Gallbladder cancer revisited: the evolving role of a radiologist

Abstract

Gallbladder cancer is the most common malignancy of the biliary tract. It is also the most aggressive biliary tumor with the shortest median survival duration. Complete surgical resection, the only potentially curative treatment, can be accomplished only in those patients who are diagnosed at an early stage of the disease. Majority (90%) of the patients present at an advanced stage and the management involves a multidisciplinary approach. The role of imaging in gallbladder cancer cannot be overemphasized. Imaging is crucial not only in detecting, staging, and planning management but also in guiding radiological interventions. This article discusses the role of a radiologist in the diagnosis and management of gallbladder cancer.

Introduction

Although gallbladder cancer (GBC) is the commonest malignancy of biliary tract it is a relatively rare disease.^1,2 According to Globocan 2018 database, GBC constituted 1.2% of all new cancer cases and 1.7% of all deaths due to cancer, worldwide, in the year 2018.³ Presentation in the early stage is with non-specific symptoms and jaundice, which is usually seen late, is due to the involvement of the bile duct by the tumor or metastatic nodes. Imaging plays an important role in diagnosis, staging and planning further management. Further, imaging guides radiological interventions and also is useful in assessing response to treatment.

Epidemiology, clinical features and pathology

The epidemiology of GBC has shown a remarkable geographic and ethnic variability, with highest prevalence in Chile, followed by India, Poland, south Pakistan, Japan and Israel in that order.² In India, North India has a very high incidence, compared to South India.^4,5 Epidemiologic studies have identified female sex, old age, obesity and cigarette smoking as predisposing factors.⁶ The other risk factors are cholelithiasis, chronic inflammation due to Salmonella typhi, S paratyphi and parasitic infection, polyp more than 1 cm and porcelain gallbladder.⁶ Among these, cholelithiasis is the most well-established risk factor. The pathophysiology of carcinoma arising in the presence of gallstone disease is through the process of chronic irritation of gallbladder (GB) mucosa which leads to mucosal metaplasia, dysplasia and subsequently carcinoma. This sequence corresponds to the flat intraepithelial neoplasia (flat IN) pathway of carcinogenesis. In WHO 2010 classification of tumors of digestive system, flat mucosal dysplasia of the GB is described as biliary intraepithelial neoplasia (BiiN).^7–9 They have been found in GB mucosa with chronic cholecystitis and when present, are frequently associated with invasive carcinoma.⁷ Chronic salmonella infection is associated with bile carcinogens which increases the risk of GBC.¹⁰

GB polyps are incidentally detected in 0.3–9.5% of hepatobiliary ultrasounds and 2–12% of cholecystectomy specimens.^11,12 Majority of these are cholesterol polyps, focal adenomyomatosis, and inflammatory polyps which are non-neoplastic. Adenomas and mesenchymal tumors constitute the benign neoplastic polyps. Intracholecystic papillary–tubular neoplasm (ICPN) of the GB is a unifying terminology, which refers to any tumoral pre-invasive neoplasm in the GB ≥1 cm, showing a mixture of papillary and tubular growth pattern and dysplasia on histology.^12,13 They are analogous to pancreatic and biliary intraductal papillary neoplasm. ICPNs follow the adenoma–carcinoma sequence of carcinogenesis, with invasive carcinoma seen in >50% at diagnosis.¹³

Historically, the incidence of GBC in porcelain GB (PGB) is varied, ranging from 7 to 60% and prophylactic cholecystectomy has been suggested.¹⁴ Based on the distribution of calcification, there are three types of PGB: (a) mucosal calcification (b) diffuse intramural calcification (c) focal intramural calcification. Selective mucosal and incomplete calcification have a higher risk of malignancy than the complete type (Figure 1a and b). However, recent studies have confirmed that the actual risk is significantly less. A systematic review of literature by Schnelldorfer et al, found the incidence of GBC in PGB to be 6%, while another review by Khan et al, found the risk to be as low as 3%.^15,16

Figure 1.

Predisposing factors. (a, b) Porcelain GB. (a) Sagittal multiplanar CT image showing thin incomplete calcification of GB wall (arrow heads) with mass in the neck region (arrow). (b) Sagittal MIP image of another patient with GBC showing complete intramural GB wall calcification (black arrowheads) and cholelithiasis (white arrow). Selective mucosal & incomplete calcification have higher risk of malignancy than the complete type. (c, d) Primary sclerosing cholangitis. (c) Coronal MRCP image showing multiple short segment strictures (white arrowheads) alternating with dilated IHBR involving both lobes with a tight stricture of left hepatic duct (arrow) suggestive of sclerosing cholangitis. (d) Axial CT image showing a mass replacing the GB with infiltration into the adjacent liver (arrows) and ascites (asterisk). GBC, gallbladder cancer; IHBR, intrahepatic biliary radicals; MIP, maximum intensity projection; MRCP,magnetic resonance cholangiopancreatography.

