Biliary Tract Malignancies Related to Gallbladder Polyps, Primary Sclerosing Cholangitis, and Choledochal Cysts

Abbreviations

APBJ

abnormal pancreaticobiliary junction

BMI

body mass index

CBD

common bile duct

CC

choledochal cyst

CCA

cholangiocarcinoma

FISH

fluorescence in situ hybridization

GB

gallbladder

GBCA

gallbladder cancer

GBP

gallbladder polyps

IBD

inflammatory bowel disease

LT

liver transplant

MRI

magnetic resonance imaging

PSC

primary sclerosing cholangitis

TAU

transabdominal ultrasound

UC

ulcerative colitis

Biliary tract neoplasia may be entirely asymptomatic or associated with symptoms and signs such as abdominal pain, jaundice, recurrent cholangitis, or pruritus. We aim to discuss key clinical and imaging features with evidence‐based management principles for benign and malignant biliary neoplastic lesions.

Gallbladder Polyps

Gallbladder polyps (GBP) are found in 3% to 7% of healthy individuals, but only 5% are considered to be true GBPs.¹ These are protrusions of the gallbladder mucosa, and not all polypoid lesions are malignant. It is crucial to differentiate between “true” polyps and pseudopolyps (Table 1). Further differentiation between malignant and benign lesions is made once a true polyp is identified.² The ideal imaging modality should be able to determine a polyp’s type, size, and malignant potential. Transabdominal ultrasound (TAU) is the imaging of choice for GBPs. Its sensitivity and specificity for true GBPs is described as 83.1% and 96.3%, respectively.³ A major shortcoming of all imaging modalities is the ability to differentiate between benign and malignant polyps, as summarized in Table 2. Age >50 years, Indian ethnicity, polyp size >10 mm, sessile polyp, and primary sclerosing cholangitis (PSC) are considered high‐risk factors for malignancy, as summarized in Table 3. Cholecystectomy is recommended when polyp size is >10 mm, polyp size is <10 mm with symptoms, or polyp size is 6 to 9 mm in high‐risk patients. High‐risk patients with polyps <6 mm and low‐risk patients with polyps measuring 6 to 9 mm should undergo surveillance at 6 months and 1‐, 2‐, 3‐, 4‐, and 5‐year intervals. All other patients should undergo surveillance at 1‐, 3‐, and 5‐year intervals. An increase in size of >2 mm on surveillance examinations also mandates cholecystectomy.⁴ Imaging features suggestive of underlying malignancy include solitary or displaced gallstone, invasive gallbladder mass, discontinuity of mucosal echo, polyp >10 mm, loss of interface or direct invasion of surrounding structures, and a porcelain (calcified) gallbladder.⁵

TABLE 1.

Classification of Gallbladder Polypoid Lesions and Key Imaging Features²

Type of Gallbladder Pathology	Key Features on Endosonography
Polypoid mimickers Tumefactive sludge	Mobile when tapped
Gall stones	Posterior acoustic shadowing
Polypoid lesions
Cholesterol polyps	Balls‐on‐the‐wall sign
Adenomyomatosis	Comet tail artifacts, twinkle artifacts
Inflammatory polyps	Associated chronic inflammation
Benign tumors (adenomas, papillomas)	Vascular signs on color Doppler
Malignant tumors	Size >10 mm
	Focal wall thickening >3 mm
	Loss of interface

TABLE 2.

Performance Characteristics of Imaging Modalities for Detection of GBPs²²

Testing Modality	Use	Limitations
TAU	First‐line modality	1. Operator dependent
	Sensitivity for all GBPs – 70%	2. Limited by BMI
	Specificity for all GBPs – 84%
Computed tomography	Staging large suspicious malignant polyps	1. Lacks superiority to TAU
		2. Not accurate for benign versus malignant polyps
MRI	Not recommended for diagnosis	Expensive
Endoscopic ultrasound	Greater sensitivity and specificity for malignant polyps	Invasive with risk for bleeding and perforation

TABLE 3.

