Biliary Tree and Gallbladder Cancer

Updated by Anusha Kalbasi

BACKGROUND

What are the 3 anatomic subtypes of biliary cancer (cholangiocarcinoma [CC])?

CC is grouped into intrahepatic (∼10%), perihilar/Klatskin (∼60%), and extrahepatic (∼30%) subtypes. Klatskin tumors involve the hepatic duct bifurcation.

How is gallbladder (GB) cancer distinct from CC?

GB cancer has unique epidemiology, presentation, staging, and surgical treatment.

What are major risk factors for CC?

Liver flukes (especially in Southeast Asia), primary sclerosing cholangitis, and choledochal cysts, all of which cause bile duct inflammation, are risk factors for CC.

What is the major risk factor for GB cancer?

Cholelithiasis increases the risk for GB cancer (presumably via chronic inflammation).

What is the annual incidence/mortality of CC and GB cancer in the U.S.?

There are ~10,000/yr new cases of CC and GB cancer in U.S. and ~3,500/yr deaths.

What is the histology of most CC and GB cancer?

Most CC and GB cancers are adenocarcinomas. They are difficult to distinguish from pancreatic adenocarcinoma on histopathology alone.

What less common pathologic subtype of GB cancer and CC has better prognosis?

Papillary adenocarcinoma is associated with improved prognosis compared with other adenocarcinomas of the biliary tree and GB.

What are the incidence and major sites of DM for CC and GB cancer?

30%–50% of CC and 40%–50% of GB cancer present with DM, most commonly to liver, peritoneum, and lung.

What is the MS for unresectable or MD?

MS is <6 mos for unresectable or metastatic CC and GB cancer.

What is the incidence of LN mets in resectable CC and GB cancer?

30%–50% of hilar and extrahepatic CC have LN mets at resection, but lower for intrahepatic CC. 40%–50% of GB cancer have LN mets at resection.

What is the LN drainage for hilar or extrahepatic CC?

Pericholedochal → portal vein LNs → common hepatic artery LNs → pancreaticoduodenal LNs → celiac axis/superior mesenteric artery (SMA) LNs → aortocaval LNs. Drainage does not ascend toward hepatic hilum.

How are LN mets different for intrahepatic CC?

Intrahepatic CC has a lower rate of LN mets than hilar or extrahepatic CC.

What is the most common route of spread for GB cancer and CC?

GB cancer and CC most commonly spread by direct extension (to the liver for GB cancer and along the biliary tree for CC).

What is the most common presenting symptom for CC? GB cancer?

Painless jaundice is the most common presenting symptom of CC. Biliary colic and chronic cholecystitis are the most common presenting symptoms of GB cancer.

How is GB cancer most commonly diagnosed?

GB cancer is most often incidentally diagnosed at cholecystectomy for presumed benign Dz.

What is a common and deadly complication of locally advanced Dz?

Biliary obstruction and sepsis is a common complication of poorly controlled locoregional Dz.

WORKUP/STAGING

What initial labs should be sent if suspecting CC or GB cancer?

Bilirubin, alk phos, aspartate, and alanine aminotransferases (can often be normal), γ-glutamyl transpeptidase, CEA, and CA19-9 are particularly helpful in CC or GB cancer.

In what patients is CA19-9 less reliable?

Pts without Lewis blood group antigen (10% of population) do not have CA19-9. Hyperbilirubinemia can decrease specificity and accuracy of CA19-9.

What initial imaging is used for suspected CC and GB cancer?

RUQ US, contrast-enhanced CT (preferably multiphase), and magnetic resonance cholangiopancreatography (MRCP) are typically performed for pts with suspected CC or GB cancer.

On contrast-enhanced CT, how can hepatocellular carcinoma and intrahepatic CC be distinguished?

On contrast-enhanced CT of the liver, hepatocellular carcinoma usually enhances during the arterial phase, while intrahepatic CC may show delayed enhancement.

What is the imaging study of choice for extrahepatic CC?

MRCP is the imaging study of choice for extrahepatic CC, as it has improved the ability to define tumor extent and LN involvement.

