Endoscopic ultrasound in the evaluation of pancreaticobiliary disorders

2.1. Choledocholithiasis 

EUS is an extremely accurate test for diagnosis of common bile duct stones (CBDS) (Fig. 1) and can be used to select patients who should undergo a therapeutic ERCP, thus avoiding the risk of complications associated with diagnostic ERCP [5]. A combination of clinical, biochemical, and morphological criteria, is used to risk stratify individuals with suspected choledocholithiasis and an intact gallbladder into three groups (Table 1). Patients with intermediate risk of choledocholithiasis benefit the most from a diagnostic test based on which a decision is made to perform a therapeutic ERCP [6]. Three recent papers have addressed this topic and found that a EUS-based approach can reduce the number of diagnostic ERCP by 60–75% in this patients’ population [7], [8], [9]. In addition, this approach is more successful in the overall evaluation of CBDS, with fewer complications than using an ERCP based approach [7], [8], [9]. Importantly, the performance of EUS for CBDS is not related to the size of the stone or to the diameter of the CBD, and it is independent on the type of echoendoscope used, with a learning curve that for this particular indication is relatively short [10]. The use of EUS instead of ERCP has been found to be cost-effective in both intermediate and high-risk patients in the context of laparoscopic cholecystectomy and in severe acute pancreatitis [11], [12].

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Fig. 1. EUS image of the mid portion of the common bile duct (CBD) just above the portal vein (PV) containing a 5.4mm stone with shadowing.

Table 1. Risk of common bile duct stones (CBDS) in patients with suspected choledocholitiasis according to clinical, biochemical, and morphological criteria.

	Risk category	Chance of CBDS	Clinical parameters	Biochemical parameters	CDB diameter
	Low	2–3%	None	Normal	≤7mm
	Intermediate	20–50%	Acute ascending cholangitis	↑ALP ≤2X ULN	8–10mm
			Pancreatitis	↑GGT
				↑ALT or ↑AST
	High	50–80%	Acute ascending cholangitis	↑ALP ≥2X ULN	≥10mm
			Jaundice

Abbreviations: ALP, alkaline phosphatase; GGT, gamma-glutamyltransferase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal.

A different and very important question is whether EUS or magnetic resonance cholangiopancreatography (MRCP) should be used as the first non-invasive test for suspected CBDS. MRCP has, in fact, replaced diagnostic ERCP for many indications, one being CBDS diagnosis. A recent systematic review of the literature, aimed at finding a consensus on the optimal strategy to investigate patients for CBDS after a negative transabdominal US and/or computed tomography (CT), found EUS and MRCP to have an overall high diagnostic performance, with no significant differences between the two tests [13]. The authors concluded that the use of one or the other test should be guided by local availability and expertise. It is argued that because of the complete non-invasive nature of MRCP, it should be considered the first-line investigation for CBDS [14]. However, in daily practice it can be difficult and time consuming to obtain an MRCP, while a EUS when available has the substantial advantage of being performed in an endoscopy suite where it can be followed by an ERCP if CBDS are found.

2.2. Pancreatitis 

In patients with pancreatitis, EUS should be proposed to determine the aetiology in idiopathic acute cases, especially if recurrent, to help establish the diagnosis in suspected chronic cases, and to search for choledocholithiasis when a biliary aetiology is suspected [7], [15]. In idiopathic acute recurrent pancreatitis (ARP) when no cause is identified after an initial thorough clinical, laboratory, and radiological evaluation, EUS can provide a valid alternative to and has gradually replaced the more invasive approach of bile crystal analysis and ERCP with or without sphincter of Oddi manometry [16]. Most frequent causes of ARP are occult CBD and/or gallbladder microlithiasis, while other aetiologies include unrecognised chronic pancreatitis, pancreas divisum, sphincter of Oddi dysfunction, and other less frequent etiological factors such as small pancreatic tumours or cysts. Studies that have evaluated the role of EUS in this clinical setting have reported a diagnostic yield that ranged from 32% to 88% [17]. In the largest study published to date in which the number of patients with ARP and those with an unexplained first episode of acute pancreatitis is clearly stated, the overall yield of EUS was 68% [18]. In the subgroup of patients with an in situ gallbladder, sludge (12%), stones (5%) or pancreas divisum (6%) were most commonly detected, whereas chronic pancreatitis (39%) and pancreas divisum (10%) were the most frequent diagnoses in patients who had previously undergone cholecystectomy [18]. In addition, a small subset of patients had duodenal bile sampling for microscopic analysis for crystals, which were found in about half of them. These results indicated that EUS with bile crystal analysis is of great value and substantially reduces the number of unnecessary diagnostic ERCP, as previously suggested by Tandon and Topazian [19]. In a more recent study by Mariani et al. [20], secretin administration to stimulate pancreatic secretion in order to obtain better visualisation of the bilio-pancreatic ductal system during both MRCP and EUS resulted in a better performance than ERCP evaluation. Based on these results, the authors recommended the use of secretin stimulation with both MRCP and EUS as complementary first-line examinations in the evaluation of patients with ARP [20]. The cost-effectiveness of this approach, however, remains to be established.

