In this issue, we will highlight the new developments in the field of endoscopic ultrasound (EUS)-guided diagnosis and therapy of pancreatic cystic neoplasms (PCNs). In this regard, the topic will be discussed under the following headings: (1) New developments in cyst diagnosis by morphology; (2) Tissue acquisition during EUS; (3) Analysis of cyst fluid-molecular markers; (4) Novel imaging techniques for PCNs; (5) EUS-based ablative therapies; and (6) Guidelines for management of PCNs.

PCNs can be broadly classified into three main types, namely serious cystic neoplasms, mucinous cystic neoplasms and cystic variants of solid tumors. Serous cystic neoplasms have low malignant potential with only 30 cases of serious cystadenocarcinomas reported till 2014.¹

Mucinous cystic neoplasms that communicate with the pancreatic ductal system are called intraductal papillary mucinous neoplasms (IPMNs) and can be further divided into main duct, side branch IPMNs or mixed IPMNs. Main duct IPMNs have the highest risk of malignancy with a mean frequency of 61.6% (range, 36%–100%).²

Mucinous cysts that do not communicate with the main pancreatic duct are called mucinous cystadenomas and the prevalence of malignancy in these is < 17.5%.³ Finally, solid variants of cystic tumors include solid pseudopapillary tumors which are rare and comprise < 4% of PCNs and cystic neuroendocrine tumors of pancreas which are generally non functional and constitute about 8% of resected pancreatic cysts.¹

With increased incidental detection of PCNs on cross sectional imaging,⁴ EUS on account of its superior ability in terms of detection of subtle morphological characteristics and pancreatic and biliary ductal abnormalities is the investigation of choice for categorizing these lesions, assessing the risk of malignancy and determination of appropriate follow up or surgical referral. Indeed, EUS is superior to multidetector computed tomography (CT) for diagnosing pancreatic neoplasms < 2 cm in size in patients with clinical symptoms suggestive of malignancy but with a negative CT scan.⁵

Research over the last several years had led to the identification of several morphologic criteria which can help risk stratify pancreatic cysts into benign versus malignant cysts. While the overall morphologic features that may suggest malignancy have not changed, recent adjuncts to determination of pancreatic cyst morphology involve use of intravenous ultrasound contrasts such as inert perflubutane microbubbles suspended in water to enhance certain anatomic characteristics of pancreatic cysts.

The diagnostic accuracy of diagnosis of a PCN on EUS morphology alone ranges from 40%–96%, when compared to surgical pathology.⁶ Although morphologic characteristics alone are rarely used to make a definitive diagnosis, several studies have identified morphologic features and developed criteria which when present suggest a higher risk of underlying malignancy. Mural nodules, pancreatic duct dilation, thickened septal walls and cyst size > 3 cm in branch duct IPMN were all associated with a higher risk of malignancy, with odds ratios (ORs) of 6, 3.4, 3.3, and 2.3, respectively. Multilocularity of cysts was not associated with increased risk of malignancy in this meta-analysis.⁷

The International Association of Pancreatology released consensus guidelines for management of IPMN and MCN and provided an algorithmic approach.²

Per these guidelines, the three high-risk features are obstructive jaundice in a patient with cystic lesion of the head of the pancreas, enhancing solid component within a cyst and main pancreatic duct > 10 mm in size. The presence of any of these should prompt surgical evaluation. The five ‘worrisome features’ on imaging include cyst size equal to or more than 3 cm, thickened or enhancing cyst walls, main pancreatic duct (MPD) size of 5–9 mm, non-enhancing mural nodules and abrupt change in the MPD caliber with distal pancreatic atrophy, and lymphadenopathy.

Contrast enhanced EUS using intravenous injection of Sonazoid which is a second-generation ultrasonography contrast agent composed of perfluorobutane microbubbles with a median diameter of 2–3 μm is an attractive adjunct to linear EUS and it’s utility is in the detection of mural nodules, which have been shown to have a an OR as high as 6 to 9.3 for prediction of malignancy in two different meta-analyses.^7,8

Mucus clots adherent to cyst wall can be mistaken for mural nodules and contrast enhanced EUS may help correctly identify mural nodules as they enhance with EUS contrast, where as mucus clots exhibit no enhancement.