What invasive imaging strategies are available?

Endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC) can help image obstruction, but MRCP/CT are preferred.

How is a pathologic diagnosis obtained for CC?

For resectable pts without obstruction, pathology can be obtained at surgery. For unresectable pts or pts with obstruction requiring stenting, duct brushings can be obtained at ERCP, or biopsy can be done at time of PTC or EUS.

How is a pathologic diagnosis obtained for GB cancer?

Definitive resection is the diagnostic approach if GB cancer is suspected. Bile cytology (low yield) or percutaneous biopsy can be performed in unresectable pts.

When is ERCP- or PTC-based stenting indicated prior to surgery?

If bilirubin is elevated (i.e., >10–15), ERCP- or PTC-guided stents are placed to decompress obstruction and allow liver recovery prior to surgery.

In addition to locoregional imaging, what staging imaging is recommended for GB cancer and CC?

In addition to locoregional imaging, staging for GB cancer and CC should include chest imaging.

What staging procedure is recommended at the beginning of surgery for GB cancer or CC?

Staging laparoscopy is generally recommended at the beginning of surgery for GB cancer or CC to r/o peritoneal dissemination.

How does the AJCC 7^th edition (2011) staging organize different sites of biliary cancers?

There is a different staging system for GB cancer, intrahepatic CC, perihilar CC, and distal extrahepatic CC. Of note, the AJCC staging for intrahepatic CC is no longer the same as primary liver tumors.

How should tumors arising from the middle of the common bile duct be staged?

These extrahepatic CCs are exceedingly rare, but they are staged according to how they are managed, either as a proximal lesion (by combined hepatic and hilar resection) or as distal lesions (by pancreaticoduodenectomy).

What is the AJCC 7^th edition (2011) T staging for intrahepatic CC?

Tis: CIS

T1: solitary tumor without vascular invasion

T2a: solitary tumor with vascular invasion

T2b: multiple tumors +/– vascular invasion

T3: tumor perforating visceral peritoneum or directly invading local extra hepatic structures

T4: periductal invasion

What is the AJCC 7^th edition (2011) T staging for perihilar CC?

Tis: CIS

T1: tumor confined to bile duct, with extension up to muscle layer or fibrous tissue

T2a: tumor invades beyond bile duct wall to surrounding fat

T2b: tumor invades liver

T3: tumor invades unilat branches of portal vein (right or left) or hepatic artery (right or left)

T4: tumor invades any of the following: main portal vein or bilat branches, common hepatic artery, 2^nd-order biliary radicals bilaterally; or unilat 2^nd-order biliary radicals with contralat portal vein or hepatic artery involvement

What is the AJCC 7^th edition (2011) T staging for distal bile duct CC?

Tis: CIS

T1: tumor confined to bile duct histologically

T2: tumor invades beyond bile duct wall

T3: tumor invades liver, gallbladder, pancreas, and/or unilat branches of the portal vein (right or left) or hepatic vein (right or left)

T4: tumor invades celiac axis or SMA

What is the AJCC 7^th edition (2011) T staging for GB cancer?

The GB and cystic duct are included in this current classification:

Tis: CIS

T1: tumor invades lamina propria (T1a) or muscle layer (T1b)

T2: tumor invades perimuscular connective tissue but not into liver or beyond serosa

T3: tumor perforates serosa and/or directly invades liver and/or invades 1 adjacent organ/structure (stomach, duodenum, colon, pancreas, omentum, or extrahepatic bile ducts)

T4: tumor invades main portal vein, hepatic artery, or multiple extrahepatic organs/structures

What is the AJCC 7^th edition (2011) N classification for perihilar CC and GB cancer?

Hilar LNs are distinguished separately from other regional LN mets:

N1 (mets to hilar nodes): nodes of cystic duct, common bile duct (CBD), hepatic artery, and/or portal vein

N2 (mets to regional nodes): periaortic, aortocaval, SMA, and/or celiac

What is the AJCC 7^th edition (2011) N classification for intrahepatic CC and distal extrahepatic CC?

