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Sameer Smadi MD.


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Cholangiocarcinoma


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Definition of Cholangiocarcinoma

Bile duct cancers arising from ductal

epithelial cells

Refers to cancers arising in the intrahepatic

(~5-15%), perihilar (~60-70%), or distal

(extrahepatic ~25%) biliary tree

Represents approx. 3% of all gastro-

intestinal malignancies


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Definition of CholangiocarcinomaBismuth-Corlette Classification subdivides

perihilar cholangiocarcinomas based on pattern

of involvement of hepatic ductsType I: tumors occurring below the confluence of the

left and right hepatic ductsType II : tumors reaching the confluenceTypes IIIA/IIIb: tumors occluding the common

hepatic duct and either the right or left hepatic ductType IV: tumors that are multicentric, or that involve

the confluence and both the right or left hepatic duct

Klatskin tumors occur at the bifurcation of the

proper hepatic duct


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(A) The anatomic location of cholangiocarcinoma can be described as intrahepatic, distal extrahepatic or hilar.Cholangiocarcinomas can be further described based on their macroscopic or cholangiographic appearance. (B) Nonhilarlesions can be described as mass-forming, periductal or intraductal, or as mixed mass-forming and periductal. Forextrahepatic lesions the terms periductal, mass-like and intraductal correspond to the alternative designations ofsclerosing, nodular and papillary. (C) Hilar lesions can be described using the Bismuth classification.70Type I tumors arefound below the confluence of the left and right hepatic ducts. Type II tumors reach the confluence of the left and righthepatic ducts. Type IIIa and IIIb tumors occlude the common hepatic duct and either the right or the left hepatic duct,respectively. Type IV tumors are multicentric or they involve the confluence and both the right and left hepatic ducts. Acombined anatomicmorphologic classification is useful for patient management and can provide consistency in clinical or

epidemiologic studies. Tumors are shown in (B) and (C) in yellow
http://www.nature.com/ncpgasthep/journal/v3/n1/full/ncpgasthep0389.htmlhttp://www.nature.com/ncpgasthep/journal/v3/n1/full/ncpgasthep0389.html


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Incidence: 1.0 per 100,000 per year

Male to female ration of 1.3:1

Average age of presentation is 50-70

Etiology: Common features of risk factors include biliary stasis, bile

duct stones, and infection.

PSC, Choledocal cysts, hepatolithiasis, chlonorchis ortyphoid infections.

Other risk factors include liver flukes, nitrosoamines,dioxin exposure.

Presentation: Typically painless jaundice, may include pruritus, RUQ

pain, anorexia, fatigue, and weight loss.


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Work-up

Typically Alk phos will be elevated to 1.5 to 5 times normal, and transaminase levels will

be 1-2 times normal. CEA or CA 19-9 may also be elevated but these test are not

diagnostic.


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PathologyAdenocarcinoma (90%) Slow growing, locally invasive, mucin-producing Perineural spread, metastases uncommon

Three subtypes of adenocarcinoma Sclerosing

Majority of cholangiocarcinomas Characterized by an intense desmoplastic reaction Early ductal invasion leads to low resectability rates

Nodular Constricting annular lesion of the bile duct

Papillary Present as bulky masses occurring in the bile duct lumen Present early with biliary obstruction Highest resectability rates


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ClinicalTriad Cholestasis

Abdominal pain (30-50 %)

Weight loss (30-50 %)Pruritus (66 %)

Clay-colored stools, dark urine.

Jaundice (~90 %)

Hepatomegaly

RUQ mass

Courvoisier's sign

Intrahepatic cholangioCA typically presents without

biliary obstruction


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LaboratoryElevations in: Total bilirubin (>10 mg/dL)

Direct bilirubin

Alkaline phosphatase (usually increased 2- to 10-fold) 5'-nucleotidase

Gamma glutamyltransferase

Transaminase levels initially normal With chronic biliary obstruction, liver dysfunction may

ensue with elevation in ALT/AST and PT


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Differential Diagnosis

Choledocholithiasis

Benign bile duct strictures (usually postoperative),

Sclerosing cholangitis

Compression of the CBD (secondary to chronic

pancreatitis or pancreatic cancer)


