HEPATOBILIARY MALIGNANCIES

LIVER TRANSPLANTATION CURRENT MANAGEMENT 0039-6109/99 $8.00 + .OO

HEPATOBILIARY MALIGNANCIES Primary Hepatic Malignant Neoplasms

Ernest0 P. Molmenti, MD, J. Wallis Marsh, MD, Igor Dvorchik, PhD, James H. Oliver 111, MD, Juan Madariaga, MD,

and Shunzaburo Iwatsuki, MD

Primary hepatic tumors are epithelial, mesenchymal, or mixed in origin. Of these, epithelial tumors are the most common and include hepatocellular carcinoma, cholangiocarcinoma, mixed hepatocholangio- carcinoma, hepatoblastoma and a variety of other more rare tumors. Hepatocellular carcinoma, also known as hepatoma or malignant hepatoma, is the most common, followed by cholangiocarcinoma. This article discusses only these two malignancies.

HEPATOCELLULAR CARCINOMA

Definition

Hepatocellular carcinoma is a malignant tumor derived from hepatocytes. It is frequently found in association with chronic liver disease, especially cirrhosis.

This work was supported by Project Grant No. DK-29961 from the National Institutes of Health and from research grants from the Veterans Administration Medical Center.

From the Thomas E. Starzl Transplantation Institute (EPM, JWM, JM, SI) and the University of Pittsburgh School of Medicine (EPM, JWM, ID, JHO, JM, SI), Pittsburgh, Pennsylva- nia

SURGICAL CLINICS OF NORTH AMERICA

VOLUME 79 * NUMBER 1 * FEBRUARY 1999 43

44 MOLMENTI et al

Epidemiology

Hepatocellular carcinoma is the predominant primary malignancy of the liver. It accounts for more than 80% of these tumors and has an annual incidence of approximately 1 million new cases.16

Sex and Age

Hepatocellular carcinoma is more common in males than females, with a ratio of 3:l. The male-female ratio varies widely according to geographic distribution and may reach up to 8:l.y

Association with Cirrhosis

Eighty to ninety percent of patients with hepatocellular carcinoma have underlying cirrhosis; alcoholic cirrhosis is the predominant type in Western countries, whereas in the Far East, posthepatic cirrhosis is more common.

Etiology

Hepatitis B Virus Infection

A strong correlation exists between hepatocellular carcinoma and hepatitis B surface antigen (HBsAg) carriers, with some authors asserting that chronic infection with hepatitis B virus may be responsible for as much as 80% of human hepatocellular carcinomas.3, 2R In addition, familial clusterings of hepatitis B virus-related cases are presumably caused by vertical transmission of the virus.1s

Hepatitis C Virus Infection

Persistent hepatitis C virus infection is closely linked to the occurrence of hepatocellular carcinoma; antibodies to hepatitis C virus are found in as many as 80% of patients with hepatocellular carcinoma in countries such as Japan, Spain, and Italy.12

A flatoxins

The toxins produced by Aspergillus flavus and Aspergillus parasiticus, which are usually associated with grains and food products, such as peanuts, are known hepatotoxins; however, chronic exposure seems to be needed for liver cancer.3'

HEPATOBILIARY MALIGNANCIES 45

Synthetic Hepatocarcinogens

hydrocarbons, and pesticides have been implicated. Azo dyes and aromatic amines, N-nitroso compounds, chlorinated

Alcohol

cirrhosis. Alcohol may act as a cocarcinogen, promoting the development of

Other Factors Associated with Hepatocellular Carcinoma

Radiation, thorotrast, smoking, a,-antitrypsin deficiency, hemochro- matosis, Budd-Chiari syndrome, porphyria, oral contraceptives, and ana- bolic androgenic steroids, among others, have been implicated.

Pathology

Advanced hepatocellular carcinoma tends to occur as an expansile or infiltrative mass with intrahepatic metastases of various sizes. Hepato- cellular carcinoma associated with liver cirrhosis is usually a well-demar- cated encapsulated tumor; hepatocellular carcinomas detected at an early stage are nodular or somewhat nodular.

