Revised Guidelines for the Treatment and Follow‐Up of Gallbladder Polyps Do Not Reduce Unwarranted Cholecystectomies: Results of the POLYP Study

ABSTRACT

Background

Gallbladder polyps are seen in up to 7% of adults and carry a low malignancy risk. Guidelines on indication for surgery and follow‐up remain controversial because of regional differences in the development of malignancy. This study compares European practice guidelines for gallbladder polyps and assesses the percentage of patients in whom cholecystectomy was indicated according to the guidelines with a true adenoma postoperatively.

Methods

Dutch patients with active follow‐up or surgery for gallbladder polyps between 2018 and 2020 in 26 participating centres were included. Data on demographics, imaging characteristics, surgery and histopathology were assessed. Indications for cholecystectomy were examined for all patients comparing 2017 and 2022 European guidelines.

Results

A cohort of 302 patients was included. Patients in follow‐up underwent imaging three times (median) and were followed up during a median of 23.2 months (IQR 10.9–47.4). In total, 88 patients (29%) underwent cholecystectomy after a median period of 23 months and a median of two instances of imaging. In 71 of 88 patients (81%) who underwent cholecystectomy, the gallbladder polyps was a valid indication for cholecystectomy according to 2017 guidelines, compared to 68 of 88 (77%) according to 2022 guidelines. The difference only occurred due to age as a risk factor which changed from 50 to 60 years of age. Of 71 operated patients, non‐neoplastic polyps were found in 49 (69%), no gallbladder wall abnormality was found in 23 (32%). An adenoma was found in six patients (9%), of which three had low grade dysplasia and one had high grade dysplasia.

Discussion

Despite revision of guidelines in 2022, a significant number of patients still undergo follow‐up and cholecystectomy for non‐neoplastic gallbladder polyps, indicating the need for a more comprehensive risk assessment algorithm in the management of gallbladder polyps.

1.

Summary.

• Summarise the established knowledge on this subject

  • ◦Gallbladder polyps are seen in up to 7% of adults and carry a low malignancy risk.
  • ◦Cholecystectomy for gallbladder polyps is only indicated for adenomas, which can be premalignant.
  • ◦European guidelines between the ESGAR, EAES, EFISDS and ESGE that provide recommendations for indication for cholecystectomy and duration of follow‐up for gallbladder polyps were updated in 2022.

• What are the significant and/or new findings of this study?

  • ◦An adenoma was found in only six of 68 (9%) patients who underwent cholecystectomy that was advised according to 2022 European guidelines.
  • ◦The revised guidelines provided only a minor decline in cholecystectomy for non‐neoplastic polyps (three patients).

2. Introduction

Gallbladder polyps are a common clinical and diagnostic dilemma. Polyps are mainly incidentally diagnosed in around 4%–7% of patients undergoing abdominal ultrasonography and are frequently asymptomatic [1, 2]. With increasing use of imaging, the number of incidentally detected gallbladder polyps is on the rise.

The majority of gallbladder polyps are benign abnormalities, such as cholesterolosis or adenomyomatosis. Gallstones may also regularly be mistaken for polyps [3, 4]. Around 4%–10% of gallbladder polyps are true adenomas, which are thought to harbour a small malignant potential [5, 6]. The pathway resulting in malignant degeneration is unclear, and malignant deterioration only occurs in a minority of adenomas. Modern imaging modalities thus far have been unable to reliably differentiate between benign and malignant polyps, so a definitive diagnosis can only be provided after resection and subsequent histopathological analysis.

Current guidelines recommend cholecystectomy in all polyps of ≥ 1 cm in size due to increased risk of malignancy [7]. However, even in polyps ≥ 1 cm, some studies find that only 0.4% of these are malignant and that most truly malignant polyps are ≥ 2 cm in size [8]. Moreover, a recent cohort study including > 600.000 patients with a follow‐up of over 20 years showed that patients with gallbladder polyps do not have a larger risk of gallbladder cancer than controls without gallbladder polyps [6]. In addition, contemporary studies have similar outcomes and call into question the practise of proactive follow‐up and cholecystectomy in all patients with polyps ≥ 1 cm in size [9].