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Diagnosis

Tumor markers

Serum CEA >5.2 ng/mL(sensitivity 68%, specificity 82%) CA 19-9

Radiographic studies Transabdominal ultrasound- may reveal ductal dilatation

(intrahepatic >6mm)

CT/helical CT- can also detect vascular invasion Helical CT (esp. portal venous phase)- can delinieate nodal

basins

May be superior to MRI with respect to predicting

resectability

MRCP- may be coming the imaging modality of choice


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Diagnosis

Cholangiography

ERCP or PTC Useful if suspected level of obstruction is distal Preoperative drainage of the biliary tree Obtain diagnostic bile samples or brush cytology (low

sensitivity)Endoscopic ultrasound Useful for visualizing distal tumors and regional nodes Can be used for EUS-guided biopsy of tumors and

enlarged nodesPET High glucose uptake of biliary duct epithelium

Angiography (rarely used)Staging laparoscopy


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Diagnosis

Role of Staging laparoscopyTissue diagnosis important in the

setting of:

Strictures of unknown origin (e.g.bile duct stones, PSC)

Family/patient request for a

definitive diagnosis

Prior to chemotherapy or radiation

therapy


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ManagementPoor prognosis- avg. 5-year survival ~5-10%

Resectability rate superior for distal tumors resectability rates for intrahepatic 60%, perihilar 56%, and

distal lesions 91% (Nakeeb A; Pitt HA, JHU 1996)

Negative margins achieved in 20-40% of proximal tumors

cases, 50% of distal tumor cases


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ManagementAccepted guidelines for resectability (accurately

determined at operative exploration) Absence of N2 nodal metastases or distant liver metastases

Absence of vascular (portal vein, hepatic artery) invasion

Absence of extrahepatic adjacent organ invasion

Absence of disseminated disease


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ManagementPre-operative biliary decompression

Liver dysfunction increases postoperativemorbidity and mortality

Arch Surg 2000 (Cherqui et. al.)Study demonstrated increased post-op morbidity injaundiced patients not undergoing pre-operativedrainage (vs. nonjaundiced patients)

Pre-operative portal vein embolization Induce liver hypertrophy to increase limits of safe

resection No demonstrated improvement in clincial outcome


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ManagementSurgical Procedures Distal lesions: pancreaticoduodenectomy (5-yr survival

rates 15-25%)

Intrahepatic cholangiocarcinoma: hepatic resection (3-yrsurvival rates 22- 66%)

Perihilar cholangiocarcinoma (5-yr survival rates 10-45%;

outcomes in PSC patients dismal)

Type I and II lesions: en bloc resection of extrahepatic

bile ducts and gallbladder with 5 to 10 mm bile duct

margins, regional lymphadenectomy with Roux-en-Y

hepaticojejunostomy.

Type III and Type IV lesions: hepatectomy and portal

vein resection


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Role of liver transplantation

Bismuth-collette Type IV Recently, an extended bile duct

resection combined with totalhepatectomy,pancreatoduodenectomy, andorthotopic liver transplantation(HPLTx) was proposed to eradicate theentire biliary tract without cutting offthe hepatoduodenal ligament.

Liver transplantation may be atherapeutic option for the patientswith 1) unresectability confirmed atlaparotomy; 2) advanced tumor withinfiltration of the adjacent tissues thatan R0 resection is hardly to beachieved; 3) local intrahepatic

recurrence of the tumor; and 4)advanced hepatic cirrhosis andprimary sclerosing cholangitis withoutenough residual functional livertissues after resection.


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Hepatic Tumors


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Benign Solid liver tumors Hepatic Adenoma

Reproductive women

75% with abdominal pain onpresentation.

Chance of rupture issignificant (25% withhepatocellular adenoma)

Increased fat signal on MRI

Cold on Tc-MAA scan.

Resection remains thestandard of therapy for lesionslarger than 4 cm.


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Benign Solid liver tumors Focal Nodular Hyperplasia

Not associated withsymptoms.

