section name header

Disease Prologue ⬇

Summary ⬆ ⬇

Cancers Staged Using This Staging System

Perihilar cholangiocarcinoma or bile duct cancer, hilar cholangiocarcinoma, Klatskin tumor

Cancers Not Staged Using This Staging System

These histopathologic types of cancer…Are staged according to the classification for…and can be found in chapter…
SarcomaSoft tissue sarcoma of the abdomen and thoracic visceral organs42
Well-differentiated neuroendocrine tumor (carcinoid)No AJCC staging systemN/A

Summary of Changes

ChangeDetails of ChangeLevel of Evidence
Definition of Primary Tumor (T)The definition of Tis has been expand ed to include high-grade biliary intraepithelial neoplasia (BilIn-3). High-grade dysplasia (BilIn-3), a noninvasive neoplastic process, is synonymous with carcinoma in situ at this site.N/A
Definition of Primary Tumor (T)Bilateral second-order biliary radical invasion (Bismuth-Corlette type IV) has been removed from T4 category.II
Definition of Regional Lymph Node (N)N category was reclassified based on number of positive nodes to N1 (one to three positive nodes) and N2 (four or more positive nodes).II
AJCC Prognostic Stage GroupsThe stage group for T4 tumors was changed from Stage IVA to Stage IIIB.II
AJCC Prognostic Stage GroupsN1 category was changed from Stage IIIB to IIIC, and N2 category is classified as Stage IVA.II

ICD-O-3 Topography Codes

CodeDescription
C24.0Proximal or perihilar bile ducts only

WHO Classification of Tumors

This list includes histology codes and preferred terms from the WHO Classification of Tumors and the International Classification of Diseases for Oncology (ICD-O). Most of the terms in this list represent malignant behavior. For cancer reporting purposes, behavior codes /3 (denoting malignant neoplasms), /2 (denoting in situ neoplasms), and in some cases /1 (denoting neoplasms with uncertain and unknown behavior) may be appended to the 4-digit histology codes to create a complete morphology code.

CodeDescription
8010Carcinoma, NOS
8010Carcinoma in situ , NOS
8013Large cell neuroendocrine carcinoma (NEC)
8020Undifferentiated carcinoma
8041Small cell neuroendocrine carcinoma (NEC)
8070Squamous cell carcinoma
8140Adenocarcinoma
8140Adenocarcinoma, biliary type
8140Adenocarcinoma, gastric foveolar type
8144Adenocarcinoma, intestinal type
8148Biliary intraepithelial neoplasia, grade 3 (BilIn-3)
8246Neuroendocrine carcinoma (NEC)
8310Clear cell adenocarcinoma
8470Mucinous cystic neoplasm with high-grade intraepithelial neoplasia
8470Mucinous cystic neoplasm with an associated invasive carcinoma
8480Mucinous adenocarcinoma
8490Signet ring cell carcinoma
8503Intraductal papillary neoplasm with high-grade intraepithelial neoplasia
8503Intraductal papillary neoplasm with an associated invasive carcinoma
8560Adenosquamous carcinoma

Bosman FT, Carneiro F, Hruban RH, Theise ND, eds. World Health Organization Classification of Tumours of the Digestive System. Lyon: IARC; 2010. Used with permission.

International Agency for Research on Cancer, World Health Organization. International Classification of Diseases for Oncology. ICD-O-3-Online.http://codes.iarc.fr/home. Accessed September 29, 2017. Used with permission.

Introduction ⬆ ⬇

Proximal or perihilar cholangiocarcinomas involve the main biliary confluence of the right and left hepatic ducts and comprise 50-70% of all cases of bile duct carcinomas. They are uncommon cancers, with an incidence of 1 to 2 per 100,000 in the United States. Complete resection with histopathologically negative margins is the most robust predictor of long-term survival. However, the apposition of perihilar cholangiocarcinoma to adjacent hepatic arterial and portal venous branches and hepatic parenchyma technically complicates complete resection.

