BJR © 2021 The Authors.

Published by the British Institute of Radiology

https://​doi.​org/​10.​1259/​bjr.​20200726
Received: Revised: Accepted:
14 June 2020 15 August 2020 02 September 2020

Cite this article as:

Ramachandran A, Srivastava DN, Madhusudhan KS. Gallbladder cancer revisited: the evolving role of a radiologist. Br J Radiol 2020; 94:
20200726.

REVIEW ARTICLE

Gallbladder cancer revisited: the evolving role of

a radiologist
ANUPAMA RAMACHANDRAN, MD, DEEP NARAYAN SRIVASTAVA, MD and
KUMBLE SEETHARAMA MADHUSUDHAN, MD, FRCR
Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India

Address correspondence to: Dr Kumble Seetharama Madhusudhan

E-mail: ​drmadhuks@​gmail.​com

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 gall-
bladder cancer cannot be overemphasized. Imaging is crucial not only in detecting, staging, and planning manage-
ment but also in guiding radiological interventions. This article discusses the role of a radiologist in the diagnosis and
management of gallbladder cancer.

INTRODUCTION mucosa which leads to mucosal metaplasia, dysplasia and

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 ciga-
rette 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)
subsequently carcinoma. This sequence corresponds to the
flat intraepithelial neoplasia (flat IN) pathway of carcino-
genesis. 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 carcin-
ogens which increases the risk of GBC.10
GB polyps are incidentally detected in 0.3–9.5% of hepa-
tobiliary 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
 Gallbladder Cancer Revisited BJR

Figure 1. Predisposing factors. (a, b) Porcelain GB. (a) Sagittal Table 1. TNM Grouping for gallbladder cancer (AJCC Cancer
multiplanar CT image showing thin incomplete calcification of Staging Manual, 8th edition)
GB wall (arrow heads) with mass in the neck region (arrow).
Category Definition
(b) Sagittal MIP image of another patient with GBC showing
complete intramural GB wall calcification (black arrowheads) pT (primary Tumor)
and cholelithiasis (white arrow). Selective mucosal & incom-  TX Cannot be assessed
plete calcification have higher risk of malignancy than the
 T0 No evidence
complete type. (c, d) Primary sclerosing cholangitis. (c) Cor-
onal MRCP image showing multiple short segment strictures  Tis In situ
(white arrowheads) alternating with dilated IHBR involving  T1 Tumor invades lamina propria or muscular layer
both lobes with a tight stricture of left hepatic duct (arrow)
suggestive of sclerosing cholangitis. (d) Axial CT image show-  T1a Tumor invades lamina propria
ing a mass replacing the GB with infiltration into the adjacent  T1b Tumor invades muscular layer
liver (arrows) and ascites (asterisk). GBC, gallbladder cancer;
 T2 Tumor invades perimuscular connective tissue on the
IHBR, intrahepatic biliary radicals; MIP, maximum intensity peritoneal side without serosal (visceral peritoneal)
projection; MRCP,magnetic resonance cholangiopancreatog- involvement Or Tumor invades perimuscular connective
raphy. 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
cholecystectomy has been suggested.14 Based on the distribution
 cM1 Distant metastases
of calcification, there are three types of PGB: (a) mucosal calci-
fication (b) diffuse intramural calcification (c) focal intramural  pM1 Distant metastases, microscopically confirmed
calcification. Selective mucosal and incomplete calcification have LN, lymph node.
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 invasion of porta hepatis and systemic symptoms like malaise
Schnelldorfer et al, found the incidence of GBC in PGB to be and weight loss.
6%, while another review by Khan et al, found the risk to be as
low as 3%.15,16 The normal GB wall has five layers: mucosa, lamina propria, a
thin muscular layer, perimuscular connective tissue and serosa.20
Association of GBC with primary sclerosing cholangitis The serosa of the GB is conspicuous by its absence in the wall
(Figure  1c and d) and congenital anomalies like choledochal adjacent to segments IVB and V of the liver, making the GB
cyst, anomalous pancreaticobiliary junction, and low insertion wall connective tissue and interlobular hepatic connective tissue
of cystic duct have also been described.6,17 contiguous. The gall bladder can therefore be considered to have
a hepatic side and peritoneal side. The lack of submucosa and
The clinical presentation often is with nonspecific symptoms serosa (on the hepatic side) and presence of only a single layer of
like abdominal pain and discomfort which delays the clinical muscularis facilitates early spread of GBC. Hence adjacent organ
diagnosis. The other symptoms include abdominal lump and invasion, most commonly into the liver, is typically present at the
jaundice, which are often seen in the late stage of the disease.18 time of diagnosis.
Early stage GBC is typically detected incidentally during imaging
evaluation or surgery for coexistent cholelithiasis or cholecys- Majority (98%) of the primary malignancies of the GB arise from
titis.18,19 In advanced stages, patients develop jaundice due to the epithelium.19 Adenocarcinoma (NOS >papillary > mucinous

