Hepatobiliary Cancer Guidelines 

Updated: Aug 08, 2017
  • Author: Elwyn C Cabebe, MD; Chief Editor: N Joseph Espat, MD, MS, FACS  more...
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Hepatocellular Carcinoma

Guidelines for the screening, surveillance, and diagnosis of hepatocellular carcinoma (HCC) have been issued by the following organizations:

  • American Association for the Study of Liver Diseases (AASLD)
  • National Comprehensive Cancer Network (NCCN)
  • American College of Gastroenterology (ACG)
  • European Association for the Study of the Liver (EASL)–European Organisation for Research and Treatment of Cancer (EORTC)
  • European Society of Medical Oncology (ESMO)–European Society of Disease Oncology (ESDO)

The AASLD and NCCN guidelines recommend screening and surveillance for HCC in patients with cirrhosis. [1, 2]   However, the AASLD suggests that patients with Child class C cirrhosis not undergo surveillance unless they are on the transplant waiting list, given their low anticipated survival. [1]

The NCCN recommends screening for patients with chronic hepatitis B virus infection who do not have cirrhosis, [2] while the AASLD considers HCC surveillance cost-effective for patients with hepatitis B whose expected HCC risk exceeds 0.2% per year, as well as in those with hepatitis C whose expected HCC risk exceeds 1.5% per year.Hepatitis B carriers who are at high risk include the following [3] :

  • Asian men ≥40 years old
  • Asian women ≥50 years old
  • Patients with a family history of HCC
  • African and North American blacks

The AASLD and NCCN agree that HCC screening should be performed in a setting in which screening tests and recall procedures have been standardized and quality control procedures are in place. Both organizations recommend surveillance with ultrasonography, with or without alfa-fetoprotein (AFP) testing, performed every 6 months. [1, 2]  

The AASLD and NCCN recommendations for follow-up of abnormal screening results include the following [3] :

  • For nodules identified on ultrasound that are <1 cm, ultrasound should be repeated at intervals of 3-6 months; if no growth is observed over a period of up to 2 years, revert to routine surveillance.
  • For nodules ≥1 cm on a cirrhotic liver, follow-up with either four-phase multidetector computed tomography (CT) or dynamic contrast enhanced magnetic resonance imaging (MRI). If the appearances are typical of HCC (ie, hypervascular in the arterial phase with washout in the portal venous or delayed phase), the lesion should be treated as HCC.

The AASLD suggests that because the pretest probability of HCC is so high in patients with cirrhosis, and the pretest probability of imaging lesions that mimic HCC is so low, the diagnosis of HCC can be established and treatment may be initiated on the basis of  imaging alone, without confirmatory biopsy. [1]

When the imaging study in a patient with cirrhosis shows an indeterminate nodule, the AASLD suggests that options for further assessment may include follow-up imaging, imaging with an alternative modality or alternative contrast agent, or biopsy; however, the AASLD cannot recommend one option over the other. [1] For lesions that are neither definitely HCC nor definitely benign, the NCCN recommends an individualized workup, which may include additional imaging or biopsy as informed by multidisciplinary discussion. [2]

AASLD recommendations regarding biopsy include the following [3] :

  • Biopsies of small lesions should be evaluated by expert pathologists; tissue that is not clearly HCC should be stained with all the available markers (including CD34, CK7, glypican 3, HSP-70, and glutamine synthetase) to improve diagnostic accuracy
  • If the biopsy is negative, the lesion should be followed by imaging at 3- to 6-month intervals until the nodule disappears, enlarges, or develops features characteristics of HCC
  • If the lesion enlarges but remains atypical for HCC, the biopsy should be repeated

The 2014 American College of Gastroenterology (ACG) guidelines for the diagnosis and management of focal liver lesions (FLLs) include the following recommendations [4] :

  • Patients with cirrhosis in whom an ultrasound shows a lesion of >1 cm should undergo an MRI or triple-phase CT scan
  • Patients with chronic liver disease who are at a very high risk for HCC and who present with a solid FLL must be considered to have HCC until proved otherwise
  • HCC can be diagnosed with CT or MRI if the typical characteristics are present
  • If an FLL in a patient with cirrhosis does not have typical characteristics of HCC, then a biopsy should be performed

Joint guidelines published in 2012 by the European Association for the Study of the Liver (EASL) and the European Organisation for Research and Treatment of Cancer (EORTC) are generally in agreement with NCCN and AASLD guidelines on noninvasive diagnosis using one imaging technique (four-phase CT or dynamic contrast-enhanced MRI). [5]