Association of GBC with primary sclerosing cholangitis (Figure 1c and d) and congenital anomalies like choledochal cyst, anomalous pancreaticobiliary junction, and low insertion of cystic duct have also been described.^6,17

The clinical presentation often is with nonspecific symptoms like abdominal pain and discomfort which delays the clinical diagnosis. The other symptoms include abdominal lump and jaundice, which are often seen in the late stage of the disease.¹⁸ Early stage GBC is typically detected incidentally during imaging evaluation or surgery for coexistent cholelithiasis or cholecystitis.^18,19 In advanced stages, patients develop jaundice due to invasion of porta hepatis and systemic symptoms like malaise and weight loss.

The normal GB wall has five layers: mucosa, lamina propria, a thin muscular layer, perimuscular connective tissue and serosa.²⁰ The serosa of the GB is conspicuous by its absence in the wall adjacent to segments IVB and V of the liver, making the GB wall connective tissue and interlobular hepatic connective tissue contiguous. The gall bladder can therefore be considered to have a hepatic side and peritoneal side. The lack of submucosa and serosa (on the hepatic side) and presence of only a single layer of muscularis facilitates early spread of GBC. Hence adjacent organ invasion, most commonly into the liver, is typically present at the time of diagnosis.

Majority (98%) of the primary malignancies of the GB arise from the epithelium.¹⁹ Adenocarcinoma (NOS >papillary > mucinous type: data from SEER 1977 to 1986)²¹ accounts for 90% of the cases, followed by adenosquamous and squamous cell types which account for 10–15%. Small cell carcinoma, neuroendocrine cell tumors and anaplastic carcinomas are the rare types. Among adenocarcinomas, papillary carcinomas have the best survival time (median 20 months), as they tend to fill the lumen of GB before infiltrating the GB wall.¹⁹ The prognosis of GBC depends on histologic type, histologic grade and stage of the tumor.

Staging, imaging modalities and imaging appearances

GBC is staged by the depth of tumor invasion (T), presence of lymph node metastases (N) and presence of distant metastases (M) according to the American Joint Committee on Cancer staging system (Table 1).^22,23 The 8th edition AJCC is being employed since January 1, 2018.

Table 1.

TNM Grouping for gallbladder cancer (AJCC Cancer Staging Manual, 8th edition)

Category	Definition
pT (primary Tumor)
TX	Cannot be assessed
T0	No evidence
Tis	In situ
T1	Tumor invades lamina propria or muscular layer
T1a	Tumor invades lamina propria
T1b	Tumor invades muscular layer
T2	Tumor invades perimuscular connective tissue on the peritoneal side without serosal (visceral peritoneal) involvement Or Tumor invades perimuscular connective tissue on the hepatic side without extension into the liver
T2a	Tumor invades perimuscular connective tissue on the peritoneal side without serosal (visceral peritoneal) involvement
T2b	Tumor invades perimuscular connective tissue on the hepatic side without extension into the liver
T3	Tumor perforates serosa and/or directly invades liver and/or 1 other adjacent organ or structure(stomach, duodenum, colon, pancreas, omentum or extrahepatic bile ducts)
T4	Tumor invades main portal vein or hepatic artery or invades 2 or more extrahepatic organs or structures
pN (Regional LNs)
Nx	Regional LNs cannot be assessed
N0	No regional lymph node metastases
N1	Metastases to 1–3 regional lymph nodes
N2	Metastases to 4 or more regional lymph nodes
Distant metastases
cM0	No distant metastases
cM1	Distant metastases
pM1	Distant metastases, microscopically confirmed

LN, lymph node.

T component describes how deeply the primary tumor has invaded into the GB wall and adjacent structures. It is the most important determinant of the type of surgical treatment in potentially resectable tumors. The tumors confined to the wall of the GB are classified as T1 or T2 and those extending beyond the wall as T3 and T4. 8th edition AJCC Staging system divides T2 tumors into T2a and T2b representing involvement of peritoneal side and hepatic side respectively. This modification addresses the difference in tumor biology, and management and prognosis of the two substages.^24,25 In an international multicenter study, Shindoh and colleagues found that T2 tumors involving the hepatic side had higher rates of vascular and neural invasion and nodal metastases and proposed that along with resection, adjuvant therapy may be needed in these tumors.²⁵ Several recent studies have found higher long-term survival and reduced recurrence rates for T2a tumors compared to T2b tumors.^24–27

N staging refers to lymph node (LN) metastases. Lymphatic invasion plays a major role in the spread of GBC. Pericholecystic lymphatics after entering hepatoduodenal ligament follows three drainage pathways: cholecystoretropancreatic (regarded as the main drainage pathway), cholecystoceliac and cholecystomesenteric. The three pathways converge at retroperitoneal LN near left renal vein.²⁸ In AJCC 8th edition, positive LNs (size >10 mm) along the hepatoduodenal ligament (around the common bile duct, hepatic artery, portal vein, cystic duct) are divided into N1 and N2 depending on the number of LNs involved. The number of positive LNs, instead of anatomic location, is now considered significant for prognosis. LNs in celiac region, superior mesenteric region, paraaortic and pericaval are classified as distant metastasis (M1).²⁹