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Figure 2. Mass replacing the gallbladder. (a) USG of a patient
of GBC showing a heteroechoic mass replacing the GB (aster-
isk) with a large calculus within (arrow). (b, c) Axial CT scans
in arterial (b) and venous (c) phases showing a large heter-
ogeneously enhancing mass (asterisk) completely replacing
the GB and infiltrating the liver parenchyma. GBC, gall bladder
cancer; USG, Ultrasonography.
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, neuroendo-
crine cell tumors and anaplastic carcinomas are the rare types.
Among adenocarcinomas, papillary carcinomas have the best
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 con-
trast enhancement. A large portocaval lymph node is noted
(arrow).
Figure 4. Asymmetric wall thickening: Ultrasonography (a)
and CT scan (b) images showing asymmetric wall thicken-
ing 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 sug-
gests malignancy.
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Ramachandran et al
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.
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, adju-
vant therapy may be needed in these tumors.25 Several recent
studies have found higher long-­term survival and reduced recur-
rence 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 cholecystomesen-
teric. 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
Figure 5. Intraluminal polypoidal mass. Ultrasonography (a)
and CT scan (b) showing a hypoechoic and enhancing poly-
poidal mass (arrow) in the lumen of gallbladder. This variety
has the best prognosis.
Br J Radiol;94:20200726
 Gallbladder Cancer Revisited
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 mul-
tifocal disease. Hyperdense calculi are also seen within (arrow
heads). GB, gall bladder.
significant for prognosis. LNs in celiac region, superior mesen-
teric 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 hematog-
enously through cystic vein which drains into right branches
of portal vein or small veins that drain directly to liver paren-
chyma.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
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.
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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 differen-
tiate 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
High-­resolution ultrasound (HRUS), may be useful for differen-
tiating 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 visualiza-
tion 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 accu-
racies 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
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 BJR Ramachandran et al

Table 2. Management guidelines for gallbladder polyps Figure 8. Local invasion: (a–c): Axial CT images of different
patients of GBC showing invasion of duodenum (arrow in a),
Polyp characteristics Management
hepatic flexure (arrow in b) and abdominal wall (arrow in c).
GB polyps ≥ 1 cm Cholecystectomyb Air foci are seen in the mass in a, b suggesting fistula. d: Cor-
Symptomatic GB polyps Cholecystectomyb onal T2W MR image showing invasion of gastric antrum and
duodenum (arrows) by GB mass (asterisk). (e, f) Perineural
Polyps measuring 6–9 mm, Risk Cholecystectomyb invasion. Axial (e) and coronal (f) venous phase CT images of
factorsa present
a patient with GBC showing a mantle of soft tissue along the
Polyps measuring 6–9 mm, No Follow up USG at 6 months, 1 year proper hepatic and common hepatic artery (hepatic plexus
risk factors and then yearly upto 5 years – arrow in e), celiac axis (black arrow in f) and SMA (white
Polyps measuring ≤ 5 mm, Risk Follow up USG at 6 months, 1 year arrow in f). GBC, gallbladder cancer; SMA, superior mesen-
factors present and then yearly upto 5 years teric artery.
Polyps measuring ≤ 5 mm, No Follow up USG at 1 year, 3 years
risk factors 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.
a
Risk factors include – age >50 years, Indian ethnicity, primary
sclerosing cholangitis and sessile polyp (focal wall thickening >4
mm).
b
Cholecystectomy to be done if patient is fit and accepts surgery. (Figures  7–9), portal vein involvement (Figure  7), local organ
invasion (Figures 7 and 8), involvement of biliary tract (Figure 9),
is diagnosed when there is loss of intervening fat plane with enlarged regional lymph nodes (Figures  3 and 9), perineural
angle of contact >180°, irregular luminal outline, narrowing of invasion (Figure 8), and liver, peritoneal and distant metastases
the calibre, or presence of tumor on both sides of the vessel.36 (Figure 10).
Portal venous phase defines the extent of the primary tumor
CT scan is inferior to USG in depicting mucosal irregularity,
mural thickening, and cholelithiasis, but is superior for evalu-
Figure 7. Local invasion. (a) Axial CT scan image showing a ating the areas of the GB wall that are obscured by gallstones or
polypoidal GB mass (asterisk) with adventitial invasion (nod- mural calcification.52 However, local spread of the disease and
ular surface – arrow). (b) Axial CT scan image showing liver involvement of the peritoneum and the omentum are frequently
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 Figure 9. Bile duct invasion: (a–d) By primary mass. (a, b)
arrow) & main portal vein (black arrow). GB, gallbladder. Axial CT images showing GB neck mass (black arrow) involv-
ing 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).