Gross Pathology

Hepatocellular carcinomas display considerable diversity in gross appearance. They can be multiple or single, with or without a capsule, and often form a bulge on the liver surface. They are usually soft, gray, brown, or yellow-green and often exhibit foci of hemorrhage or necrosis; they can range from a few millimeters to more than 30 cm in diameter. The right lobe is involved more frequently than the left, although bilobar involvement is seen in as many as 80% of cases; in advanced cases, the large veins (portal or hepatic) tend to be involved. The original gross anatomic classification6 distinguished three patterns of spread: (1) nodular, (2) massive, and (3) diffuse. More recent classifications based on the mode of tumor growth and its relationship with the healthy liver parenchyma distinguish only between expanding and spreading types. These classifications, however, are of little use in surgical pathology because examination of the whole liver is usually required, and the patterns correlate poorly with etiology and prognosis.

Multicentric cancers may or may not represent separate entities; pedunculated tumors, extension into the bile ducts, and intra-arterial growth may be observed. Extrahepatic metastases occur at a late stage; the incidence ranges from 50% to 70% in Western countries and is higher in cases of hepatocellular carcinoma without ~ i r rhos is .~~ Hematogenous metastases are more common than lymphatic metastases.

46 MOLMENTI et al

Microscopic Pathology

Histologically, architectural and cellular features vary according to the degree of differentiation. The hallmark of hepatocellular carcinoma is a trabecular pattern of growth that resembles the hepatic plates of normal liver and is present to a greater or lesser extent in all tumors; a branching or papillary arrangement is sometimes seen. A microglandu- lar pattern that mimics biliary ducts may be encountered and may lead to the incorrect diagnosis of adenocarcinoma. Tumor cells can resemble hepatocytes but may also feature cytologic atypia. The various histologic grades of differentiation correlate with the DNA content and cellular proliferation indices of the tumor.5, Most small carcinomas tend to be well differentiated; larger tumors tend to be moderately to poorly differentiated. Dense intracytoplasmic eosinophilic globules, usually dia- stase-periodic acid-Schiff (PAS) positive, contain alpha-fetoprotein (AFP), a,-antitrypsin, and a,-antichymotrypsin. At the interface with healthy liver tissue, hepatocellular carcinomas adopt either a pushing or merging histologic configuration. Rarely, an infiltrating sinusoidal configuration is observed.

lmmunochemistxy

Hepatocellular carcinomas demonstrate a specific canalicular staining pattern with polyclonal antibodies to carcinoembryonic antigen (CEA) in 60% to 90% of AFP immunoreactivity is immediately suggestive of hepatocellular carcinoma; however, AFP is an insensitive marker found in fewer than 40% of hepatic cancers. In general, hepatocellular carcinomas stain with antibodies to normal liver cytokeratins (Moll numbers 8 and 18).

Cytopathologic Aspects

Fine-needle aspiration specimens are characterized by the same elements found in histologic specimens. A trabecular pattern is usually observed. Tumor cells are polygonal, with eosinophilic and prominent cytoplasms, central round nuclei with clumped chromatin, and conspicu- ous nucleoli.

Clinical Features

Initial Complaints

General malaise, upper abdominal pain, anorexia, abdominal fullness, weight loss, ascites, palpable mass, nausea, vomiting, jaundice, and wasting are the most common presenting symptoms. In individuals without cirrhosis, abdominal pain and a palpable abdominal mass are the most common initial complaints. Acute abdominal pain is almost


always associated with hernoperitoneum caused by tumor rupture or bleeding.

Clinical Manifestations

When a mass is palpated, an arterial bruit may rarely be heard on auscultation. The right diaphragm may be elevated. In addition, other less common clinical observations include hepatomegaly, ascites, spleno- megaly, jaundice, dilated abdominal veins, varices, gastrointestinal bleeding, fever, and encephalopathy.

Diagnosis

Histologic diagnosis is ideal but may rarely result in severe complications if a coagulopathy is present and cannot be corrected. A percutaneous biopsy with ultrasound or computed tomography (CT) guidance is almost always possible; open biopsy is rarely necessary. A presumed diagnosis without histologic confirmation may be made based on a cirrhotic liver, a space-occupying lesion(s), and elevated levels of AFP or des-y-carboxy prothrombin (DCP).