This prospective multicentre cohort study evaluates the outcomes of the European guidelines for the treatment of gallbladder polyps, in order to identify areas for optimisation and subsequently prevent follow‐up or surgical intervention for non‐neoplastic gallbladder polyps.

3. Methods

3.1. Study Design and Patient Inclusion

This study was designed as a prospective observational multicentre cohort study. In total, 26 hospitals participated in the study, of which 21 general hospitals and five university medical centres. The Medical Ethics Review Committee of the region Arnhem‐Nijmegen provided a waiver for ethical approval. The STROBE statement for observational cohort studies was followed [10]. Patients aged 18 years and above with gallbladder polyps identified on imaging studies (including ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI)) or through pathology after surgery were included from participating centres between 2018 and 2020. Both newly diagnosed patients and patients in follow‐up were included. Patients with known gallbladder malignancy or incomplete imaging or clinical data were excluded from the study.

Per centre, inclusion of patients was performed through an appointed local principal investigator of the department of surgery, department of gastroenterology and/or the department of radiology. Informed consent was obtained from all participants prior to enrolment. After the end of the inclusion period, clinical data from the included patients was retrieved at the participating hospitals by a member of the research group. All information was recorded by using a standardized pseudonymised case report form in CastorEDC, a secure online data management system [11].

3.2. Data Collection and Variable Definitions

Detailed demographic information including age and gender was recorded. Clinical data such as presenting symptoms, comorbidities, and medication history were documented. Imaging characteristics of gallbladder polyps including size, number, location and morphology were analysed. Laboratory investigations, including liver function tests, were obtained where available. If cholecystectomy was performed, surgery and pathology reports were also obtained. Indication for cholecystectomy was based on both the 2017 and 2022 joint guidelines for management and follow‐up of gallbladder polyps between the ESGAR, EAES, EFISDS and ESGE [7, 12].

3.3. Statistical Analysis and Outcomes

Descriptive statistics were used to summarize patient demographics, clinical characteristics, and imaging findings. Compliance with existing guidelines for follow‐up and management of gallbladder polyps was used as a primary outcome, and pathology outcomes of cholecystectomies performed in concurrence with these guidelines were analysed as a secondary outcome. Continuous variables were expressed as median with interquartile range (IQR), and categorical variables were reported as frequencies with percentages. All statistical analyses were carried out using the SPSS 26.0 statistical package (IBM Corporation, Armonk, NY, USA).

4. Results

4.1. Demographics

In total, 302 patients were included, 178 women (59%) and 124 men (41%). Median age at diagnosis was 56 years (IQR 46–63). No patients were known to have primary sclerosing cholangitis and hepatitis B or C was described in the medical history of two patients (1%). Eighty‐seven patients (29%) were estimated to have an ASA‐classification of I, 153 patients (51%) an ASA‐classification of II and 48 patients (16%) an ASA‐classification of III. ASA‐classification could not be estimated in 14 patients (5%) (Figure 1, Table 1).

FIGURE 1.

Pathway for inclusion of patients with gallbladder polyps. Of 482 identified patients, 302 patients with gallbladder polyps met inclusion criteria and signed informed consent. Only six of 88 patients who underwent cholecystectomy were diagnosed with a gallbladder adenoma. The remaining 214 did not undergo cholecystectomy at the time of data collection and were dismissed from or were still in follow‐up.

TABLE 1.

Patient characteristics of included patients with gallbladder polyps (n = 302).

