Suspicious Gallbladder Wall Thickening: A Tertiary Cancer Institute Observation on Malignant Potential

Abstract

In India, gallbladder cancer (GBC) is most prevalent in the northern and northeastern states as reported by Nandakumar et al. (Int J Cancer 116(5):740–754, 2005). The presenting symptoms are typically vague, and diagnosis commonly occurs at an advanced stage. Structural changes in the gallbladder include mass (40–65%), focal or diffuse parietal thickening (20–30%), and intraluminal polyps (15–25%) as discussed by Pilgrim et al. (Dig Dis Sci 58(9):2455–2462, 2013). Patient data were collected retrospectively from the hospital database between December 2020 and July 2023. A total of 82 patients were included. Surgical procedures included both open and laparoscopic cholecystectomies. Intraoperative frozen sectioning was performed for every patient, and further surgical planning was performed. All the statistical analyses were performed using SPSS for Windows. Fifty-one patients (62%) had malignant disease according to final histopathology. In that subset of patients (malignant), the mean age was 54.8 years and female to male ratio was 4.6:1. On cross-sectional imaging, most of the patients (82%) had thickening of the fundus and body region. On frozen section, 47 patients (57.3%) were positive, and 10 (12.2%) were suspicious for malignancy. On final histopathology, the most common histology was well-differentiated adenocarcinoma (45%). Forty-three percent of malignant patients had concomitant gallstones. Only 22 patients had positive lymph nodes (N +). The mean number of lymph nodes harvested was 8.23 ± 0.57, while the mean positive yield was 1.15 ± 0.3. The observed 62% malignant transformation rate combined with high incidence of female disease and late-stage diagnosis emphasizes the need for improved diagnostic strategies and timely intervention. This study highlights the utility of frozen sections in surgical decision-making and the pressing need for specialized centers, multidisciplinary collaboration, and standardized protocols to address the challenges of identifying gallbladder malignancies.

Introduction

In India, gallbladder cancer (GBC) is most prevalent in the northern and northeastern states [1]. The presenting symptoms are typically vague, and diagnosis commonly occurs at an advanced stage. Structural changes in the gallbladder include mass (40–65%), focal or diffuse parietal thickening (20–30%), and intraluminal polyps (15–25%) (2). Gallbladder wall thickening is a very common finding on ultrasound and can be related to a wide spectrum of gallbladder diseases ranging from infectious to benign and even malignant conditions. The pattern of gallbladder wall thickening has a variable presentation ranging from diffuse thickening related to benign conditions to focal asymmetric wall thickening with malignancies [3]. In India, especially around the Indo-Gangetic Plain, gallbladder stone disease is very common. Moreover, this region also has a high incidence of gallbladder cancer. According to the 2017 National Centre for Disease Informatics and Research (NCDIR) data, gallbladder malignancy is the 5th most common cancer in women in the northeastern parts of India. Early diagnosis of gallbladder cancer remains a challenge despite advances in cross-sectional imaging and overall healthcare services. This is mainly due to nonspecific symptoms and upper gastrointestinal discomfort. Jaundice is a late sign of disease and is usually associated with a dismal prognosis and advanced disease. Due to the high prevalence of gallstones, gallbladder wall thickening is often overlooked by treating physicians, and patients undergo surgery without proper evaluation. In such scenarios, intraoperative surprises perplex operating surgeons, leading to a high rate of subtotal cholecystectomies and incomplete surgeries due to advanced presentation and lack of surgical expertise. This study illustrates the malignant potential of suspicious gallbladder wall thickening patients and the implications of having a high index of suspicion in such cases.

