Keywords

Introduction

The term gallbladder polyp generally refers to any mucosal projection into the gallbladder lumen regardless of whether it is neoplasm or not [1]. Compared with‘gallbladder polyps’ or other terms, the morphological term ‘polypoid lesions of the gallbladder’ could be more comprehensive and clinically useful for this heterogeneous group of diseases, among which true gallbladder polyps are relatively rare.

Most gallbladder polyps are not neoplastic lesions. Actually, 70% of these elevated lesions are pseudopolyps, which include cholesterol polyps, cholesterol stones (crystal), cholesterolosis, or adenomyomatosis. Pseudopolyps do not in themselves have malignant potential. True gallbladder polyps can be benign or malignant. Benign true gallbladder polyps are most commonly adenomas while malignant polyps are usually adenocarcinomas.

Clinically, diagnosis, routine medical check-up, and follow-up of these elevated lesions are almost always performed by ultrasonography (US). Despite gallbladder polyps being common, only a few develop to carcinoma, which usually presents late in diagnosis and carries a poor prognosis. Prognosis of advanced gallbladder cancer is dismal (5-year survival rate less than 5%), but 5-year survival rate of T1 gallbladder cancer is reported 71–100%.

Although it is ideal to treat true gallbladder polyps early, after histological diagnosis, clinicians must decide to recommend cholecystectomy based on indirect information such as the radiographic appearance of the polyp, patient demographics, and symptoms. It may be difficult, therefore, for the practicing radiologist or clinician to know what to recommend when they encounter a gallbladder polyp. This was also suggested by the results from a survey that there is inhomogeneity of surgical practice in the management of gallbladder polyps [2].

The current literature lacks uniformity and a single consensus on gallbladder polyps because a majority of data was acquired by individual, observational, and retrospective studies which involved limited numbers of participants and might have been biased. Currently, larger gallbladder polyps, for example, larger than 1 cm, are recommended for surgical removal in view of the higher chance of malignancy. On the other hand, patients with smaller polyps usually require repeated US and follow-up. This policy not only imposes a certain degree of anxiety on the part of patients, but also carries with it significant economic cost to the health care system.

Epidemiology

Due to the rising prevalence of gallbladder polyp and more frequent use of abdominal imaging modalities, the detection of gallbladder polyps has been increasing in past decades, affecting approximately 5–10% of the global adult population [3,4,5,6]. However, only 5% of these are considered to be “true” gallbladder polyps [7].

Most of the cases are diagnosed by abdominal US especially for periodic health examination. Otherwise, gallbladder polyps are often found incidentally during cholecystectomy. The frequency of resected gallbladder polyps in cholecystectomy specimens ranges from 2.6 to 12.1%; it seems to vary widely among reports and appears to be related to the indications for cholecystectomy, as well as to the study design [8].

Although the detection of gallbladder polyps has been increasing, the risk factors and natural history remain unclear. In contrast to the well-known risk factors for gallstones, no consistent relationship has been found between the formation of gallbladder polyps and sex, age, or medical conditions, such as diabetes, hyperlipidemia, and metabolic syndrome.

Histologic Type

Nonneoplastic polyps account for 95% and most of the neoplastic polyps are adenoma. Histological diagnostic terms are more scientific and accurate for each subtype of these lesions, but they could only be obtained postoperatively and therefore are difficult to be commonly used in clinical application and with imaging modalities. A worldwide, uniformly accepted classification is still lacking.

Cholesterol Polyps

Cholesterol polyps are the most common type (60%) of gallbladder polyp. Usually they are multiple, pedunculated, and less than 10 mm in diameter (Fig. 1) [9]. However, the sizes of these polyps vary quite widely, in some cases measuring over a centimeter. About 20% may be single lesions. They are not neoplastic polyps, but variants of cholesterolosis resulting from infiltration of lipid-laden foamy macrophages in the lamina propria.

