Gallbladder pathologies through a decade: Insights into emerging trends and premalignant lesions from a single-center experience: An observational study

Abstract

Gallbladder diseases, including chronic cholecystitis and cholesterolosis, impose a significant burden on global health. Monitoring their evolving trends is vital to refine diagnostic strategies and improve clinical outcomes. This study evaluates a decade of gallbladder pathology data to identify epidemiological shifts and associated risk factors. This retrospective study analyzed 6665 cholecystectomy specimens from January 2014 to December 2023. Diagnoses included chronic and acute cholecystitis, cholesterolosis, metaplasia, dysplasia, and adenocarcinoma. Annual trends, demographic patterns, and risk factor correlations were examined using advanced statistical analyses, including multivariable logistic regression. Chronic cholecystitis remained the most common diagnosis (87.92%), showing a stable incidence and strong female predominance (4115:1745; P < .001). Cholesterolosis (24.07%) exhibited a rising trend, peaking in 2022, linked to dietary and metabolic changes. Notably, premalignant lesions such as metaplasia (12.54%) and dysplasia (3.11%) increased significantly, with dysplasia peaking in 2022–2023. Adenocarcinoma was rare (0.33%) but strongly correlated with dysplasia (r = 0.186, P < .001). Logistic regression analysis identified age and intestinal metaplasia as independent predictors of dysplasia. For adenocarcinoma, high-grade dysplasia (odds ratio [OR] = 308.9), polyps (OR = 2.9), and intestinal metaplasia (OR = 3.8) emerged as significant risk factors, while chronic cholecystitis (OR = 0.18) and gallstones (OR = 0.31) were independently associated with a reduced risk. The rise in premalignant gallbladder conditions, particularly dysplasia, underscores the importance of routine histopathological examinations following cholecystectomy. Targeted monitoring for high-risk patients and standardized early detection strategies are critical. Future studies should aim to validate these findings in larger, prospective cohorts and investigate the underlying mechanisms—both protective and promotive—by which various histopathological and clinical factors may influence the progression from benign to malignant gallbladder lesions.

1. Introduction

Gallbladder diseases (GABDs) represent a spectrum of diseases ranging from benign conditions like chronic cholecystitis and cholesterolosis to premalignant lesions and adenocarcinoma. These conditions collectively contribute to a significant global health burden, driven by shifts in dietary habits, increasing obesity rates, and an aging population.^[1] Chronic cholecystitis, the most prevalent GABD in clinical practice, often arises from prolonged cholelithiasis. Similarly, cholesterolosis, characterized by lipid-laden macrophages in the gallbladder wall, reflects alterations in lipid metabolism and is becoming increasingly common.^[2]

The clinical relevance of studying gallbladder pathologies extends beyond their prevalence, given their potential to progress to malignancy. Metaplastic transformations, especially intestinal metaplasia, serve as precursors to dysplasia and adenocarcinoma. Although rare, gallbladder adenocarcinoma has a dismal prognosis due to late-stage diagnosis.^[3] Understanding trends in gallbladder pathology is therefore pivotal for early detection, timely intervention, and improved patient outcomes.

While previous studies have explored the epidemiology of GABD, comprehensive longitudinal analyses capturing decade-long trends within specific populations remain limited. Globally, the burden of GABD has undergone a complex transformation. Although age-standardized incidence and prevalence rates have declined over recent decades, the absolute number of cases, deaths, and disability-adjusted life years continues to rise due to population growth and aging. For instance, between 1990 and 2021, the global age-standardized incidence rate of GABD decreased by 12.84%, but the absolute number of cases increased by over 60%.^[3] Similarly, the incident cases of GABD nearly doubled from 1990 to 2019, with a 97% increase in total cases and a 58.9% rise in age-standardized incidence.^[4] Gallstones, as a major component of GABD, were found to have a pooled global prevalence of 6.1%, with higher rates in females, older adults, and residents of upper-middle-income regions.^[5]

This study bridges that gap through a comprehensive review of histopathological reports spanning 10 years at a single tertiary care center. It examines the temporal dynamics of chronic cholecystitis, cholesterolosis, metaplasia, dysplasia, and adenocarcinoma, shedding light on demographic variations and potential risk factors.