Laboratory Findings

Alpha-fetoprotein, fucosylated AFP, DCP, variant alkaline phospha- tase (ALP), carcinoembryonic antigen (CEA), novel gamma-glutamyl- transpeptidase isoenzyme, a-L-fucosidase, thrombin-antithrombin I11 complex, isoferritins, and transcobalamin 1, among others, have been used with various degrees of success as tumor proteins.2' AFP, DCP, and CEA are the most commonly used.

Radiologic Diagnosis

Sonography. Real-time sonography can detect liver masses, changes associated with cirrhosis, and the status of hepatic vessels and bile ducts. Most hepatocellular carcinomas tend to be faintly hypoechoic, although they may be difficult to detect in patients with advanced cirrhosis because of the heterogeneous parenchymal patterns commonly seen in these patients.

Computed Tomography. Most hepatic neoplasms appear as low attenuation lesions on contrast-enhanced CT; however, hypervascular hepatic tumors, such as hepatocellular carcinoma, can be isodense to the liver during peak parenchymal enhancement. The CT detection rate for metastatic tumor in the liver approaches 85%; however, because hepatocellular carcinoma is a hypervascular tumor that usually arises in cirrhotic livers with altered morphology (e.g., regenerative nodules, fibrosis, and portal hypertension), the CT detection rate for hepatocellular carcinoma is less than yo%, even when using biphasic helical CT techniques with high-flow-rate bolus injections. Biphasic CT can be used

48 MOLMENTI et a1

to differentiate tumor thrombus from bland portal venous thrombus because tumor thrombus often demonstrates enhancement during the arterial phase. Hepatocellular carcinomas tend to enhance to a greater degree than surrounding liver parenchyma during the early (arterial) phase of hepatic enhancement and tend to decrease in attenuation more rapidly than liver parenchyma so that they are isodense or hypodense during the portal venous phase of hepatic enhancement. The addition of arterial phase images to conventional portal venous phase CT images results in detecting an additional 25% to 30% of hepatocellular carcinoma foci. If the tumor is encapsulated, the capsule is usually most conspicu- ous on delayed (3-5 minutes) contrasted images because of the fact that fibrous tissue remains enhanced much longer than the liver parenchyma or nonfibrous neoplastic tissue. In contrast, delayed imaging of metastatic lesions usually shows central enhancement.

Angiographic Computed Tomography (CT-Arteriography). This modality, in which contrast is injected directly into the hepatic artery, is the most sensitive method for detecting small hepatocellular carcinomas and should be considered in patients believed to be surgical candidates to avoid unnecessary surgery.

Lipiodol Computed Tomography. A CT scan is obtained 10 days to 2 weeks after injection with this contrast (iodized oil) material. Lipiodol remains in the tumor for a prolonged period of time and can detect lesions as small as 3 mm. Small hepatocellular carcinomas poorly arteri- alized or poorly differentiated may not be detected; small hemangiomas also take up and retain lipiodol.

Magnetic Resonance Imaging. Magnetic resonance (MR) imaging and CT scanning have similar diagnostic accuracies; however, MR imaging can provide insight into blood flow and tissue diagnosis. Hepato- cellular carcinoma is usually of higher intensity than the surrounding liver with T2-weighted images, whereas it is of lower intensity on T1- weighted images. While some hepatocellular carcinomas are well-defined focal lesions, others can be infiltrative and difficult to detect. Dynamic bolus gadolinium techniques with arterial phase imaging can result in higher detection rates for hepatocellular carcinoma. Higher T2 values, in most cases, differentiate hemangiomas from hepatocellular carcinomas.

Angiography. Most hepatocellular carcinomas are characterized by an enlarged feeding artery, hypervascularity, tumor neovasculature, tumor stains, displaced arteries, arterial encasement, vascular channels and lakes within the tumor, arterioportal communications, portal regur- gitation, and capsular radiolucency in the late phase. The absence of these findings in areas of the liver presumed to be tumor free may be used as a confirmatory test. Cavernous hemangiomas are distinguished by the lack of an enlarged feeding artery, the filling of the lesion from the periphery toward the center, and the fact that the contrast stain remains for a prolonged period of time (up to several minutes).


