DR NILESH TULASKAR

CholangiocarcinoCholangiocarcinomama

Bile duct anatomy

Definition of Cholangiocarcinoma

Cholangiocarcinoma is a rare tumor arising from the biliary epithelium and may occur anywhere along the biliary tree.

About two-thirds are located at the hepatic duct bifurcation. (60%-80% of cases )

Most cholangiocarcinomas present with jaundice, and the diagnosis of cholangiocarcinoma should be considered in every patient with obstructive jaundice

Surgical resection offers the only chance for cure, however, many patients have advanced disease at the time of diagnosis.

Most patients with unresectable disease die within a year of

diagnosis.

Incidence

The incidence of cholangiocarcinomas increases with age, and the majority of patients are 65 years and older.

The peak incidence is in the eighth decade of

life and more common in men.

Overall, the incidence of cholangiocarcinoma in the United States is approximately 1.0/100 000 people per year

Risk Factors

Primary sclerosing cholangitis

Liver flukes infestation (Opisthorchis viverrini and Clonorchis sinensis)

Choledochal cysts and Caroli's disease

Cholelithiasis and Hepatolithiasis

Chemicals (e.g., Thorotrast and Dioxin)

Hepatitis C

Lynch syndrome II

Bile duct adenoma and multiple biliary papillomatosis

Classification

This classification correlates with the anatomic distribution and indicates the preferred treatment for each site.

Classification

Intrahepatic cholangiocarcinomas present as liver masses.

Hilar cholangiocarcinoma involves the confluens of the left and right duct and usually both intra- and extrahepatic ducts. It is also known as Klatskin's tumor.

Distal cholangiocarcinomas involve the common and/or proper hepatic duct without extension to the confluens of the right and left ducts.

Distal cholangiocarcinomas usually involve the intrapancreatic portion of the bile duct

Bismuth-Corlette ClassificationType I Type II

Type III Type IV

Pathology

More than 90% of cholangiocarcinomas are adenocarcinomas.

Other types, which account for less than 5% each, are squamous cell carcinomas, sarcomas, small cell cancer, and lymphomas.

Cholangiocarcinomas may be divided into the following types: sclerosing,

nodular (mass-forming), papillary,

Sclerosing type most frequently seen.

Pathology

Sclerosing tumors, which comprise over 80% of cholangiocarcinomas, are associated with an intense desmoplastic reaction, tend to be highly invasive, and are associated with low resectability rates.

Nodular tumors have the appearance of constricting annular lesions and are also associated with low resectability rates.

Papillary tumors are rare and present as bulky masses that project into the bile duct lumen.

Because these lesions tend to cause symptomatic obstructive jaundice relatively early in their progression, they are associated with higher resectability rates than sclerosing or nodular tumors. It is associated with a favorable outcome

Molecular features of cholangiocarcinogenesis

Clinical Presentation

Most CCs remain clinically silent until the advanced stage.

Painless jaundice is the most common complaint of patients with cholangiocarcinoma, seen in about 70% to 90% of patients

Pruritis (66%),

Abdominal pain,

Weight loss (30% to 50%),

Fever in about 20%.

Clay coloured stool

Tumors of the bile ducts within the liver often have pain without jaundice.

On physical examination, right upper quadrant abdominal tenderness present .

A palpable liver may be noted in patients with intrahepatic cholangiocarcinoma.

A palpable gallbladder (Courvoisier's sign ).

Obstruction of the bile duct and biliary stasis may lead to bacterial colonization and cholangitis.

Cachexia and malaise.

Patients with cholangitis present in a dramatic fashion, with high fever, pain, nausea, vomiting, and rigors .

Diagnostic Evaluation

Laboratory Tests

Liver function tests generally reveal elevated bilirubin, alkaline phosphatase, and γ-glutamyltransferase.

Serum carcinoembryonic antigen (CEA) and CA 19-9 levels are most commonly elevated in cholangiocarcinoma.

In patients with intrahepatic cholangiocarcinoma, laboratory studies usually reveal an increased alkaline phosphatase level in the setting of normal bilirubin levels.