Fig. 1
figure 1

Cholesterol polyp. a Sonographic view of multiple gallbladder polyps (0.8 cm, 0.6 cm size). b Sonographic view of another 1.1 cm-sized polyp. c Photograph of the gross pathologic specimen after cholecystectomy shows multiple yellowish cholesterol polyps. d H-E stain of the specimen demonstrating lipid-laden macrophages (arrow)

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The cholesterol in bile is absorbed by the gallbladder epithelium and taken up by macrophages and accumulates in the lamina propria. Cholesterol deposition within the lamina propria creates a mass and protrudes out of the mucosa into the lumen, and these masses are called cholesterol polyps. They are surrounded by vascular connective tissue and attached to the fibromuscular layer of the gallbladder wall protruding into the gallbladder lumen. They are covered with a single layer of epithelium enveloping a core of cholesterol filled macrophages. In cases where cholesterol deposits are tiny and diffuse, creating tiny, yellow excrescences on the surface of the gallbladder mucosa, having an almost strawberry-like appearance, the condition is referred to as cholesterolosis.

Diagnosis is easier in cases when there are multiple polyps. When there is one large cholesterol polyp, differentiation from the far less common adenoma is difficult (Fig. 2). Rarely, they may detach and behave clinically as gallstones, causing biliary colic, bile duct obstruction, or pancreatitis [10]. Cholesterol polyps have no malignant potential and no proven relation to gallstones. Surgery is not required unless the patient is symptomatic.

Fig. 2
figure 2

CT view of single, large gallbladder polyp. a 1.4 cm-sized cholesterol polyp (after cholecystectomy). b 1.1 cm-sized gallbladder adenoma (after cholecystectomy). c 2.1 cm-sized gallbladder adenocarcinoma (after cholecystectomy)

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Adenomyoma

Adenomyomatosis of the gallbladder is characterized by excessive proliferation of the epithelium and hypertrophy of the muscle. This proliferation is associated with invagination of the proliferated epithelium into the muscularis propria. The invaginated epithelium forms an intramural diverticulum referred to as Rokitansky–Aschoff sinuses. In addition to mucosal hyperplasia, the smooth muscle layer is hypertrophied, both of these pathologic processes causing marked thickening of the gallbladder wall. The Rokitansky–Aschoff sinus is usually confined to the thickened muscle, but in some cases, the sinus extends into the perimuscular connective tissue like a colonic diverticulum. Occasionally, Rokitansky–Aschoff sinuses are impacted with cholesterol crystals, debris, or fragments of stone.

There are three different types: the localized type, the segmental type, and the diffuse type. The focal type, the most common form, is referred to as adenomyoma. In the segmental type, there is a focal circumferential thickening of the gallbladder wall, often at the fundus or body. When it occurs at the body, there is a segmental narrowing of the gallbladder, dividing the gallbladder lumen into two separate compartments, mimicking an hour-glass. Segmental adenomyomatosis commonly occurs in the Phrygian cap and also gallstones are frequently entrapped in the cap. The diffuse form of adenomyomatosis causes diffuse thickening of the gallbladder wall and it may be difficult to distinguish adenomyomatosis from acute or chronic cholecystitis.

Localized form of gallbladder adenomyomatosis, confined to the fundus, may resemble a polyp. It is not neoplastic and confined to the gallbladder muscle layer. The average size is about 10–20 mm. Focal or segmental adenomyomatosis of the gallbladder fundus may be difficult to distinguish from intraluminal polyps or small carcinomas (Fig. 3). Surgery is not required unless it is symptomatic or indistinguishable from a tumor.

Fig. 3
figure 3

Gallbladder cancer that mimicks segmental adenomyomatosis. a, b Sonographic and CT view of annular wall thickening of the gallbladder body. c Photograph of the gross pathologic specimen after cholecystectomy shows irregular wall thickening of the gallbladder body

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Inflammatory Polyps

Inflammatory polyps are small, sessile lesions, and the average size is about 5–10 mm, although inflammatory polyps larger than 1 cm have been described. These large polyps can be confused with gallbladder carcinoma [11]. About 50% may be single lesions. In about half, 2–5 lesions are observed. Surgery is not required and most are found incidentally during cholecystectomy.