Characteristic	Number of patients (%)
Age at diagnosis in years a	56 (46–63)
Gender (female)	178 (58.9)
ASA class
I	87 (28.8)
II	153 (50.7)
III	48 (15.9)
Unknown	14 (4.6)
Comorbidity
Gastroenterological	81 (26.8)
(History of) malignancy	62 (20.5)
Respiratory	46 (15.2)
Cardiac	41 (13.6)
Endocrine	41 (13.6)
Hepatitis B/C	2 (0.7)
Primary sclerosing cholangitis	0
Symptoms before diagnosis
Non‐specific abdominal pain	149 (49.3)
Nausea/vomiting	40 (13.2)
Bilairy colic (pain in upper right abdomen)	32 (10.6)
Weight loss	26 (8.6)
Dyspepsia	22 (7.3)
Coincidental finding	125 (41.4)
Primary imaging type
Transabdominal ultrasonography	290 (96.0)
CT	9 (3.0)
MRI	1 (0.3)
Endoscopic ultrasound	1 (0.3)
Unknown	1 (0.3)
Types of imaging used
Transabdominal ultrasonography
1	82 (27.2)
2–5	183 (60.6)
≥ 6	36 (11.9)
CT	29 (9.6)
MRI	10 (3.3)
Endoscopic ultrasound	2 (0.7)
Unknown	1 (0.3)
Cholecystectomy after first instance of imaging	34 (11.3)
Time from diagnosis to last follow‐up in months a (n = 231)	23.2 (10.9–47.4)
Surgery type (n = 88)
Laparoscopic cholecystectomy	86 (97.7)
Open cholecystectomy	2 (2.3)
Time from diagnosis to surgery in months a	6.2 (2.8–27.5)

^a values are median (IQR).

4.2. Presenting Symptoms

Symptoms described at diagnosis were biliary colic (defined according to the ROME III criteria, with episodes of pain in the right upper quadrant) in 32 patients (11%), non‐specific abdominal pain in 149 (49%), nausea and/or vomiting in 40 (13%), other dyspeptic symptoms in 22 (7%) and weight loss in 26 (9%). No patients were jaundiced before diagnosis. In 125 patients (41%), there were no related symptoms and the gallbladder polyp was an incidental finding (Table 1).

4.3. Imaging

The primary imaging modality used was transabdominal ultrasonography in 290 patients (96%), CT in nine (3%), MRI in one and endoscopic ultrasonography in one. The primary imaging modality was unknown in one patient. Seventy‐one patients (24%) did not undergo any follow‐up after the first diagnosis at the time of data collection. In 34 of these patients, surgery was performed after the first instance of imaging. Of 231 patients who did undergo more than one instance of imaging, the mean number of instances of imaging was 3.7 per patient, with a median of three instances (IQR 2–4). For patients who underwent follow‐up, the median time from diagnosis to the last instance of imaging was 23.2 months (IQR 10.9–47.4). With patients who underwent surgery excluded, the mean number of instances of imaging in the remaining 178 patients was 3.9 per patient and the median time from diagnosis to the last instance of imaging was 24.5 months (IQR 11.9–49.7). At the time the data was collected, 40 patients (13%) were officially dismissed from follow‐up, 88 patients (29%) had undergone cholecystectomy and 174 patients (58%) were not yet officially dismissed (Table 1).

4.4. Surgery and Indication for Surgery

In total, 88 patients (29%) underwent cholecystectomy. Only two patients (2%) underwent open cholecystectomy; one as part of an open resection of liver segment VII and lymph node dissection for hepatocellular carcinoma, and the other as a specific reason for open resection was not given. The median time from diagnosis to surgery was 6.2 months (IQR 2.8–27.5) and on average, patients underwent radiological imaging 2.3 times with a median of two instances (IQR 1–3).

Of those who underwent surgery, when comparing 2022 European guidelines to those of 2017, polyp size and/or growth were an indication for cholecystectomy in 68 versus 71 patients (77% vs. 81%); three less due to age as a risk factor being changed from 50 to 60 years. Age was also the only reported risk factor. Other reasons for surgery indication were the same for both guidelines; the indication was a size of at least 10 mm or more of the biggest polyp in 31 patients, size of 10 mm ánd growth of 2 mm or more in 22 patients and size of at least 6 mm and growth of 2 mm or more in six patients. In 17 patients (19%), polyp characteristics did not warrant cholecystectomy but it was performed regardless; in 14 patients, there was a clinical reason for surgery, such as symptomatic cholecystolithiasis or cholecystitis. In three patients, cholecystectomy was performed for various reasons such as an expressive wish of the patient (Figure 1, Table 2).

TABLE 2.

Surgery and pathology characteristics of patients with an indication for cholecystectomy according to 2017 or 2022 guidelines.