Recent advances in dimensional imaging, perioperative care, and operative technique have increased rates of resectability. Specifically, the understand ing that perihilar cholangiocarcinoma extends proximally to involve intrahepatic bile ducts, with or without direct hepatic invasion and lobar hepatic atrophy, has led to routine incorporation of major hepatectomy, whether lobar, extended lobar, or total hepatectomy with transplantation, as an essential component of resection. These approaches have resulted in increased rates of margin-negative resection and improved overall survival.1-4

Before the AJCC Cancer Staging Manual, 7th Edition, perihilar and distal cholangiocarcinomas were grouped together as extrahepatic bile duct cancer. The prognostic accuracy of the separate perihilar cholangiocarcinoma TNM staging was validated independently.5

Anatomy ⬆ ⬇

Primary Site(s)

Cholangiocarcinoma develops anywhere within the biliary tree and arises from the most proximal intrahepatic bile ducts to the most distal intraduodenal bile duct. Extrahepatic cholangiocarcinoma was separated traditionally into perihilar, mid-duct, and distal cholangiocarcinoma. However, mid-duct cholangiocarcinomas do not comprise a separate site for staging. The AJCC Cancer Staging Manual, 8th Edition, affirms the prior stratification of cholangiocarcinoma into proximal and distal cholangiocarcinoma.

Perihilar cholangiocarcinoma is defined as arising predominantly in the main lobar extrahepatic bile ducts distal to segmental bile ducts and proximal to the cystic duct. Perihilar cholangiocarcinoma is characterized predominantly by local and regional growth patterns. Perineural invasion is typical for perihilar cholangiocarcinoma, and spread through periductal lymphatic channels is common. Cholangiocarcinoma may extend intrahepatically or proximally with involvement of the lobar sectoral and segmental bile ducts. Cholangiocarcinoma may extend radially with involvement of the hepatic parenchyma and hepatic arterial or portal venous vasculature, or both.

Regional Lymph Nodes

Hilar, cystic duct, choledochal, portal, hepatic arterial, and posterior pancreaticoduodenal lymph nodes are classified as regional lymph nodes.

Metastatic Sites

Lymph node metastasis distant to the hepatoduodenal ligament is classified as distant disease. Unilateral portal venous obstruction results in hepatic lobar atrophy, reflecting locally advanced disease, and increases the prevalence of distant disease. Peritoneum and liver are the most common sites of distant metastases. Other sites include lung, bone, brain, and skin.

Classification Rules ⬆ ⬇

Clinical Classification

Most patients diagnosed with perihilar cholangiocarcinoma are older than 60 years, with peak incidence in the eighth decade of life.6 Risk factors for developing perihilar cholangiocarcinoma include hepatolithiasis, biliary parasites, and choledochal cysts. In the United States, the most common identifiable risk factor is primary sclerosing cholangitis, an autoimmune disease that predisposes the entire biliary tree to the development of malignancy. Most cases of perihilar cholangiocarcinoma are sporadic, without identifiable risk factors.

Early symptoms are nonspecific and include constitutional symptoms of abdominal discomfort, anorexia, and weight loss. Symptoms and signs from bile duct obstruction, with jaundice, acholic stools, dark urine, and pruritus, occur frequently, regardless of disease stage.7 Diagnosis of perihilar cholangiocarcinoma may be challenging, with frequent indeterminate or false negative results from bile duct biopsies and biliary brushing cytology. Elevated serum cancer antigen 19-9 (CA 19-9) levels greater than 100 U/mL lend support to the diagnosis.8 Fluorescence in situ hybridization (FISH) analysis increases the sensitivity of cytology in diagnosing perihilar cholangiocarcinoma. In a patient with a resectable, malignant-appearing stricture involving the proximal biliary tree, pathological diagnosis of cancer is not compulsory before surgical exploration.