Materials and Methods

This was a retrospective observational study from an apex referral cancer center in northeast India (Assam). Patient data was retrospectively collected from the hospital database (both electronic and manual case sheets) from 1 December 2020 to 31 July 2023. All eligible patients with suspicious gallbladder wall thickening on ultrasound or computed tomography (CECT) scan (> 3 mm thickness) were included in the analysis. Most of the patients were referred cases from other medical colleges for suspected malignancy. All patients underwent routine blood tests, serum tumor markers (CA-199, CEA) and a contrast-enhanced CT scan of the thorax, abdomen, and pelvis as a standard staging procedure in our institute. Patients with incidental carcinoma of the gallbladder, any GB mass/polyp, gallstones without gallbladder wall thickening (> 3 mm), acute cholecystitis, and metastatic/locally advanced (N +) gallbladder cancer were excluded. The collected data was filled up in a study proforma which included patient demographics, imaging findings, operative details, and final histopathology reports. A total of 82 patients who fulfilled the inclusion criteria were included in the study. All patients underwent multidisciplinary tumor board clearance as a part of our institutional protocol prior to surgery. Open cholecystectomy was preferred for most patients because of the risk of intraoperative perforation and biliary spillage during laparoscopic cholecystectomy (as a relative contraindication for gallbladder malignancies, leading to an upstage of clinical disease). In patients with a blurred or indistinct GB-hepatic interface, extended cholecystectomy was performed en bloc with a wedge of the liver. All resected gallbladder specimens were sent for frozen section analysis for diagnosis (benign or malignant), and those suspicious or positive for malignancy further underwent radical cholecystectomy (i.e., inter-aortocaval lymph nodal sampling f/b extended cholecystectomy with wedge resection of the liver and regional lymphadenectomy (stations 8, 12, 13a). Inter-aortocaval lymph node sampling was performed for all patients who were positive for malignancy before proceeding with radical cholecystectomy (Fig. 1). The final histopathological findings were rigorously studied for histology, lymph node harvested and positivity and final stage.

Fig. 1.

Algorithm for approaching a patient with suspected GB wall thickening

Statistical Analysis

Descriptive statistics were used to summarize the characteristics of the study population and the distribution of the outcome measures. Continuous variables were represented as mean and categorical variables as percentages. Sensitivity and specificity of frozen section were calculated and represented as percentage. The results were tabulated and are presented in a graphical format.

Results

A total of 164 patients with operable gallbladder malignancies were analyzed over a 3-year period, and 82 patients with suspicious GB wall thickening (> 3 mm wall thickness on USG/CECT scan) were included in the study. Fifty-one patients were positive for malignancy on final histopathology (~ 62%), 38% had benign disease, and 11% had xanthogranulomatous cholecystitis. According to the subgroup analysis of the malignant subset, the mean age was 54.8 years, and the female preponderance was 4.6 times higher than males. Only 4 patients out of 51 had presented with jaundice (Table 1).

Table 1.

Patient demographics

Parameters	Chronic cholecystitis	Malignancy	Xanthogranulomatous cholecystitis
Patients—82 (percentage)	22 (38%)	51 (62%)	9 (11%)
Mean age (years)	50.22	54.88	51.44
Female	14	42	7
Male	8	9	2
Female to male ratio	1.75:1	4.6:1	3.5:1
Presence of jaundice	1/22	4/51	1/9

On staging workup by cross-sectional imaging (CECT), the fundus of the gallbladder was the most common site of thickening (51.2%), and 27% of the patients had clinical nodal enlargement (cN +) (Fig. 2). Three patients had contiguous thickening of the bile duct wall. All the patients were subjected to frozen section analysis of the resected gallbladder, which revealed that the sensitivity and specificity were 96% and 71%, respectively (Fig. 3). In all malignant patients, inter-aortocaval node sampling was performed, and the samples were sent for frozen section before proceeding to radical cholecystectomy. Among 47 patients who were positive for malignancy according to frozen sectioning, inter-aortocaval lymph node sampling was performed, and 5 of them were positive. For those subsets in which the nodal frozen section was positive, further surgery was abandoned. Two patients had cystic duct margins positive for malignancy on frozen section, for which extrahepatic bile duct excision was performed followed by end to side hepaticojejunostomy using PDS 4–0.

Fig. 2.

Subsites of GB wall thickening

Fig. 3.

