Cholangiocarcinoma

Cholangiocarcinoma

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Cholangiocarcinomas (CCCs) are malignancies of the biliary duct system that may originate in the liver and extrahepatic bile ducts, which terminate at the ampulla of Vater. [1, 2, 3, 4, 5] CCCs are encountered in three anatomic regions: intrahepatic, extrahepatic (ie, perihilar), and distal extrahepatic. See the image below.

Perihilar tumors are the most common CCCs, and intrahepatic tumors are the least common. Perihilar tumors, also called Klatskin tumors (after Klatskin’s description of them in 1965 [6] ), occur at the bifurcation of right and left hepatic ducts. [7] Distal extrahepatic tumors are located from the upper border of the pancreas to the ampulla. More than 95% of these tumors are ductal adenocarcinomas; many patients present with unresectable or metastatic disease.

Complete surgical resection is the only therapy to afford a chance of cure for cholangiocarcinoma. Unfortunately, many patients present with unresectable disease. Additional treatment measures in cholangiocarcinoma may include the following [8] :

See Treatment and Medication.

Cholangiocarcinomas arise from the intrahepatic or extrahepatic biliary epithelium. More than 90% are adenocarcinomas, and the remainder are squamous cell tumors. The etiology of most bile duct cancers remains undetermined. Long-standing inflammation, as with primary sclerosing cholangitis (PSC) or chronic parasitic infection, has been suggested to play a role by inducing hyperplasia, cellular proliferation, and, ultimately, malignant transformation. Intrahepatic cholangiocarcinoma may be associated with chronic ulcerative colitis and chronic cholecystitis.

Cholangiocarcinomas tend to grow slowly and to infiltrate the walls of the ducts, dissecting along tissue planes. Local extension occurs into the liver, porta hepatis, and regional lymph nodes of the celiac and pancreaticoduodenal chains. Life-threatening infection (cholangitis) may occur that requires immediate antibiotic intervention and aggressive biliary drainage.

United States

Each year, approximately 2500 cases of cholangiocarcinoma occur, compared with 5000 cases of gallbladder cancer and 15,000 cases of hepatocellular cancer. The average incidence is one case per 100,000 population per year.

A study by Singal et al found that the frequency of intrahepatic cholangiocarcinoma has increased over time and is most commonly noted in women older than 60 years. [9]

International

Incidence in most Western countries ranges from 2 to 6 cases per 100,000 people per year. The highest annual incidences are in Japan, at 5.5 cases per 100,000 people, and in Israel, at 7.3 cases per 100,000 people.

Occupational cholangiocarcinoma has been documented in workers at printing companies in Japan who had been exposed to high concentrations of chemical compounds, including 1,2-dichloropropane (1,2-DCP) and/or dichloromethane. [10] Heavy infestation by the liver flukes Clonorchis sinensis (endemic predominantly in Asian countries, including Korea, China, Taiwan, Vietnam, and far eastern Russia) and Opisthorchis viverrini (the Southeast Asian liver fluke) has been linked to the development of cholangiocarcinoma. [11]

Despite aggressive anticancer therapy and interventional supportive care (ie, wall stents or percutaneous biliary drainage), the median survival rate is low, since most patients (90%) are not eligible for curative resection. The overall survival is approximately 6 months.

Native Americans have the highest annual incidence in North America, at 6.5 cases per 100,000 people. This rate is about 6 times higher than that in non–Native American populations. The high prevalence of cholangiocarcinoma in people of Asian descent is attributable to endemic chronic parasitic infestation.

In both males and females, cholangiocarcinoma is most common in persons in their 60s and 70s. The male-to-female ratio for cholangiocarcinoma is 1:2.5 in patients in their 60s and 70s and 1:15 in patients younger than 40 years. According to the American Cancer Society, the number of new cases of liver and intrahepatic bile duct cancer in 2018 is estimated to be 30,610 for men and 11,610 for women, with deaths estimated at 20,540 and 9,660, respectively. The estimated number of new cases of gallbladder and other biliary cancers (extrahepatic cholangiocarcinoma) are 5,450 for men and 6,740 for women, with estimated deaths of 1,530 and 2,260, respectively. [12]  

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Singal AK, Vauthey JN, Grady JJ, Stroehlein JR. Intra-hepatic cholangiocarcinoma–frequency and demographic patterns: thirty-year data from the M.D. Anderson Cancer Center. J Cancer Res Clin Oncol. 2011 Jul. 137(7):1071-8. [Medline].