Most patients with perihilar cholangiocarcinoma have locoregional extension or distant metastasis that precludes resection and thus are treated, and do not qualify for pathological staging. A single TNM classification must apply to both clinical and pathological staging. Therefore, in most patients with perihilar cholangiocarcinoma, the basis for TNM staging is high-quality cross-sectional imaging. Peritoneal metastases may be radiographically occult and in patients undergoing surgery, identified only at time of staging laparoscopy.

The 7th edition of the AJCC Cancer Staging Manual reclassified adjacent hepatic parenchymal invasion as T2 but maintained unilateral vascular involvement as T3. The current edition affirms findings supporting that classification.9

The 7th edition of the AJCC Cancer Staging Manual defined T4 cholangiocarcinoma as cholangiocarcinoma with bilateral involvement of hepatic arterial or portal vasculature, bilateral ductal extension into the secondary or segmental bile ducts (Bismuth-Corlette type IV), and ductal extension into the secondary or segmental bile ducts with contralateral involvement of the hepatic vasculature. The current edition of AJCC Cancer Staging Manual eliminates bilateral ductal extension into the secondary or segmental bile ducts (Bismuth-Corlette type IV) alone from T4 cholangiocarcinoma. Thus, the current T category definitions exclude any Bismuth-Corlette typing. Such tumors were previously classified as Stage IVA disease and now are distributed by other T and N criteria into overall disease stage. The modified T categories have resulted in improved stratification of overall survival (Figure 25.1).10

Lobar hepatic atrophy of variable extent is often associated with perihilar cholangiocarcinoma. Atrophy typically is associated with an advanced T category and ipsilateral portal venous obstruction. Because hepatic atrophy in advanced degrees reduces resectability, it has been proposed as a group component.4 However, because the spectrum of hepatic atrophy is based on radiographic and gross clinical findings and not by histopathological criteria, atrophy is not incorporated into the current staging system.

Imaging

Clinical evaluation usually depends on the results of duplex ultrasound, computed tomography (CT), and magnetic resonance cholangiopancreatography (MRCP). Patients typically present with jaundice and undergo ultrasound as their first imaging modality. High-quality multidetector CT should demonstrate the level of biliary obstruction, vascular involvement, liver atrophy, and presence of nodal and distant metastases. The biliary extent of disease is assessed with percutaneous transhepatic cholangiography or MRCP. CT and /or MRCP should be performed before placement of biliary stents, which can obscure anatomic detail.

Cross-sectional imaging can also demonstrate the presence of lobar atrophy, which indicates the presence of biliary and /or vascular involvement and represents a gross and significant reduction of expected stand ard liver volume of the involved liver. Lobar atrophy is an important consideration before surgery, since an inadequate liver remnant volume can preclude hepatic resection or require preoperative portal vein embolization to induce hypertrophy of the remnant liver.

Clinical staging also may be based on findings from surgical exploration when the main tumor mass is not resected.

Suggested Report Format
  1. Primary tumor (T)
    1. Size of tumor: bidimentional
    2. Location
      1. Proximal common hepatic duct
      2. Confluence of the left and right hepatic ducts
      3. Left or right hepatic duct
    3. Morphology: growth type
  2. Local extent, if present describe:
    1. Segmental duct involvement on each side, including Bismuth-Corlette type; mention biliary variant anatomy, if present
    2. Lobar atrophy
    3. Vascular involvement (left, right, or main portal vein or hepatic artery on each side)
  3. Regional lymph nodes (N)
    1. If present, describe abnormal or suspicious nodes along the hilus, cystic duct, extrahepatic bile duct, head of pancreas, proximal duodenum, hepatic artery, and portal vein.
  4. Metastasis (M): if present, describe metastatic lesions seen on CT, MR imaging or PET/CT scans in the noncontiguous liver, peritoneum, lung, brain, bone, or other areas
    1. If present, describe abnormal or suspicious periaortic, pericaval, superior mesenteric, or celiac artery nodes