The most common sites of distant metastases (M) in GBC are the liver and the peritoneum. Pathways of liver metastases are through lymphatic flow along glissonian pedicles or hematogenously through cystic vein which drains into right branches of portal vein or small veins that drain directly to liver parenchyma.²⁵ Sites of peritoneal spread are influenced by gravity, negative pressure in subdiaphragmatic region and pooling of ascitic fluid in dependent areas and recesses. There are case reports of metastases to unusual sites like brain, bone, cervical vertebra, cheek and heart.^30–34

Stages I and II are potentially resectable with curative intent.^20,35 Stage IVb represents unresectable disease as a consequence of distant metastases. In stages III and IVA, which are locally advanced tumors, the salient features of nonresectability can be summarized as: extensive local contiguous organ spread, lobar portal vein, lobar hepatic artery and lobar hepatic duct or secondary biliary confluence involvement (at least one of the above in each lobe), main portal vein or proper or common hepatic artery invasion.³⁶ Involvement of the vessels by nodes also makes the tumor unresectable.

Perineural invasion is another recognized mode of spread of GBC attributed to the rich autonomic innervation of the GB and extrahepatic biliary tract.^37–39 Perineural invasion, which usually occurs in high grade GBC, is associated with higher incidence of failure of curative resection and early post-operative recurrence leading to poor overall survival.^38–40

GBC has three morphologic types on imaging: (a) Mass replacing the GB, which is the most common type (40–60%) (Figures 2 and 3); (b) Focal wall thickening or asymmetric diffuse wall thickening (20–30%) (Figure 4); (c) Intraluminal growth or polyp (15–25%) (Figure 5). In general, intraluminal polypoid tumors are reported to be better differentiated histologically and are associated with better prognosis.⁴¹

Figure 2.

Mass replacing the gallbladder. (a) USG of a patient of GBC showing a heteroechoic mass replacing the GB (asterisk) with a large calculus within (arrow). (b, c) Axial CT scans in arterial (b) and venous (c) phases showing a large heterogeneously enhancing mass (asterisk) completely replacing the GB and infiltrating the liver parenchyma. GBC, gall bladder cancer; USG, Ultrasonography.

Figure 3.

MRI of mass replacing the gallbladder: Axial T₁W (a), T₂W fat saturated (b), diffusion weighted (c) and contrast-enhanced arterial (d), venous (e) and delayed (f) phase MR images showing a large gallbladder mass (asterisk) infiltrating liver and appearing hypointense on T₁W, hyperintense on T₂W, and showing restriction of diffusion and heterogeneous contrast enhancement. A large portocaval lymph node is noted (arrow).

Figure 4.

Asymmetric wall thickening: Ultrasonography (a) and CT scan (b) images showing asymmetric wall thickening in the fundus (white arrow) and body (black arrow) of gallbladder. Calculus is seen in the neck region (arrow head). Thickening which is asymmetric, nodular and >1 cm thick suggests malignancy.

Figure 5.

Intraluminal polypoidal mass. Ultrasonography (a) and CT scan (b) showing a hypoechoic and enhancing polypoidal mass (arrow) in the lumen of gallbladder. This variety has the best prognosis.

Rarely, GBC is multifocal (Figure 6). The proposed pathogenesis for this is dysplasia – carcinoma in situ sequence at multiple sites. However, it may be difficult to differentiate synchronous lesion from metastasis.

Figure 6.

Multifocal disease: Axial (a, b) and sagittal (c) CT images showing separate soft tissue masses in the fundus (white arrow) and neck (black arrow) of GB, suggesting multifocal disease. Hyperdense calculi are also seen within (arrow heads). GB, gall bladder.

Imaging plays a critical role in detecting, staging and post-treatment restaging of GBC. The modalities used for imaging are: Ultrasonography (USG), including endoscopic ultrasound (EUS) and contrast-enhanced ultrasonography (CEUS), CT scan, magnetic resonance imaging (MRI) and positron emission tomography (PET)-CT.

Ultrasonography

USG, the initial investigation of choice in patients presenting with abdominal complaints or jaundice, has high sensitivity in detecting gall stones and any mass or focal wall thickening in the GB (Figures 2, 4 and 5). In locally advanced disease, USG has a sensitivity of 85% and overall diagnostic accuracy of 80% in the staging of GBC.⁴² However, USG fails to detect subtle flat lesions, and sometimes even larger lesions, especially when the GB is filled with calculi. USG, at times, is inadequate to differentiate between mural thickening associated with cholecystitis and GBC and has an accuracy of 68.8%.⁴³ Asymmetric and irregular wall thickening and thickness of more than one cm should raise a suspicion of GBC. Also, conventional grayscale USG is of limited value for the differentiation of neoplastic from non-neoplastic polyps.⁴⁴ Color Doppler USG often does not add much to the diagnostic performance due to its low sensitivity for slow blood flow.^45,46 True malignant polyps constitute only 0.6% of all GB polyps.⁴⁷ Evidence based consensus guidelines were formulated by the European Society of Gastrointestinal and Abdominal Radiology (ESGAR) for the management of incidentally detected GB polyps and are shown in Table 2.¹¹

Table 2.