Cytology analysis: Obtained by brush cytology or bile duct biopsy during ERCP. Percutaneous biopsy of the primary tumor is not advised.( tumor

spread)

Radiologic Evaluation

The radiologic evaluation of patients with cholangiocarcinoma should delineate the overall extent of the tumor,

Including involvement of the bile ducts, liver, hilar vessels, and distant metastases .

Transabdominal ultrasonography is a useful initial test may reveal ductal dilatation (intrahepatic >6mm) .

Radiologic Evaluation

Imaging studies are used to determine the level of biliary obstruction and hepatic involvement and to assess for vascular invasion or metastatic disease.

Ultrasonography

Computed tomography

Magnetic resonance cholangiopancreatogram

Endoscopic cholangiogram

Percutaneous transhepatic cholangiography

Ultrasonography

Non-invasive

Uses sound waves to determine the level of biliary obstruction, hepatic involvement and overall extend of disease.

Operator dependent

Sensitivity and specificity is poor in the diagnosis of CC, and staging relies on other imaging modlities.

Computed tomography

Helpful in the staging, pre-op planning, and evaluation of vascular encasement.

Hilar tumor masses are difficult to visualize by CT.

Evaluation of intraductal spread and detection of lymph nodes and peripheral metastasis by CT is suboptimal

Cholangiography

MRCP is the best imaging modality for CC.

Provides information about tumor extend, biliary and hepatic parenchymal anatomy, and intrahepatic metastasis.

Non invasive

Distal extrahepatic CC is optimal evaluated by ERCP.

PTC and ERCP allow bile duct sampling for diagnostic analysis and stents insertion.

Preoperative drainage of the biliary tree.

MRI/MRCP

ERCP: Distal CBD Cancer

Diagnosis

Endoscopic ultrasound Useful for visualizing distal tumors and regional nodes

Can be used for EUS-guided biopsy of tumors and enlarged nodes

PET

High glucose uptake of biliary duct epithelium

Angiography (rarely used)

Staging laparoscopy

Angiography

It shows the anatomical location of hepatic artery and portal vein.

To evaluate the resectability.

Staging laparoscopy

Staging for Extrahepatic Cholangiocarcinoma

T1= Tumor confined to the bile duct

T2= Tumor invades beyond the wall of the bile duct

T3= Tumor invades the liver, gallbladder, pancreas, and/or unilateral branches of the portal vein (right or left) or hepatic artery (right or left)

T4= Tumor invades any of the following: main portal vein or its branches bilaterally, common hepatic artery, or other adjacent structures, such as the colon, stomach, duodenum, or abdominal wall

N1= Regional lymph node metastasis

M1= Distant metastasis

Treatment criteria

Based on the location and extent of the tumor, distant disease, comorbidity and cirrhosis.

Potentially curative treatment: -surgery!

Goal of surgery: Complete excision of the tumor with negative histologic margins and biliary reconstruction.

Palliative : Surgical biliary- entric bypass, biliary endoprosthesis, Chemotherapy, Radiotherapy, photodynamic therapy and supportive care.

Radiologic Criteria to Suggest Unresectability of

Cholangiocarcinoma

Bilateral hepatic duct involvement up to secondary radicals  

 Bilateral hepatic artery involvement   

Encasement of the portal vein proximal to its bifurcation  

 Atrophy of one hepatic lobe with contralateral portal vein encasement  

 Atrophy of one hepatic lobe with contralateral biliary radical involvement   

Distant metastasis

Management

Surgical excision is the only potentially curative treatment for cholangiocarcinoma.

In the past 1 to 2 decades, improvements in surgical techniques have resulted in lower mortality and better outcome for patients undergoing aggressive surgical excision for cholangiocarcinoma.

Patients should undergo surgical exploration if they have no signs of metastasis or locally unresectable disease.

Operative Approach

Surgical exploration should be undertaken in good-risk patients without evidence of metastatic or locally unresectable disease;

However, intraoperatively, more than half of these patients are found to have either peritoneal or hepatic metastases or, more likely, locally unresectable disease.