A retrospective study involving 70 patients from Japan by Kamata et al⁹ compared the utility of contrast enhanced EUS with conventional B mode EUS, with histopathology as gold standard and found that contrast enhanced-EUS was significantly more accurate than conventional EUS in diagnosing malignant lesions from non-malignant cysts using mural nodules alone. The results of this study showed a sensitivity of 95% for both groups, specificity of 75% vs 40%; accuracy 84% vs 64% for contrast enhanced EUS and conventional EUS respectively, with the analysis being significant with P = 0.0001.

Also, the presence of a mural nodule height of > 4 mm using contrast enhanced EUS was a sign of malignancy in this study, with an area under the receiver operating characteristic of 0.93.⁹

Another Japanese study involving 17 patients with mural nodules diagnosed on B-mode EUS who subsequently underwent surgical resection showed that contrast enhanced EUS increased the specificity of detection of mural nodules, due to ability of contrast enhanced EUS to allow visualization of flow within mural nodules. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of contrast-enhanced endoscopic sonography for mural nodule detection were 100%, 80%, 92%, 100%, and 94%, respectively in this study.¹⁰

Although there are several commercially available fine needles and core biopsy needles from 19–25 gauge with a variety of bevel configurations, the basic principle of EUS-guided core or fine needle biopsy or aspiration has not changed over the years. Two accessories for tissue acquisition, namely the cytobrush and the microforceps deserve mention.

Cytobrush

Establishing a correct diagnosis of a pancreatic cystic lesion has great implications for further management and is contingent upon obtaining specimens with adequate cellularity. Because of this, there has been recent interest in EUS-guided brushings of pancreatic cysts after cyst aspiration. The EchoBrush (Cook Endoscopy, Winston-Salem, NC, USA) is an EUS cytology brush designed for use with a 19-gauge EUS needle.

Sendino et al¹⁰ conducted a prospective study involving 30 patients comparing yield from EUS-fine needle aspiration (FNA) vs EUS-cytology brushing. The EUS-brush cytology yield was superior to cyst fluid aspirated by conventional FNA for detecting diagnostic cells (73% vs 36%, P = 0.08) and mucinous cells (50% vs 18%, P = 0.016). However, one patient had a subacute retroperitoneal hemorrhage that was fatal.

Similarly, a prospective study by Al-Haddad et al¹¹ involving 37 patients with PCNs at least 2 cm in size showed that cytobrush was more likely to find intracellular mucin that FNA alone. However, this study also had a high complication rate of 8%, namely two patients with acute pancreatitis and one with hemosuccus pancreaticus requiring angiography and embolization.

Another larger study from Spain involving 127 patients with PCNs found that EUS brush cytology provided more samples with adequacy of cellular material compared to FNA (85% vs 64% with statistical significance) In this study, the authors did not aspirate and empty the cyst fluid prior to brushing, as was done in most other studies of EUS brush cytology.¹²

Bruno et al¹³ enrolled 30 consecutive patients with pancreatic masses and showed that the first pass of Cytobrush revealed diagnostic material in 50% of pancreatic cysts which is an encouraging finding. The authors did not perform additional passes with cytobrush to avoid risk of complications, and thus, the actual yield of cytobrush could be higher in theory.

In contrast to the above studies, a retrospective British study by Thomas et al¹⁴ comparing adequacy of cellular yield between EUS-guided aspiration alone versus EUS-guided aspiration and cyst wall brushing showed no difference in between the two techniques.

More studies are required in this regard, in terms of multi-center involvement and standardization of needle size, technique and number of passes as well as preoperative and final postoperative or consensus diagnosis to determine whether cytobrush truly has an added advantage with acceptably low rate of adverse events. At present, cytobrush is not used extensively due to concern for complications.^10,11

Endoscopic ultrasound-guided microforceps biopsy

Recent efforts in device miniaturization have allowed endoscopists to evaluate the pancreatobiliary ductal system in ways that were previously not possible, and this has, in addition to the development of cholangioscope and radiofrequency ablation (RFA) catheters, led to the development of EUS-guided microforceps, which has a catheter diameter of 0.8 mm and jaw opening width of 4.3 mm which can be passed through a 19 gauge FNA needle (Moray Microforceps, US Endoscopy).

One of the earliest reports was published by Samarsena et al,¹⁵ when the diagnosis of a mucinous neoplasms of the was reported using microforceps.