Management guidelines for gallbladder polyps

Polyp characteristics	Management
GB polyps ≥ 1 cm	Cholecystectomyb
Symptomatic GB polyps	Cholecystectomyb
Polyps measuring 6–9 mm, Risk factorsa present	Cholecystectomyb
Polyps measuring 6–9 mm, No risk factors	Follow up USG at 6 months, 1 year and then yearly upto 5 years
Polyps measuring ≤ 5 mm, Risk factors present	Follow up USG at 6 months, 1 year and then yearly upto 5 years
Polyps measuring ≤ 5 mm, No risk factors	Follow up USG at 1 year, 3 years and 5 years
During follow-up:
Polyp increases by ≥ 2 mm	Cholecystectomy
Polyp disappears	Discontinue follow-up

EAES, European association for endoscopic surgery and other interventional techniques; EFISDS, International society of digestive surgery – European federation; ESGAR, Joint guidelines between the European societyof gastrointestinal and abdominal radiology; ESGE, European society of gastrointestinal endoscopy; GB, gallbladder; USG, Ultrasonography.

Adapted from reference¹¹: Management and follow up of gallbladder polyps.

^aRisk factors include – age >50 years, Indian ethnicity, primary sclerosing cholangitis and sessile polyp (focal wall thickening >4 mm).

^bCholecystectomy to be done if patient is fit and accepts surgery.

High-resolution ultrasound (HRUS), may be useful for differentiating GBC from benign conditions like adenomyomatosis and xanthogranulomatous cholecystitis.^48,49

Another important limitation of conventional USG is its inability to stage early disease accurately. EUS allows detailed visualization of the layers of the GB wall and can be used for pre-operative T staging.⁵⁰ However, a prospective study by Jang and colleagues showed no significant difference between the diagnostic accuracies of EUS (55.5%), HRUS (62.9%) and multidetector CT (44.4%).⁵¹

CEUS, although not routinely used in the evaluation of GBC, may be helpful in the differentiation of benign from malignant GB diseases. Xie et al,⁴³ in their study on 80 patients, found that early enhancement followed by washout and disruption of intact GB wall favor the diagnosis of GBC over benign disease with an accuracy of 96.3%.

Computed tomography

CT scan is the imaging modality of choice for detecting and staging GBC, quantifying the volume of future liver remnant (FLR) and identifying any anatomical variations of the vessels. Dual phase contrast-enhanced CT scan is recommended, which consists of an arterial phase at 25–30 s and a portal venous phase at 70 s after injection of contrast. Arterial phase images help to evaluate the involvement of hepatic arterial branches (Figure 7) and the presence of arterial anatomical variants such as replaced and accessory left and right hepatic arteries. Vascular invasion is diagnosed when there is loss of intervening fat plane with angle of contact >180°, irregular luminal outline, narrowing of the calibre, or presence of tumor on both sides of the vessel.³⁶ Portal venous phase defines the extent of the primary tumor (Figures 7–9), portal vein involvement (Figure 7), local organ invasion (Figures 7 and 8), involvement of biliary tract (Figure 9), enlarged regional lymph nodes (Figures 3 and 9), perineural invasion (Figure 8), and liver, peritoneal and distant metastases (Figure 10).

Figure 7.

Local invasion. (a) Axial CT scan image showing a polypoidal GB mass (asterisk) with adventitial invasion (nodular surface – arrow). (b) Axial CT scan image showing liver infiltration (arrow) of a GB mass (asterisk). (c, d) Vascular invasion. Axial CT images in arterial (c) & venous (d) phases showing GB mass involving common hepatic artery (white arrow) & main portal vein (black arrow). GB, gallbladder.

Figure 8.

Local invasion: (a–c): Axial CT images of different patients of GBC showing invasion of duodenum (arrow in a), hepatic flexure (arrow in b) and abdominal wall (arrow in c). Air foci are seen in the mass in a, b suggesting fistula. d: Coronal T₂W MR image showing invasion of gastric antrum and duodenum (arrows) by GB mass (asterisk). (e, f) Perineural invasion. Axial (e) and coronal (f) venous phase CT images of a patient with GBC showing a mantle of soft tissue along the proper hepatic and common hepatic artery (hepatic plexus – arrow in e), celiac axis (black arrow in f) and SMA (white arrow in f). GBC, gallbladder cancer; SMA, superior mesenteric artery.

Figure 9.

Bile duct invasion: (a–d) By primary mass. (a, b) Axial CT images showing GB neck mass (black arrow) involving common hepatic duct (white arrow) as wall thickening. (c, d) Axial T₂W MR images of the same patient showing GB neck mass (arrowhead in d) & biliary dilatation (white arrows in c). (e, f) By lymph nodes. (e, f) Axial CT scans showing small GB mass (arrow head in f) with multiple peripancreatic nodes compressing the bile duct (white arrows).