Any regional lymph node metastasis is classified as N1.

N0: no regional LNs

N2: regional LN mets present

What are the AJCC 7^th edition (2011) groupings for biliary cancers (GB and perihilar)?

Stage 0: TisN0

Stage I: T1N0M0

Stage II: T2N0M0

Stage IIIA: T3N0M0

Stage IIIB: T1-3N1M0

Stage IVA: T4N0-1M0

Stage IVB: Any N2 or M1

What are the AJCC 7^th edition (2011) groupings for intrahepatic CC?

Stage 0: TisN0

Stage I: T1N0M0

Stage II: T2N0M0

Stage III: T3N0M0

Stage IV: T4N0M0

Stage IVA: T4N0M0 or TxN1M0

Stage IVB: Any M1

What AJCC stage grouping do distal extrahepatic CC have in common?

Pancreatic cancer, including N staging (N0 or N1), since it is managed with similar approaches.

TREATMENT/PROGNOSIS

What % of CC and GB cancer pts have potentially resectable Dz at presentation?

Resectability varies widely depending on site

Intrahepatic: 30%–90%

Hilar: ∼50%

Distal extrahepatic: 80%–90%

GB cancer: 10%–30%

What is the classification system used to determine resectability of hilar CC?

Bismuth classification; type IV is unresectable

Type I/II: involving CBD without involving left/right hepatic ducts

Type III: involving either left or right hepatic duct in addition to CBD

Type IV: involves both left and right hepatic ducts

What is the surgical approach for each subtype of CC and GB cancer?

The surgical approach depends on site:

Intrahepatic: usually requires a lobectomy.

Hilar: at least lobectomy, resection of extrahepatic bile duct, roux-en-Y hepaticojejunostomy, and LN staging.

Distal extrahepatic: pancreaticoduodenectomy (Whipple) with LN staging

GB cancer: extended cholecystectomy with LN staging

When is a routine cholecystectomy sufficient surgery for an incidentally diagnosed GB cancer?

Following cholecystectomy for presumed benign Dz, pts with £T1a (not beyond the lamina propria) GB cancer do not require a 2^nd oncologic resection. 5-yr survival rates approach 100%.

How is an extended cholecystectomy different from a routine cholecystectomy?

Extended cholecystectomy should include en bloc resection of GB, segments IVb and V of liver, and regional LN dissection.

What 2^nd surgery should be performed after ≥T1b GB cancer is discovered on cholecystectomy?

Following cholecystectomy for presumed benign Dz, pts with incidentally discovered ≥T1b GB cancer require radical re-resection of the GB bed (2-cm margins), regional nodal dissection, and resection of the port sites.

What is the 5-yr survival for patients after resection for CC?

Based on numerous retrospective studies, the MS based on site:

Intrahepatic: 17%–40% (MS 26–37 mos)

Hilar: 10%–35% (MS 14–37 mos)

Distal extrahepatic: 23%–50% (MS 18–36 mos)

GB cancer (T3-T4): 0%–45%

What are the prospective data supporting adjuvant chemo, RT, or CRT in CC or GB cancer?

Gemcitabine + cisplatin has been shown to be superior to gemcitabine alone in a phase III RCT of locally advanced or metastatic CC or GB cancer (Valle J et al., NEJM 2010), with MS 11.7 mos vs. 8.2 mos. There are no prospective data for RT alone or CRT.

What is the recommended adj Tx for localized (but >T1a) GB cancer?

Single-institution retrospective series suggest that adj 5-FU–based CRT may benefit resected GB cancer pts. (Kresl JJ et al., IJROBP 2002; Ben-David MA et al., IJROBP 2006; Czito BG et al., IJROBP 2005; Yu JB et al., JCO 2008; Gold DJ et al., IJROBP 2009)

What is the range of MS in studies of adj RT or CRT for GB cancer?

MS ranges from 23–58 mos in retrospective studies of adj treatment in resected GB cancer.

What is the treatment approach for localized, unresectable GB cancer?

