EUS of the Gallbladder

Abstract

Endoscopic ultrasound (EUS) is an increasingly used imaging modality in the diagnosis and management of biliary disease. The advantage of EUS is that it allows for a precise examination of the pancreaticobiliary system due to the proximity of the endoscopic probe within the gastrointestinal tract. As EUS becomes more prevalent within gastroenterology practice, clinicians should become familiar with the endosonographic findings of the gallbladder. This chapter will review normal endosonographic gallbladder anatomy in addition to benign and malignant gallbladder pathology. The identifying endosonographic characteristics of gallbladder lesions will be discussed. We will also provide a brief review of EUS-guided tissue acquisition of the gallbladder.

1. Introduction

Endoscopic ultrasound (EUS) has become an important tool in the diagnosis and management of gallbladder disease. EUS utilizes high ultrasound frequencies of 5 mHz to 20 mHz and produces images with high spatial resolution, allowing for a more precise evaluation than with transabdominal ultrasound (TAUS) [1, 2]. Gallbladder structures can be closely examined for fine details such as depth of tumor invasion or subtle morphologic features of small gallbladder lesions which are normally obscured to examiners using TAUS. It also offers a unique advantage over TAUS by allowing the operator to perform fine needle aspiration (FNA) or fine needle biopsy (FNB) for tissue sampling at a closer location to the gallbladder. EUS is often preceded by cross-sectional imaging such as computed tomography (CT) or magnetic resonance cholangiopancreatography (MRCP) due to the unpredictable orientation of the gallbladder that is difficult to predict with EUS alone [3].

EUS of the gallbladder itself is often overlooked during the EUS examination. Endosonographers should be competent in recognizing normal and pathologic findings of the gallbladder and biliary tree. This chapter will provide an overview of the normal anatomy of the biliary tree as well as typical endosonographic characteristics of both benign and malignant gallbladder pathology. With the increasing use of EUS in clinical practice, it is important for physicians to be proficient in the interpretation of EUS findings and to be able to integrate these findings into the overall management of patients with gallbladder disease.

2. Normal gallbladder anatomy

The gallbladder is a pear-shaped organ in the right upper quadrant of the abdomen. It is located within a fossa separating the right and quadrate lobes on the liver [4]. The fundus of the gallbladder is the widest and most distal aspect, which tapers into the body, followed by the neck (or infundibulum) at its most proximal aspect. The neck lies in the porta hepatis and is connected to the cystic duct, forming a hook-like shape, which then drains into the common bile duct in a downward fashion. Within the cystic ducts are valvular structures known as the valves of Heister, which contribute to the controlled release of bile from the gallbladder. The fundus of the gallbladder abuts the anterior abdominal wall due to its projection beyond the inferior border of the liver. In some people, there is a benign outpouching of the fundus known as a Phrygian cap. A pouch-like structure located near the infundibulum may also be present and is known as Hartmann’s pouch [5].

EUS of the gallbladder can be performed from 3 major areas: the gastroesophageal junction/fundus of the stomach, antrum/duodenal bulb, and descending duodenum. The endosonographer should become familiar with varying positions required to obtain adequate views of the gallbladder and its surrounding structures in each of these areas. EUS probe positioning and maneuvers to obtain adequate views of the surrounding gallbladder structures, and their unique orientations at each viewpoint are beyond the scope of this chapter. Notable structures observed from these positions in addition to the gallbladder itself include the portal vein, hepatic artery, right and left hepatic ducts, common hepatic duct, common bile duct, cystic duct, and inferior vena cava [5].

The layers of the gallbladder wall consist of the surface epithelium, lamina propria, muscularis propria, perimuscular subserosal connective tissue, and serosa [6]. On EUS, the normal gallbladder wall is depicted by three distinct layers. The innermost hyperechoic layer represents a boundary echo [3]. The middle layer is hypoechoic and consists of the mucosa, the muscularis propria, and the fibrous layer of the subserosa. The outer layer is hyperechoic, consisting of the adipose portion of the subserosal layer and serosa (Figure 1) [7, 8, 9]. A normal gallbladder wall is less than 4 mm in thickness. The inner layer of the gallbladder should demonstrate a smooth contour [10].