Characteristic	Number of patients (%)	Number of patients (%)
	2017 guidelines	2022 guidelines
Total cohort of patients who underwent cholecystectomy	88	88
Polyp was valid indication for cholecystectomy	71 (80.7)	68 (77.2)
Clinical indication for cholecystectomy	14 (15.9)	14 (15.9)
No indication according to guidelines	3 (3.4)	6 (6.8)
Reason of polyp as a valid indication for surgery
Polyp ≥ 10 mm	31 (43.7)	31 (45.6)
Polyp ≥ 10 mm + ≥ 2 mm growth	22 (31.0)	22 (32.4)
Polyp 6–9 mm + ≥ 2 mm growth	6 (8.5)	6 (8.8)
Polyp 6–9 mm + age as risk factor a	12 (16.9)	9 (13.2)
Surgery type of those with valid indication
Laparoscopic cholecystectomy	70 (98.6)	67 (98.5)
Open cholecystectomy	1 (1.4)	1 (1.5)
Pathology b
Cholesterolosis	35 (49.3)	34 (50.0)
Adenomyomatosis	5 (7.0)	5 (7.4)
Other non‐neoplastic (pseudo)polyps	9 (12.7)	9 (13.2)
Adenoma	6 (8.5)	6 (8.8)
No gallbladder wall abnormalities found	23 (32.4)	21 (30.9)

^a For 2017 guidelines, age of 50 years or older was considered a risk factor, while for 2022 guidelines, age of 60 years or older was considered a risk factor.

^b Some gallbladders contained more than one pathological finding.

4.5. Pathology

Of the 68 patients in whom polyp characteristics were an indication for cholecystectomy following 2022 guidelines versus 71 patients following 2017 guidelines, cholesterolosis or other non‐neoplastic wall abnormalities were described in 41 (60%) versus 42 patients (59%). In 21 versus 23 patients (31% vs. 32%), no gallbladder polyp or wall abnormality was found (Table 2).

An adenoma was found in six patients (9%): two without dysplasia, three with low grade dysplasia and one with high grade dysplasia. When analysed, the six patients with adenomas are a heterogeneous group in demographic characteristics such as age, gender and symptoms as well as radiological characteristics. Although age as a risk factor was changed from 50 to 60 years in the new guidelines, two patients with an adenoma were between 50 and 60 years old, and one was 25 years old. All patients had an indication for cholecystectomy at diagnosis, except for patient #1, whose largest gallbladder polyp grew from 9 to 11 mm in the span of 2 years. In patient #4 ultrasound was used to confirm CT findings. In only one patient, there was a solitary polyp at imaging, which was over 15 mm in size and was the only polyp with high grade dysplasia (Table 3).

TABLE 3.

Characteristics of six patients with an adenoma found in pathology after cholecystectomy.

Characteristic	Patient #1	Patient #2	Patient #3	Patient #4	Patient #5	Patient #6
Age at diagnosis	25	50	55	62	64	65
Gender	Female	Female	Male	Male	Female	Female
Symptoms	Nausea	Dyspepsia	Nausea	Pain in right flank	Pain in right flank	Nausea
	Dyspepsia		Dyspepsia			Weight loss
	Weight loss		Weight loss			Pain in upper right abdomen
	Abdominal pain
Amount of follow‐up ultrasounds	3	0	0	1	0	0
Days between diagnosis and last ultrasound	750	N/a	N/a	68	N/a	N/a
Growth during follow‐up	2 mm	N/a	N/a	0 mm	N/a	N/a
Number of polyps (radiology)	3	2	Multiple	Multiple	Multiple	1
Maximum polyp size (radiology)	11 mm	10 mm	10 mm	12 mm	9 mm	17 mm
Concurrent gallstones	No	No	Yes	Yes	No	No
Number of polyps (pathology)	Multiple	1	1	1	± 20	1
Maximum polyp size (pathology)	5 mm	8 mm	‘Small’	10 mm	7 mm	20 mm
Dysplasia	No	Low grade	Low grade	Low grade	No	High grade
Other findings in pathology	Multiple polypoid structures (< 2 mm)	Cholesterolosis	Cholesterolosis Rokitansky‐Aschoff	—	—	Cholesterolosis

In the 17 patients where polyp characteristics were not a valid indication for cholecystectomy, non‐neoplastic polyps were found in 13 patients, no gallbladder wall abnormalities were found in three and one gallbladder was not submitted to pathology.

