Navigating the Diagnostic Dilemma of Evaluating Gallbladder Wall Thickening: Are We There Yet?

In a recently published article in the Journal of Clinical and Experimental Hepatology, Kalage et al. prospectively compared the diagnostic accuracy of contrast-enhanced CT and MRI for evaluating gallbladder wall thickening type of gallbladder carcinoma (GBC).¹ They prospectively studied 33 patients with gallbladder wall thickening undergoing diagnostic contrast-enhanced CT and MRI by assessing various morphological features of gallbladder wall thickening including the pattern of involvement, symmetry, presence of intramural cysts or nodules, the pattern of enhancement, diffusion restriction and presence of ancillary features such as pericholecystic fat stranding, interface with liver, biliary obstruction, abdominal lymphadenopathy. Pathological confirmation was obtained through surgical resection performed within 4 weeks of imaging. The authors report that MRI had higher diagnostic accuracy for identification of malignant gallbladder wall thickening. Certain morphological characteristics were specific for malignant involvement such as heterogenous enhancement, indistinct interface with liver and diffusion restriction. Heterogenous enhancement had the highest accuracy (81.8%) while diffusion restriction provided highest sensitivity (100%) followed by indistinct with liver surface (92.3%). However, indistinct liver interface had higher specificity (75%) compared to diffusion restriction (60%). The presence of T2 hyperintense intramural cysts on MRI was highly specific (100%) for diagnosis of benign gallbladder wall thickening but had low sensitivity (40%). This imaging feature that has been previously described with adenomyomatosis was encountered in cases with chronic cholecystitis and xanthogranulomatous cholecystitis in this study. The authors state that MRI performs better; however, they advocate that CT and MRI have a complementary role in the evaluation of gallbladder wall thickening in order to achieve higher diagnostic confidence for the diagnosis of malignant involvement.

Gallbladder cancer is an uncommon malignancy arising from gallbladder epithelium, associated with an overall poor prognosis. In 2022, the global incidence of GBC reached 122,491 cases, with Asia bearing the highest burden at 71.9%, followed by Europe at 10.3%, and Latin America and the Caribbean at 8.5%.² According to the latest SEER statistics, the five-year relative survival rate for localized GBC is 69%, and for distant GBC, it is 3%.^3,4 The development of gallbladder cancer is related to chronic inflammation and is associated with multiple risk factors such as gallstones, porcelain gallbladder, ethnicity, geography, choledochal cysts, gallbladder polyps (>10 mm), primary sclerosing cholangitis, abnormal pancreaticobiliary junction and typhoid fever.⁵ Early and prompt diagnosis of precursor lesions such as gallbladder adenoma or identifying high-risk populations for GBC is imperative for effective management and improved patient outcomes. Various treatment options for localized and locally advanced GBC comprise surgical resection, external-beam radiation therapy, and ongoing clinical trials investigating the efficacy of radiation therapy combined with radiosensitizer drugs to enhance local control.⁶ Imaging not only plays an important role in the diagnosis, staging, and restaging of GBC but also in incidental detection of gallbladder polyps, wall thickening, or early gallbladder cancer, facilitating appropriate follow-up and surveillance.

Gallbladder cancer can have varied imaging appearances. Large mass replacing the entire gallbladder is most frequently encountered, accounting for 40–65% cases, followed by wall thickening in 20–30% and intraluminal polypoidal mass in 15–25% cases.^7,8 While GBC can manifest as focal or diffuse wall thickening or polypoidal lesions, this imaging appearance is often non-specific and is attributed to a wide spectrum of pathological conditions.⁹ In a large cohort study conducted by Szpakowski and Tucker, 0.054% of patients with gallbladder polyps developed GBC.¹⁰ However, incidental detection of these lesions often leads to frequent and prolonged follow-up imaging of questionable benefit, unnecessary surgical resection, patient anxiety, and inconvenience. For screening and risk stratification of non-acute gallbladder wall thickening and gallbladder polyps, ultrasound is the most commonly used modality.¹¹ The Society of Radiologists in Ultrasound (SRU) consensus conference committee in 2021 provided guidelines to stratify polypoidal lesions of gallbladder or gallbladder polyps into extremely low-risk, low risk, and indeterminate-risk polyps to allow for appropriate management of incidental gallbladder polyps at ultrasound.¹² A recent study by Anderson et al., found substantial agreement for polyp risk categorization and surgical consultation recommendations among 10 radiologists, supporting the reproducibility of the SRU recommendations.¹³ Similar efforts in standardization and interpretation of gallbladder wall thickening include gallbladder reporting and data system (GB-RADS), a risk stratification system for gallbladder wall thickening reported by an international multidisciplinary expert consensus group in 2021.¹⁴ The lexicon provided includes details such as intraluminal changes (distension, contents) and mural changes (symmetry, extent of involvement, site of thickening, mural layering, intramural changes and interface with liver). GB-RADS is a first collaborative effort and a significant step towards improving objective assessment and accuracy in reporting gallbladder wall abnormalities, thereby providing streamlined management recommendations. Soundararajan et al. conducted a multi-reader validation study to evaluate the agreement of GB-RADS.¹⁵ Their findings revealed moderate intrareader consensus but highlighted a concerning low interreader agreement for individual GB-RADS categories. This underscores the pressing need for expansive multi-centric studies with larger cohorts for validation of GB-RADS.