The diagnosis of chronic pancreatitis (CP) can be very challenging. In particular, the real dilemma in CP is to recognize and diagnose the disease in its early stages, for which there are insufficient sensitive and specific tests available. If EUS is demonstrated to be sensitive and specific for early CP, it would really make this procedure a major breakthrough in the evaluation of this condition [21]. Of the EUS parenchymal and ductal criteria used to diagnose CP (Table 2), three of the parenchymal ones (hyperechoic foci, hyperechoic strands and parenchymal lobularity) can be visualised by EUS only, making it the most theoretical valuable test to diagnose early CP. Two major problems, however, may limit EUS in this important task: (i) some of the EUS abnormalities associated with the mild forms of CP are encountered in the elderly or in heavy alcohol drinkers [22], [23]. Therefore, it is not clear whether these abnormalities, especially when isolated, indicate physiological aging of the pancreas or mild signs of asymptomatic CP and their recognition may lead to an over-estimation in the diagnosis of CP; (ii) these subtle changes of the pancreas are uncommon and may be easily missed by inexperienced endosonographers, creating a problem of under-diagnosis. Scepticism about a possible role of EUS in early CP diagnosis comes from the observation of a high rate of EUS findings suggestive of CP in both healthy subjects and patients with abdominal pain of possible pancreaticobiliary origin [24], [25]. On the other hand, two studies have reported that about 65% of patients with early CP detected on EUS but not on other tests such as CT and secretin function tests or ERCP will eventually develop CP, which can then be detected on repeated tests that were previously negative [26], [27]. These latter results need further confirmation in prospectively followed cohorts of patients. These cohorts should contain a significant number of individuals and include both positive and negative EUS cases for early CP to assess the overall accuracy of EUS in this setting. This difficult diagnostic task might benefit from the recently published Rosemont classification for CP [28], a consensus-based system that allocated EUS features of CP into major or minor criteria with a very good inter-observer variability. Of note, the use of the EUS-guided Tru-Cut needle for the obtainment of tissue samples from patients with early CP has been attempted, but it is not recommended because of the potential complications and limited diagnostic yield [29].

Table 2. EUS criteria of chronic pancreatitis.

	Parenchymal criteria	Ductal criteria
	Hyperechoic foci	MPD dilatation
	Hyperechoic strands	Irregular MPD contour
	Lobularity	Hyperechoic MPD margins
	Shadowing calcifications	Visible branch ducts
	Cysts	Intraductal stones

3.1. Pancreatic cancer 

EUS has a manifold role in the evaluation of patients with clinical suspicion of a pancreatic mass, and in those in whom a solid pancreatic lesion has already been identified. Despite recent advances in both CT and MR technologies and software, EUS is still the most accurate diagnostic test for the detection of pancreatic lesions, particularly for those smaller than 2cm [30]. Because of this characteristic, when other non-invasive cross-sectional imaging modalities have reported equivocal results, EUS should always be considered and performed when available [31], [32]. The major advantage of EUS is its high negative predictive value, close to 100%, indicating that the absence of a focal mass at EUS reliably excludes pancreatic cancer [33], [34]. However, it should be kept in mind that missed pancreatic neoplasms even in very expert hands have been reported [35]. These missed lesions occurred mainly in patients with underlying chronic pancreatitis, diffuse infiltrating carcinoma, prominent ventral/dorsal anlage, or a recent episode of acute pancreatitis; this highlights the importance of performing a follow-up EUS in cases with a strong clinical suspicion, a strategy that has been shown to have clinical value [36].