While global and multinational datasets offer valuable insight into GABD, regional analyses remain essential due to genetic, ethnic, environmental, and healthcare system-related differences that can significantly affect disease presentation, diagnostic practices, and treatment strategies. Local data help tailor region-specific surveillance protocols and improve clinical outcomes within the populations they serve. The rising incidence of premalignant gallbladder conditions underscores the importance of routine histopathological examination in cholecystectomy specimens. By identifying temporal trends and associated risk factors within this histopathological spectrum, the study informs both clinical decision-making and public health planning—especially for high-risk groups. Beyond its immediate clinical relevance, the findings also highlight potential directions for future research into the genetic and environmental drivers of gallbladder pathology. Finally, the results may support public health efforts aimed at addressing modifiable risk factors, such as obesity and dietary habits, which are closely linked to GABD.^[6] By providing a decade-long perspective, this study contributes to the broader understanding of gallbladder pathology and paves the way for targeted interventions to mitigate the burden of these diseases.

2. Materials and methods

2.1. Study design and setting

This retrospective, observational, and single-center study took place in the Department of General Surgery at the University of Health Sciences, Umraniye Education and Research Hospital, Istanbul, Turkey. The study examined all gallbladder pathology reports from patients who underwent cholecystectomy for cholelithiasis in our clinic between January 2014 and December 2023. The study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology guidelines to ensure methodological rigor and transparent reporting.^[7]

2.2. Study population

The study included all patients aged 18 years and older who underwent elective or emergency cholecystectomy for GABD during the study period. Only patients with cholelithiasis as the surgical indication were included. Suspected malignant conditions, such as porcelain gallbladder, gallbladder polyps, or adenocarcinoma, were excluded. Exclusion criteria also comprised incomplete pathology reports and unrelated incidental findings. Power analysis was not performed due to retrospective nature of the study. All eligible histopathology reports were included in the study.

2.3. Data collection and variables

Data were gathered from the hospital’s pathology database, including patient demographics (age, sex), histopathological diagnoses, and year of surgery. Primary diagnoses of interest were chronic cholecystitis, acute cholecystitis, cholesterolosis, metaplasia, dysplasia, polyp, and adenocarcinoma. Patients with suspected malignant conditions were excluded to focus exclusively on cholelithiasis-related pathologies. Age was recorded as a continuous variable, while sex was categorized as male or female. Additional variables included the type of surgical procedure (elective vs emergency) and whether the surgery was laparoscopic or open. Annual case distributions were analyzed to identify temporal trends.

2.4. Study flow diagram

A flow diagram was created to outline the inclusion and exclusion criteria used in selecting the study population (Fig. 1). This diagram, following Strengthening the Reporting of Observational Studies in Epidemiology guidelines, summarizes the patient selection process from the initial cohort to the final sample included in the analysis. It provides transparency in patient selection.

Figure 1.

Study flow diagram.

2.5. Statistical analysis

Descriptive statistics summarized the data, with continuous variables expressed as means and standard deviations, and categorical variables as frequencies and percentages. Normal distribution of the data was assessed using Shapiro–Wilk test. Continuous variables without normal distribution expressed as median with minimum–maximum values. Age differences across diagnoses were assessed using independent t tests, while chi-square tests compared gender distributions. Temporal trends were analyzed by comparing annual incidence rates of each pathological diagnosis.

Univariate analysis was performed to identify risk factors associated with adenocarcinoma and dysplasia. Significant positive and negative risk factors in univariate analysis were included in multivariate regression model.

All statistical analyses in this study were conducted using two-sided P-values, with a significance threshold set at P < .05. Statistical analyses were performed on SPSS version 26.0 (IBM Corp., Armonk, NY) and data visualization was performed on RStudio ver. 4.6.

2.6. Additional analysis

Subgroup analyses explored potential differences in histopathological findings by age and sex. A multivariable logistic regression analysis was performed to evaluate potential associations between age, sex, and histopathological findings, aiming to strengthen the conclusions. The analysis extended to assess if metaplasia, dysplasia, or adenocarcinoma incidence correlated significantly with increasing age or gender differences.

2.7. Ethical considerations

The study followed the Declaration of Helsinki principles. Ethical approval was obtained from the University of Health Sciences, Umraniye Training and Research Hospital Ethics Committee in 2024 (approval number: 323, date: October 3, 2024), and no informed consent was necessary due to the retrospective nature of the study. Patient privacy was maintained by anonymizing all records and excluding personally identifiable information from the analysis.