Figure 1.

Normal EUS of the gallbladder demonstrating multiple wall layers.

3. Abnormal gallbladder findings

The differential diagnosis of abnormal gallbladder lesions on EUS can be broadly divided into protuberant and wall-thickening lesions [10]. Protuberant lesions describe anomalies confined to the luminal surface of the gallbladder wall. Features such as lesion size, pedunculation, morphology, surface characteristics, and internal echo are considered in formulating the differential diagnosis.

Gallbladder wall thickening refers to lesions that cause the gallbladder wall to become diffusely thickened with a diameter ≥ 4 mm. Features such as the extent of wall thickening, surface structure, disruption of the gallbladder wall layers and presence of Rokitansky-Aschoff sinuses are considered in the differential diagnosis.

4. Protuberant lesions

Protuberant gallbladder lesions can be divided by morphologic features into pedunculated and sessile lesions. The differential diagnosis of protuberant and sessile lesions is important in the assessment of a lesion’s malignant potential. Pedunculated lesions may include gallbladder polyps, adenomas, and gallbladder carcinoma, while sessile lesions may signify gallbladder carcinoma, adenomyosis, and sludge. While sessile shape is strongly associated with gallbladder carcinoma, pedunculated shape is more likely to represent a benign lesion or an early stage carcinoma confined to the mucosa [11].

Another way to further classify protuberant lesions is to subdivide them into neoplastic and non-neoplastic lesions. Neoplastic lesions are either adenomatous or carcinomatous, and non-neoplastic lesions largely consist of gallbladder polyps, and can be described as focal elevations or protrusions easily distinguished from the surrounding mucosa (Figure 2) [12]. The majority of gallbladder polyps are asymptomatic and may be discovered incidentally. Size of the lesion is also important; protuberant lesions greater than 20 mm in diameter are often easy to detect, even by TAUS, and are often malignant in nature. However, for those less than 20 mm, the differential diagnosis is broad, and they are challenging to diagnose by EUS features alone. Therefore, knowledge of the specific endosonographic features unique to each etiology, both benign and malignant is essential.

Figure 2.

Gallbladder polyp (red arrow) depicted next to a gallstone (yellow arrow).

4.1 Benign protuberant gallbladder lesions

4.1.1 Gallbladder polyps

EUS is not ideal at distinguishing different types of gallbladder polyps. Cholesterol polyps are the most common type of gallbladder polyps, and account for approximately 95% of all raised gallbladder lesions [3]. Gallbladder polyps ≤10 mm are likely to be cholesterol polyps, but malignant polyps of this size are also found on occasion. Cholesterol polyps are pedunculated lesions, typically round in shape with a notched granular surface, and have a hyperechoic to isoechoic internal echo with echogenic punctiform foci representing cholesterosis [1, 10]. Larger cholesterol polyps greater than 10 mm in diameter may be more irregular or oblong in shape [1]. As cholesterol polyps enlarge to a size greater than 10 mm, they become more lobulated in appearance, and the internal echo decreases, taking on an appearance that can appear similar to adenomas or gallbladder cancer [10]. Due to this, they may be difficult to distinguish from malignant polyps and therefore cholecystectomy may be considered in this setting. Contrast-enhanced US may be useful for differentiating benign polyps from cancer [13].

The other types of gallbladder polyps are much less common. Hyperplastic polyps are benign protrusions consisting of hyperplasia of the gallbladder mucosa. They are typically ≥10 mm in diameter with a smooth surface, papillated or lobulated morphology, pedunculated base, and have uniform low echogenicity [12]. Inflammatory polyps are typically a result of chronic inflammation. They represent focal epithelial proliferations of inflammatory cells and are often associated with chronic cholecystitis. They consist of granulation and fibrous tissue and have no malignant potential. They are typically <10 mm in size and are often associated with chronic cholecystitis [14, 15]. On ultrasound, they may appear sessile or pedunculated. The internal echo is homogeneous and more echogenic than the liver parenchyma [15].