Treatment

Surgical-The University of Pittsburgh Experience

Surgical Resection. Between 1981 and 1996,101 patients underwent hepatic resection (Hx) for hepatocellular carcinoma. Of these, 31.7% had concomitant cirrhosis, 32.7% had bilobar tumors, 35.6% had multiple tumors, 26.7% had macrovascular invasion, 15.8% had positive margins on pathologic examination, and none had positive lymph nodes. The perioperative mortality rate was 15.8%. The 1-, 3-, and 5-year survival rates for the entire Hx group were 72.7%, 44.9%, and 29.2%, respectively (median survival, 27.2 mo). When patients with positive nodes, margins, metastases, and macrovascular invasion were excluded, the remaining patients (n = 70) achieved 1-, 3-, and 5-year survival rates of 78.3%, 54%, and 37.1%, respectively (median survival, 43.1 mo). If patients with multiple tumors were also excluded, the survival rates of those remaining ( n = 53) improved to 86.6%, 6l%, and 41.9%, respectively (median survival, 47.9 mo).

Liver Transplantation-General Observations. Between 1981 and 1996, 307 patients underwent orthotopic liver transplantation (OLTx) in the presence of hepatocellular carcinoma at the University of Pittsburgh Medical Center. Of these, 92.2% had concomitant cirrhosis, 50.8% had multiple tumors, 33.6% had bilobar tumors, 20.2% had macrovascular invasion, 5.9% had positive margins on pathologic examination, and 3.6% had positive lymph nodes. The perioperative mortality rate was 14%. The 1-, 3-, and 5-year survival rates for the entire OLTx group were 72.3%, 57.5%, and @.I%, respectively (median survival, 58.1 mo). (These relatively high survival rates are attributed to the fact that the program has become more restrictive about transplantation for hepatocellular carcinoma over the past several years, in fact, perhaps becoming too restrictive secondary to concerns about organ donor shortages.) When patients with positive nodes, margins, metastases, and macrovascular invasion were excluded, the remaining patients (n = 238) achieved 1-, 3-, and 5-year survival rates of 81.1%, 70.6%, and 6l.8%, respectively (median survival, 84.3 mo).

Prediction of Recurrence. In an effort to reduce placing donor livers in patients with certain, early hepatocellular carcinoma recurrence but at the same time not denying transplantation to those who would enjoy long-term survival after OLTx for hepatocellular carcinoma, the authors recently developed a multivariate clinical model that could predict, on an individual patient basis, the risk for hepatocellular carcinoma recurrence and the time from transplant to recurrence.2o The results of the model allowed the authors to determine those combinations of risk factors that have not led to recurrence (Table 1) and those combinations that have nearly always led to recurrence (Table 2). In addition, the authors' analyses led to the following conclusions:

50 MOLMENTI et al

Table 1. VALUES OF THE RISK FACTORS THAT SHOULD NOT LEAD TO HEPATOCELLULAR CARCINOMA RECURRENCE AFTER ORTHOTOPIC LIVER TRANSPLANTATION

Vascular Lobar Tumor Number Invasion Distribution Number Gender Tumor Size of Cases

None None None None None None Micro Micro Micro Micro Micro

Unilobar Unilobar Unilobar Bilobar Bilobar Bilobar Unilobar Unilobar Unilobar Bilobar Bilobar

Single Multiple Multiple Single Single Multiple Single Multiple Multiple Single Multiple

Any Any Female Male Female Female Any Any Female Female Female

Any

Any

Any Any

58.0 cm

54.0 cm

54.0 cm 52.0 cm 54.0 cm 54.0 cm 52.0 cm

38 14 3 0 1 2 7 0 2 0 1

1. Grade of vascular invasion (i.e., none, microvascular, or macrovascular invasion) is the most influential risk factor in hepatocellular carcinoma recurrence.

2. In addition to the previously known risk factors, gender exerts a powerful effect on hepatocellular carcinoma recurrence. Without exception, female patients have a lower risk of recurrence than male patients with identical tumor characteristics.