Results of frozen section analysis of the GB specimen

On final histopathology, the most common histology was well-differentiated adenocarcinoma (45.09%), followed by moderately differentiated adenocarcinoma (43.13%) (Fig. 4). Twenty percent of patients had lympho-vascular and perineural invasion. In 3 patients, a contiguous resected wedge of the liver was invaded by the tumor but the hepatic cut margin was free (R₀). Final histopathological analysis revealed that 43% of the patients had pathological nodal involvement (pN +) (Fig. 5).

Fig. 4.

Histological variation in malignant subsets

Fig. 5.

Distribution of pathological nodal status among malignant subset

The mean lymph node harvest was 8.23, and the positive nodal yield was 2.95. Concomitant gallstone disease was present in 22 out of 51 patients (43%) of malignancy. Further analysis of the pathological stage of the malignant subset revealed 25.4% to be stage II, followed by IIIB in 21.5%. Surprisingly, 14 patients (26%) had stage IV disease (either N2 or M1 disease) (Table 2). There were six patients of stage IVb, where three of them had subcentimetric peritoneal deposits, two had liver surface deposits, and one had non-contiguous deposit over hepatic flexure of colon. Among the 9 stage I patients, only 1 patient was pT1a, and the rest were all pT1b. Preoperatively determining pT status in this subset was not possible on either imaging or frozen section analysis.

Table 2.

Stage distribution on final histopathology

Stage of CA gallbladder	Cases (percentage)
I (pT1 N0 M0)	09 (17.6%)
II (pT2a/b N0 M0)	13 (25.4%)
III A (pT3 N0 M0)	04 (7.84%)
III B (pT1-3 N1 M0)	11 (21.5%)
IV A (pT4 N0-1 M0)	00
IV B (N2)	08 (15.6%)
IV B (M1)	06 (11.7%)

Discussion

Gallbladder malignancies have the highest incidence in the North Indian Gangetic Belts (Uttar Pradesh, Bihar, Jharkhand, Bengal, Orissa, Assam). According to the population-based cancer registry in Delhi, the incidence is significantly greater in the north than in the south of India (4.5 per 100,000 for men and 10.1 per 100,000 for women in the north vs. 1.2 per 100,000 for men and 0.9 per 100,000 for women in the south) [4]. In the northeastern states of India, carcinoma gallbladder is the 5th most common malignancy among women according to ICMR 2017 data [5]. In our study, the male to female ratio of gallbladder malignancies was 1:4.6, which is comparable to that in similar Indian literature [3, 4, 6, 7].

Gallbladder wall thickening can be associated with both benign and malignant pathologies. Focal asymmetrical thickening of the gallbladder wall on imaging is usually associated with malignancy, and symmetrical diffuse thickening suggests a benign etiology. In our study, out of the 82 patients, 94% (77) had focal wall thickening, and only 5 had diffuse wall thickening. Of the 5 patients with diffuse wall thickening on imaging, only 1 patient had malignant disease according to histopathology. Surgeons should have a high index of suspicion for focal asymmetric thickening of the gallbladder, as in our study, in patients with focal asymmetrical thickening, around 66.2% of them turned malignant. One of the benign conditions that closely mimics gallbladder malignancy on imaging is xanthogranulomatous cholecystitis [8]. In our study, 11% of the patients had xanthogranulomatous cholecystitis on either the frozen section or final HPE, and most of them warranted extended cholecystectomy on the operating table due to dense adhesion with the adjacent liver parenchyma. We utilized frozen sectioning to diagnose the gallbladder after resection. In this study, the sensitivity and specificity of frozen section analysis was 96% (49 out of 51) and 71% (22 out of 31), respectively. In a few xanthogranulomatous cases (6 out of 9–66%), due to the high suspicion of malignancy, regional lymphadenectomy was also performed for oncological safety, but all were pN₀ on final biopsy.