3. Results

3.1. Trend analysis of gallbladder pathologies from 2014 to 2023

This study analyzed the pathology reports of 6665 (4568 female and 2097 male) patients who underwent cholecystectomy for cholelithiasis between 2014 and 2023. The mean age was 49.64 ± 14.42. The most common histopathological diagnosis was chronic cholecystitis, followed by cholesterolosis and metaplasia. Malignant cases, including dysplasia and adenocarcinoma, were rare but clinically significant (Table 1). Below is a detailed analysis of each pathology.

Table 1.

Age and gender comparison of common gallbladder pathologies.

Category	n (%)	Age (mean ± SD)	P-value 1	Female/male	P-value 2
All cases	6665 (100%)	49.64 ± 14.42	N/A	4568/2097	N/A
Chronic cholecystitis	5860 (87.92%)	49.15 ± 14.33	<.001	4115/1745	<.001
Acute cholecystitis	59 (0.89%)	51.02 ± 15.37	.461	33/26	.036
Cholesterolosis	1604 (24.07%)	47.52 ± 13.05	<.001	1276/327	<.001
Metaplasia	836 (12.54%)	50.35 ± 14.71	.129	614/222	.001
Dysplasia	207 (3.11%)	52.97 ± 14.18	.001	140/67	.776
Polyp	55 (0.83%)	50.71 ± 13.01	.580	39/16	.772
Adenocarcinoma	21 (0.32%)	57.67 ± 15.13	.008	13/8	.620

t test for age comparison (P-value 1), Pearson chi-square for gender distribution (P-value 2).

3.2. Chronic cholecystitis

Chronic cholecystitis was identified in 5860 (87.92%) patients, with a mean age of 49.15 ± 14.33 years. The condition was more prevalent among females, with a female-to-male ratio of 4115:1745 (P < .001). The annual distribution (Table 2) showed a gradual increase in chronic cholecystitis diagnoses, peaking in 2018 and maintaining a relatively stable incidence afterward. The highest numbers were recorded in 2017 (689 cases), 2018 (737 cases), and 2019 (731 cases). The increasing trend correlates with the rising global burden of GABD. Age distribution over the years remained stable, with a slight increase in the average age in recent years (Table 3).

Table 2.

Ten-year distribution of gallbladder pathologies.

Categories	n (%)	2014	2015	2016	2017	2018	2019	2020	2021	2022	2023
All cases	6665 (100%)	401	427	507	754	827	821	555	800	807	766
Chronic cholecystitis	5860 (87.92%)	370	401	460	689	737	731	465	653	677	677
Acute cholecystitis	59 (0.89%)	14	8	5	3	8	3	2	3	8	5
Cholesterolosis	1604 (24.07%)	113	89	136	179	185	213	138	169	215	173
Metaplasia	836 (12.54%)	64	52	93	162	88	71	56	90	85	89
Dysplasia	207 (3.11%)	3	4	11	20	13	10	24	27	43	52
Polyp	55 (0.83%)	4	0	6	4	4	6	6	7	6	12
Adenocarcinoma	21 (0.32%)	0	2	4	3	2	0	3	4	1	2

Table 3.

Ten-year mean age values of gallbladder pathologies.

Categories	10 years age, mean	2014	2015	2016	2017	2018	2019	2020	2021	2022	2023
All cases	49.64	48.85	48.79	50.10	49.22	49.12	50.58	49.32	49.11	50.34	50.22
Chronic cholecystitis	49.15	48.23	48.49	49.79	48.73	48.71	49.96	48.59	48.36	49.77	50.20
Acute cholecystitis	51.02	57.00	43.13	51.40	26.33	48.38	40.67	45.00	56.33	55.63	63.60
Cholesterolosis	47.53	47.24	46.62	47.21	47.36	47.86	48.01	46.82	47.98	47.12	47.63
Metaplasia	50.35	49.31	48.06	50.09	50.67	49.94	50.99	50.89	50.60	50.40	51.18
Dysplasia	52.97	56.00	49.00	54.82	51.90	53.15	53.10	52.71	50.78	53.49	54.19
Polyp	50.71	49.25	N/A	52.17	53.00	54.00	46.33	47.50	54.86	55.50	47.58
Adenocarcinoma	57.67	N/A	61.00	48.50	48.67	48.50	N/A	66.33	59.50	56.00	69.50

3.3. Acute cholecystitis

Acute cholecystitis was diagnosed in 59 (0.89%) patients, with a mean age of 51.02 ± 15.37 years. Although less common, there was a slightly higher incidence among males (P = .036). Annual trends (Table 2) showed fluctuations, with the highest incidence in 2014 (14 cases) and a decline in recent years. The age distribution (Table 3) varied significantly year-to-year, reflecting the heterogeneous presentation of this acute condition. Care should be taken that acute cholecystitis diagnosis mentioned here depends on the histopathological examination reports only, but not on the clinical and radiological examinations, thus real life number of acute cholecystitis cases might be expected to be higher.