Adenomas

Unlike other gastrointestinal adenomatous polyps, gallbladder adenoma is a rare lesion, found in only 0.15% of resected gallbladders [12]. Adenoma is characteristically a single lesion with a diameter of 5–20 mm (Fig. 4). Commonly, adenoma appears as sessile or pedunculated polypoid nodules. It can occur anywhere in the gallbladder. When multiple, as they are in approximately one-third of cases, 2–5 polyps are usually present. Adenomas may cause symptoms but are typically incidentally found. They are most frequently seen in patients with primary sclerosing cholangitis (PSC) and gastrointestinal polyposis syndromes, such as Peutz–Jegher and Gardner syndromes.

Fig. 4
figure 4

Gallbladder adenoma. a, b Sonographic and CT view of 2.4 cm-sized solitary polypoid mass (arrow). c Photograph of the gross pathologic specimen after cholecystectomy shows lobulated polypoid mass. d H-E stain of the specimen demonstrating tubular adenoma, pyloric gland type

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Histopathologically, adenomas are classified into tubular, papillary, and tubulopapillary types. Tubular adenomas are the most common and appear lobular, possessing smooth contours, while papillary adenomas appear cauliflower-like.

It is the only polyp in the gallbladder that has a premalignant potential. Several studies do support this potential progression [13, 14]. However, the frequency of progression from adenoma to carcinoma is much lower than that for colon polyps. Gallbladder cancer is 4 times more common than gallbladder adenoma. Furthermore, adenomas are rarely found around invasive gallbladder cancers, and adenomas are less frequently associated with gallstones than gallbladder cancers. Therefore, this progression is not felt to be the predominant pathway of carcinogenesis in the gallbladder, and K-ras mutations have not been detected in gallbladder carcinomas associated with an adenoma. The frequency of transition from adenoma to cancer is unclear [13].

The pathologic diagnosis of adenoma or adenocarcinoma can only be made after cholecystectomy. In general, malignant tumors account for 3–8% of the gallbladder polyps. Virtually all adenomas with a focus of carcinoma are >12 mm in diameter; lesions <10 mm can be monitored with US. For lesions 10–18 mm in size, laparoscopic cholecystectomy should be considered in good surgical candidates. For lesions >18 mm in size, open rather than laparoscopic cholecystectomy should be considered because invasive cancer is more likely and extended resection may be required.

Other Polyps

Fibromas, leiomyomas, neurofibromas, carcinoids, and lipomas of the gallbladder have been reported, but are less than 0.1%. Pathology cannot be diagnosed before resection.

Clinical Features and Diagnosis

Because clinical findings alone cannot distinguish the histological types of gallbladder polyps, surgery is determined based on symptoms and image findings.

Most gallbladder polyps do not cause symptoms. Polyps can be found incidentally after cholecystectomy for the treatment of gallstone or by imaging studies performed for periodic health exams or other indications. Rarely, biliary pain may appear [15, 16]. Rare cases of acute acalculous cholecystitis and even hemobilia have been reported [17]. It is unclear whether the polyps primarily drive the symptoms, and it is difficult to distinguish the symptoms from those associated with gallstones. There is no sufficient evidence to show that tumor markers will assist in the decision-making process for gallbladder polyps.

Although imaging features of gallbladder polyps may, at times, indicate a specific diagnosis, there is a large degree of overlap in the appearances of benign and potentially malignant gallbladder lesions. About 85% of the polyps found by US are less than 5 mm in size. Only 2% are more than 10 mm in size.

Radiologic findings can be used to stratify gallbladder polyps into three groups: those that need no further follow-up, those that require follow-up, and those that should undergo cholecystectomy. In addition to the likelihood of malignancy on the basis of imaging findings, a surgeon’s judgment on whether to perform cholecystectomy relies on clinical factors, such as patient age, medical comorbidities, and the presence of symptoms that are attributable to gallbladder disease.