Pathological Classification

Macroscopically, perihilar cholangiocarcinoma is classified into three subtypes: papillary, nodular, and sclerosing.14 Sclerosing cholangiocarcinoma, the most frequent subtype, is characterized by periductal infiltration and desmoplasia. The nodular subtype is characterized by local irregular infiltration into the bile duct. Often, features of both nodular and sclerosing subtypes are observed together. Papillary tumors account for 5-10% of cases and frequently are soft and friable, with limited mural invasion. Papillary cholangiocarcinoma is more often surgically resectable and has a better prognosis than nodular and sclerosing subtypes.

Tumors classified as Tis cytologically resemble carcinoma, with diffuse, severe distortion of cellular polarity, but invasion through the basement membrane is absent.15

Complete resection of perihilar cholangiocarcinoma requires en bloc resection of the liver (usually major anatomic hepatectomy), extrahepatic bile duct, and hepatoduodenal lymph nodes. If involved, the portal vein and /or hepatic artery may need resection and reconstruction. The extent of resection (R0, complete resection with grossly and microscopically negative margins of resection; R1, grossly negative but microscopically positive margins of resection; R2, grossly and microscopically positive margins of resection) is a descriptor in the TNM staging system, is the most important stage-independent prognostic factor, and should be reported.

Patients who undergo surgical resection for localized perihilar cholangiocarcinoma have a median survival of approximately 3 years and a 5-year survival rate of 20-40%. In carefully selected patients with primary sclerosing cholangitis and locally unresectable lymph node-negative perihilar cholangiocarcinoma, excellent survival has been reported after neoadjuvant chemoradiation and liver transplantation.

Extended hepatic resections (trisectorectomy) with resection and reconstruction of the hepatic remnant portal vein and hepatic artery have been used increasingly, with promising early outcomes. Complete resection with negative histopathologic margins is the major predictor of outcome. Invasive, but not in situ, carcinoma at the margin of resection adversely affects survival. Hepatic resection is considered integral to achieving negative proximal intrahepatic margins. Factors adversely associated with survival include high tumor grade, vascular invasion, and lymph node metastasis.

The prevalence of lymphatic metastases increases directly with T categories and ranges overall from 30-53% by site. Nodal involvement adversely correlates with survival.16 Accurate localization of the site of lymph nodes in the hepatoduodenal ligament is difficult. Because the total number of metastatically involved lymph nodes correlates with survival, the number of positive lymph nodes has been added to classify N categories. Regional lymph node involvement is stratified into three N groupings: N0 (no lymph node involvement), N1 (one to three positive lymph nodes), and N2 (four or more positive lymph nodes).

Prognostic Factors ⬆ ⬇

Prognostic Factors Required for Stage Grouping

Beyond the factors used to assign T, N, or M categories, no additional prognostic factors are required for stage grouping.

Additional Factors Recommended for Clinical Care

Tumor Location and Extent

The Bismuth-Corlette classification describes the location and extent of biliary infiltration by tumor. Bismuth-Corlette type IV tumors, defined as tumor invasion of second-order biliary radicals bilaterally, are associated with a higher rate of positive surgical margins and significantly poorer 5-year overall survival after resection than Bismuth-Corlette types I to III.10

25.1 Bismuth-Corlette classification

TypeDefinition
ITumor is limited to the common hepatic duct, below the level of the confluence of the right and left hepatic ducts
IITumor involves the confluence of the right and left hepatic ducts
IIIaTumor with type II involvement plus extension to the right 2nd-order ducts
IIIbTumor with type II involvement plus extension to the left 2nd-order ducts
IVTumor extends into both right and left 2nd-order ducts
AJCC Level of Evidence: II

Papillary Histology

Papillary tumors account for approximately one quarter of hilar cholangiocarcinomas in surgical series. They are characterized by an intraductal growth pattern, are more often well-differentiated, and confer a higher median disease-specific survival after resection: 58 months, compared with 36 months for nonpapillary tumors (p = 0.01).4