The European Society of Medical Oncology (ESMO)–European Society of Disease Oncology (ESDO) 2012 joint guidelines for diagnosis and treatment of HCC require biopsy for diagnosis except in the following patients with cirrhosis [5] :

  • Not candidates for any therapy due to serious comorbidity
  • On the waiting list for a liver transplantation
  • Candidates for resection

HCC Staging

NCCN guidelines note that although a number of staging systems for HCC have been devised, all have limitations; no universal staging system exists that could be used across all institutions in different countries. Consequently, NCCN guidelines do not use any particular staging system, except for the Chlid-Pugh score and—in the minority of patients who undergo surgical resection—the The tumor-node-metastasis (TNM) classification of the American Joint Cancer Committee/Union for International Cancer Control/ (AJCC/UICC).

Instead, the NCCN recommends using the initial workup to stratify HCC into one of the following categories:

  • Potentially resectable or transplantable, operable by performance status or comorbidity
  • Unresectable disease
  • Inoperable by performance status or comorbidity with local disease only
  • Metastatic disease

Hepatic resection is a potentially curative option in patients who are medically fit for a major operation and who meet the following criteria [2] :

  • Adequate liver function (Child-Pugh class A without portal hypertension; limited resection may be feasible in patients with mild portal hypertension)
  • A solitary mass without major vascular invasion
  • Adequate post-resection liver remnant

Liver transplantation can be considered for patients who meet United Network for Organ Sharing (UNOS) criteria (single lesion ≤5 cm, or two or three lesions ≤3 cm). Some institutions will consider selected patients whose tumor characteristics are marginally outside of the UNOS guidelines for transplantation. [2]

Since most patients have unresectable disease and prognosis depends more on the state of the liver than on the size of the tumor, the AASLD, EASL-EORTC, and ESMO-ESDO guidelines recommend the Barcelona Clinic Liver Cancer (BCLC) system for prognostic prediction and treatment stratification. [1, 4, 5, 6]

The BCLC staging system attempts to overcome the limitations of previous staging systems by identifying prognostic stages (0 and A through D) based on five variables [7] :

  • Tumor stage
  • Functional status of the liver
  • Physical status
  • Cancer-related symptoms

The BCLC staging system also links each HCC stage to appropriate treatment modalities as follows:

  • Patients with early-stage HCC (stage 0 and A) may benefit from curative therapies (ie, liver transplantation, surgical resection, radiofrequency ablation).
  • Patients with intermediate-stage(stage B) or advanced-stage (stage C) disease may benefit from palliative treatments (ie, transcatheter arterial chemoembolization and sorafenib)
  • Patients with end-stage disease (stage D) are offered supportive care and palliation

HCC Treatment

The guidelines agree that resection is the treatment of choice for solitary tumors in non-cirrhotic patients or cirrhotic patients with well-preserved liver function. Pre- or post-resection adjuvant therapy is not recommended.

The guidelines further concur that liver transplantation is the best available curative option for patients with early-stage non-resectable HCC who meet the Milan criteria (single tumors ≤5 cm in diameter or no more than three nodules ≤3 cm in diameter in patients with multiple tumors).

The AASLD suggests using resection rather than radiofrequency ablation for adults with Child A cirrhosis and resectable T1 or T2 HCC. [1] However, ablation should be considered as definitive treatment for patients with stage 0-A tumors who are not candidates for resection or transplantation. [1, 2, 5, 6]

In patients who are on the liver transplantation waiting list, bridging therapy is used to decrease tumor progression and the dropout rate from the list. The NCCN found insufficient evidence to support recommendations regarding bridging therapy. [2] The AASLD guidelines suggest using bridging therapy to maintain tumor burden within Organ Procurement and Transplant Network (OPTN) T2 (Milan) criteria, but the AASLD does not recommend any one form of liver-directed bridging therapy over another. [1] Both the NCCN and the AASLD support the use of downstaging therapy to bring selected patients within the Milan criteria. [1, 2]

The AASLD recommends transarterial chemoembolization as first-line noncurative therapy for advanced disease. Sorafenib is recommended for patients who have preserved liver function and cannot benefit from surgery, transplantation, ablation, or transarterial chemoembolization. Yttrium-90 radioembolization is not recommended outside of clinical trials. Systemic or selective intra-arterial chemotherapy is not recommended. [1]

