pancreatic masses that resemble pancreatic carcinoma both clinically and radiographically. While the neoplasms are usually managed by surgical resection, pancreatitis is managed nonsurgically.
OCT is an interferometric high-resolution optical imaging technique and therefore it enables tissue imaging at depths that far surpass CEM capability. Up to 2 mm imaging depth is possible with OCT, depending on the tissue structure. In addition, OCT has the potential to image tissue structures at the scale of several microns and produce cross-sectional or en face images that resemble a histology slide Citation[13,15,16]. However, OCT imaging at the subcellular level has not yet been demonstrated.
Both ex vivo and in vivo studies have demonstrated the capability of this technique to identify and recognize the gastrointestinal and pancreaticobiliary wall structure Citation[12,14], as well as to differentiate between the wall structure and cystic fluid scattering properties of serous and mucinous cysts Citation[13,17]. Key imaging features of the mucinous cystic lesions were the high scattering of the mucinous fluid and the presence of a large amount of homogenous high-scattering tissue between the microcysts that corresponds to the intervening fibrocollagenous tissue, as well as the increased epithelial thickness of the malignant cysts. The OCT images of the serous cysts showed multiple tiny cysts with well-defined outlines. The thin septae between the cysts showed homogenously high scattering, creating a honeycomb appearance. Significantly, OCT images also showed that the serous cyst content is homogenously dark and lacked scattering effect. Strong correlations between histology and OCT images of serous and mucinous cysts were also found. Based on these correlations, OCT criteria for differentiating between these two classes of cysts were developed. The cysts were determined to be mucinous or nonmucinous based on pre-established OCT criteria and the results were compared with histology findings. Despite modest training and little experience with OCT imaging, the clinicians were able to identify mucinous cysts with high levels of accuracy (96–100%) Citation[13].
Although preliminary, these studies suggest that CEM and OCT may offer significant potential for clinical use to differentiate between various cysts and complement EUS-FNA findings.
Conclusion
High-resolution optical imaging may be a suitable tool for complementing EUS findings and help clinicians to more reliably differentiate between various cystic lesions of the pancreas. Cystic wall morphology and scattering properties of the cystic fluid may be the main cystic features that can be exploited by OCT. The thickness and the cellular appearance of the cystic epithelium could be investigated by CEM. Therefore, high-resolution optical imaging may play an important role in the diagnosis of cystic lesions of the pancreas, as well as in other organs.
Financial & competing interest disclosure
The referenced work in Citation[13] about pancreatic studies was supported by the NExT NIH grant 2R44CA117218. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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