AJCC Level of Evidence: II

Primary Sclerosing Cholangitis

Primary sclerosing cholangitis is an idiopathic chronic liver disease characterized by inflammation and fibrosis of the entire biliary tree. The chronic inflammation and injury to ducts may lead to cirrhosis and predispose to cholangiocarcinomas at any site in the biliary tree. Patients with primary sclerosing cholangitis are advised to receive neoadjuvant chemoradiation and liver transplantation.14

AJCC Level of Evidence: II

The authors have not noted any emerging factors for clinical care.

Risk Assessment ⬆ ⬇

Risk Assesment Models

The AJCC recently established guidelines that will be used to evaluate published statistical prediction models for the purpose of granting endorsement for clinical use.17 Although this is a monumental step toward the goal of precision medicine, this work was published only very recently. Therefore, the existing models that have been published or may be in clinical use have not yet been evaluated for this cancer site by the Precision Medicine Core of the AJCC. In the future, the statistical prediction models for this cancer site will be evaluated, and those that meet all AJCC criteria will be endorsed.

Recommendations ⬆ ⬇

There are no recommendations for clinical trial stratification at this time.

TNM Definitions ⬆ ⬇

Definition of Primary Tumor (T)

T CategoryT Criteria
TXPrimary tumor cannot be assessed
T0No evidence of primary tumor
TisCarcinoma in situ/high-grade dysplasia
T1Tumor confined to the bile duct, with extension up to the muscle layer or fibrous tissue
T2Tumor invades beyond the wall of the bile duct to surrounding adipose tissue, or tumor invades adjacent hepatic parenchyma
T2aTumor invades beyond the wall of the bile duct to surrounding adipose tissue
T2bTumor invades adjacent hepatic parenchyma
T3Tumor invades unilateral branches of the portal vein or hepatic artery
T4Tumor invades the main portal vein or its branches bilaterally, or the common hepatic artery; or unilateral second-order biliary radicals with contralateral portal vein or hepatic artery involvement

Definition of Regional Lymph Node (N)

N CategoryN Criteria
NXRegional lymph nodes cannot be assessed
N0No regional lymph node metastasis
N1One to three positive lymph nodes typically involving the hilar, cystic duct, common bile duct, hepatic artery, posterior pancreatoduodenal, and portal vein lymph nodes
N2Four or more positive lymph nodes from the sites described for N1

Definition of Distant Metastasis (M)

M CategoryM Criteria
M0No distant metastasis
M1Distant metastasis

Stage Prognostic ⬆ ⬇

!!Calculator!!

AJCC PROGNOSTIC STAGE GROUPS

When T is…and N is…and M is…Then the stage group is…
TisN0M00
T1N0M0I
T2a-bN0M0II
T3N0M0IIIA
T4N0M0IIIB
Any TN1M0IIIC
Any TN2M0IVA
Any TAny NM1IVB

Registry Data ⬆ ⬇

Registry Data Collection Variables

  1. Tumor location and extent according to Bismuth-Corlette classification
  2. Papillary histology
  3. Primary sclerosing cholangitis

Histopathologic type ⬆ ⬇

Adenocarcinoma that is not further subclassified is the most common histologic type.