3.4. Cholesterolosis

Cholesterolosis was present in 1604 (24.07%) cases, with a mean age of 47.52 ± 13.05 years. It predominantly affected females (1276:327, P < .001). The number of cases gradually increased over the years, peaking in 2022 (215 cases) and slightly decreasing in 2023 (173 cases) (Table 2). The rising prevalence of cholesterolosis may reflect dietary and metabolic shifts contributing to cholesterol deposition in the gallbladder. The age distribution for cholesterolosis (Table 3) was consistent across the study period.

3.5. Metaplasia

Metaplasia was observed in 836 (12.54%) patients, with a mean age of 50.35 ± 14.71 years. Females were more frequently affected (614:222, P = .001). The annual distribution (Table 2) indicated a peak in 2017 (162 cases), followed by fluctuations in subsequent years. The presence of metaplasia is clinically significant due to its potential role as a precursor for dysplastic and neoplastic changes. The mean age for metaplasia varied slightly over the years, with some peaks in specific years (Table 3).

3.6. Dysplasia

Dysplasia, including both low-grade and high-grade forms, was identified in 207 (3.11%) patients. The mean age was 52.97 ± 14.18 years, with no significant gender difference (P = .776). Notably, the number of dysplasia cases increased steadily, with a marked rise in 2022 (43 cases) and 2023 (52 cases) (Table 2). This trend underscores the importance of vigilant screening and follow-up, particularly for patients with metaplastic changes, as dysplasia serves as a critical precursor for gallbladder carcinoma. Age distribution data (Table 3) also indicate variability, particularly in the earlier years.

3.7. Gallbladder polyps

Gallbladder polyps were found in 55 (0.83%) patients, with a mean age of 50.71 ± 13.01 years. The condition showed no significant difference in gender distribution (P = .772). The incidence of polyps was low and relatively stable throughout the study period, with the highest number recorded in 2023 (12 cases) (Table 2). Given the potential for polyps to develop into dysplasia or malignancy, close monitoring is warranted, especially for polyps larger than 1 cm.

3.8. Adenocarcinoma

Adenocarcinoma was diagnosed in 22 (0.33%) cases, with a mean age of 57.73 ± 15.13 years. The incidence remained low but consistent across the study period, with a few isolated peaks. The highest numbers were reported in 2016 (4 cases) and 2021 (4 cases) (Table 2). The stable yet concerning presence of adenocarcinoma aligns with previous studies highlighting the incidental nature of gallbladder carcinoma, often discovered during routine cholecystectomy for benign conditions. The age distribution (Table 3) for adenocarcinoma showed significant variability, reflecting the heterogeneity of this condition.

3.9. Correlation analysis

The relationships between patient age, metaplasia, dysplasia, polyps, and adenocarcinoma were evaluated using Pearson correlation coefficients. Figure 2 presents the correlation matrix summarizing these relationships.

Figure 2.

Heatmap matrix of correlations. P-value heatmap of pairwise associations between age, metaplasia, dysplasia, polyp, and adenocarcinoma. Darker red indicates more significant P-values. White reflects nonsignificant results. Diagonal and redundant values were omitted for clarity.

• Age was significantly correlated with dysplasia (r = 0.041, P = .001) and adenocarcinoma (r = 0.032, P = .008). No significant correlation was found between age and metaplasia (r = 0.019, P = .129) or polyp presence (r = 0.007, P = .58).

• Metaplasia exhibited a significant positive correlation with dysplasia (r = 0.214, P < .001), but it did not show significant correlations with age (r = 0.019, P = .129), polyp presence (r = ‐0.005, P = .713), or adenocarcinoma (r = ‐0.014, P = .257).

• Dysplasia was significantly associated with polyps (r = 0.041, P = .001) and adenocarcinoma (r = 0.186, P < .001). Additionally, dysplasia showed a positive correlation with age (r = 0.041, P = .001) and metaplasia (r = 0.214, P < .001).

