Guidelines Summary

Guidelines Contributor: Elwyn C Cabebe, MD Physician Partner, Valley Medical Oncology Consultants; Medical Director of Oncology, Clinical Liason Physician, Cancer Care Committee, Good Samaritan Hospital

Diagnosis

The National Comprehensive Cancer Network (NCCN) recommends the following intrahepatic cholangiocarcinoma workup in patients with an isolated intrahepatic mass that has imaging characteristics consistent with malignancy but not consistent with hepatocellular carcinoma^[40]:

History and physical examination
Multiphasic abdominal/pelvic computed tomography (CT)/magnetic resonance imaging (MRI) with intravenous contrast
Chest CT with or without contrast
Consider baseline carcinoembryonic antigen (CEA) and CA 19-9 testing
Liver function tests (LFTs)
Surgical consultation
Esophagogastroduodenoscopy (EGD) and colonoscopy (to assess for T3 disease and rule out endobiliary metastasis from colorectal cancer mimicking intrahepatic cholangiocarcinoma ^[46])
Consider viral hepatitis serologies
Consider biopsy
Consider alpha fetoprotein (AFP) testing

For the workup of extrahepatic cholangiocarcinoma, in patients who present with pain, jaundice, abnormal LFTs, and obstruction or abnormality on imaging, the NCCN recommends the following workup^[40]:

History and physical examination
Multiphasic abdominal/pelvic CT/MRI (to assess for vascular invasion) with IV contrast
Chest CT with or without contrast
Cholangiography
Consider baseline CEA and CA 19-9
LFTs
Consider endoscopic ultrasound (EUS) after surgical consultation
Consider serum IgG4 to rule out autoimmune cholangitis

Guidelines from the American Society for Gastrointestinal Endoscopy (ASGE) recommend magnetic resonance cholangiography (MRCP) to assess for resectability if a CT scan suggests cholangiocarcinoma. ERCP is recommended to obtain tissue or facilitate further evaluation of indeterminate strictures.^[47]

Staging

Cholangiocarcinoma cancer staging follows the tumor-node-metastasis (TNM) classification of the American Joint Cancer Committee/Union for International Cancer Control/ (AJCC/UICC) and is staged separately for intrahepatic, perihilar, and distal bile duct tumors.^[27]

TNM groupings by stage are as follows for each group:^[27]

Table. 1 (Open Table in a new window)

Intrahepatic bile duct tumor
Stage	T	N	M
0	Tis	N0	M0
IA	T1a	N0	M0
IB	T1b	N0	M0
II	T2	N0	M0
IIIA	T3	N0	M0
IIIB	T4	N0	M0
	Any T	N1	M0
IV	Any T	Any N	M1

Table. 2 (Open Table in a new window)

Perihilar bile duct tumor
Stage	T	N	M
0	Tis	N0	M0
I	T1	N0	M0
II	T2a-b	N0	M0
IIIA	T3	N0	M0
IIIB	T4	N0	M0
IIIC	Any T	N1	M0
IVA	T4	N2	M0
IVB	Any T	Any N	M1

Table. 3 (Open Table in a new window)

Distal bile duct tumor
Stage	T	N	M
0	Tis	N0	M0
I	T1	N0	M0
IIA	T1	N1	M0
	T2	N0	M0
IIB	T2	N1	M0
	T3	N0	M0
	T3	N1	M0
IIIA	T1-3	N2	M0
IIIB	T4	N0-2	M0
IV	Any T	Any N	M1

Treatment

The NCCN and ESMO guidelines concur that the only potentially curative treatment for cholangiocarcinoma is complete surgical resection with negative margins. However, few patients are diagnosed with early-stage resectable tumors.^{[40, 48]}

With cholangiocarcinomas that are resected with negative margins and negative regional nodes, the NCCN recommends observation or systemic therapy (with gemcitabine as the preferred agent) for both intrahepatic and extrahepatic cholangiocarcinomas; for extrahepatic cholangiocarcinomas, fluoropyrimidine chemoradiation is also an option.