4.1.2 Cholelithiasis and sludge

Gallstones appear on EUS as intraluminal hyperechoic foci with or without acoustic shadowing (Figure 2) [16]. They may be gravity dependent. One study of patients presenting with typical biliary pain and a negative initial TAUS found that small, undetected culprit gallstones less than or equal to 3 mm in size were often found in the infundibulum or cystic duct when examined by EUS [16]. EUS is also useful for the detection of biliary sludge or microlithiasis in patients presenting with seemingly idiopathic acute pancreatitis (IAP). The sensitivity of EUS for detecting a case in IAP surpasses that of MRCP [17, 18, 19, 20, 21]. Biliary sludge appears as a gravity-dependent, homogeneous, echogenic substance without acoustic shadowing in the gallbladder lumen (Figures 3 and 4) [17].

Figure 3.

Hyperechoic gallstone with shadowing.

Figure 4.

Biliary sludge.

4.1.3 Adenomyomatosis

Adenomyomatosis may present as a protuberant lesion or a wall thickening lesion, and in both cases may mimic gallbladder carcinoma. As a protuberant lesion, adenomyomatosis tends to be sessile in nature, with a single or multiple anechoic internal areas (i.e. microcysts) corresponding to Rokitansky-Aschoff sinuses (RAS) (Figure 5). The surface is relatively granular and irregular. Some lesions may demonstrate internal echoes with a comet tail artifact due to multipath reflection from RAS or intramural calculi [1, 12]. They tend to appear oval in shape. Although adenomyomatosis are typically benign lesions, cases of co-existing gallbladder carcinoma with adenomyomatosis have been reported [12, 22].

Figure 5.

Protuberant adenomyomatosis with an internal anechoic area representing a Rokitansky-Aschoff sinus.

Adenomyomatosis can also appear as focal or diffuse gallbladder wall thickening. Comet tail artifacts and RAS are also present in the wall-thickening lesions. The layers of the gallbladder wall tend to be preserved within the lesion, and the surface is usually smooth in appearance, although in some cases it may feature some degree of irregularity due to mucosal hyperplastic changes [12]. Surface irregularity should raise suspicion for the presence of gallbladder carcinoma within the adenomyomatous lesions [3].

4.2 Neoplastic protuberant gallbladder lesions

4.2.1 Gallbladder adenoma

Gallbladder adenomas are uncommon and comprise 10% of all gallbladder polyps diagnosed by ultrasound [15]. They are generally homogeneously isoechoic with multiple microcysts within the polyp. They are oval with a relatively smooth surface and may be pedunculated or sub-pedunculated. They typically range from between 5 mm to 20 mm in diameter [3, 12]. On EUS, adenomas are difficult to distinguish from gallbladder carcinoma, but certain distinguishing features such as an intralesional vascular spot on color Doppler investigation or uniform contrast enhancement may aid in differentiating the two [3, 15, 23]. They have malignant potential and are at risk of progressing to gallbladder cancer through the adenoma-carcinoma sequence, although the incidence of this requires further elucidation [3, 24].

4.2.2 Gallbladder carcinoma

Gallbladder carcinoma typically demonstrates invasion of the gallbladder mucosa [25]. They are more commonly sessile than pedunculated, and the internal echo is heterogeneously dense, with increased echogenicity and scattered hypoechoic areas in the core. The outer surface of the carcinoma is typically nodular, and the shape is round [12]. In contrast to cholesterol polyps which tend to become irregular in shape beyond a diameter of 10 mm, carcinomas retain their rounded structure after reaching this size [1]. Prior studies investigating large polyps >10 mm in size, singular polyps >14 mm were 92.3% sensitive for differentiating neoplastic from non-neoplastic polyps, and sessile structure or polyp size >22 mm were 93.5–95.7% sensitive for differentiating carcinomas from adenomas [26]. Kozuka et al. in their examination of surgical gallbladder specimens found that a diameter of 12 mm or greater was associated with cancerous foci, and most invasive carcinomas were greater than 30 mm in diameter [24]. Sessile shape increases the odds of malignancy by a factor of 7.32 [27].