There have been several further case reports of diagnosis of IPMN established using EUS-microforceps when EUS-FNA or cyst fluid aspiration was non-diagnostic.^16–19

Nakai et al²⁰ showed that EUS-guided microforceps biopsy in combination with EUS-FNA for cytology had an accuracy of 83% per pass and 94% per session in study of 17 patients with solid pancreatic tumors in a study from Japan.

The advantage of the microforceps is that it allows biopsy of the cyst wall yielding a histologic core which can be helpful in providing a diagnosis, rather than relying on surrogate indices such as cyst fluid markers. Additionally, the same needle puncture site can be used for microforceps biopsies when cellular aspirate is paucicellular or non-diagnostic. Microforceps biopsy seems to be a promising technique for increasing diagnostic yield of EUS-guided tissue acquisition and future studies should include prospective multicenter studies involving the use of microforceps for biopsy of PCNs.

Despite best efforts, the sensitivity of cytology from EUS-FNA aspirates is in the range of 63% and specificity of 88% according to a meta-analysis by Thosani et al.²¹ There is a need for development and adoption of reliable surrogate cytological and molecular markers that can identify the type of pancreatic cyst and the degree of dysplasia.

In the landmark Cooperative Pancreatic Study by Brugge et al²² done more a decade ago, CEA level was found to be significantly more accurate at distinguishing mucinous pancreatic cysts from non mucinous cysts when compared to EUS morphology and cytology and a combination thereof and showed that a CEA cutoff level of 192 nm/mL having the most area under the receiver operating characteristic curve for diagnosis of mucinous cysts. However, a study by Kucera et al²³ that included 47 resected IPMNs showed that CEA level is a poor predictor of invasive cancer within an IPMN.

Thus, there is a pressing need for identification of markers which will correctly diagnose patients with high-risk pathology for determining those who will benefit from surgical resection.

A study by Wu et al²⁴ which evaluated for 169 different types of mutations in a pilot set of 19 IPMNs found that KRAS was mutated in 14 of the 19 IPMNs and GNAS was mutated in 6 IPMNs. Subsequent analysis on 119 surgically resected IPMN showed that GNAS mutations were present in 66% of IPMNs and 0% of the 44 resected serous cystadenomas. Either KRAS or GNAS mutations could be identified in 96% of IPMNs and that none of the 21 resected mucinous cystadeomas had KRAS mutations.

In terms of molecular markers mutated in pancreatic cysts, much more has been recently discovered, thanks to the pioneering efforts from several groups. Mutations in BRAF, CDKN2A, CTNNB1, GNAS, KRAS, NRAS, PIK3CA, RNF43, SMAD4, TP53 and VHL and loss of heterozygozity (LOH) at CDKN2A, RNF43, SMAD4, TP53, and VHL tumor suppressor loci as well as aneuploidy have been implicated in pancreatic cysts.

A large retrospective multicenter study by Springer et al,²⁵ analyzing multiple mutations is notable in this regard. Cyst fluid from 130 resected PCNs was analyzed for a host of mutations and they showed that solid pseudopapillary tumors could identified with 100% sensitivity and 100% specificity by the presence of a CTNNB1 mutation and the absence of KRAS, GNAS, or RNF43 mutations or chromosome 18 LOH. MCNs were identified with 100% sensitivity and 75% specificity by the absence of CTNNB1 or GNAS mutations, chromosome 3 LOH, or aneuploidy in chromosome 1q or 22q. IPMNs were identified with 76% sensitivity and 97% specificity by the presence of a mutation in GNAS, RNF43, LOH in chromosome 9, or aneuploidy in chromosome 1q or 8p.

Utilization of markers such as KRAS, GNAS, and the multitude of markers investigated by Springer et al²⁵ in their study can help in accurate diagnosis of the type of PCN which is the first step in predicting biologic behavior. However, when an IPMN or MCN is diagnosed, the more important question that needs to be answered is whether there are dysplastic or malignant changes within the cyst.

Another new candidate biomarker for determining the degree of dysplasia within an IPMN is the high-mobility group A2 (HMGA2) protein, which affects transcription by binding to active chromatin. A recent study by DiMaio et al²⁶ showed that median HMGA2 protein concentration in banked cyst fluid from 31 surgically resected specimens was significantly higher in the IPMN in the HGD group (4.2 ng/mL, interquartile range [IQR] 1.7–9.2 ng/ mL) compared with the concentration in the low-risk group (1.1 ng/mL, IQR 0.6–2.7 ng/mL, P = 0.03).