For intrahepatic and extrahepatic cholangiocarcinomas resected with microscopic margins or positive regional nodes, options include the following:

Systemic therapy
Fluoropyrimidine-based chemoradiation
Fluoropyrimidine- or gemcitabine-based chemotherapy followed by fluoropyrimidine-based chemoradiation
Fluoropyrimidine-based chemoradiation followed by fluoropyrimidine- or gemcitabine-based chemotherapy

For intrahepatic or extrahepatic resections with residual local disease, or unresectable disease, NCCN suggestions include systemic therapy, external beam radiation therapy (EBRT) with concurrent fluoropyrimidine, or best supportive care. The choice of care may be guided by the extent and/or location of disease and institutional capabilities.^[40]

For metastatic disease, options for intrahepatic cholangiocarcinomas include systemic therapy, consideration of locoregional therapy (eg, EBRT, arterially directed therapies), or best supportive care. For extrahepatic cholangiocarcinomas, options are systemic therapy or best supportive care.^[40]

Medication

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Media Gallery

Bismuth classification for perihilar cholangiocarcinoma. Shaded areas represent tumor location.
Tight stricture of a common hepatic duct in a patient presenting with jaundice. Cytologic studies confirmed cholangiocarcinoma.
Three-dimensional treatment planning uses CT scan slices to reconstruct the patient as a volume. Shown here is the display for planning external-beam radiotherapy to the cholangiocarcinoma (green structure). A biliary catheter (red tube) runs through the tumor volume and was used to deliver brachytherapy, which was given in addition to external-beam radiotherapy. Such technology has assisted greatly in the delivery of high doses to the tumor, while sparing vital normal structures, such as the kidney and spinal cord.

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Table 1. TNM staging for intrahepatic bile duct tumors

T - Primary tumor
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
Tis	Carcinoma in situ (intraductal tumor)
T1	Solitary tumor without vascular invasion, ≤5 cm or > 5 cm
	T1a		Solitary tumor ≤5 cm without vascular invasion
	T1b	Solitary tumor > 5 cm without vascular invasion
T2	Solitary tumor with intrahepatic vascular invasion, or multiple tumors with or without vascular invasion
T3	Tumor perforating the visceral peritoneum
T4	Tumor involving local extrahepatic structures by direct invasion
N – Regional lymph nodes
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Regional lymph node metastasis present
M – Distant metastasis
M0	No distant metastasis
M1	Distant metastasis present

Table 2. TNM staging for perihilar bile duct tumors.

T - Primary tumor
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
Tis	Carcinoma in situ – high-grade dysplasia
T1	Tumor confined to the bile duct, with extension up to the muscle layer or fibrous tissue
T2	Tumor invades beyond the wall of the bile duct to surrounding adipose tissue, or tumor invades adjacent hepatic parenchyma
	T2a		Tumor invades beyond the wall of the bile duct to surrounding adipose tissue
	T2b	Tumor invades adjacent hepatic parenchyma
T3	Tumor invades unilateral branches of the portal vein or hepatic artery
T4	Tumor invades main portal vein or its branches bilaterally, or the common hepatic artery; or unilateral second-order biliary radicals bilaterally with contralateral portal vein or hepatic artery involvement
N – Regional lymph nodes
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	One to three positive lymph nodes typically involving the hilar, cystic duct, common bile duct, hepatic artery, posterior pancreatoduodenal, and portal vein lymph nodes
N2	Four or more positive lymph nodes from the sites described for N1
M – Distant metastasis
M0	No distant metastasis
M1	Distant metastasis

Table 3. TNM staging for distal bile duct tumors.

T - Primary tumor
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
Tis	Carcinoma in situ – high-grade dysplasia
T1	Tumor invades the bile duct wall with a depth less than 5 m
T2	Tumor invades the bile duct wall with a depth of 5–12 m
T3	Tumor invades the bile duct wall with a depth greater than 12 mm
T4	Tumor involves the celiac axis, superior mesenteric artery, and/or common hepatic artery
N – Regional lymph nodes
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Metastasis in 1-3 regional lymph nodes
N2	Metastasis in ≥4 regional lymph nodes
M – Distant metastasis
M0	No distant metastasis
M1	Distant metastasis