EUS can be used to assess the presence of pancreatic cancer in patients with non-specific changes on CT, such as an enlarged or a prominent pancreatic head. Three studies evaluating this clinical setting have found pancreatic cancer in 8%, 8.7%, and 22% of the patients, respectively [37], [38], [39]. In the latter study [39], the mean size of the pancreatic malignant lesions was 3.5cm, a very surprising result that may be the consequence of poor quality CT technique and interpretation in the community hospitals, where most of these exams were performed.

Another clinical scenario is a patient with a pancreatic mass detected on cross-sectional imaging studies. If the mass is clearly unresectable based on CT or MRI results, either percutaneous image-guided or EUS-FNA can be performed for tissue sampling to obtain a definitive diagnosis and offer proper treatment [40]. The choice between one or the other sampling method is highly dependent on the local expertise and the availability of EUS or interventional radiology. The percutaneous route may be indicated in patients who are at risk for sedation-related complications and in those with surgically altered upper GI anatomy. On the other hand EUS is advantageous because it provides additional staging information, i.e. the presence of lymph node metastases in the celiac, lumboaortic, retroduodenopancreatic and superior mesenteric regions and sample small pocket of previously undetected ascites. EUS offers the possibility of performing EUS-guided celiac plexus neurolysis (EUS-CPN) in patients with significant pain not controlled by narcotics during the same EUS-FNA session. When other biopsy techniques have failed, or in cases of a previous EUS-FNA not performed in a tertiary centre, the use or the repetition of EUS-FNA is strongly supported [41], [42]. Overall, EUS-FNA of pancreatic masses is safe [43], has a mean accuracy of about 85% [44], and carries a lower risk of tumour seeding than percutaneous techniques [45]. Higher accuracy rates are achieved with on-site cytopathological examination to assess specimen adequacy [46] which, however, is not available in all centres and may increase the cost of the procedure.

If after performing a CT or MRI scan the resectability of a pancreatic mass is equivocal, EUS±FNA is the next logical step to distinguish with high accuracy patients who benefit from a major surgical intervention from those with locally advanced or metastatic disease who should not undergo surgery. In terms of performance of CT and EUS for pancreatic cancer staging, a recent review has concluded that due to the heterogeneity in study design, quality and results of all the published studies it is impossible to draw definitive conclusions on the relative value of each test [47]. The best approach is to use both tests in a complementary fashion because the highest accuracy in predicting resectability is obtained by the combination of the two imaging tests [48]. If EUS demonstrates the mass to be clearly unresectable (Fig. 2A), one can proceed with FNA for tissue acquisition (Fig. 2B). In potentially resectable lesions, on the other hand, the argument for a definitive diagnosis before undergoing surgery is debated [49]. Arguments made for EUS-FNA in potentially respectable lesions include an established protocol of preoperative neoadjuvant therapy, a demand by the patient for a conclusive diagnosis of cancer before consenting to surgery, and lastly to exclude unusual histology (lymphoma, acinar cell carcinoma, solid pseudopapillary tumour and pancreatic metastases), that can be found in up to 5% of individuals with pancreatic masses and would not benefit from operation [50]. A proposed algorithm for the evaluation of solid pancreatic masses is shown in Fig. 3.

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Fig. 2. Unresectable pancreatic mass. (A) Pancreatic uncinate process mass with invasion of the superior mesenteric artery (SMA). (B) EUS-FNA of the mass.

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Fig. 3. Algorithm for the evaluation of suspicious solid pancreatic masses.