High‐Risk Factors for Malignancy in Gallbladder Polyps

Age >50 years Indian ethnicity Polyp size >10 mm Sessile polyp PSC

PSC

PSC is a chronic, idiopathic, cholestatic liver disease composed of multifocal inflammation and fibrosis of intrahepatic and extrahepatic bile ducts resulting in biliary strictures. The prevalence of PSC is 16.2 per 100,000 people, it is more common in males than females, and median age at diagnosis is 41 years.⁶, ⁷ About 70% of patients with PSC have underlying inflammatory bowel disease (IBD), most frequently ulcerative colitis (UC) in more than 75% of cases. Long‐term sequelae include liver cirrhosis with associated complications.⁸, ⁹, ¹⁰ Figure 1 illustrates a guideline‐based management of various hepatic and extrahepatic manifestations of PSC. PSC is also a risk factor for cholangiocarcinoma (CCA), gallbladder cancer (GBCA), and colorectal cancer,⁹ with malignancies accounting for 44% of deaths in patients with PSC. CCA constitutes the majority of malignancies in PSC with an incidence rate of approximately 20%. About 50% of patients are diagnosed with CCA in the first year after an initial diagnosis of PSC.¹¹ The pathogenesis is largely unknown and is postulated to be secondary to various factors, such as genetics, recurrent inflammation, and physiological and immunological dysfunctions.¹² Patients with extrahepatic CCA present with signs and symptoms of biliary obstruction as opposed to patients with intrahepatic PSC, who typically present with weight loss, fatigue, and night sweats with a predominant elevation of alkaline phosphatase.¹¹ There should be a high index of suspicion for PSC in the setting of dominant strictures, which are defined as a common bile duct (CBD) stricture of <1.5 cm and a hepatic duct stricture of <1.0 mm.¹³ Endoscopic retrograde cholangiopancreatography with brush cytology has a high specificity of 95%; the sensitivity, however, is considerably low at 43%.¹⁴ It can be enhanced to 45% to 59% with the use of fluorescence in situ hybridization (FISH)¹⁵ and to 65% with the use of cholangioscopy and targeted biopsies. Endoscopic ultrasound has the advantage of being less invasive and demonstrates an overall sensitivity for malignancy of 88% and specificity of 100%. Bile duct wall thickness >3 mm has a sensitivity and specificity of 79% for malignancy. The addition of fine needle aspiration increases the sensitivity and specificity to 84% and 100%, respectively. The caveat is increased risk for tumor seeding and subsequent peritoneal metastases leading to exclusion from liver transplant (LT) candidacy as per Mayo Clinic protocol.¹⁶ Currently, there is a lack of consensus on screening of patients with PSC for CCA. The American Association for the Study of Liver Diseases states that “in the absence of evidence based information, many clinicians screen patients with an imaging study plus a CA 19‐9 at annual intervals.”⁸

FIG 1.

Manifestations of PSC and guideline‐based management.⁸

Choledochal Cysts

Choledochal cysts (CCs) are rare, congenital, single or multiple, intrahepatic and/or extrahepatic bile duct dilations. These are most commonly found in Asian females.¹⁷ Previously, 90% of CCs used to be a childhood diagnosis; however, recently, incidental diagnoses in asymptomatic adults have increased from 10% to 36% because of increased utilization of body imaging.¹⁸ As per Todani classification, CCs are categorized from I through V (Table 4 and Fig. 2), with type I being the most common type universally. Proposed mechanisms for CC formation include abnormal pancreaticobiliary junction (APBJ), sphincter of Oddi dysfunction, and aganglionosis of distal CBD. Nonspecific recurrent abdominal pain remains the most common presenting symptom; in addition, patients may present with palpable abdominal mass and jaundice, also known as the classic triad.¹⁹ Magnetic resonance cholangiopancreatography remains 90% to 100% sensitive in detecting CCs; however, it may not be accurate in detecting minor APBJ.²⁰ CCs can be complicated by choledocholithiasis, cholangitis, pancreatitis, secondary biliary cirrhosis, spontaneous cyst rupture, GBCA, and CCA. The risk for malignant transformation is reported to be as high as 21%; it is four times higher with concomitant APBJ. The risk is highest in type I and lowest with type III. The risk for CCA and GBCA is higher in patients with CC and APBJ. Patients with APBJ in the absence of CC are at a greater risk for GBCA only.¹⁹ Surgical excision of CC with cholecystectomy is the mainstay of treatment, unless type III, which can be treated with biliary sphincterotomy at endoscopic retrograde cholangiopancreatography. Biliary continuity can be subsequently established by Roux‐en‐Y hepaticoenterostomy.²¹ Table 4 details individualized management of each CC type.

TABLE 4.

Todani Classification of CCs and Management¹⁹, ²³

Type	Description	Management
I	Solitary extrahepatic cyst	Complete cyst excision of the extrahepatic component Cholecystectomy
		60‐cm Roux‐en‐Y biliary reconstruction
II	Extrahepatic supraduodenal diverticulum	Resection with preservation of the main bile duct
		In the presence of APBJ → cholecystectomy
III	Intraduodenal cyst (choledochocele)	Endoscopic sphincterotomy plus cholecystectomy
IV	Both extrahepatic and intrahepatic cysts	Complete cyst excision of the extrahepatic component Cholecystectomy
		60‐cm Roux‐en‐Y biliary reconstruction
V	Multiple intrahepatic cysts (Caroli disease)	Localized unilobar disease → liver resection
		Bilobar disease, cirrhosis, carcinoma, recurrent cholangitis → consider LT

FIG 2.

Todani classification of CCs. Figure reprinted with permission from Surgical and Radiologic Anatomy.²³ Copyright 2016, Springer Nature Switzerland AG.