5. Discussion

The long‐term follow‐up of a multicentre cohort of 302 Dutch patients with gallbladder polyps illustrates minor differences in outcome after revision of the European guidelines. The polyp was a valid indication for cholecystectomy in around 80% of patients who underwent surgery for both the 2017 and 2022 guidelines. A dysplastic adenoma was found in only four patients, which is around 6% of patients where the polyp was a valid indication for cholecystectomy for both guidelines and around 1% of all included patients, suggesting both overdiagnosis and overtreatment. No truly malignant polyps were found.

The management of gallbladder polyps has been widely examined in scientific studies. Concurring with the findings of this study, existing literature acknowledges the challenges in accurately assessing the malignant potential of gallbladder polyps. Multiple studies have highlighted the limitations of relying solely on polyp size as a criterion for cholecystectomy [13, 14, 15, 16]. Although guidelines recommend cholecystectomy for polyps of more than 1 cm in size, data suggest that the incidence of true malignancy in this subgroup is relatively low [17]. Furthermore, an association between gallbladder polyps and the development of gallbladder cancer remains unproven, as shown by a recent large‐scale cohort study in an American population of over 600.000 patients during a 20‐year follow‐up period in which the incidence of gallbladder carcinoma was equal for patients with previous gallbladder polyps to patients without gallbladder polyps [6].

The results from the current study, as well as existing literature, show that the refinement of criteria for follow‐up and cholecystectomy in patients with gallbladder polyps is necessary to minimise overdiagnosis and overtreatment which introduce patient morbidity as well as significant healthcare costs. Given that the main driver towards surgery is the size cutoff and other differences between the 2017 and 2022 guidelines were minimal, the small difference in their efficiency in preventing unnecessary cholecystectomy is unsurprising. As none of the dysplastic adenomas were smaller than 10 mm at presentation, it may be considered to remove growth in polyps of 6–9 mm from the guidelines as an indication for surgery. Similarly, a shortened follow‐up time of 2 years seems warranted. To truly minimise over‐diagnosis and ‐treatment, a more comprehensive risk assessment outside of polyp size and growth is necessary by incorporating additional factors such as morphological polyp characteristics into decision‐making algorithms. Literature describes the relationship between echogenicity, internal structure and vascularisation of the polypoid structure with adenomas or (beginning) gallbladder carcinomas versus cholesterol polyps and adenomyomatosis [15, 18, 19, 20, 21]. Characteristics such as hyperechoic foci may be used to preclude further follow‐up [18, 21]. Given the described connection between vascularisation and neoplastic polyps, more advanced types of radiological imaging such as contrast‐enhanced ultrasound would improve the diagnostic accuracy in the characterisation of gallbladder polyps, as supported by multiple studies [22, 23, 24, 25, 26].

The strengths of this study are its multicentre design and comprehensive prospective collection of data from patient medical records, including demographic data as well as data from imaging, surgery reports and pathology reports. This ensures that the study provides accurate insights into current clinical practices regarding gallbladder polyps and a correlation with the relevant guidelines. Limitations include that outside guidelines, patient preferences might not be fully captured in patient medical records. Furthermore, the study included patients prospectively at different stages in the management of gallbladder polyps, including patients at first diagnosis or during follow‐up. Not all follow‐up trajectories were concluded at the time of data collection, which limits the use of study data to predict the value of radiological follow‐up for polyps of various sizes. As most patients were included through surgical departments, the percentage of patients who underwent cholecystectomy might be larger in this cohort than in the general population with gallbladder polyps. Lastly, all included patients were residing in a Western European country. As such, our findings may not be applicable to non‐Western patients.

In conclusion, despite recent revisions in guidelines, a significant number of patients undergo follow‐up and cholecystectomy for non‐neoplastic gallbladder polyps, indicating the need for a more comprehensive risk assessment algorithm in the management of gallbladder polyps.

Author Contributions

M.v.D. and E.d.S.L collected and compiled data, performed analyses and wrote the draft manuscript text. All authors were local principal investigators and collected data for their respective hospitals. All authors and collaborators reviewed the manuscript. P.R. supervised the study.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.