This is indeed a promising finding, given that this will help delineate the natural history of progression of dysplasia as well as allow appropriate referral of patients with high grade dysplasia for surgery. Since this was a study on surgically resected specimens, future studies should prospectively validate the use of HMGA2 protein levels on EUS-FNA aspirates in patients who are surgical candidates per current International Consensus guidelines.

There has been interest in the micro RNAs (miRNA) in pancreatic cyst fluid. miRNAs are a class of small noncoding RNA molecules that regulate and serve as tumor suppressor genes and oncogenes by binding to the 3′-untranslated region of the mRNA. An important feature of miRNAs is their stability in tissues and body fluids due to their small size compared to proteins and other mRNA, thus allowing reliable measurement and excellent candidate biomarkers of early progression to pancreatic malignancy.²⁷

A study by Farrell et al²⁸ published in 2013 merits specific mention. Using previously known miRNA expression from surgically resected specimens,^27,29 the investigators profiled the expression of six different types of miRNAs in 38 patients who underwent EUS-FNA of PCNs and eventually surgical resection. Their findings showed that a type of miRNA called miR-21 was not only expressed at significantly higher levels in malignant cysts (P < 0.01) but was miR-21 was significantly higher in premalignant cysts than benign cysts (P = 0.03).

Another miRNA called miR-221 was expressed at significantly higher levels in malignant cysts compared with benign or premalignant cysts (P = 0.05).²⁸

This study is relevant, since it helps classify PCNs along the spectrum of malignant potential and possibly identify the natural history of progression and optimal time for resection.

A study by Frampton et al³⁰ from the United Kingdom involving 55 patients with suspicious PCNs showed that the combination of microRNA miR-21 and miR-155 had excellent accuracy for distinguishing benign lesions from malignant pancreatic lesions, with an area under the curve of 0.930; and a sensitivity of 81.5% and specificity of 85.7%.

Table 1^{24–26,28,30} gives a summary of relevant studies to date, which have utilized new molecular markers to diagnose PCNs and determine degree of dysplasia or malignancy.

With advancements in probe based imaging techniques, the optical diagnosis of PCNs and identification of dysplasia and malignancy which has been the holy grail of advanced imaging technology has been now made possible. A novel needle based confocal laser endomicroscopy (nCLE) probe (AQ Flex-19) has 10,000 optical fibers, a diameter of 0.85 mm, a field of view of 320 μm, and a lateral resolution of 3.5 μm³¹ can be passed through a 19 gauge needle passed through the biopsy channel of the EUS scope to make contact with pancreatic cysts or cyst contents after cyst wall puncture.

The INSPECT trail (In vivo Needle based CLE Study in the Pancreas with Endosonography of Cystic Tumors) was an 8 center trial in which 66 patients underwent nCLE of pancreatic cysts. This study established descriptive terminologies for nCLE imaging findings from pancreatic parenchyma, cyst structures and cyst lumen and their histopathologic correlates.

Imaging findings such as ‘finger like papillary projections’, ‘dark lobular structures’ and ‘dark aggregates of cells’ were established to correspond to villous structures, acinar cells and neoplastic tissue respectively. Villous structures on nCLE was highly associated with PCNs and had a sensitivity of 59%, specificity of 100%, positive predictive value of 100% for the diagnosis of PCNs.³²

The DETECT Study (Diagnosis of Pancreatic Cysts: Endoscopic Ultrasound-guided, Through-the-Needle Confocal Laser-Induced Endomicroscopy and Cystoscopy Trial) involved 30 patients with PCNs who underwent pancreatic cystoscopy using a 0.7-mm diameter through the needle probe (SpyGlass fiberoptic probe; Boston Scientific, Natick, MA, USA) as well as with a nCLE probe (AQ-Flex 19; Mauna Kea Technologies, Paris, France) and showed that the finding of mucin on Spyglass pancreatic cystoscopy has a sensitivity of 71% and specificity of 100% for diagnosis of mucinous cysts. Papillary projections had a sensitivity of 77% and specificity of 100% for diagnosis mucinous cysts. When the two findings, namely mucin on cystoscopy and papillary projections on nCLE were combined, the sensitivity reached 88%, specificity of 100% and accuracy of 100% in 30 for correctly identifying mucinous cysts.³³

A study from France by Napoléon et al³⁴ involved 31 patients who underwent nCLE and identified a superficial vascular network pattern seen on nCLE which corresponded to histologic finding of dense and subepithelial capillary vascularization only seen in serous cystic adenoma (SCA). The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of this sign for the diagnosis of SCA were 87%, 69%, 100%, 100%, and 82%, respectively.

