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Page 4 of 16 Chandrasekar et al. Mini-invasive Surg 2021;5:33 https://dx.doi.org/10.20517/2574-1225.2021.12

Tumor markers
Carbohydrate antigen 19-9 (CA 19-9) and carcinoembryonic antigen (CEA) have been studied for the
diagnosis of biliary tumors. Although they may be of some diagnostic value, they are not specific for the
diagnosis of biliary tumors, especially since they can also be elevated in some benign conditions [15-17] . The
role of CA 19-9 in patients with PSC is particularly helpful and can help with the diagnosis of CCA,
[18]
especially if there is a sudden increase in the level . Studies on CA 19-9 have shown wide variations in
sensitivity (46%-90%) and specificity (54%-98%) [19-21] . It can be elevated in benign conditions like cholangitis,
biliary obstruction due to other reasons, liver cirrhosis and other malignancies like pancreatic cancer. Kim
et al. in their analysis suggested a cut-off value of 37 U/mL with a sensitivity of 78% and specificity of 83%
[17]
for the diagnosis of pancreatobiliary malignancies but dropped to 74% and 42% respectively in the presence
of cholangitis/cholestasis. CA 19-9 assay can be used for surveillance of CCA in patients with PSC. Levy
[21]
et al. used a cut-off of 129 U/mL and demonstrated a sensitivity of 79% and specificity of 99% for the
diagnosis of CCA, but the positive predictive value was lower at 57%. CEA has demonstrated lower
sensitivity and specificity compared to CA 19-9 and can be elevated in other malignancies. If levels of either
marker are increased, it may be used to monitor response to treatment in the setting of CCA.

TISSUE SAMPLING TECHNIQUES
Endoscopic retrograde cholangiopancreatography
ERCP is still considered the gold standard for biliary imaging with the ability to obtain tissue sampling for
diagnosis. Due to recent advances in imaging modalities with CT and MRI/ MRCP, studies have shown
[22]
comparable diagnostic accuracy with ERCP . ERCP is useful in the diagnosis of ECCA and peri-hilar
CCA. Cholangiograms reveal a stricture in the biliary tract with or without upstream biliary ductal
dilatation. Malignant strictures usually appear as long segments with irregularity and asymmetry with
shelving [Figure 1] . Histopathological diagnosis could be obtained with ERCP with one of the three
[23]
modalities: (1) brush cytology; (2) aspiration of biliary fluid; and (3) biopsy with endobiliary forceps. The
sensitivity of these techniques varies when performed individually versus in combination and carries a
specificity of almost 100% [Table 2].

Cytology and aspiration
Bile duct brushings are commonly performed to differentiate benign from malignant strictures. Several
[24]
studies have shown variable sensitivity rates from 23%-86% . Kurzawinski et al. in the prospective study
[25]
of 100 patients with biliary strictures reported a 33% sensitivity for detection of CCA. A meta-analysis of
[26]
more than 1500 patients by Burnett et al. reported a sensitivity of 42%. Frequently cytology is combined
with fluorescent in situ hybridization (FISH) or mutation profiling (MP) to increase sensitivity. Kushnir
et al. demonstrated in their study that sensitivity for cytology alone was 26% but when combined with
[27]
FISH and MP, it was 44% and 56% respectively. When all 3 modalities were combined it was 66%. Dudley
et al. in their study combined next generation sequencing with cytology improving their sensitivity from
[28]
67% to 85%.

Sugimoto et al. demonstrated that aspiration of bile in 76 patients with biliary strictures demonstrated a
[29]
sensitivity of 32% for the diagnosis of biliary cancers but the sensitivity improved to 70% when aspiration
was performed after biliary brushings. The sensitivity also improved with the aspiration of a higher amount
of fluid, protruding type tumors compared to flat type and for tumor with longer stricture segments. The
Presence of a desmoplastic reaction and inflammatory changes can decrease the sensitivity.

Biliary forceps biopsy
Endoluminal biopsy using biliary forceps is technically more challenging compared to brushings and
generally requires a sphincterotomy. It can also be difficult to perform in narrow bile ducts and tumors