US is the most commonly used and best available imaging modality because it is the simplest and sensitive diagnostic methods for the detection of gallbladder polyps. However, US is often limited by the body habitus of the patient, and technical limitations can lead to intraobserver variability in interpretation. It cannot reliably distinguish between nonneoplastic and neoplastic polyps (see chapter “Differential Diagnosis of Benign and Malignant Lesions with Imaging”) [18]. On US, a gallbladder polyp is seen as an elevation of the gallbladder wall that protrudes into the lumen. It should not be mobile or demonstrate posterior acoustic shadowing (which would suggest it is more likely a calculus). It may be sessile or pedunculated. A clearly infiltrating or large mass should be treated as a gallbladder cancer rather than a polyp (Fig. 5). If there is clear reverberation or “comet tail” artifact present posterior to the lesion, this should be identified as a focal adenomyomatosis [19, 20]. The general sensitivity of US in detecting gallbladder polyp ranges from 36 to 90%, reaching 99% in patients without gallstones [21]. It was noted that gallstones mask the presence of polyps [22,23,24]. Besides, small polyps can also be obscured on US by thickened gallbladder wall [25].

Fig. 5
figure 5

Gallbladder adenocarcinoma. a, b Sonographic and CT view of 1.9 cm-sized, solitary polypoid mass (arrow). c Photograph of the gross pathologic specimen after cholecystectomy shows large, solid mass. d H-E stain of the specimen demonstrating adenocarcinoma

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Endoscopic US (EUS) is a more sensitive and specific method for diagnosing gallbladder polyps because of its use of high-frequency probes, which provide better resolution of small lesions (see chapter “Role of EUS”). EUS may be useful for identifying benign features of a polyp—such as cystic spaces or comet-tail artifact, which is associated with adenomyomatosis—that may not be visible with a transabdominal approach [26]. An EUS scoring system to predict malignancy in a gallbladder polyp on the basis of its size, its internal echo pattern, and the presence of hyperechoic spotting has been suggested, with sensitivity and specificity of 78% and 83%, respectively [20, 27, 28]. One study comparing transabdominal US and EUS found that the diagnostic accuracy of EUS for differentiating polyp types exceeded 90% [20]. However, EUS alone is not sufficient to determine treatment plan in many cases. Also, it is limited due to the need for equipment and skilled endosonographers and the risk of adverse events.

High-resolution ultrasound (HRUS) operates at a higher frequency than conventional US (5–7 MHz) but a lower frequency than EUS (5–12 MHz) and therefore theoretically has a better diagnostic accuracy than US but is less accurate than EUS [29]. However, it does have the benefit over EUS, in that it is a noninvasive procedure. The diagnostic accuracy of HRUS has been shown to be comparable with EUS for the differential diagnosis of gallbladder polyps [30]. Perhaps most importantly, considering patient comfort and the lack of requirement for sedation, HRUS has real potential as an important diagnostic modality for the differential diagnosis and staging of malignant gallbladder polyps and early gallbladder cancer.

Contrast-enhanced ultrasound (CE-US) has also been used to assess gallbladder polyps. It was reported that CE-US may facilitate the detection of gallbladder polyps by helping to distinguish them from mural folds, gallbladder contents, or sludge and also to detect invasion into the liver and metastasis [31, 32]. Moreover, it may offer more useful information for distinguishing adenoma from cholesterol polyps compared with conventional US, especially in cases in which the polyp was larger than 1 cm [33, 34].

Computed tomography (CT) or magnetic resonance imaging (MRI) has been reported to be less sensitive than ultrasound and it has limitation in differential diagnosis of small gallbladder polyps (see chapter “Differential Diagnosis of Benign and Malignant Lesions with Imaging”). Enhanced helical CT could reveal gallbladder polyps larger than 5 mm and could differentiate neoplastic or nonneoplastic lesions [35, 36]. Attempts have also been made to predict the malignant potential of gallbladder polyps using MRI with diffusion weighted imaging [37]. If malignant polyps are suspected by abdominal US, additional abdominal CT or MRI is performed to detect the invasion into surrounding tissue, presence of lymphadenopathy, or distant metastasis.

Several cases in which preoperative 18-fluorodeoxyglucose positron emission tomography (PET) accurately predicted the presence of malignant tumor of the gallbladder in patients with gallbladder polyps have been reported (Fig. 6) [38]. However, it was applicable for the assessment of 1–2 cm gallbladder polyps and false-positive results may occur in the presence of acute cholecystitis, a limitation of FDG PET.