5. Gallbladder wall thickening

Gallbladder wall thickening is defined as a thickness of the gallbladder wall greater than 4 mm. Wall thickening lesions are further classified as local (<50%) or diffuse (>50%) depending on the extent of the involved portion. Furthermore, focal wall thickening may also refer to instances in which there is a focal presence of an inner hypoechoic layer, even if the wall is less than 4 mm thick [11, 12].

Diffuse gallbladder wall thickening is caused by several gallbladder disorders and non-gallbladder disorders, including extra-cholecystic inflammation, liver disease, systemic disease, and pseudo-thickening. However, in comparison, focal gallbladder wall thickening is more specific for intrinsic gallbladder disease and in the context of some diseases such as xanthogranulomatous cholecystitis, is more concerning for gallbladder carcinoma [25, 28].

Thus, although the differential diagnosis of gallbladder wall thickening is broad, in general it can be further classified into diffuse and focal involvement. In some cases, gallbladder wall thickening may be due to malignancy and thus distinguishing these from benign causes is important. EUS features that may assist with delineating this include the contour of the lesion, patterns of the wall thickness, the presence of intramural cystic spaces, and patterns of gallbladder wall enhancement [12].

5.1 Benign gallbladder wall thickening

5.1.1 Adenomyomatosis

See the above section on “Benign Protuberant Gallbladder Lesions.”

5.1.2 Cholecystitis

Typical sonographic findings of acute cholecystitis include the presence of gallstones, gallstone impaction in the gallbladder neck or cystic duct, gallbladder distention, gallbladder wall thickening, and pericholecystic fluid [29]. Typical findings on EUS include diffuse gallbladder wall thickening, a smooth inner mucosal layer, and preservation of the gallbladder wall layer structure [12]. However, EUS, at the present, is not the imaging modality of choice for diagnosis of acute cholecystitis, whereas TAUS and CT scan are preferred. The appearance of chronic cholecystitis is similar to that of acute cholecystitis.

Chronic xanthogranulomatous cholecystitis (XGC) is a subtype of chronic cholecystitis characterized by irregular gallbladder wall thickening and fibrosis due to chronic inflammation related to intramural infection. Granulomas form in the gallbladder wall due to the phagocytosis of purulent bile by histiocytes. Known causes of XGC include impaction of stones in the gallbladder neck or leakage of bile into the gallbladder wall due to rupture of RAS or mucosal ulceration. XGC may closely resemble gallbladder carcinoma on EUS and may require biopsy for diagnosis [3, 10, 12]. On EUS, the extent of wall thickening may be focal or diffuse, and the mucosa retains a smooth surface. In some cases, intramural hyperechoic nodules may be present. The wall may demonstrate a mixed hyperechoic and hypoechoic echotexture with irregularity or disruption of the gallbladder wall layers [12].

5.1.3 Other causes of benign gallbladder wall thickening

Other causes of gallbladder wall thickening include pseudothickening, systemic disease, liver disease, or neighboring inflammatory conditions. Focal pseudothickening is associated with the presence of debris and sludge within the gallbladder lumen, whereas diffuse pseudothickening is seen in postprandial states. States of fluid overload or and third-spacing, such as heart failure, renal failure, cirrhosis, hypoalbuminemia, and sepsis are common systemic diseases associated with diffuse gallbladder wall thickening. Inflammation of nearby organs, such as that which occurs during pancreatitis, hepatitis, or peritonitis may also lead to diffuse gallbladder wall thickening [11].