Mimaki S, Totsuka Y, Suzuki Y, Nakai C, Goto M, Kojima M, et al. Hypermutation and unique mutational signatures of occupational cholangiocarcinoma in printing workers exposed to haloalkanes. Carcinogenesis. 2016 Aug. 37 (8):817-26. [Medline].

Kim TS, Pak JH, Kim JB, Bahk YY. Clonorchis sinensis, an Oriental Liver Fluke, as a Human Biological Agent (Carcinogen) of Cholangiocarcinoma: A Brief Review. BMB Rep. 2016 Jul 7. [Medline].

Cancer Facts & Figures 2018. American Cancer Society. Available at https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-2018.pdf. Accessed: August 29, 2018.

McGee EE, Castro FA, Engels EA, Freedman ND, Pfeiffer RM, Nogueira L, et al. Associations between autoimmune conditions and hepatobiliary cancer risk among elderly US adults. Int J Cancer. 2018 Aug 28. [Medline].

Koshiol J, Ferreccio C, Devesa SS, Roa JC, Fraumeni JF Jr. Biliary Tract Cancer. Thun MJ, Linet MS, Cerhan JR, Haiman CA, Schottenfeld D, eds. Cancer. Epidemiology and Prevention. 4th Edition. New York, NY: Oxford University Press; 2018. 661-671.

Chalasani N, Baluyut A, Ismail A, et al. Cholangiocarcinoma in patients with primary sclerosing cholangitis: a multicenter case-control study. Hepatology. 2000 Jan. 31(1):7-11. [Medline].

Travis LB, Hauptmann M, Gaul LK, Storm HH, Goldman MB, Nyberg U, et al. Site-specific cancer incidence and mortality after cerebral angiography with radioactive thorotrast. Radiat Res. 2003 Dec. 160(6):691-706. [Medline].

Li JS, Han TJ, Jing N, Li L, Zhang XH, Ma FZ, et al. Obesity and the risk of cholangiocarcinoma: a meta-analysis. Tumour Biol. 2014 Apr 13. [Medline].

Ramage JK, Donaghy A, Farrant JM, Iorns R, Williams R. Serum tumor markers for the diagnosis of cholangiocarcinoma in primary sclerosing cholangitis. Gastroenterology. 1995 Mar. 108 (3):865-9. [Medline]. [Full Text].

Bergquist JR, Ivanics T, Storlie CB, Groeschl RT, Tee MC, Habermann EB, et al. Implications of CA19-9 elevation for survival, staging, and treatment sequencing in intrahepatic cholangiocarcinoma: A national cohort analysis. J Surg Oncol. 2016 Jul 20. [Medline].

Keiding S, Hansen SB, Rasmussen HH, et al. Detection of cholangiocarcinoma in primary sclerosing cholangitis by positron emission tomography. Hepatology. 1998 Sep. 28(3):700-6. [Medline].

Petrowsky H, Wildbrett P, Husarik DB. Impact of Integrated PET and CT on staging and management of glabladder cancer and cholangiocarcinoma. J Hepatol. 2006. Epub Apr 19:

Fritscher-Ravens A, Broering DC, Knoefel WT, et al. EUS-guided fine-needle aspiration of suspected hilar cholangiocarcinoma in potentially operable patients with negative brush cytology. Am J Gastroenterol. 2004 Jan. 99(1):45-51. [Medline].

American Joint Committee on Cancer. Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, et al, eds. AJCC Cancer Staging Manual. 8th Edition. New York: Springer; 2017.

Simmons DT, Baron TH, Peterson BT. A Novel Endoscopic Approach to Brachytherapy in the Management of Hilar Cholangiocarcinoma. Am J Gastroenterol. 2006. Epub ahead of print:

Butros SR, Shenoy-Bhangle A, Mueller PR, Arellano RS. Radiofrequency ablation of intrahepatic cholangiocarcinoma: feasability, local tumor control, and long-term outcome. Clin Imaging. 2014 Feb 7. [Medline].