Cross-sectional imaging, including CT, MRI, and magnetic resonance cholangiopancreaticogram (MRCP) are widely used in the assessment of gallbladder lesions and to accurately diagnose GBC. Prospective efforts by Kalage et al. highlight the importance of the utilization of CT and MRI in the characterization of gallbladder wall thickening to precisely identify the presence of GBC.¹ Cha and colleagues compared the robustness of MDCT and MRI with and without gadolinium-based contrast medium administration in distinguishing GBC from benign disease.¹⁶ In this study of 101 patients, they found that non-contrast MRI was superior to MDCT for diagnosis of GBC that present as mild wall thickening on MDCT. He et al. reported similar findings and found that a combination of layered pattern on DWI and papillary growth on non-contrast MRI were optimal indicators to differentiate benign from malignant gallbladder wall thickening.¹⁷ In another recent study comparing multiparametric MRI (mpMRI) with conventional MRI, Kalage et al. found that mpMRI (encompassing diffusion-weighted imaging (DWI), intravoxel incoherent motion (IVIM), diffusion tensor imaging (DTI), and dynamic contrast-enhanced (DCE) perfusion MRI) had significantly higher sensitivity (90% vs 80%) for identifying malignant gallbladder wall thickening without benefits of higher specificity or diagnostic accuracy.¹⁸ However, widespread clinical adoption of mpMRI for gallbladder evaluation is limited due to lack of standardization of protocols, acquisition and reporting due to limited experience and lack of access to innovative technology. Advanced functional imaging techniques such as PET/CT has been utilized to assess gallbladder wall thickening. Gupta and colleagues evaluated the diagnostic accuracy of ¹⁸F-FDG PET/CT in 33 patients to differentiate between benign and malignant thickening of gallbladder. They found that PET/CT had higher sensitivity (91%), moderate specificity (79%) and good diagnostic accuracy (84%).¹⁹ However, PET/CT is not recommended to be routinely used as a diagnostic tool to discriminate between benign and malignant gallbladder pathologies.²⁰

The emergence of newer therapies with emphasis on patient-tailored approaches necessitates a critical role for imaging to facilitate multidisciplinary care of patients with gallbladder cancer. Technological advancements in CT and MRI will continue to improve management. However, there is a noticeable dearth of collaborative endeavors across multiple centers and multidisciplinary panels to develop strategies for early imaging-based diagnosis, risk stratification, and management approaches in patients with gallbladder wall thickening and cancer. To enable this, we need large cohort prospective multicentric studies integrating ultrasound, contrast-enhanced ultrasound, CT, and MRI to provide a comprehensive scoring system and formulate strategies for objective reporting, timely detection, appropriate follow-up, and effective management of gallbladder wall thickening and cancer.

Conflicts of interest

Avinash Kambadakone: Research grants (GE, Philips Healthcare, and PanCAN; not relevant to this manuscript).

Funding

This manuscript received no specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Other author does not have any relevant financial relationships to disclose.

Commentary on: Kalage D, Gupta P, Gulati A, Reddy KP, Sharma K, Thakur A, Yadav TD, Gupta V, Kaman L, Nada R, Singh H, Irrinki S, Gupta P, Das CK, Dutta U, Sandhu M. Contrast Enhanced CT Versus MRI for Accurate Diagnosis of Wall-thickening Type Gallbladder Cancer. J Clin Exp Hepatol. 2024 Sep-Oct;14(5):101397. doi: 10.1016/j.jceh.2024.101397. Epub 2024 Mar 14. PMID: 38595988; PMCID: PMC10999705.