• Polyp presence was positively correlated with both dysplasia (r = 0.041, P = .001) and adenocarcinoma (r = 0.053, P < .001), but there were no significant correlations with age (r = 0.007, P = .58) or metaplasia (r = ‐0.005, P = .713).

• Adenocarcinoma was significantly correlated with dysplasia (r = 0.186, P < .001) and polyp presence (r = 0.053, P < .001). It also exhibited a weak but significant correlation with age (r = 0.032, P = .008), while its correlation with metaplasia was not significant (r = ‐0.014, P = .257).

3.10. Multivariable logistic regression analysis

To strengthen the findings, a multivariable logistic regression analysis was performed to evaluate the factors independently associated with dysplasia and adenocarcinoma. Variables included age, gender, presence of metaplasia, and presence of gallbladder polyps. Detailed results of the univariate and multivariate analyses are presented in Table 4.

Table 4.

Univariate and multivariate analysis of risk factors associated with adenocarcinoma and dysplasia.

Adenocarcinoma
Univariate					Multivariate
	B	P-value	Exp(B)	95% CI	B	P-value	Exp(B)	95% CI
Age	0.039	.009	1.040		0.023	.160	1.023
Gender	0.220	.621	1.246
Gallstones	−1.434	.003	0.238	0.09–0.61	−1.168	.036	0.311	0.10–0.91
Acute cholecystitis	−15.502	.998	0.000
Low-grade dysplasia	−15.512	.997	0.000
High-grade dysplasia	6.191	.000	488.162	120.58–1976.20	5.733	.000	308.980	63.49–1984.71
Chronic cholecystitis	−2.368	.000	0.094	0.04–0.22	−1.677	.001	0.187	0.05–0.45
Polyps	2.520	.001	12.434	2.83–54.53	2.940	.000	18.923	4.12–92.51
Intestinal metaplasia	4.370	.000	79.036	8.47–737.07	3.887	.005	48.767	4.74–831.10
Pyloric Metaplasia	−15.566	.993	0.000
Constant						.00	0.01

Dysplasia
	Univariate				Multivariate
	B	P-value	Exp(B)	95% CI	B	P-value	Exp(B)	95% CI
	0.020	.001	1.021	1.09–1.03	0.023	.000	1.023	1.01–1.03
Age	0.064	.730	1.066	0.65–1.35
Gender	−0.103	.919	0.902	0.12–6.56
Polyps	2.923	.000	18.601	12.94–26.72	2.936	.000	18.848	13.06–27.19
Intestinal metaplasia	0.514	.065	1.671	0.96–288	0.205	.490	1.227	0.68–2.19
Pyloric metaplasia	−17.325	.997	0.000	0.00–0.00	−17.325	.997	0.000
Acute cholecystitis	−0.124	.627	0.883	0.53–1.45
Chronic cholecystitis	−0.088	.618	0.915	0.64–1.29
Gallstones
Constant						.00	0.04

The bold values indicate statistical significance at P < .05.

3.11. Key findings

3.11.1. Dysplasia

In the univariate analysis, age (P = .001) and intestinal metaplasia (P < .001) were significantly associated with dysplasia, while pyloric metaplasia showed a borderline association (P = .065). These variables were included in the multivariate model. In the multivariate analysis, both age (P < .001) and polyps (P < .001) emerged as independent predictors. Specifically, each additional year of age increased the odds of dysplasia by 2.3% (odds ratio [OR] = 1.023, 95% CI:1.01–1.03), and the presence of polyps increased the odds by nearly 19-fold (OR = 18.8, 95% CI:13.1–27.2). Other variables—including gender, gallstones, and cholecystitis—were not significantly associated with dysplasia

3.11.2. Adenocarcinoma

Univariate analysis revealed significant associations with age (P = .009), gallstones (P = .003), high-grade dysplasia (HGD) (P < .001), chronic cholecystitis (P < .001), polyps (P = .001), and intestinal metaplasia (P < .001). Nonsignificant variables, including gender, acute cholecystitis, low-grade dysplasia, and pyloric metaplasia, were excluded from the multivariate model.

In multivariate analysis, age lost statistical significance, while the following remained independently associated with adenocarcinoma:

• ○HGD (P < .001): OR = 309 (95% CI:63.5–1984.7),
• ○Polyps (P < .001): OR = 18.9 (95% CI:4.1–92.5),
• ○Intestinal metaplasia (P = .005): OR = 48.8 (95% CI:4.7–831.1).