Another important finding on cross-sectional imaging that can guide surgeons and clinicians is the presence of regional lymphadenopathy. Prominently enlarged regional lymph nodes, such as periportal, retro-duodenal, peripancreatic, and para-aortic stations, can suggest a greater chance of malignancy. Contrast-enhanced CT of the abdomen is highly sensitive for identifying these enlarged lymph nodes. However, these lymph nodes, when resected during radical surgery, were reactive in approximately half of the time according to the final histopathology. In our subset, the sensitivity of CECT for detecting metastatic lymph nodes was only 54%. Frozen section analysis of the lymph nodes provided on-table results regarding the involvement of the lymph nodes by tumor. This approach can alter the course of management in gallbladder cancer patients. According to the latest National Comprehensive Cancer Network (NCCN) and American Joint Committee on Cancer (AJCC) recommendations, the involvement of para-aortic or inter-aortocaval lymph nodes is a poor prognostic factor. These stations are located within a nonregional group of lymph nodes and indicate metastatic disease (M1). As such, the involvement of the inter-aortocaval group of lymph nodes by tumors precludes any further surgery. Likewise, we performed frozen section analysis of sampled inter-aortocaval lymph nodes in all malignant subsets before performing radical cholecystectomy. Here, the sensitivity and specificity of frozen sectioning (for node) were 89% and 83.7%, respectively. However, the addition of frozen sections increases the operative time and additional costs. In a similar study by Chan et al., frozen sections had a very high negative predictive value of 99.6% and were associated with a significantly longer operative time (p value = 0.0004) [9]. Despite the risk to benefit ratio, frozen sections are a very important adjunct to the current armamentarium of the surgical oncologist and can prevent unnecessary radical surgeries.

In our study, 62% of the patients were malignant on final histopathological examination. Two patients required extrahepatic bile duct excision and end-to-side hepaticojejunostomy because they had positive cystic duct margins on frozen section. Approximately 20% of the malignant subset had either lympho-vascular or perineural invasion, which again is a poor prognostic factor. Only 3 patients had involvement of the resected wedge of the liver by the tumor (5.88%). However, the liver cut margin was free of tumor in all cases (R₀). According to the recent edition of the AJCC staging system, a minimum of 6 lymph nodes need to be resected for adequate oncological clearance [10]. In our study, the mean number of lymph nodes harvested was 8.23 ± 0.57, and the mean positive lymph node yield was 2.95 ± 0.3, thus highlighting the adequacy of the surgical procedure.

Gallstones have been historically associated with an increased risk of biliary tract malignancies. According to a meta-analysis by Huang et al., an elevated risk of BTC (OR, 4.38; 95% CI, 3.23 to 5.93; I² = 91.2%) and GBC (OR, 7.26; 95% CI, 4.33 to 12.18) was linked to the presence of gallstones [11]. In this study, 43% of the malignant patients had gallstones. However, in the entire study population, only 33 patients had gallstones (40.24%).

In this study, we intended to determine the prevalence of malignancy among patients with suspicious gallbladder thickening. To our surprise, most of the malignant patients had locally advanced cancer (stage II and above—82.4%). This highlights the fact that all suspected gallbladder wall thickening cases should be evaluated with a high index of suspicion. These patients should be thoroughly evaluated via cross-sectional imaging (CECT) and ideally be referred to higher centers for better outcomes.

Conclusion

The observed malignant transformation rate of 62% among patients with such presentation coupled with the high female predilection and late-stage diagnosis emphasizes the urgent need for improved diagnostic strategies and timely intervention. This research highlights the utility of intraoperative frozen section analyses in guiding surgical decision-making. The correlation between gallstone disease and malignancy suggests a potential avenue for preventative strategies. This study underscores the pressing need for enhanced diagnostic techniques, early referral to surgical experts, multidisciplinary approaches, and public health initiatives to address the challenges posed by gallbladder cancer.

Abbreviations

GBC

Gallbladder cancer

GB

Gallbladder

USG

Ultrasound

CECT

Contrast-enhanced computed tomography

HPE

Histopathology

Author Contribution

All the authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Mohammad Masoom Parwez, Naveen Saini, and Rohit Tewari. The first draft of the manuscript was written by Mohammad Masoom Parwez, and all the authors commented on previous versions of the manuscript. All the authors read and approved the final manuscript.

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Declarations

Ethics Approval

This was a retrospective observational study. The Institutional Research Ethics Committee has confirmed that no ethical approval is needed.

Consent to Participate

Informed consent was obtained from all individual participants included in the study.

Competing Interests

The authors declare no competing interests.