5.2 Neoplastic wall thickening

5.2.1 Gallbladder carcinoma (wall thickening type)

Wall-thickening gallbladder carcinoma is difficult to diagnose based on EUS alone, because it is mimicked by other conditions such as adenomyomatosis and XGC. The examination reveals an irregular or papillated mucosa, and non-uniform wall thickening marked by non-uniform hypoechoic patterns. In addition, the structure of the wall layers is ill-defined and may appear disrupted depending on the depth of invasion. Gallbladder carcinoma is differentiated from adenomyomatosis by the absence of RAS and intramural microcysts. Predictive findings of gallbladder carcinoma may include loss of the multiple layer wall pattern, wall thickness greater than 10 mm, absence of gallstones, and hypoechoic internal echogenicity [12, 30, 31].

6. EUS-guided tissue acquisition

6.1 Introduction

Endoscopic ultrasound-guided fine needle aspiration (FNA) is a useful method for the diagnosis of gallbladder disease. Differentiating malignant from benign gallbladder lesions is important due to the high short term mortality rates of gallbladder carcinoma, and because imaging alone is often insufficient to establish a diagnosis. Obtaining gallbladder tissue to establish a diagnosis is therefore necessary to guide clinical decision-making. Prior techniques such as endoscopic brush biopsy during endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic transpapillary gallbladder drainage (ETP-GBD) were shown to have low sensitivities of 47.4% and 71%, respectively [32, 33]. These methods are technically difficult, and entering the major papilla inherently carries the risks of complications such as post-ERCP pancreatitis, cholangitis, and sepsis [32]. With ETP-GBD in particular, the incidence of these major complications in addition to perforation of the cystic duct is between 0 and 14% [32]. Furthermore, bile duct biopsy using ERCP is unable to provide direct samples of the gallbladder lesion itself, and is primarily indicated when a biliary stricture is present. If a biliary stricture is absent, biliary cytology through ETP-GBD was previously required [10]. Now, EUS-FNA is increasingly being used in the diagnosis and management of pancreaticobiliary lesions, including those of the gallbladder. The diagnostic sensitivities of EUS-FNA exceed that of both ERCP and ETP-GBD [32, 33]. A meta-analysis combining nine studies analyzing the use of EUS-FNA for the diagnosis of gallbladder lesions reported a combined sensitivity of 84%, and other studies have reported specificities of 100% [3, 34, 35, 36, 37, 38, 39].

6.2 Current indications

The current use of EUS-FNA of the gallbladder itself from a diagnostic standpoint is mostly limited to gallbladder wall thickening lesions due to paucity of data and concern for complications. In terms of gallbladder cancer, Hijioka et al. propose the use of this procedure for some cases of resectable gallbladder cancer, especially when there is ambiguity about the malignant potential of a lesion or when surgery is considered extremely invasive [3]. EUS-FNA is not recommended for most cases of resectable gallbladder cancer because there is no role for neoadjuvant chemotherapy. Due to the similarity in endoscopic appearance of XGC and gallbladder cancer, EUS-FNA can guide the diagnosis and avoid extensive high-risk surgery for the patient. Nonetheless, they recommend taking EUS-FNA biopsy results with skepticism in some cases of XGC due to the propensity of the disease to co-exist with gallbladder carcinoma in a small percentage of cases [40]. Complete examination of the gallbladder including the neck and cystic duct are recommended, as obstructive gallbladder carcinoma may occur in this area and lead to XGC of the gallbladder body and fundus. Another technique to differentiate XGC from gallbladder carcinoma involves biopsy of the surrounding lymph nodes [3].

6.3 Complications

Current data on the safety of EUS-FNA of the gallbladder suggest low complication rates. Potential complications of the procedure include cholangitis, bleeding, or bile leak, although several studies report no serious adverse events after the procedure [32, 33, 36]. Although this suggests that EUS-FNA is safe, the possibility of reporting bias necessitates further research to elucidate the potential harms of the procedure [36].