Conversely, gallstones (P = .036; OR = 0.31, 95% CI: 0.10–0.91) and chronic cholecystitis (P = .001; OR = 0.19, 95% CI: 0.05–0.45) were found to be protective, each significantly reducing the risk of adenocarcinoma.

4. Discussion

This ten-year observational study provides insights into gallbladder pathologies in a tertiary care setting, focusing on chronic cholecystitis, cholesterolosis, metaplasia, dysplasia, and adenocarcinoma. The study reveals a rising incidence of these pathologies, with chronic cholecystitis being the most common GABD. Moreover, there is an increasing trend in precancerous lesions like metaplasia, dysplasia, and polyps, emphasizing the importance of vigilant screening and appropriate management strategies. The increase in chronic cholecystitis cases may be linked to lifestyle factors such as high-fat and high-carbohydrate diets, sedentary behavior, obesity, and metabolic syndrome.^[1,2] Cholesterolosis, another prevalent condition observed, reflects the impact of these lifestyle factors. The rise in metaplasia and dysplasia cases, especially in recent years, is concerning due to their potential progression to gallbladder carcinoma. Metaplasia, a precursor to dysplasia and adenocarcinoma, may result from increased awareness, improved diagnostics, and environmental or genetic factors.^[5,8] This highlights the necessity of early intervention protocols and follow-up mechanisms to manage high-risk patients effectively. Despite the rarity of adenocarcinoma, routine histopathological examination of gallbladder specimens post-cholecystectomy is crucial. Our findings align with a previous study highlighting chronic cholecystitis as the most common diagnosis in elective laparoscopic cholecystectomy cases.^[9] Incidental gallbladder cancer was rare but underscores the importance of histopathological examination for early detection. The study extends these observations, showing a rise in precursor lesions like metaplasia and dysplasia. Understanding risk factors like chronic inflammation, metabolic disturbances, and environmental exposures is crucial for early detection and targeted prevention strategies.^[8–10]

Our study supports these findings by showing an increase in metaplasia and dysplasia cases over the last decade. Metaplasia was present in 12.54% of cases, and dysplasia in 3.11% of cases, indicating a growing concern for malignancy progression. Enhanced surveillance, especially in patients with chronic gallbladder conditions, is essential due to the strong association of these pathological changes with increased cancer risk. Further studies exploring the clinical course of patients with dysplasia and metaplasia post-cholecystectomy could provide deeper insights into progression risks.

During the 10-year study period, chronic cholecystitis remained the most common diagnosis, accounting for 88% of cases, in line with global trends influenced by increasing obesity and dietary factors. Although its incidence peaked in 2018, it remained stable thereafter. There was a notable increase in dysplasia and metaplasia, particularly between 2017 and 2023, which are known precursors to gallbladder cancer. Notably, standardized diagnostic criteria were not consistently employed throughout the study period, which may influence these findings and highlights the need for uniformity in future studies. This trend underscores the importance of regular histopathological evaluations for early identification of high-risk patients. While gallbladder polyps were less common (0.83%), larger polyps (>1 cm) and their association with dysplasia require close monitoring to prevent potential malignant progression.

In this study, logistic regression analysis identified key factors associated with dysplasia and adenocarcinoma in gallbladder specimens. Age and intestinal metaplasia emerged as independent predictors of dysplasia, suggesting a possible age-related metaplastic sequence in the early stages of gallbladder carcinogenesis. The presence of polyps was also strongly associated with dysplasia, underscoring their clinical significance even in asymptomatic cases.

For adenocarcinoma, HGD, polyps, and intestinal metaplasia were found to significantly increase the odds of malignancy, highlighting their roles as important markers in the malignant transformation pathway. This is further supported by recent evidence from a large pathological series in which neoplastic transformation was identified in 9.9% of adenomyomatous lesions, including mural intracholecystic neoplasms and flat-type HGD. Although only 1.8% of these cases showed carcinoma confined to and arising from adenomyomatosis, the findings reinforce the malignant potential of certain polypoid gallbladder lesions.^[10]

Interestingly, both chronic cholecystitis and gallstones were inversely associated with adenocarcinoma risk in the adjusted model. Although this may appear counterintuitive—given that chronic inflammation is typically implicated in cancer development—certain inflammatory processes may instead activate immune surveillance pathways that inhibit neoplastic progression. For example, acute inflammation has been linked to dendritic cell maturation and enhanced antigen presentation, thereby facilitating antitumor immune responses.^[11] Beyond immunologic factors, the clinical manifestation of cholecystitis often involves more pronounced symptoms, potentially leading to earlier diagnosis and expedited surgical intervention, which could shorten the window for malignant transformation. It is also important to note that in this study, the diagnosis of cholecystitis—whether acute or chronic—was based solely on histopathological findings, which may not fully capture clinical severity and could introduce classification bias.