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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 nod-
ules in right lung (arrows). (c) Bone. Coronal CT image in
bone window showing lytic lesions in multiple vertebral bod-
ies (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.
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
Figure 11. Complications. (a–b) Cholecystitis: Axial (a) and
coronal (b) CT images showing GB wall thickening with per-
icholecystic 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.
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Figure 12. Dual energy CT. (a, b) Iodine overlay CT maps of
two patients with GB wall thickening (arrows) due to chole-
cystitis (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 over-
lay 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.
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 emer-
gency cholecystectomy as it helps in planning an open radical
surgery and avoidance of intraoperative bile spillage. Laparo-
scopic 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
Dual energy CT (DECT) enables acquisition of data simultane-
ously 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 visu-
alized more easily compared to benign conditions like adenomy-
omatosis 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.
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 BJR
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 hyper-
dense lesion in the lumen of GB (arrow). (d–f) Axial T2W (d),
DWI (e) and ADC map (f) shows that the lesion is T2 hypoin-
tense with free diffusion. Hyperdensity on CT, T1 hyperin-
tensity & free diffusion suggest tumefactive sludge. ADC,
apparent diffusioncoefficient; 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 involve-
ment by GBC (Figures 1 and 9).60 Kim et al, in their retrospec-
tive 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 differen-
tiating tumefactive biliary sludge from a solid tumor (Figure 13).
Further, DWI may assist in the characterization of incidentally
detected liver lesions.
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).
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Ramachandran et al
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 manage-
ment 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 appear-
ances. These pathologies, along with their salient features are
summarized in Table 3.74–76 Among the differentials, GB adeno-
myomatosis 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 hyper-
echoic foci with posterior acoustic shadowing due to calcifica-
tion and twinkling artifact on color Doppler are other diagnostic
clues on USG as these are not observed in GBC.
Br J Radiol;94:20200726
 Gallbladder Cancer Revisited BJR

Table 3. Radiological differential diagnoses of GBC

Morphologic type of Imaging differential diagnosis Remarks

GBC
Focal or diffuse wall Xanthogranulomatous cholecystitis (XGC) A chronic inflammatory condition with focal or diffuse
thickening 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 Mimics Stage 3A tumor
abscess, fistula formation with bowel
Intraluminal Polypoid Adenomatous polyp (neoplastic), Hyperplastic, Size is the most important predictor of malignancy in neoplastic
mass cholesterol polyp (non-­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 TREATMENT

ultrasound image of gallbladder shows an area of mural thick-
ening 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 enhance-
ment in the region of mural thickening (block arrows). Fea-
tures are suggestive of localized form of adenomyomatosis.
Surgical resection is the standard treatment for patients with
resectable GBC (Table 4).24,78,79
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 meta-
static 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 hyperen-
hancement in delayed phase due to sub lobular venoocclusion;
and chronic phase (beyond 6 months) characterized by fibrosis
and volume loss.83

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

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 BJR Ramachandran et al

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) Removal of the GB and adjacent liver bed (segments 4B and 5). Higher recurrence
cholecystectomya rate of T1b tumors compared to T1a tumors. Hence radical cholecystectomy is
recommended for T1b tumors, though debated.78,79
T2 (perimuscular connective tissue) - Radical cholecystectomy Higher possibility for micrometastases in liver and lymph nodes compared to T1.
T2a: peritoneal side - T2b: hepatic side 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 Radical resection Removal of all involved organs to achieve R0 resection and locoregional lymph
and /or one adjacent organ) node clearance
T4 (invade two or more extrahepatic Unresectable
organs or invade MPV /HA)
GBC, gallbladder cancer; HA, hepatic artery; MPV, main portal vein.
a
Radical 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

Figure 16. Post-­radiation changes. (a) Axial CT image show-
ing low attenuation focal area with straight margins (arrow-
heads) 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.
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 guid-
ance 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

Figure 17. Limitation of CT in assessing response. CT scans (a,

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.
c) & PET-­CT (b, & d), before and after chemotherapy respec-
tively. 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.

Radiological evaluation is usually done after 3–6 cycles of chemo-

therapy, 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 immedi-
ately 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

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 Gallbladder Cancer Revisited
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 coeffi-
cient; DWI, diffusion-­weighted imaging.
Figure 20. Portal vein embolization. Right portal venogram,
before (a) & portal venogram after (b) embolization with n-­bu-
tyl 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 emboliza-
tion shows hypertrophy of left lateral segments (asterisk) and
atrophy of embolized right lobe. PV, portal vein.
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 intrac-
table 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
10 of 14 birpublications.org/bjr
BJR
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).
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 conflu-
ence. 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 exter-
nal–internal drainage catheter, when the external end is closed
(Figure 19).
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 hyper-
trophy 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).
CONCLUSION
GBC is an aggressive biliary malignancy with dismal survival rates.
Clinical symptoms are often non-­specific and present late in the
Br J Radiol;94:20200726
 BJR
course of the disease. Imaging is required at all stages of the work-
flow of the patients with suspected GBC – starting from detection,
staging, restaging post-­chemotherapy to the management of unre-
sectable cases. Biliary drainage and pre-­operative portal vein embo-
lization are two relevant procedures in the management where role
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