For inoperable HCC in patients who are not transplant candidates, NCCN guidelines recommend the following options:

  • Locoregional therapy (preferred) - Ablation, arterially-directed therapies, or external beam radiation therapy (EBRT)
  • Systemic therapy - Sorafenib or chemotherapy
  • Clinical trial
  • Best supportive care

For metastatic disease or extensive liver tumor burden, NCCN guidelines recommend the following options:

  • Systemic therapy- Sorafenib or chemotherapy
  • Clinical trial
  • Best supportive care

For both inoperable and metastatic disease, the NCCN recommends sorafenib for patients in Child-Pugh class A (category 1 recommendation) or B. Patients with disease progresison on or after sorafenib may be treated with regorafenib. [2]

 

 

 

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Gallbladder Cancer

Gallbladder Cancer Diagnosis

According to the National Comprehensive Cancer Network (NCCN) guidelines, gallbladder cancer may be diagnosed as an incidental finding in patients who undergo laparoscopic cholecystectomy, either at surgery or on pathologic review. The recommended workup for clinical suspicion of gallbladder disease includes the following [2] :

  • Liver function tests and assessment of hepatic reserve
  • Multiphasic abdominal/pelvic computed tomography (CT)/magnetic resonance imaging (MRI)  with intravenous contrast plus chest CT with or without contrast, for evaluation of tumor penetration and detection of nodal and distant metastases
  • CT is preferred over ultrasound for detection of lymph node involvement, adjacent organ invasion, and distant metastasis
  • MRI is useful for distinguishing benign conditions from malignancies.
  • For patients with jaundice, cholangiography to evaluate hepatic and biliary invasion; magnetic resonance cholangiography (MRCP) is preferred.
  • Consider carcinoembryonic antigen (CEA) and CA 19-9 testing
  • Consider staging laparoscopy

The European Society of Medical Oncology clinical practice guidelines for biliary cancer published in 2016 recommend diagnosis on the basis of MRI with magnetic resonance cholangiopancreatography (MRCP), contrast-enhanced and diffusion-weighted imaging. CT was deemed less useful. Pathological diagnosis is required before any nonsurgical therapy, but is not critical in patients with characteristic findings of resectable tumors. Endoscopic retrograde cholangiopancreatography (ERCP)-guided biopsies are preferred to biliary brush cytology. [8]

In 2013, the American Society for Gastrointestinal Endoscopy (ASGE) released guidelines for the use of endoscopy in the evaluation of biliary neoplasia. The recommendations for gallbladder polyps included the following [9] :

  • Endoscopic ultrasound (EUS) or FNA if the results would change the management
  • Cholecystectomy for symptomatic patients with gallbladder polyps, asymptomatic patients with gallbladder polyps >10 mm, and any patient with gallbladder polyps and primary sclerosing cholangitis
  • Asymptomatic patients with gallbladder polyps ≥6 mm but no other risk factors for gallbladder cancer should receive annual transabdominal ultrasound screening

Gallbladder Cancer Staging

Gallbladder cancer staging follows the tumor-node-metastasis (TNM) classification of the American Joint Cancer Committee/Union for International Cancer Control/ (AJCC/UICC) and is classified into four stages based on the depth of invasion into the gallbladder wall and the extent of spread to surrounding organs and lymph nodes. The classification and staging scheme was changed in the 7th edition of the AJCC/UICC manual, published in 2010, to better correlate with the extent of cystic duct and lymph node involvement, resectability of the tumor, and patient outcome. [10]

TNM groupings by stage are as follows: [10]

  • Stage 0- Tis N0 M0
  • Stage I - T1 N0 M0
  • Stage II - T2 N0 M0
  • Stage IIIA - T3 N0 M0
  • Stage IIIB - T1-3 N1 M0
  • Stage IVA - T4 N0-1 M0
  • Stage IVB - Any T N2 M0 any T any N M1

Gallbladder Cancer Treatment

The NCCN guidelines include the following recommendations for resectable disease [2] :

  • Simple cholecystectomy for T1a lesions (limited to the mucosa)
  • Staging laparoscopy, followed immediately (in the same session) by definitive resection; biopsy is not required
  • For patients with T1b or greater lesions, radical cholecystectomy and lymphadenectomy with or without bile duct excision; hepatic resection is performed to obtain clear margins, which usually consists of segments IV B and V but may need to be extended beyond that in some patients
  • For patients with suspicious mass on imaging or with jaundice, cholecystectomy plus en bloc hepatic resection and lymphadenectomy with or without bile duct excision
  • Jaundice that is not amenable to drainage is considered a relative contraindication to surgery; only a portion of those with node-negative disease potentially benefit from complete resection; surgery should only be performed with curative intent
  • Fluoropyrimidine-based chemoradiotherapy, or fluoropyrimidine or gemcitabine chemotherapy alone may be considered for adjuvant treatmen, except for individuals with resected T1a or T1b N0 tumors