Selective use of laparoscopy in patients with locally advanced but potentially resectable perihilar cholangiocarcinoma may avoid laparotomy in some patients with metastatic disease.

In patients who are found to have extensive metastatic disease, biliary stents should be left in place.

In patients with locally advanced unresectable perihilar tumors, several operative approaches are available for palliation, including a Roux-en-Y hepaticojejunostomy to segment III or V.

Intrahepatic Cholangiocarcinoma

The goal of resection is to remove all liver parenchyma at risk for intrahepatic metastases based on the proximal extent of the tumor.

Usually this requires a lobectomy. If both lobes of the liver are involved with metastases, curative resection is unlikely, and other forms of therapy should be considered.

Extrahepatic spread pretends a poor prognosis and in general should be considered a contraindication to resection.

Intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma is treated by hepatic resection, and outcomes depend on disease stage (particularly the status of the lymph nodes) and the ability to achieve negative margins.

There is a broad range of long-term outcomes in patients undergoing complete resection (3-year survival rates of 22%-66% )

Distal Cholangiocarcinoma

Extrahepatic cholangiocarcinoma not involving the confluens of the right and left main hepatic ducts involves the common hepatic duct and commonly involves the intrapancreatic portion of the duct.

This usually requires a pancreaticoduodenectomy with resection of the extrahepatic bile duct to the level of the confluens for complete clearance of disease.

Rarely, the tumor may be confined to a small region of the duct and an extrahepatic bile duct resection can be performed without a pancreaticoduodenectomy.

In any case, the resection should again include a complete clearance of the periportal lymph nodes: all tissue in the porta hepatis excluding the portal vein and hepatic artery.

Distal Cholangiocarcinoma

For extensive involvement of the bile duct without distant spread, consideration can be made for en bloc combined hepatic and pancreatic resections. The morbidity of such extensive surgery is high, and the overall prognosis is poor with extensive disease.

The incidence of distal common bile duct tumors compared with hilar cholangiocarcinomas is low, but the resectability rate is higher.

If resection is not possible owing to vascular encasement, cholecystectomy, Roux-en-Y hepaticojejunostomy proximal to the tumor, and a gastrojejunostomy to prevent gastric outlet obstruction should be performed.

Median survival is expected to be between 18 and 33 months, and expected 5-year survival is between 14% and 40%

Roux-en-Y Hepaticojejunostomy

Perihilar cholangiocarcinoma

For perihilar cholangiocarcinomas, bile duct resection alone leads to high local recurrence rates due to early involvement of the confluence of the hepatic ducts and the caudate lobe branches.

Surgical treatment depends on the Bismuth-Corlette classification .

For type I and II lesions, the procedure is en bloc resection of the extrahepatic bile ducts and gallbladder with 5- to 10-mm bile duct margins, and regional lymphadenectomy with Roux-en-Y hepaticojejunostomy.

In addition to the above operations, type II tumors may require hepatic lobectomy. Because type II and III lesions often involve the ducts of the caudate lobe, many surgeons recommend routine caudate lobectomy.

Type III and IV tumors are amenable to potentially curative resection in centers with expertise in these procedures. Aggressive techniques such as hepatectomy and portal vein resection to achieve negative margins are now routine in specialized centers.

Treatment modalities- Palliative interventionsPalliative interventions

Biliary decompression To palliate associate symptoms: jaundice, pruritus

and cholangitis.

Surgical biliary- enteric bypass: for patients with unresectable disease

Disadvantages: they are major operative procedures with associate morbidity

Nonsurgical palliative procedure

Percutaneous An internal / external catheter + bag or internal metal stent is

used for biliary decompression.

At times, multiple stents are reguired to obtain adequate drainage.

Endoscopic

Is able to see the biliary ducts and place the biliary endoprothesis( plastic/ metallic stent)

Plastic: occlude easily, change every 2-3mons

Metallic: offer a long period of patency , but not removable or exchangeable.

Complication: cholangitis, pancreatitis

Other palliative treatment modalties

Chemotherapy: limited! No proven role in the treatment of CC.

Patients with unresectable disease often are offered treatment with 5-fluorouracil alone or in combination with mitomycin C and doxorubicin, but the response rates are low

Radiation: No benefit or increase in survival time.