Fig. 6
figure 6

Gallbladder adenocarcinoma. a CT view of 2 cm-sized, enhancing gallbladder polypoid mass (arrow). b PET view of the increased FDG-uptaken mass (arrow)

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In summary, alternative imaging modalities, particularly EUS, may provide additional information in the diagnosis of gallbladder polyps. At present, however, there is insufficient data to suggest that they should be used ahead of conventional US in the investigation of gallbladder polyps. In addition, transabdominal US is a relatively low cost, low risk, and widely available technique. Some specific centers with sufficient resources and expertise may find the additional information available useful, especially in patients for whom cholecystectomy may have additional risk.

When gallbladder polyps are detected by imaging, such as US, they are sometimes not found in cholecystectomy specimen. Such false positive finding of gallbladder polyps on US ranges from 6 to 43% [22, 25, 39, 40]. Normal mucosal folds, sludge, or small stones impacted in the gallbladder wall can be misinterpreted as polyps. In addition, small polyps may fall off during processing of surgical specimens. Thus, patients should be informed before operation of the possibility of negative findings or of finding a gallstone instead.

Treatment

When a gallbladder polyp is identified on abdominal US, the two major questions are (1) is this causing any symptoms and (2) does this need to be removed? As discussed above, most polyps are generally thought to be asymptomatic. Therefore, the main role for the clinician in managing these polyps is recommending when to proceed with surgery and when to take a watchful waiting approach, recognizing that gallbladder cancer, while quite rare, carries a poor prognosis. The main concern in the management of gallbladder polyps is to identify and treat malignant lesions that are usually still at a relatively early stage and amendable to surgical cure. Currently, there remain controversies and challenges in many aspects of gallbladder polyps. It is difficult to differentiate benign lesions from malignant gallbladder polyps based on available diagnostic modalities. Prophylactic cholecystectomy is sometimes performed too early or is even absolutely unnecessary for well-functioning gallbladders with some subtypes of gallbladder polyps.

As mentioned earlier, the commonly reported rate of malignancy in gallbladder polyps is around 3 to 8%. Obviously, operation will be overdone if cholecystectomy is offered to every patient with gallbladder polyps. The issue is further complicated by the reliability of US which is usually the diagnostic tool used. The reported sensitivity and specificity of US in diagnosing gallbladder polyps is widely variable. Unnecessary operations would occur in case of false positive findings. The risks associated with surgery include damage to intra-abdominal structures during port insertion, bile duct injury (between 0.3 and 1%), and bile leak [41, 42]. Furthermore, endoscopic retrograde cholangio-pancreatography (ERCP) to manage a bile leak and bile duct injury are associated with significant adverse events [43, 44].

It is unlikely that small gallbladder polyps themselves cause patient’s symptoms. There is evidence, however, that gallbladder polyps may be indicative of underlying inflammation or stone disease that may not have been detected on US [45]. The relationship between symptoms and risk of malignancy is not established. Patients with biliary pain and US evidence of both polyps and stones in the gallbladder should undergo elective cholecystectomy (Fig. 7). The decision is more complicated for patients in whom gallbladder polyps without concurrent gallstones are discovered. For these patients, the decision to operate depends on the severity of symptoms, confidence of the clinician that the symptoms are biliary in origin, and US features (particularly the size) of the polyp.

Fig. 7
figure 7

Sonographic view of gallbladder polyp and gallbladder stone (arrow). After laparoscopic cholecystectomy, the diagnosis of the polyp reveals cholesterol polyp

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Most polyps do not grow over time. About 7% of the polyps increase in size during follow-up (Fig. 8). Polyps less than 5 mm rarely grow. Sometimes (7–34%) polyps are reported to disappear [46,47,48,49,50,51].

Fig. 8
figure 8

a, b Sonographic view of increasing single gallbladder polyp (from 0.3 cm (arrow) to 1.1 cm) over 10 years. After laparoscopic cholecystectomy, the diagnosis reveals cholesterol polyp

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Because polyps 10 mm in size or larger have a greater likelihood of being cancerous, elective laparoscopic cholecystectomy should be considered in acceptable surgical candidates with asymptomatic polyps of this size [45, 52, 53]. In a patient who is a poor surgical risk with a polyp that is 10 mm or larger, periodic monitoring for polyp growth (perhaps every 6 months) with US or additional characterization with EUS may be reasonable.