Figure 10.

Metastasis: (a–c) Hematogeneous. (a) Liver. Axial CT image showing multiple hypodense lesions in liver. (b) Lung. Axial CT image in lung window showing multiple nodules in right lung (arrows). (c) Bone. Coronal CT image in bone window showing lytic lesions in multiple vertebral bodies (arrows). (d–f) Peritoneal. (d, e) Axial CT images showing soft tissue mass in the omentum (arrow in d) and solid-cystic lesions in both ovaries (arrows in e). (f) Coronal T₂W MR image showing mass in GB (asterisk) with nodular peritoneal thickening (arrows). GB, gallbladder.

CT scan is inferior to USG in depicting mucosal irregularity, mural thickening, and cholelithiasis, but is superior for evaluating the areas of the GB wall that are obscured by gallstones or mural calcification.⁵² However, local spread of the disease and involvement of the peritoneum and the omentum are frequently underestimated on CT scan, compared to intraoperative extent.⁴¹ Ohtani and colleagues compared CT findings with pathologic findings in 59 GBC patients and reported a low sensitivity (17–78%) for detecting involvement of lymph node stations and a higher sensitivity (50–65%) for detecting tumor invasion into liver and adjacent organs.⁵²

Rarely, patients with GBC present to the emergency department with complications like acute cholecystitis, pancreatitis, tumor rupture and hemobilia due to GB wall pseudoaneurysm and an underlying GBC is detected on the CT scan performed for acute abdomen (Figure 11). Approximately, one-fifth of patients with GBC present with acute cholecystitis.⁵³ When a discrete mass is not present, features like irregular mural thickening and enhancement without regional fat stranding and a low CRP level in the clinical setting of acute cholecystitis should raise suspicion of GBC.⁵⁴ Pre-operative identification is important before emergency cholecystectomy as it helps in planning an open radical surgery and avoidance of intraoperative bile spillage. Laparoscopic cholecystectomy in these patients might cause recurrence of GBC along the port tract.⁵⁵ Unexpected GBC, defined as GBC unsuspected on pre-operative imaging but found on histology post-cholecystectomy for acute cholecystitis or other indications, occurs in <1% of cholecystectomies.⁵⁶ Rupture of GBC is a rare complication, with few case reports.⁵⁷ Pseudoaneurysm of the small arteries of GB wall have been associated with inflammatory as well as malignant wall thickening. Also, hemocholecyst due to ruptured pseudoaneurysm may mimic GBC and at times cause diagnostic difficulties on imaging.⁵⁸

Figure 11.

Complications. (a–b) Cholecystitis: Axial (a) and coronal (b) CT images showing GB wall thickening with pericholecystic fluid (arrows) in a patient with GB neck mass. (c–d) Tumor rupture: Axial CT images showing large GB mass (asterisk) with rupture and perihepatic fluid collection (arrow). (e–f) Cystic artery pseudoaneurysm. Axial venous phase (e) & sagittal arterial phase (f) CT images showing GB mass (black arrow) with calculus (white arrow) and pseudoaneurysm from cystic artery (arrow head). GB, gallbladder.

Dual energy CT (DECT) enables acquisition of data simultaneously using X-ray spectra of two different energies. DECT has the potential to enhance detection and characterization of GBC employing the iodine map. On the iodine map, GBC can be visualized more easily compared to benign conditions like adenomyomatosis and xanthogranulomatous cholecystitis, as GBC shows higher uptake of contrast agent (Figure 12).⁵⁹ Hence, whenever available, it is suggested that imaging be done using DECT in the evaluation of patients of GBC.

Figure 12.

Dual energy CT. (a, b) Iodine overlay CT maps of two patients with GB wall thickening (arrows) due to cholecystitis (a) and GBC (b). The degree of mucosal enhancement is higher in wall thickening due to malignancy (b) compared to that due to chronic inflammation (a). (c, d) Iodine overlay CT maps of two patients with intraluminal tumefactive sludge (arrowheads in c) and polypoid mass filling the lumen of GB (asterisk in d). Tumefactive sludge shows no evidence of iodine uptake compared to tumor, which shows diffuse and heterogeneous uptake. GB, gallbladder.

Magnetic resonance imaging

MRI is a modality less frequently used for the staging of GBC. However, its higher contrast resolution, ability to better depict biliary anatomy and availability of diffusion-weighted sequences make MRI a more informative problem-solving tool (Figure 3). Magnetic resonance cholangiopancreatography (MRCP) helps in a better definition of the level and extent of hilar involvement by GBC (Figures 1 and 9).⁶⁰ Kim et al, in their retrospective study on 86 operated and histologically proven patients of GBC, showed that a combination of MRI with MRCP and dynamic contrast-enhanced sequences has an accuracy of 84% for determining the T stage.⁶¹ In another retrospective study, Schwartz and colleagues demonstrated that a combination of conventional MRI with MRCP achieved a sensitivity of 100% for liver invasion and 92% for nodal involvement in staging GBC.⁶²

Diffusion-weighted imaging (DWI) needs special mention as it has high sensitivity in the detection of liver and lymph node metastases, although specificity is poor.⁶³ It also helps in differentiating tumefactive biliary sludge from a solid tumor (Figure 13). Further, DWI may assist in the characterization of incidentally detected liver lesions.