Endoscopic ultrasound-guided chemical ablation therapy for pancreatic cysts

The International consensus guidelines from 2012 recommend surgical resection for all lesions with high-risk features or those with worrisome features and mural nodules of suspicious or positive cytology.²

However, in a select group of patients, a non-surgical, minimally invasive option is required because of the relatively high morbidity associated with pancreatic surgery.³⁵ Chemical ablation of the cyst generally involves aspiration of cyst fluid following by instillation of an equal volume of desired concentration of ethanol, usually 80%–100% ethanol followed by cyst lavage and eventual aspiration of ethanol. Some other studies have included injection of the cyst with paclitaxel or gemcitabine after ethanol lavage. The EUS Working Group Proceedings in 2008 identified the need for larger, well-designed, randomized, controlled studies with long-term follow-up to assess to benefits and risks of EUS-guided cyst ablation and investigation of other chemical agents for ablation other than ethanol.³⁶

One of the earliest studies on EUS-guided ethanol ablation of pancreatic cysts was done more than a decade ago by Gan et al³⁷ and they showed that in 25 patients who underwent ethanol ablation, the rate of complete resolution of the PCNs was 35%. The results from several studies involving chemical ablation of cysts have been variable (Table 2).^37–46

Gómez et al³⁸ conducted a single center prospective study involving 23 patients, with a relatively long median follow-up period of 40 months (9–82 months) utilizing 80% alcohol for ablation of pancreatic cysts > 1 cm in diameter. Only 2 patients (9%), both of whom had unilocular cysts had complete resolution of PCNs. Also, there were no differences with respect to initial cyst volume, CEA level and final cyst ethanol concentrations when cysts showing > 80% size reduction were compared to those showing < 80% size reduction. This study clearly demonstrates that ethanol alone may not be enough for achieving pancreatic cyst ablation with a high rate of success.

Oh et al³⁹ conducted a study involving intracystic ethanol and paclitaxel injection showing 79% response rate. A likely reason for such a variable range of cyst resolution after chemical ablation is the heterogeneity among these studies with respect to the type of PCN, number of ablation sessions, choice of ablative agents and variable duration of follow-up.

Whether cyst ablation induced changes in the DNA of cyst fluid was studied by DeWitt et al⁴⁷ in which 22 patients underwent pre-ablation DNA analysis for K ras mutation and LOH and half of them, or 11 patients had DNA mutations. Of these, patients of 72% (or 8 patients) had elimination of all baseline mutations at a median 27 month follow-up. In the future, a determination of whether post ablative changes in a PCN are indicative of treatment effect or residual malignancy may be addressed by cyst DNA analysis; however this approach has limited use at present.

While most studies have used alcohol ablation for cysts, a recent study by Moyer et al⁴⁶ randomized patients to alcohol versus saline lavage and both groups were subsequently treated with intracystic paclitaxel and gemcitabine and the investigators found that there was no statistically significant difference in between the two groups in terms of rates of complete resolution. Irrespective of the method used, the endoscopist should be aware of potential adverse events with chemical ablation of cyst, which include pancreatitis and abdominal pain not related to pancreatitis^37,40,43,48 and portal vein thrombosis.⁴⁹

Endoscopic ultrasound-guided radiofrequency ablation of pancreatic cystic neoplasms

Experience with radiofrequency ablation of pancreatic cysts has been limited compared to the numerous prospective trials evaluation chemical ablation of PCNs. The Habib^TM EUS-FNA is a 1 Fr (0.33 mm) RFA probe that can be passed through the biopsy channel of an EUS scope to ablate pancreatic lesions.

A South Korean pilot study involving 6 patients with histologically confirmed pancreatic cancer showed that EUS-RFA using a 18 gauge catheter was technically feasible, without significant adverse events other than abdominal pain that was controlled with analgesics.⁵⁰ Lakhtakia et al⁵¹ demonstrated successful EUS-RFA of three patients with insulinomas smaller than 22 mm who remained symptom free at a 12 months follow-up with biochemical improvements in fasting insulin and blood sugars.