Polyps larger than 18 mm in diameter pose a significant risk of malignancy and should prompt cholecystectomy if possible. One study found that lesions of this size often contain advanced, invasive cancer that involves the serosal surface of the gallbladder and requires a more extensive dissection than can be accomplished by laparoscopy [54]. As a result, the investigators advocate open cholecystectomy for these large polypoid lesions of the gallbladder. Unfortunately, trials comparing these surgical approaches are not available. Thus, the ideal surgical approach for gallbladder polyps with suspicion of malignancy is unsettled.

How best to manage patients with polyps that are 6–9 mm in size is debated. Multiple polyps, pedunculated polyps, and those that are hyperechoic compared with the liver are usually cholesterol polyps, while solitary and sessile polyps that are isoechoic with the liver are more likely to be neoplastic. In this generally low-risk population, periodic surveillance for polyp growth or change may be prudent. One group of investigators has recommended transabdominal US evaluation 3–6 months after the initial discovery of such polyps to exclude a rapidly growing tumor, followed by ongoing surveillance at 6–12-month intervals. The optimal duration of surveillance is unknown. Two studies have suggested that the 10-mm cut-off value for cholecystectomy may be too high, as premalignant or malignant gallbladder lesions were found in persons with polyps that were initially 6–9 mm in size [49, 55]. So, some other investigators have advocated aggressive approach of performing cholecystectomy for polyps of this size given the small but possible risk of neoplasia such as increased size of polyp (>2 mm) [20], single [48, 56], sessile polyp (including focal gallbladder wall thickening >4 mm) [48, 57,58,59,60,61,62,63,64,65,66,67,68], Indian ethnicity [58] or old age [46, 56, 57, 60, 61]. As with most other cancers, the risk of a gallbladder polyp being malignant increases with increasing patient age. Currently, there is insufficient data to determine what the most appropriate threshold is. Also, there was insufficient evidence to include gallstones as a strong risk factor, but some of these patients are likely to be symptomatic and as such will undergo cholecystectomy anyway.

The best practice for gallbladder polyp surveillance needs clarification. Given the rarity of gallbladder cancer, the cost of universal gallbladder polyp surveillance may not be justifiable; the cost-effectiveness might be improved by limiting surveillance to polyps between 5 and 10 mm in size because no study has reported neoplasia in an asymptomatic polyp less than 6 mm in size [50]. Polyps less than 6 mm in size are usually benign and most frequently represent cholesterolosis. However, although no malignant polyps have been shown to be below 4 mm, there is still a risk of adenomas and these polyps therefore would still require follow up but on a less frequent basis [46]. If the gallbladder polyp disappears, then it was likely a pseudopolyp and does not require further follow-up.

The recommendations for following small gallbladder polyps expectantly may not apply to patients with PSC, in whom the risk of malignancy in polypoid lesions of the gallbladder may be as high as 60% [62,63,64,65]. These patients should undergo a more intensive follow-up and have a lower threshold for cholecystectomy than non-PSC patients. In this high-risk population, cholecystectomy for polyps smaller than 10 mm should be considered. This, however, is challenged by observations that gallbladder cancer is seen only in polyps greater than 8 mm and that cholecystectomy in patients with PSC and cirrhosis is associated with high morbidity [65,66,67]. There was insufficient data to support cholecystectomy in all patients with PSC and a gallbladder polyp, because of the potential increased morbidity.

Recently, the European Society of Gastrointestinal and Abdominal Radiology (ESGAR) developed a consensus-based guideline. A summary of the recommendations is described in the algorithm (Fig. 9) [68].

Fig. 9
figure 9

(Reproduced from Wiles et al. [68])

Management algorithm of gallbladder polyp

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Conclusion

Currently, there remain controversies and challenges in many aspects of gallbladder polyps. It is difficult to differentiate benign lesions from malignant gallbladder polyps based on available diagnostic modalities. Patients with gallbladder polyps should be treated with personalized and differentiated strategies. Better understanding of the clinicopathologic characteristics, risk factors, classification and natural history of gallbladder polyps are necessary and larger prospective trials involving multiple centers should be conducted.