A very important clinical challenge is the differentiation of pancreatic cancer from inflammatory masses due to focal chronic pancreatitis. In this respect, EUS imaging has not proven to be reliable. New techniques such as contrast-enhanced EUS and elastography have emerged in an attempt to overcome some of the limitations of EUS [51]. Contrast-enhanced EUS to better assess the perfusion inside the pancreatic mass has been evaluated in one study using Levovist [52] and more recently using the second generation contrast agent SonoVue (Fig. 4) [53]. Both studies reported pancreatic cancer to be relatively hypoenhancing and inflammatory masses hyperenhancing compared with the surrounding pancreatic tissue, while the latter study clearly showed benefit from the use of contrast agent with an increase in the sensitivity and specificity 73.2% and 83.3% to 91.1% and 93.3% after its administration [53]. Improved results may be obtained using the contrast harmonic imaging technique as preliminary reported by Kitano et al. [54], Another new imaging technique is elastography. This technique is able to characterize the stiffness of the tissue under examination by calculating and visualizing real-time tissue elasticity. This information can be used to distinguish neoplastic pancreatic “hard” tissue from inflammatory pancreatic “soft” tissue (Fig. 5). After a preliminary experience from Giovannini et al. [55], that proved this method to be feasible, more recent studies have reported conflicting results [56], [57], [58]. Finally, DNA analysis of FNA aspirates [59] and digital imaging analysis of EUS images [60] seem promising but need further confirmation in larger patient populations.

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Fig. 4. EUS image of a pancreatic neuroendocrine tumour after contrast enhancement with Sonovue that enhance tumour vascularisation.

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Fig. 5. EUS elastographic image of a pancreatic adenocarcinoma showing mainly hard tissue (in blue) with a soft area (in green) between the lesion and the vessel below.

In parallel to the growing importance and widespread use of EUS-FNA for the evaluation of pancreatic masses, efforts have been made to develop a role for this procedure in the treatment of pancreatic cancer. The first approach involved the injection of anti-neoplastic agents under EUS guidance directly into the pancreatic tumour. Chang et al. [61] demonstrated the feasibility and safety of the injection of an allogeneic mixed lymphocyte culture (cytoimplant) in eight patients with unresectable pancreatic adenocarcinoma. Subsequently, Hecht et al. delivered an anti-tumour viral therapy, the ONYX-015 (dl1520) repeatedly into the tumour of 21 patients with advanced adenocarcinoma [62]. The ONYX-015 (dl1520) is an E1B-55kDa gene-deleted replication-selective adenovirus that preferentially replicates in and kills malignant cells, This therapy in association with intravenous administration of gemcitabine during the last 4 sessions resulted in partial disease regression in 2 patients, stabilisation in 6, minimal changes in 2 and progression in 11. Major complications were sepsis in 2 patients and duodenal perforation in 2 other patients. These complications were subsequently avoided by administration of antibiotic prophylaxis and performance of transgastric injection, respectively [62]. At the time of this review, we await the publication of the long-term results presented at DDW in 2006 of a multicentre American trial involving EUS or CT guided injection of TNFerade, a replication-deficient adenovector containing human TNFα gene, regulated by a radiation-inducible promoter Egr-1 [63]. TNFerade was injected weekly for 5 weeks in combination with continuous intravenous 5-FU (200mg/m2/d×5d/wk) and radiation (50.4Gy) in 50 patients with unresectable tumour. The preliminary results were encouraging and reported that four of the five patients whose tumours became surgically resectable had pathologically negative margins and three survived longer than 24 months [63].

More recently other EUS-guided treatment strategies have been attempted. Two series by Sun et al. [64] and Jin et al. [65] have reported EUS-guided direct instillation of radioactive seeds (brachytherapy) in 15 and 22 patients, with a modest benefit regarding reduction of pain only. On the other hand, EUS has been also used to place fiduciary markers in pancreatic tumours for image-guided radiotherapy, with a very high rate of successful placement even in patients with head or uncinate lesions [66]. Other form of therapies such as EUS-guided pancreatic photodynamic therapy and radiofrequency ablation have been evaluated in animal models [67], [68], [69], [70], but are still awaiting clinical trials.

3.2. Bile duct cancer 

Malignant bile duct tumours, i.e. cholangiocarcinomas, present as biliary strictures that need to be differentiated from strictures of benign origin, which in the proximal biliary tree corresponding to the hepatic hilum can be responsible for up to 20% of all cases [71]. In the presence of jaundice, ERCP with brush cytology and/or endobiliary forceps biopsy is usually first performed to reach a definitive diagnosis, while EUS-FNA has been used in some centres as the second diagnostic modality in case of ERCP failure [72], [73]. Studies that have investigated the role of EUS-FNA in this clinical setting have found a sensitivity ranging from 43% to 86% for all biliary strictures and from 25% to 83% for those limited to the hilum [72], [74], [75], [76], [77], [78], [79]. This wide range of sensitivity of EUS-FNA for the evaluation of hilar strictures may reflect the high skills required to sample the hilum, which can underestimate EUS-FNA performance if the sample size is small as in most of the published studies.