Another multicenter study by Pai et al⁵² involving 8 patients (six with PCNs and two with neuroendocrine tumors) who underwent RFA showed complete resolution of cysts in 25% (or 2 patients) and 48.4% reduction in volume in three other patients.

The data for outcomes with regards to success, safety and long-term efficacy for ablation of PCNS with RFA is still limited. Ablation of functional neuroendocrine tumors for palliation of symptoms due to biochemical perturbations is an attractive option and an achievable short term goal; however, more multi-center studies are needed before this can be pursued as a first line therapy for neuroendocrine PCNs.

In spite of several recent advances in pancreatic cyst tissue acquisition, novel imaging techniques and molecular markers, none of these modalities have been formally incorporated into guidelines by the major gastroenterology societies. Accurate diagnosis is essential to ensure that malignancy is not missed and to also ensure that unnecessary resections are not done.

The most widely known and practiced guidelines are the International Consensus Guidelines by International Association of Pancreatology published in 2012, which defined high risk and worrisome criteria for IPMNs and MCNs.² A retrospective study from Singapore which involved 114 cases mucinous cystic pancreatic neoplasms showed that the presence of symptoms, obstructive jaundice, elevated serum carcinoembryonic antigen (CEA)/carbohydrate antigen (CA) 19-9, solid component, main pancreatic duct ≥ 10 mm, and main pancreatic duct of 5 mm was associated with high grade dysplasia or invasive carcinoma in all pancreatic mucinous neoplasms, thus validating the International consensus guidelines.⁵³ Another Japanese study which included 177 patients who underwent curative resection for IPMNs showed that obstructive jaundice (OR, 23.9; P < 0.0001), abrupt change in MPD diameter (OR, 3.01; P = 0.017) and lymphadenopathy (OR, 5.84; P = 0.027) were independent predictive factors of malignancy, with an accuracy of 69.8%, 67.4%, and 66.3%, respectively.⁵⁴

The American Gastroenterological Association (AGA) recently published guidelines for management of asymptomatic neoplastic pancreatic cysts. One of the major differences from the International Association of Pancreatology guidelines was the requirement of presence of two high risk features (such as cyst > 3 cm, dilated main pancreatic duct or solid component within the cyst) to merit an EUS-FNA.⁵⁵ The recent AGA guidelines have come under criticism by several authors, due to the relatively high rate of missed malignancy or dysplasia in these new guidelines and lack of specific recommendations for branch duct IPMNs.⁵⁶

Kohli et al⁵⁷ showed that the requirement of two high risk criteria per the new AGA guidelines would reduce the sensitivity of the examination to only 50% and also reduce the number of EUS procedures by 91%, whereas the requirement of only one high risk criteria would have a sensitivity of 100%.

Singhi et al⁵⁸ conducted a retrospective study to assess the performance characteristics of the AGA guidelines and found that 45% of IPMNs with adenocarcinoma or high-grade dysplasia would have been missed. They also proposed a new a novel algorithmic pathway using molecular testing of pancreatic cyst fluid detecting advanced neoplasia with 100% sensitivity, 90% specificity, 79% positive predictive value, and 100% negative predictive value.

A recent study by Lekkerkerker involving a retrospective review of 115 patients compared the AGA guidelines, international consensus guidelines and the European Study Group on Cystic Tumors of the Pancreas Guidelines and found that 12% of patients with high grade dysplasia or malignancy would have been missed with the AGA guidelines compared to the other two.⁵⁹

There has been a flurry of development of novel biomarkers, techniques of tissue acquisition such as the microforceps and advanced imaging technology such as needle based CLE over the last five years. Future studies should focus on multicenter collaboration with prospective enrollment of patients for head to head trials comparing biomarker panels and novel imaging tools. This will lead to accrual of data, which will hopefully lead to the incorporation of some of the new advances into more evidence based formal guidelines resulting in improved care of patients with PCNs. Long term studies assessing the outcomes of various cyst ablation techniques and their effects on patient survival are required.

To summarize, EUS has emerged as an extremely valuable tool for the imaging, diagnosis, and therapy of PCNs. Numerous advances have been made, thanks to the work of many pioneering endosonographers and researchers from around the world.⁶⁰ In today’s era of personalized medicine, an individualized approach to PCNs, based on imaging characteristics, biochemical and molecular profile will go a long way in providing optimal management of PCNs with reducing unnecessary investigations at the same time.