The 2016 ESMO guidelines recommendations for resectable disease include the following [8] :

  • Every T-stage above T1a and positivity of any mentioned parameters requires a reoperation and a segment IVb/V liver resection with a ligamentary lymphadenectomy 
  • If the gallbladder was not removed with a bag during laparoscopic resection or the gallbladder perforated (an adverse prognostic factor), the port sites should also be resected 
  • When patients present with jaundice, evaluation of potential resectability is needed 
  • Advanced T-stage (including T4 tumors) is not a contraindication for resection provided they are located in the fundus; these tumors require major liver resection with potential resection of the transverse colon.
  • Achieving a curative resection of an advanced tumor located at the infundibulum requires the resection of the bile duct, the duodenal bulb and, potentially, the pancreatic head together with a major hepatectomy, especially if right-sided vessels (right hepatic artery, right portal vein) are involved

For management of patients with unresectable or metastatic disease, NCCN makes the following recommendations [2] :

  • Enrollment in clinical trial
  • Fluoropyrimidine or gemcitabine chemotherapy
  • Fluoropyrimidine chemoradiation
  • Supportive care
  • For patients with jaundice, biliary drainage for palliation before instituting chemotherapy
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Cholangiocarcinoma

Cholangiocarcinoma Diagnosis

The National Comprehensive Cancer Network (NCCN) recommends early surgical consultation with a multi-disciplinary team as part of the initial workup for suspected intrahepatic cholangiocarcinoma. Direct visualization of the bile duct with directed biopsy is ideal. Additional recommendations for diagnostic testing include the following [2] :

  • Liver function tests
  • Consider carcinoembryonic antigen (CEA) and CA 19-9 testing
  • Multiphasic abdominal/pelvic computed tomography (CT)/magnetic resonance imaging (MRI) with intravenous contrast plus chest CT with or without contrast,
  • Esophagogastroduodenoscopy and colonoscopy, in patients with intrahepatic cholangiocarcinoma, to assess for T3 disease and rule out endobiliary metastasis from colorectal cancer mimicking intrahepatic cholangiocarcinoma [11]

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. [9]

Cholangiocarcinoma 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. [10]

TNM groupings by stage are as follows for each group: [10]

Table. 1 (Open Table in a new window)

Intrahepatic bile duct tumor
Stage T N M
0 Tis N0 M0
I T1 N0 M0
II T2 N0 M0
III T3 N0 M0
IVA T4 N0 M0
  Any T N1 M0
IVB 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 T1-3 N1 M0
IVA T4 N0-1 M0
IVB Any T N2 M0
  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
IA T1 N0 M0
IB T2 N0 M0
IIA T3 N0 M0
IIB T1 N1 M0
  T2 N1 M0
  T3 N1 M0
III T4 Any N M0
IV Any T Any N M1

Cholangiocarcinoma 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. [2, 8]

For intrahepatic cholangiocarcinomas that are resected with microscopic margins or extrahepatic cholangiocarcinomas that are resected with negative margins and negative regional nodes, the NCCN recommends fluoropyrimidine chemoradiation, or fluoropyrimidine-based or gemcitabine-based chemotherapy.

For intrahepatic resections with residual local disease, gemcitabine/cisplatin combination therapy is a category 1 recommendation by the NCCN. Enrollment in clinical trials, and fluoropyrimidine-based or gemcitabine-based chemotherapy are also options. [2]

For extrahepatic resections with positive margins, residual disease or positive regional nodes, the NCCN recommends fluoropyrimidine chemoradiation followed by fluoropyrimidine-based or gemcitabine-based chemotherapy. For positive regional nodes, fluoropyrimidine-based or gemcitabine-based chemotherapy is also an option.

For management of patients with unresectable or metastatic disease, NCCN makes the following recommendations [2] :

  • Gemcitabine/cisplatin combination therapy (category 1)
  • Enrollment in clinical trial
  • Fluoropyrimidine or gemcitabine chemotherapy
  • Fluoropyrimidine chemoradiation Locoregional therapy
  • Supportive care
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