Kida M, Miyazawa S, Iwai T, et al. Endoscopic management of malignant biliary obstruction by means of covered metallic stents: primary stent placement vs. re-intervention. Endoscopy. 2011 Dec. 43(12):1039-44. [Medline].

Ortner MA, Liebetruth J, Schreiber S, et al. Photodynamic therapy of nonresectable cholangiocarcinoma. Gastroenterology. 1998 Mar. 114(3):536-42. [Medline].

Ortner ME, Caca K, Berr F, et al. Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study. Gastroenterology. 2003 Nov. 125(5):1355-63. [Medline].

Jackson MW, Amini A, Jones BL, Rusthoven CG, Schefter TE, Goodman KA. Treatment Selection and Survival Outcomes With and Without Radiation for Unresectable, Localized Intrahepatic Cholangiocarcinoma. Cancer J. 2016 Jul-Aug. 22 (4):237-42. [Medline].

Mosconi C, Gramenzi A, Ascanio S, Cappelli A, Renzulli M, Pettinato C, et al. Yttrium-90 radioembolization for unresectable/recurrent intrahepatic cholangiocarcinoma: a survival, efficacy and safety study. Br J Cancer. 2016 Jul 26. 115 (3):297-302. [Medline].

Thongprasert S, Napapan S, Charoentum C, Moonprakan S. Phase II study of gemcitabine and cisplatin as first-line chemotherapy in inoperable biliary tract carcinoma. Ann Oncol. 2005 Feb. 16(2):279-81. [Medline].

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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

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 

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

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

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

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

Peter E Darwin, MD Professor of Medicine, Director of GI Endoscopy, Department of Medicine, Division of Gastroenterology, University of Maryland School of Medicine

Peter E Darwin, MD is a member of the following medical societies: American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Andrew Scott Kennedy, MD Physician-in-Chief, Radiation Oncology

Andrew Scott Kennedy, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Research, American Society for Radiation Oncology, Radiological Society of North America, Americas Hepato-Pancreato-Biliary Association, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Jennifer Lynn Bonheur, MD Attending Physician, Division of Gastroenterology, Lenox Hill Hospital

Jennifer Lynn Bonheur, MD is a member of the following medical societies: American Gastroenterological Association, American Society for Gastrointestinal Endoscopy, New York Society for Gastrointestinal Endoscopy, New York Academy of Sciences, Sigma Xi

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Benjamin Movsas, MD 

Benjamin Movsas, MD is a member of the following medical societies: American College of Radiology, American Radium Society, American Society for Radiation Oncology

Disclosure: Nothing to disclose.

N Joseph Espat, MD, MS, FACS Harold J Wanebo Professor of Surgery, Assistant Dean of Clinical Affairs, Boston University School of Medicine; Chairman, Department of Surgery, Director, Adele R Decof Cancer Center, Roger Williams Medical Center

N Joseph Espat, MD, MS, FACS is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Research, American College of Surgeons, American Medical Association, American Society for Parenteral and Enteral Nutrition, American Society of Clinical Oncology, Americas Hepato-Pancreato-Biliary Association, Association for Academic Surgery, Central Surgical Association, Chicago Medical Society, International Hepato-Pancreato-Biliary Association, Pancreas Club, Sigma Xi, Society for Leukocyte Biology, Society for Surgery of the Alimentary Tract, Society of American Gastrointestinal and Endoscopic Surgeons, Society of Surgical Oncology, Society of University Surgeons, Southeastern Surgical Congress, Southern Medical Association, Surgical Infection Society

Disclosure: Nothing to disclose.

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

Elwyn C Cabebe, MD is a member of the following medical societies: American Association for Cancer Research, American Society of Clinical Oncology, Philippine Medical Society of Northern California, Santa Clara County Medical Association, Monterey County Medical Society, Association of Northern California Oncologists

Disclosure: Nothing to disclose.

Cholangiocarcinoma

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