The approach is similar to unresectable pancreatic cancer: a combination of systemic chemo alone and/or CRT. Gemcitabine and cisplatin is the reference systemic regimen.

What is the recommended adj Tx for localized, resectable CC with good PS?

Single-institution series suggest that 5-FU or gemcitabine based CRT is an appropriate adj Tx for localized resectable CC (Hughes MA et al., IJROBP 2007; Nelson JW et al., IJROBP 2009; Shinohara T et al., IJROBP 2008; Kim TH et al., IJROBP 2011). This is also appropriate for unresectable CC. (Pitt HA et al., Ann Surg 1995)

What is the recommended Tx for localized, unresectable CC?

A combination of chemo alone and CRT is recommended for definitive treatment of unresectable CC. (Urego M et al., IJROBP 1999; Leong E et al., J GI Cancer 2012; Morganti AG et al., IJROBP 2000; Crane CH et al., IJROBP 2002; Ben-David MA et al., IJROBP 2006 )

What is the range of MS in studies of adj RT or CRT for hilar or extrahepatic CC?

MS ranges from 20–37 mos in studies of adj Tx in resected hilar and extrahepatic CC.

What RT approaches have been used for adj and definitive treatment of CC?

EBRT (most common), intraoperative RT, intraluminal brachytherapy, combination brachytherapy and EBRT, and more recently hypofractionated RT and SBRT.

Define target structures and doses for adjuvant treatment for hilar/extrahepatic CC.

The CTV is defined by the LN basin (initial volume, 45 Gy in 1.8 Gy/fx) and surgical bed (boost volume, 5–15 Gy, depending on extent of resection). LN basin includes porta hepatis, hepatic artery, pancreaticoduodenal, celiac, and superior mesenteric artery LNs. Inferior aortocaval nodes are often omitted.

Define target structures and doses for adj Tx for intrahepatic CC and GB cancer.

Same as above, except for GB cancer and intrahepatic CC, and LN basin includes pericholedochal LNs. For intrahepatic CC, LN basin may be limited to pericholedochal LNs if LN dissection was negative at surgery.

What is the appropriate target and dose for definitive RT of CC and GB cancer?

For hilar/extrahepatic CC, the CTV includes the gross Dz + margin and the LN basin (controversial). For intrahepatic CC and GB cancer, the CTV includes the gross Dz + margin only. Gross Dz is treated to the highest dose possible, considering organs at risk, usually ∼60 Gy in 1.8–2 Gy/fx.

Is liver transplantation more appropriate for intrahepatic CC or for extrahepatic CC?

Although liver transplantation is generally considered to be contraindicated for intrahepatic CC (due to poor outcomes), single-institution studies show promising results for transplantation in well-selected, early-stage, hilar/extrahepatic Dz. (Rea DJ et al., Ann Surg 2005)

Describe the clinical scenarios for consideration of SBRT.

Safety and efficacy of SBRT for liver lesions has been shown in mets and hepatic CC. Retrospective studies have reported feasibility of SBRT for hilar CC, and some intrahepatic CC, +/– concurrent gemcitabine or FU-based chemo. Dose and fractionation were 30 Gy in 3 fx (with gemcitabine) to 45 Gy in 3 fx (no chemo). (Polistina FA et al., Radiother Oncol 2011; Kopek N et al., Radiother Oncol 2010)

What are the transarterial treatment approaches for CC and in which Dz subset have they been utilized?

Transarterial embolization, chemoembolization, and radioembolization have been studied in unresectable intrahepatic CC. A large retrospective study examined each of these modalities in 198 pts with unresectable intrahepatic CC. (Hyder O et al., Ann Surg Oncol 2013) MS was 13.2 mos.

Which vessel is used to radioembolize liver tumors and why?

The hepatic artery is used for embolization because it is the major blood supply to liver tumors, unlike normal liver tissue, which derives its blood supply primarily from the portal vein.

What is the most used radioisotope for radioembolization in CC? What are its properties?

Yttrium-90 labeled spheres made of glass or resin are used for radioembolization. Yttrium-90 undergoes β-decay, with a half-life of 64 hrs (2.7 days).