In a diagnostic algorithm proposed by Pavey and Gress [73], on the other hand, EUS should be considered the test of choice in patients with biliary strictures and a normal bilirubin. In these patients EUS may reveal the presence of a pancreatic mass or changes consistent with chronic pancreatitis and allows the performance of FNA for a definitive diagnosis during the same procedure. Interestingly, preliminary results from an ongoing experience have used EUS-FNA, performed with a newly developed forward viewing scope that seems to have some advantages over the conventional linear EUS scope for the visualisation of the hilar region, as a first diagnostic modality even in jaundice patients (Fig. 6) [80].

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Fig. 6. Common bile duct (CBD) mass at the hilum detected using a newly developed forward viewing therapeutic EUS scope (GF-UCT160J-AL5, Olympus Medical System Europe, Hamburg, Germany).

Another important aspect of EUS-FNA in the evaluation hilar cholangiocarcinoma is the possibility of investigating the presence of regional lymph nodes that can be sampled providing important additional staging information. This information has a tremendous clinical impact in the selection of patients with unresectable hilar tumours who are suitable for a multidisciplinary therapeutic approach recently developed at the Mayo Clinic including chemo- and radiation-therapy in association with liver transplantation [81]. Lymph nodes can be identified in all of these patients, as reported by a landmark study from the Mayo Clinic's group, with EUS-FNA performed to distinguish benign from malignant lymph nodes with a very high accuracy, thus avoiding unnecessary transplantation in about 20% of patients [82].

3.3. Ampullary cancer 

The number of studies that have evaluated the usefulness of EUS with or without FNA in the diagnosis and staging of ampullary tumours is much lower than for pancreatic cancer. In patients with ampullary neoplasms, EUS and intraductal US (IDUS) can be helpful in assessing depth of tumour invasion and the presence of periampullary lymph nodes [83]. This information can help to decide between endoscopic versus surgical therapy and to guide the type of surgical intervention. Despite some controversy [84], EUS staging is mandatory to establish T1 stage and thus to select candidates for endoscopic resection, and when available should always be considered before endoscopic or surgical resection is performed for ampullary tumours [83].

5.1. Celiac block/neurolysis 

EUS-guided celiac plexus block (EUS-CPB) for pain control in chronic pancreatitis and EUS-CPN for cancer related pain control are the most well established interventional procedures performed under EUS guidance [107]. The plexus is composed of two ganglia, usually located anterior and lateral to the aorta at the level of the celiac trunk. Using a curvilinear array echoendoscope, this region can be easily visualised from the lesser curvature of the stomach by following the aorta to the origin of the main celiac artery. With careful inspection it also possible to directly visualize the celiac ganglia as 1–5 elongated hypoechoic structures [108], [109].

The technique for EUS-CPB and EUS-CPN is identical. A mixture of triamcinolone and bivucaine is used for CPB, while an injection of bivucaine followed by a second injection of absolute alcohol is used for CPN. The procedure is usually performed using a 19-gauge needle or a dedicated 20-gauge needle with multiple side holes and injection done at the base (central) or on either side (bilateral) of the celiac axis. In addition, direct injection into the ganglia has been retrospectively evaluated in a recent study [110]. However, this technique requires a prospective confirmatory study before it can become part of routine clinical practice.

Despite the first report was published more than 10 years ago [111], no available studies have compared EUS with radiological or surgical techniques for CPN. Similarly, only two comparative studies for CPB have been performed and found EUS to be slightly better than CT or fluoroscopic guided techniques in relieving pain in chronic pancreatitis [112], [113]. The paucity in the published data that are mainly based on observational, uncontrolled studies, resulted in a recent meta-analysis in an attempt to draw a more definitive conclusion on the usefulness of EUS-guided pain control treatments [114]. Overall, this meta-analysis found EUS-CPN and EUS-CPB to be able to relieve pain in about 80% and 60% of patients with pancreatic cancer or chronic pancreatitis, respectively. Thus the authors recommended EUS-CPN as a valid treatment for pancreatic pain, but always in adjunct with opioid analgesics and adjuvant therapy [114]. On the other hand, the evidence to support the use of steroid injection in chronic pancreatitis is lacking and future studies involving different techniques or other injected compounds are warranted [114].