Figure 13.

Tumefactive sludge. (a) Ultrasonography shows echogenic mass-like area in the GB (arrow). (b, c) Axial CT images in arterial (b) and venous (c) phases showing hyperdense lesion in the lumen of GB (arrow). (d–f) Axial T2W (d), DWI (e) and ADC map (f) shows that the lesion is T2 hypointense with free diffusion. Hyperdensity on CT, T1 hyperintensity & free diffusion suggest tumefactive sludge. ADC, apparent diffusioncoefficient; GB, gallbladder.

Positron emission tomography

GBC are ¹⁸F-FDG (fluoro deoxyglucose) avid tumors and hence FDG PET is an imaging modality that has high sensitivity in detecting primary and metastatic lesions in GBC.^64,65 Corvera et al, also found that PET detected occult metastases and thereby changed the management in nearly one-fourth of their study patients.⁶⁴ PET-CT is a hybrid imaging modality, combining the functional and anatomical information to overcome the shortcomings of CT and PET when interpreted alone. PET-CT is increasingly being used for staging and follow up of GBC.⁶⁶ (Figure 14).

Figure 14.

Assessing response to chemotherapy. (a, b) CT scans, before (a) and after (b) 6 cycles of chemotherapy shows reduction in the tumor size. (c, d) PET-CT images before (c) and after (d) chemotherapy also shows reduction in size and activity. PET-CT thus is better as it still shows residual activity. PET, positron emission tomography.

Albazaz et al⁶⁷, compared findings on FDG PET-CT with CT and MRI and found that PET-CT had a major impact in the management decisions in 39% patients of GBC, including upstaging of the disease, identifying occult disease sites not detected by CT or MRI and detecting unsuspected recurrence.

Radiomics

Texture analysis, which falls under the aegis of Radiomics, is a recent innovation in the realm of quantitative image analysis.^68,69 The application of texture analysis in hepatocellular carcinoma and rectal carcinoma has shown promising results.^70,71 In 2018, Choi and colleagues performed texture analysis of 136 GB polyps measuring more than one cm on HRUS images. They identified predictors for malignant nature of polyps to be sessile shape, larger size, higher skewness and lower grey level co-occurrence matrices contrast.⁷² Ji et al in 2019, developed a Radiomics model/signature-based on portal venous phase CT images and showed it to have good performance in predicting metastatic lymph nodes.⁷³ Texture analysis, frequently used in radiology research, is yet to be adopted for routine practice in GBC.

Differential diagnoses

Certain inflammatory conditions and a few other neoplasms of gallbladder can mimic GBC due to overlapping imaging appearances. These pathologies, along with their salient features are summarized in Table 3.^74–76 Among the differentials, GB adenomyomatosis is a commonly encountered incidental finding on USG. Confident differentiation of adenomyomatosis from GBC on imaging helps to avoid unnecessary cholecystectomy. Focal or diffuse GB wall thickening containing small cystic spaces are pathognomonic for adenomyomatosis (Figure 15).⁷⁷ Presence of comet-tail artifact due to cholesterine crystals or tiny hyperechoic foci with posterior acoustic shadowing due to calcification and twinkling artifact on color Doppler are other diagnostic clues on USG as these are not observed in GBC.

Table 3.

Radiological differential diagnoses of GBC

Morphologic type of GBC	Imaging differential diagnosis	Remarks
Focal or diffuse wall thickening	Xanthogranulomatous cholecystitis (XGC)	A chronic inflammatory condition with focal or diffuse infiltration of foamy macrophages in the GB wall; may have pericholecystic inflammation with formation of adhesions and lymphadenopathy. Imaging characteristics: USG : Hypoechoic nodules (representing xanthogranulomas or abscesses) in the thickened GB wall74 CT: Hypodense intramural nodules, continuity of the mucosa is maintained MRI: T1 and T2 hyperintense foci in the wall
	Adenomyomatosis	Characterised by epithelial and smooth muscle proliferation secondary to chronic obstruction. Show prominent Rokitansky Aschoff sinuses containing cholesterol, bile and sludge. No malignant potential Imaging characteristics: USG: ring down reverberation artefact due to cholesterol crystals MRI: “pearl - necklace sign” on T2 weighted images
	Acute cholecystitis complicated by pericholecystsic abscess, fistula formation with bowel	Mimics Stage 3A tumor
Intraluminal Polypoid mass	Adenomatous polyp (neoplastic), Hyperplastic, cholesterol polyp (non-neoplastic)	Size is the most important predictor of malignancy in neoplastic polyp; Multiple numbers suggest benignity; Comet tail artefact suggests cholesterol polyp
	Carcinoid tumor	Rare tumor constituting 0.2% of all neuroendocrine tumors75
	Metastatic melanoma	50–60% of metastases to GB are from melanoma76
Mass replacing GB	Hepatocellular carcinoma (HCC)	Characteristic enhancement of HCC helps in differentiation
	Metastases to Gall bladder

GB, gall bladder; USG, ultrasonography; XGC, xanthogranulomatous cholecystitis.