Gallstones are known to be the primary risk factor associated with gallbladder cancer.^[12] However, in our study, the presence of gallstones was paradoxically associated with a reduced risk of adenocarcinoma. This unexpected finding may reflect reporting biases, as histopathological documentation often prioritizes malignant diagnoses, potentially underrepresenting coexisting benign conditions such as cholelithiasis. Additionally, overlapping histologic features between reactive and neoplastic changes could lead to underdiagnosis or misclassification. These results should therefore be interpreted with caution and underscore the need for prospective, mechanistically driven studies to determine whether the observed protective association is biologically plausible or merely an artifact of sampling or diagnostic practices.

5. Interpretation and clinical implications

Our study highlights significant pathological relationships in GABD. The positive correlation between dysplasia and adenocarcinoma underscores the importance of early detection and monitoring of dysplastic changes in gallbladder specimens. While age shows a weak correlation with dysplasia and adenocarcinoma, it remains a relevant factor in assessing patient risk.

Although these correlations are generally weak to moderate, suggesting associations between variables, they may not be strong predictors in isolation. Future multivariable analyses incorporating comorbid conditions, genetic predispositions, and lifestyle factors could provide a more robust understanding of these associations. Genetic predispositions, lifestyle factors, and comorbid conditions may also play critical roles and warrant further investigation.

6. Limitations and biases

This single-center study has limitations that affect the generalizability of the results. The study’s setting, patient demographics, and local healthcare practices may differ from other populations, limiting the broader applicability of our findings. Future multicenter studies with diverse patient populations are needed to confirm these trends.

The retrospective design introduces selection bias by including only patients who underwent cholecystectomy, potentially excluding less severe cases managed conservatively. Additionally, reliance solely on histopathological findings may introduce diagnostic bias, as clinical context and severity were not considered. Future prospective studies with broader inclusion criteria are recommended to capture the full spectrum of gallbladder pathologies. Incorporating clinical and imaging data in future studies would enhance understanding of how these factors influence disease progression.

Improved diagnostic accuracy and increased awareness over time may contribute to higher detection rates of metaplasia and dysplasia, potentially inflating observed trends. Standardizing diagnostic approaches could help mitigate this bias in future studies. Misclassification bias due to subjective histopathological interpretation and interobserver variability should be addressed by implementing uniform diagnostic criteria and involving multiple pathologists in complex cases.^[13,14]

7. Conclusions

This large-scale retrospective analysis of cholecystectomy specimens over a 10-year period highlights the predominance of chronic cholecystitis and cholesterolosis in gallbladder pathology, while also identifying important associations with premalignant and malignant conditions. Dysplasia and adenocarcinoma, though relatively rare, showed significant associations with advancing age, polyps, and intestinal metaplasia. Multivariate analysis confirmed that polyps and age were independent predictors of dysplasia, whereas HGD, polyps, and intestinal metaplasia were strong independent risk factors for adenocarcinoma. Interestingly, chronic cholecystitis and gallstones were inversely associated with adenocarcinoma, suggesting a possible protective effect that warrants further investigation. These findings underscore the importance of routine histopathological examination following cholecystectomy and highlight the need for vigilant surveillance in patients with polyps or metaplastic changes due to their strong association with neoplastic progression.

Author contributions

Conceptualization: İlyas Kudaş, Fatih Basak, Yahya Kemal Çalişkan.

Data curation: Hüsna Tosun, Aylin Acar, Tolga Canbak, Kemal Tekeşin.

Formal analysis: İlyas Kudaş, Fatih Basak, Yahya Kemal Çalişkan, Olgun Erdem.

Investigation: Fatih Başak, Aylin Acar.

Methodology: Hüsna Tosun, Aylin Acar, Tolga Canbak, Kemal Tekeşin.

Writing – original draft: Hüsna Tosun, Aylin Acar, Tolga Canbak, Kemal Tekeşin.

Writing – review & editing: İlyas Kudaş, Fatih Basak, Yahya Kemal Çalişkan, Olgun Erdem.