No risk of rupture or

malignant degeneration Characteristic central scar,

hot on Tc-MAA scan.

Early embryologic vascularinjury.

If symptomatic, lesion may beresected.

Lesions are often peripheraland thus lap. Resection shouldbe advocated.


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Benign Solid liver tumors

Hemangiomas

Chronic RUQ pain CT or MRI diagnostic

Resection if symptomsare ascribed to the

hemangioma


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Malignant Liver Tumors HCC is one of the most common solid human

cancers, with an annual incidence estimated to beapproximately 1 million new patients.

In addition the liver is second only to lymph nodesas a common site of mets from other solid tumors. It is not uncommon, particularly with colorectal

cancer for the liver to be the only site of metastasis.

Resection of both primary disease and isolatedmetastatic disease may result is significant longterm survival benefits in 20-45% of patients.


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Presentation:

Mostly diagnosed through imaging performed for someother indication, as part of a screening protocol, or during

follow-up for a known primary malignancy of anotherorgan site.

Symptoms may include dull right upper quadrant pain,fullness or bloating, and in some instances nausea or

vomiting, or systemic complaints. History: high-risk behaviors or known hepatitis virus

infection, travel to areas where hepatitis B or C is endemic,alcohol use, exposure to hepatotoxins, use of oral

contraceptives or hormone replacement therapy, or ahistory of hereditary liver diseases


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Imaging for suspected liver neoplasm

CT scan: highly sensitive at spatial discrimination andquantification of lesions in the liver, good for pre-opplanning.

MRI: better for detecting early HCC, and distinguishingbetween HCC and macroregenerative nodules.

U/S: Useful for guiding biopsy, determining tumorvascularity, and intraoperatively to guide resections.

Other studies: PET, Angiography, Dx laporoscopy.


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Treatment


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HCC Treatment Options

Curative

Transplantation

Surgical Resection

Ablative Therapy

RadioFrequency Ablation (RFA)

Cryoablation

Percutaneous ETOH ablation

Non-Curative

Trans-Arterial Chemo-Embolization (TACE)

Sorafenib


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Treatment Surgery Ultimately complete resection of the liver mass remains

the optimal choice for treatment.

Newer techniques continue to decrease the morbidityassociated with hepatic resection including staplingtechniques and laparoscopic approaches.

For patients with a single lesion and preserved liverfunction, resection is curative, with 5-year survival rates of

50% to 70% Recurrent HCC occurs in 50% to 80% of patients at 5 years

after resection, with the majority occurring within 2 years


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Treatment Radiofrequency ablation thermal necrosis to tumors by

delivering electromagnetic energythrough needle electrodes.

RFA versus resection for patients withsingle small lesions show comparable

1- and 3-year overall survival results(100% and 72.7% versus 97.9% and83.9%, respectively.

higher 1- and 3-year local recurrencerates (16.3% and 18.2% versus 1.1% and2.2%, respectively).

May also be considered as a bridge to

transplantation.


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Treatment

Transplantation Choosing the patient who can maximize each organ is of

paramount importance and is dictated by the Milancriteria.

The consensus is that liver transplantation is indicated inpatients with HCC with at least a 50% chance of survival at5 years

Most series demonstrate a survival advantage for HCCpatients from transplantation over all other modalities.

In an ideal world without an organ shortage, timely livertransplantation would offer better survival rates thanresection by offering both decreased tumor recurrence anda treatment of the underlying liver disease.

Mil it i f HCC i li


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Milan criteria for HCC in liver

cirrhosis

Cha, et al: Ann Surg, Volume 238(3).September 2003.315-323


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Colorectal neuroendocrine

Non Colorectal neuroendocrine


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Surgical resection is currently acceptedas a safe, and also the only potentiallycurative treatment available for patients

with colorectal liver metastases.

Chance of long-term survival with

rates ranging from 25% to 50% at 5years


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During the last decade, significanttechnical advances have beenaccomplished in liver surgery.