5.2. Pancreatic pseudocyst drainage 

Another well established interventional EUS-guided procedure is the endoscopic drainage of pancreatic pseudocyst (PP) (Fig. 9). The theoretical advantages of using EUS instead of the traditional “blind” endoscopic approach with a therapeutic gastroscope to create a fistulous tract between the PP and the gastric (cyst-gastrostomy) or the duodenal lumen (cyst-duodenostomy) are multiple: (i) the capability of identifying a cyst with a different diagnosis; (ii) the ability to perform the procedure in cases without obvious bulging; (iii) the ability to identify intervening vessels with the aid of the Doppler with a decreased risk of bleeding, (iv) a better evaluation of the PP's content that may influence the number of stents or the type of drainage placed (stent vs. naso-cystic drainage) [115]. Despite these theoretical advantages, there is still no consensus on which technique should be utilised and in most cases the use of one or the other approach for endoscopic transmural PP drainage is guided by local expertise [116], [117]. In particular, many institutions presently still lack adequate EUS equipment and expertise to perform the procedure, as can be inferred by the results of a survey conducted among both U.S. and non-U.S. members of the American Society for Gastrointestinal Endoscopy [118].

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Fig. 9. Fluoroscopic image of a EUS-guided transgastric placed double-pig tail plastic stent for pseudocyst drainage.

Studies have tried to answer the question whether the use of EUS is really advantageous over the “blind” endoscopic technique. A paper from Kahaleh et al. [119], prospectively compared 99 patients who underwent PP drainage according to a predetermined treatment algorithm: patients with bulging and no portal hypertension were treated with conventional transmural endoscopic drainage (CTED), all the other with EUS-guided drainage. No difference in safety and efficacy was found [119]. A more recent study with a prospective randomised comparative design by Varadarajulu et al. [120] has reported EUS to be significantly superior to CTED mainly because of the capability of draining non-bulging lesions. The lack of bulging was, in fact, the reason to switch from CTED to EUS in 9 out of the 10 patients in whom the CTED approach failed. In all of them the second attempt under EUS guidance was successful. Because of these results and their previous experience [121], the authors concluded that EUS should be considered the first-line modality for PP drainage. Despite this, these results may reflect a possible bias due the authors high expertise in EUS procedures, a therapeutic algorithm presented and tested by Barthet et al. also strongly advocated the use of EUS in the absence of bulging and in the presence of portal hypertension [122].

5.3. EUS-guided access and treatment of biliary and pancreatic ducts 

Since the first cases of EUS-assisted cholangiopancreatography described more than a decade ago [123], [124], EUS-guided drainage of the biliary and pancreatic ductal systems has been increasingly used as an alternative procedure to percutaneous transhepatic cholangiography (PTC) or surgery in patients who had failed prior ERCP or in whom ERCP could not be performed because of altered anatomy of the upper GI tract [125], [126], [127], [128], [129], [130], [131], [132], [133]. Both techniques involve puncture of the target duct with a EUS needle, preferably a 19-gauge needle, which is followed by passage of a guide wire. For the biliary system, access can be done from the stomach into the left intrahepatic ducts or from the duodenum directly into the CBD. The main pancreatic duct is usually accessed transgastrically. Once in place the guide wire when possible is advanced in the direction of and through the papilla into the duodenum to allow for the performance of a rendezvous ERCP or for direct EUS transpapillary stent placement in malignant conditions. Occasionally, when the guide wire cannot be pushed into the duodenum, direct transgastric or transduodenal stent placement can be performed. Biliary drainage is reported to be highly successful with a low complication rate, while MPD drainage appears a little more difficult as proven by a higher failure and complication rates [134].

Finally, transgastric drainage of biloma and the gallbladder in high-risk patients with acute cholecystitis as a definitive treatment or as a bridge to surgery have also been described [135], [136], [137].