Figure 15.

Gallbladder adenomyomatosis. (a) Longitudinal ultrasound image of gallbladder shows an area of mural thickening containing multiple foci of comet tail artifacts (arrows), representing cholesterol crystals. (b–d) Axial T₂ weighted MRI image (b) of another patient shows smooth mural thickening (arrowheads) in the fundus of gallbladder with hypointense signal. Contrast enhanced T₁ weighted arterial (c) and portal venous (d) phase images show uniform mucosal enhancement in the region of mural thickening (block arrows). Features are suggestive of localized form of adenomyomatosis.

Treatment

Surgical resection is the standard treatment for patients with resectable GBC (Table 4).^24,78,79

Table 4.

Summary of surgical management of GBC

Stage of GBC	Type of surgery	Rationale
Tis (mucosa) and T1a (lamina propria)	Simple cholecystectomy	Removal of the gallbladder. Tis and T1a tumor are considered as local disease
T1b (muscularis)	Radical (extended) cholecystectomya	Removal of the GB and adjacent liver bed (segments 4B and 5). Higher recurrence rate of T1b tumors compared to T1a tumors. Hence radical cholecystectomy is recommended for T1b tumors, though debated.78,79
T2 (perimuscular connective tissue) - T2a: peritoneal side - T2b: hepatic side	Radical cholecystectomy	Higher possibility for micrometastases in liver and lymph nodes compared to T1. Interestingly, a recent study suggested that radical cholecystectomy without hepatic resection is a reasonable option for T2a as they did not find a significant difference in 5 year survival.78
T3 (perforate serosa and/or invade liver and /or one adjacent organ)	Radical resection	Removal of all involved organs to achieve R0 resection and locoregional lymph node clearance
T4 (invade two or more extrahepatic organs or invade MPV /HA)	Unresectable

GBC, gallbladder cancer; HA, hepatic artery; MPV, main portal vein.

^aRadical cholecystectomy includes cholecystectomy, hepatic bed resection (wedge resection or 4b and 5 segmentectomy) and portal lymphadenectomy (nodes in porta hepatis, gastrohepatic ligament and retroduodenal space – preferably 6 or more for complete staging).²⁴

Chemotherapy (Gemcitabine and Cisplatin) with or without radiotherapy is used either as adjuvant therapy or as the primary therapy in locally advanced unresectable disease and metastatic disease.⁸⁰ Studies have found improved locoregional control and survival rates in patients treated with adjuvant chemoradiation.^81,82

After high dose focal irradiation, radiation induced imaging changes occur in organs within the radiation field, mainly liver and stomach (Figure 16). The liver parenchyma surrounding the GBC shows a focal reaction, which has three phases – acute phase (within 3 months) characterized by hypodensity due to diffuse fatty infiltration and sinusoidal congestion; subacute phase (3–6 months) characterized by hypodensity and hyperenhancement in delayed phase due to sub lobular venoocclusion; and chronic phase (beyond 6 months) characterized by fibrosis and volume loss.⁸³

Figure 16.

Post-radiation changes. (a) Axial CT image showing low attenuation focal area with straight margins (arrowheads) corresponding to radiation portal suggestive of radiation induced liver injury. (b) Axial CT image of another patient with GBC, showing circumferential low density gastric wall thickening (arrows) and luminal narrowing predominantly in the gastric antrum and pyloric region suggestive of post radiation gastritis. GBC, gallbladder cancer.

Imaging in response assessment

Neoadjuvant chemotherapy to downstage locally advanced GBC (T3, T4 disease) is increasingly being used. Initial reports showed that neoadjuvant chemotherapy in GBC had only limited success.^84,85 A prospective study by Engineer and colleagues, in 2016, showed that R0 resection was achieved in 50% of the patients after neoadjuvant chemotherapy, suggesting that neoadjuvant chemotherapy facilitates curative resection.⁸⁶ In another study by Sirohi et al,⁸⁷ neoadjuvant chemotherapy increased the chances of resectability and survival of patients of locally advanced GBC. Hence, restaging on imaging becomes important.

Radiological evaluation is usually done after 3–6 cycles of chemotherapy, according to the RECIST criteria. There is scarcity of literature on the use of PET-CT for response assessment during or after therapy for GBC. Comparison of post treatment PET-CT with pretreatment PET-CT is more reliable than response assessment on CECT alone. This is because PET-CT assesses the functional nature of the disease after treatment (Figure 17). MRI, especially DWI is increasingly being used to assess the response of malignant tumors to chemotherapy.⁸⁸ DWI immediately after the first cycle of chemotherapy helps in differentiating responding from non-responding tumors based on the increase in the ADC values (Figure 18). This helps in avoiding further inappropriate chemotherapy.⁸⁸

Figure 17.