They allow bilobar resections with verylow mortality (around 1%) and lowmorbidity


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HV Analysis labeled


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Colon cancer with liver metastasis

Unless there is an absolute prohibitivemedical risk, all patients with

potentially liver mets.should havecareful evaluation todetermine whether they havepotentially resectable disease .


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SYNCHRONOUS COLORECT L LIVERMET ST SESLiver mets is detected in 15-25% of

colorectal cancer cases

Have been presumed to representmore aggressive tumour

No evidence that these patients do

worse after liver resection


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Should these patients have

concurrent or staged liver

resection?


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YOKOH M EXPERIENCE

39 consecutive patients 39 concurrent multivariate analysis for safety and

success rate

Poor overall survival with poorly differentiated and

mucinous adenocarcinomas (p


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TOKYO EXPERIENCE

187 consecutive patients, 1980-2002 142 concurrent, 27 staged resections

Prognosis affected by

multiple liver metastases

4 or more lymph node metastases around the primary

tumour

Conclusion: Simultaneous resection inpatients with 3 or less colorectal lymph node

metastases only

Minigawa M et al (Makuuchi). Arch Surg 2006; 141: 1006-12.


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STR SBOURG EXPERIENCE 97 consecutive patients (1987-2000)

35 concurrent vs 62 staged Concurrent resection if


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BERLIN EXPERIENCE

219 consecutive patients (1988-2005) 40 concurrent vs 179 staged

Morbidity similar

Mortality higher in concurrent group (p=0.012)

Mortality in concurrent group (n=4) after majorhepatectomy and age >70 yrs

No significant difference in long-term survival

Conclusion: decision should be based onage and extent of liver resection

Thelen A et al. (Neuhaus) Int J Colorectal Dis 2007; Feb 21 (Epub ahead of print).


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MSKCC EXPERIENCE 240 consecutive patients (1984-2001)

134 concurrent vs 106 staged Concurrent resection: more right colon primaries (p


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Clinical score for predicting recurrence after hepatic resection for

metastatic colorectal cancer - analysis of 1001 consecutive cases

Fong et al, Annals of Surgery 1999; 230: 309

Nodal status of primary

Disease-free interval from primary to discovery of the livermetastases of < 12 months

Number of tumours > 1

Preoperative CEA level > 200 ng/ml

Size of largest tumour > 5 cm

Overall actuarial survival 37% at 5 years, 22% at 10 years

Clinical Risk Score (CRS) predictive of long term outcome

(p


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Case No. 155 years old femalemedically freeLeft hemicolectomy 2.5 years ago

-ve nodal status of primary colonic tumourNo chemotherapyLost follow up for two years then came withCEA 150

CT scan


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Ist Right portal vein ligation


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Extended Rt hepatectomy


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Extended Rt. hepatectomy


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Extended Rt. hepatectomy


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60 years old female, diabetic

Left hemicolectomy one year ago for recto-sigmoidtumour

3 Lymph nodes +veReceived chemotherapy

CEA = 25

CT Scan


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2nd case


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2 caseExtended Lt. Hepatectomy

LEFT TRISECTIONECTOMY


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S C O C O

One of the most difficult of the major hepatectomies

Technically hazardous because: Absence of landmarks for the right fissure

Anatomic variations of the right portal structures

Remains a useful technique for: Centrally located tumours

Hilar cholangiocarcinomas with predominant left ductinvolvement

Experience with this technique is rarely reported


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Extended Lt. Hepatectomy


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62 years old male , diabetic , hypertensive

Rt. Hemicolectomy 6 months ago

He received chemotherapy

CEA 14

CT scan


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3rdCase Resection of


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Posterior Sector (Seg VI + VII)


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3rdcase

Posterior Sector (Seg VI and VII)

Resection


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Segmental Resection


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Posterior sector (Seg. VI+VII)


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58 years old female , diabeticLeft hemicolectomy 8 months ago inPalastine

Developed reco-vaginal fistulaTreated by diversion ileostomy

Referred from west bank for

chemotherapyCEA 25


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SegmentalResection

(Seg. Vand Seg VI


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Segmental resection


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Segmental resection

The best is yet tocome.


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