The combination of radiation and chemotherapy may be more effective than either treatment alone for unresectable disease, but no data from randomized trials are available

Adjuvant Therapy

Postoperative adjuvant radiotherapy is administered after resection with curative intent to reduce the risk of local recurrence and potentially improve survival.

Postoperative adjuvant radiotherapy for biliary tract cancer can be administered either by external-beam radiotherapy (EBRT), brachytherapy, intraoperative radiotherapy (IORT), or a combination of radiotherapy modalities.

EBRT is the most commonly used radiotherapy modality for biliary tract cancer.

Adjuvant radiotherapy

Advantages of EBRT include the widespread availability of this modality, its noninvasive nature, and the ability to deliver a homogeneous high dose to a large volume.

Most commonly, radiotherapy is administered in a continuous course during 5 to 6 weeks.

In most series, EBRT has been used to deliver a dose of 40 to 50 Gy (at 1.80 Gy/d) to the tumor bed and draining lymph node basin.

Palliative treatment

Photodynamic therapy: inject photosensitive agent to the body→appropriate light wave to produce tumor cell death via cholangioscopy→ biliary decompression.

Best supportive care:

Treat the patient symptomatically( pain, ascites, anorexia, and jaundice with pruritus).

Comfort is the goal!

Psychosocial support also is essential.

Photodynamic treatment

PDT uses laser, or other light sources, combined with a light-sensitive drug (sometimes called a photosensitising agent) to destroy cancer cells.

A photosensitising agent is a drug that makes cells more sensitive to light. Once in the body, the drug is attracted to cancer cells.

When the light is directed at the area of the cancer, the drug is activated and the cancer cells are destroyed.

Some healthy, normal cells in the body will also be affected by PDT, although these cells will usually heal after the treatment

Transplantation for Cholangiocarcinoma

Transplantation as a primary treatment modality for hilar and intrahepatic cholangiocarcinoma is a viable option.

Organ availability has been the most limiting factor for this modality, but the success of living-related transplantation may rejuvenate the use of transplant for hilar and intrahepatic cholangiocarcinoma.

Complete hepatectomy provides the best chance of a complete resection for these tumors, and may be an alternative for patients who are unresectable by conventional means.

The real possibility of achieving a cure for unresectable tumors exists only with liver transplantation.

Transplantation for Cholangiocarcinoma

Meyer et al reported the results of liver transplantation for cholangiocarcinoma in 207 patients collected by the Cincinnati Transplant Tumor Registry.

Fifty-one percent of the transplanted patients suffered recurrence; the median time from transplantation to recurrence was 9.7 months, and the median time between recurrence and death was 2 months.

Extrahepatic nodal disease or metastases are a contraindication to transplant.

Complications of surgical intervention

BilomaAbscess formationLiver failure after partial hepatectomyRenal insufficiency resulting from liver failureBiliary obstructionWound infectionCholangitis

Prognosis

Poor

The prognosis varies based on resectibility and anatomical location of tumor.

Average survival time is approximately 14 months.

The mean survival for patients with unresectable lesions is 6-12 months.

Follow-up after Resection

No clear guidelines exist for surveillance and follow-up after surgery.

A physical examination with routine laboratory tests every 3 to 4 months for the first 3 years after surgery and then at longer interval of 6 months till year 5 is reasonable.

The role of CA 19-9 as surveillance is not clear, but persistently rising levels often precede radiologic evidence of recurrence by a number of months.

The role of CT scans for surveillance has not been evaluated in clinical trials, but because of the high risk of recurrence, radiological evaluation with CT scans of the abdomen, every 6 months for 2 to 3 years after surgery may detect recurrent disease.

Summary

Cholangiocarcinoma is a highly malignant tumor and the second most common form of primary hepatic carcinoma.

The mean survival for unresectable lesions is 6~12 months.

Surgical resection is the only treatment modality that offer a potential cure and prolonged survival.

Nurses work with physicians and hospice team to coordinate pain management, infectious complications, biliary drain management, and terminal care.

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