Limitation of CT in assessing response. CT scans (a, c) & PET-CT (b, & d), before and after chemotherapy respectively. CT scan shows persistent mass (arrow in c) suggesting residual disease, but PET-CT shows no residual activity (arrow in d). PET-CT thus assesses functional nature of the disease after treatment. PET, positron emission tomography.

Figure 18.

DWI for treatment response assessment: T₂W & DWI images – before (a, c) and after (b, d) three cycles of chemotherapy, shows reduction in the size of the lesion & also the diffusion restriction. ADC maps before (e) and after (f) first cycle of chemotherapy shows increase in ADC values from 1.14 (×10⁻³ mm² s⁻¹) to 1.39 (×10⁻³ mm² s⁻¹), suggesting response to chemotherapy. ADC, apparent diffusion coefficient; DWI, diffusion-weighted imaging.

Role of radiological interventions

Role in diagnosis - lesion sampling

The diagnosis of GBC is established by percutaneous fine needle aspiration cytology (FNAC) or biopsy, mostly under USG guidance and occasionally under CT guidance, depending on the Institutional protocol. Sampling of the primary mass, as well as any distant suspected metastatic lesions, should be done for deciding management. USG-guided FNAC is shown to have a diagnostic sensitivity of 90%.⁸⁹ Percutaneous FNAC is safe and is associated with minor abdominal pain in 4.5% of cases and biliary peritonitis in 1–6%. EUS-guided FNAC is an option for lesions which are small, particularly the ones located in the neck of the GB. Jacobson and colleagues and Varadarajulu et al have shown that EUS-guided FNAC is safe and provides definitive diagnosis.^90,91

Role in palliative care

The median survival of patients with advanced GBC, who are deemed inoperable, is limited to 2–4 months.^18,92 In these patients, palliation of symptoms should be the primary goal. These patients typically suffer from jaundice, pruritus and fever due to cholangitis all of which require biliary drainage and intractable abdominal pain, which may need celiac plexus neurolysis.

Biliary drainage

Biliary drainage is an important radiological intervention in GBC, required to improve liver function and to relieve symptoms due to biliary obstruction like pruritus, cholangitis and sepsis and other deleterious effects of hyperbilirubinemia like renal failure and myocardial dysfunction.⁹³ Percutaneous transhepatic biliary drainage (PTBD) is the drainage of choice when the level of biliary obstruction is high and involves the primary confluence. Catheters help in either external drainage (pigtail catheter) or combined external–internal drainage (ring biliary catheter). Internal drainage is possible with metallic stents or with external–internal drainage catheter, when the external end is closed (Figure 19).

Figure 19.

Biliary drainage: (a) External catheter drainage (arrow). (b, c) Internal-external catheter drainage, unilobar (arrow in b) & bilobar (arrows in c). (d) Internal drainage with bilobar stenting (arrows).

Pre-operative portal vein embolisation

When GBC involves the right lobar artery or portal vein or primary or right secondary confluence, right hepatectomy becomes necessary and the surgery is usually a right extended hepatectomy as a part of curative surgical resection. In such cases, volume of the FLR, which is the difference between the total liver volume and volume of segments intended to be resected, remains a major limiting factor. Post-hepatectomy liver failure is more prone to occur when volume of FLR is <25% in normal liver and <30% in steatotic liver.⁹⁴

Percutaneous portal vein embolization is a method to increase the volume of FLR prior to surgery. The portal vein branches of the lobe of liver to be resected are embolized to induce hypertrophy of the contralateral lobe. Embolizing agents used are polyvinyl alcohol particles, fibrin glue with lipiodol, absolute alcohol and coil.⁹⁵ Hypertrophy of the contralateral lobe occurs in 2–4 weeks (Figure 20).

Figure 20.

Portal vein embolization. Right portal venogram, before (a) & portal venogram after (b) embolization with n-butyl cyanoacrylate (arrow). Glue cast is seen in the branches of right PV (arrow heads in b). Axial contrast enhanced MR images before (c) and 3 weeks after (d) portal vein embolization shows hypertrophy of left lateral segments (asterisk) and atrophy of embolized right lobe. PV, portal vein.

Conclusion

GBC is an aggressive biliary malignancy with dismal survival rates. Clinical symptoms are often non-specific and present late in the course of the disease. Imaging is required at all stages of the workflow of the patients with suspected GBC – starting from detection, staging, restaging post-chemotherapy to the management of unresectable cases. Biliary drainage and pre-operative portal vein embolization are two relevant procedures in the management where role of an interventional radiologist is indispensable. Knowledge of the imaging findings and interventional procedures are necessary for the judicious management of these patients.