Histologic grade ⬆ ⬇

HISTOLOGIC GRADE (G)

GG Definition
GXGrade cannot be assessed
G1Well differentiated
G2Moderately differentiated
G3Poorly differentiated

Survival ⬆ ⬇

25.1 Overall survival after surgical resection of perihilar cholangiocarcinoma at Nagoya University, Japan. Changes from the 7th Edition include removal of Bismuth-Corlette type IV tumors from the T4 category and downstaging of T4 tumors from stage IVA to IIIB (Data from Ebata et al.10)

Bibliography ⬆

  1. Nagino M, Ebata T, Yokoyama Y, et al. Evolution of surgical treatment for perihilar cholangiocarcinoma: a single-center 34-year review of 574 consecutive resections. Annals of surgery. Jul 2013;258(1):129-140.
  2. Natsume S, Ebata T, Yokoyama Y, et al. Clinical significance of left trisectionectomy for perihilar cholangiocarcinoma: an appraisal and comparison with left hepatectomy. Annals of surgery.Apr 2012;255(4):754-762.
  3. Croome KP, Rosen CB, Heimbach JK, Nagorney DM. Is Liver Transplantation Appropriate for Patients with Potentially Resectable De Novo Hilar Cholangiocarcinoma? Journal of the American College of Surgeons.Jul 2015;221(1):130-139.
  4. Matsuo K, Rocha FG, Ito K, et al. The Blumgart preoperative staging system for hilar cholangiocarcinoma: analysis of resectability and outcomes in 380 patients. Journal of the American College of Surgeons. Sep 2012;215(3):343-355.
  5. Juntermanns B, Sotiropoulos GC, Radunz S, et al. Comparison of the sixth and the seventh editions of the UICC classification for perihilar cholangiocarcinoma. Annals of surgical oncology. Jan 2013;20(1):277-284.
  6. Carriaga MT, Henson DE. Liver, gallbladder, extrahepatic bile ducts, and pancreas. Cancer. Jan 1 1995;75(1 Suppl):171-190.
  7. Razumilava N, Gores GJ. Classification, diagnosis, and management of cholangiocarcinoma. Clin Gastroenterol Hepatol. Jan 2013;11(1):13-21 e11; quiz e13-14.
  8. Blechacz B, Komuta M, Roskams T, Gores GJ. Clinical diagnosis and staging of cholangiocarcinoma. Nature reviews. Gastroenterology & hepatology. Sep 2011;8(9):512-522.
  9. Ito T, Ebata T, Yokoyama Y, et al. The Pathologic Correlation Between Liver and Portal Vein Invasion in Perihilar Cholangiocarcinoma: Evaluating the Oncologic Rationale for the American Joint Committee on Cancer Definitions of T2 and T3 Tumors. World journal of surgery. 2014;38(12):3215-3221.
  10. Ebata T, Kosuge T, Hirano S, et al. Proposal to modify the International Union Against Cancer staging system for perihilar cholangiocarcinomas. The British journal of surgery. Jan 2014;101(2):79-88.
  11. Rizvi S, Gores GJ. Current diagnostic and management options in perihilar cholangiocarcinoma. Digestion. 2014;89(3):216-224.
  12. Deoliveira ML, Schulick RD, Nimura Y, et al. New staging system and a registry for perihilar cholangiocarcinoma. Hepatology. Apr 2011;53(4):1363-1371.
  13. Engelbrecht MR, Katz SS, van Gulik TM, Lameris JS, van Delden OM. Imaging of perihilar cholangiocarcinoma. American Journal of Roentgenology. 2015;204(4):782-791.
  14. Zaydfudim VM, Rosen CB, Nagorney DM. Hilar cholangiocarcinoma. Surg Oncol Clin N Am. Apr 2014;23(2):247-263.
  15. Zen Y, Adsay NV, Bardadin K, et al. Biliary intraepithelial neoplasia: an international interobserver agreement study and proposal for diagnostic criteria. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. Jun 2007;20(6):701-709.
  16. Aoba T, Ebata T, Yokoyama Y, et al. Assessment of nodal status for perihilar cholangiocarcinoma: location, number, or ratio of involved nodes. Annals of surgery. Apr 2013;257(4):718-725.
  17. Kattan MW, Hess KR, Amin MB, et al. American Joint Committee on Cancer acceptance criteria for inclusion of risk models for individualized prognosis in the practice of precision medicine. CA: a cancer journal for clinicians. Jan 19 2016.