One of the most feared complications of EUS-FNA is the possibility of bile leak as a result of gallbladder perforation, leading to peritoneal dissemination of infection or malignancy [41, 42]. The risk of this may be higher in cases of gallbladder polyps, where biopsy would require traversing the gallbladder lumen, and EUS-FNA should be avoided in such cases [3]. Nonetheless, cases of successful EUS-FNA of gallbladder intraluminal lesions have been reported [37, 38, 43]. Wall thickening lesions usually carry a lower risk of gallbladder perforation because the needle tract may travel tangentially with respect to the gallbladder, and as such are more amenable to EUS-FNA. The risk of needle tract seeding leading to intragastric metastases may be increased in EUS-FNA, although the occurrence of this is rare [44, 45]. Alternative sites than the gallbladder itself should be surveyed for metastatic disease, such as the liver or neighboring lymph nodes, as these are usually safer to biopsy. According to some authors, the portion of the gallbladder wall that makes contact with the liver parenchyma is a technically preferred location for biopsy [10].

6.4 EUS-FNB

EUS-FNA with rapid onsite evaluation of cytopathology (ROSE) is the current preferred approach to tissue sampling of pancreaticobiliary lesions due to a high diagnostic yield of greater than 90% [46]. However, this method is not without limitations; it requires considerable expertise, personnel, and resources, and is unavailable outside of most tertiary care centers. Another disadvantage is that it relies on adequate cellularity of the sample, where in some cases if a lesion is significantly fibrotic or necrotic the diagnostic yield is poor [47].

Novel fine needle biopsy (FNB) devices were developed for use with EUS and have produced optimistic results. Specifically, the development of the fork-tip needle (SharkCore, Medtronic, USA) in 2016 and the Franseen tip needle (Acquire, Boston Scientific, USA) in 2017 have allowed endosonographers to perform endoscopic biopsies with excellent diagnostic yield. A striking benefit of FNB is that it allows for the acquisition of larger tissue samples that can be analyzed histopathologically, potentially obviating the need for EUS-FNA with ROSE. Emerging studies on FNB in pancreaticobiliary lesions other than that of the gallbladder have shown promising results. Adequate tissue acquisition rates with the Franseen tip needle were reported to be greater than 90% in one multicenter study [48]. A recent meta-analysis demonstrated that the addition of ROSE did not improve the diagnostic accuracy of FNB [49]. Randomized controlled trials have demonstrated diagnostic accuracies of greater than 90% with both FNB needle types, and a subsequent multicenter randomized controlled trial showed that the diagnostic accuracy of FNB was non-inferior to EUS-FNA with ROSE [47, 50, 51]. Furthermore, FNB was associated with fewer needle passes, shorter procedure times, and comparable associated costs when compared to EUS-FNA with ROSE [47]. Yet, the use of FNB for gallbladder lesions remains uncommon, with limited data available reporting both high diagnostic accuracy and safety in the context of gallbladder lesions [43, 52]. The development of large multicenter trials focusing on the use of FNB in gallbladder lesions is necessary to guide future indications for this technique.

Another perk to FNB is that in the retrieval of larger tissue volumes, this permits histopathological analysis by immunohistochemistry, and in turn, empowers diagnostic capabilities by introducing next-generation genetic sequencing. Several potential targetable genes have already been identified in gallbladder carcinoma and cholangiocarcinoma, and trials specifically targeting HER2-positive cholangiocarcinoma are currently underway [53, 54, 55]. The treatment landscape of gallbladder and biliary tract cancer is fairly young, but there is optimism that FNB will become increasingly useful in advancing our ability to identify targeted therapies for gallbladder cancers.

7. Conclusion

Endoscopic ultrasound is an essential tool in the evaluation of biliary disease. The gallbladder examination from an endoscopic point of view provides clinicians with a unique advantage in identifying pathology that may be difficult to visualize by other imaging modalities such as cross-sectional imaging and TAUS. However, this technique does have limitations, namely in its ability to distinguish gallbladder polypoid lesions and to ascertain malignant lesions from those that are benign. Tissue diagnosis is often required, which is in some cases achievable by EUS as well. EUS-guided tissue acquisition has propelled our diagnostic capabilities of gallbladder and other pancreaticobiliary lesions and paved bright avenues toward the possibility of targeted treatments in the future.

Conflict of interest

The authors declare no conflict of interest.