3. A bilobar tumor distribution correlates strongly with hepatocellular carcinoma recurrence.

4. In general, the larger the diameter of the largest tumor, the greater the risk for hepatocellular carcinoma recurrence.

5. Essentially all patients with positive margins succumb to recurrent disease within 1 year after OLTx.

Table 2. VALUES OF RISK FACTORS THAT SHOULD LEAD TO HEPATOCELLULAR CARCINOMA RECURRENCE AFTER ORTHOTOPIC LIVER TRANSPLANTATION

Vascular Lobar Number Invasion Distribution Tumor Number Gender Tumor Size of Cases

Micro Micro Micro Macro Macro Macro Macro Macro Macro Macro

Unilobar Bilobar Bilobar Unilobar Unilobar Unilobar Unilobar Bilobar Bilobar Bilobar

Single Single Single Single Single Multiple Multiple Single Multiple Multiple

Male Male Female Male Female Male Female

Male Female

Any

X . 0 cm >4.0 cm >8.0 cm

>2.0 cm >2.0 cm >8.0 cm >4.0 cm >2.0 cm >4.0 cm

Any

1 2 0 4 0 4 1 4

25 3 -


Nonsurgical Treatment

Systemic Chemotherapy. The response rate in most studies is poor? although successes have been reported.23 Currently, chemotherapy should be reserved for cases in which other modalities are not possible or as an adjunct to surgical therapy.

Intra-Arterial Chemotherapy. Chemotherapy is directed in high concentrations at the tumoral site by catheterization of the hepatic artery. Results have not met the initial expectations,23 and complications are not infrequent.

Arterial Embolization. Gelfoam embolization of the arterial supply to the tumor with 1-mm to 2-mm particles has shown encouraging results in select cases.32 Rearterialization may occur, and frequent treatments may be required. Complications from this modality of treatment include aseptic cholecystitis, splenic infarcts, and pancreatitis.

Chemoembolization and Targeting Chemotherapy. Chemothera- peutic agents are added to the arterial embolization technique, sometimes mixed with lipiodol. Results have varied in success.

Radiation Therapy. External radiation has associated complications, such as late hepatic failure in cirrhotics. Results for both external and internal radiation are less than encouraging.

Intratumor Ethanol Injection. Injection of absolute ethanol into tumors of inoperable patients has been used by various groups with relative success.'*, l9

CHOLANGIOCARCINOMA

Definition

Cholangiocarcinoma is an intrahepatic malignant tumor made up of cells that resemble biliary epithelium. To achieve a precise definition, it is necessary to note that the distinction between intrahepatic and extrahepatic bile ducts is defined as the point at which the second-order bile ducts join to become the first-order ducts (right and left hepatic).

Epidemiology

Cholangiocarcinoma has less of a geographic variation than does hepatocellular carcinoma, except for areas such as Hong Kong and Thailand, where liver fluke infestation is endemic. Its frequency in Western countries is approximately 20%, whereas it is less than 10% in African and Asian nations that are endemic for hepatocellular carcinoma.22, 27

52 MOLMENTI et a1

Sex and Age

The age of occurrence is considerably older than hepatocellular carcinoma. The mean age is approximately 65 years, with most patients ranging from 50 to 70 years of age. Male preponderance is modest and varies from 1.0 to 2.2.

Etiology

Opistorchis and Clonorchis Infection

Correlation has been shown between liver fluke infection and cholangiocarcinoma.2' Studies have found an incidence of liver cancer of 56.6% in patients with opistorchiasis; 77% of these malignancies were cholangiocarcinomas.

Gallstones

Intrahepatic stones have been implicated as causing persistent irrita- tion of the biliary epithelium that may eventually degenerate into cholangiocarcinoma.

Ulcerative Colitis and Primary Sclerosing Cholangitis

Ulcerative colitis and primary sclerosing cholangitis have a well- established association with bile duct carcinoma. Cholangiocarcinoma occurs in approximately 1 in 256 patients with ulcerative colitis; one third of these tumors are within the liver. The colitis precedes cholangiocarcinoma, when present, by an average of 5 years (range, 0-30 years).26 In patients with primary sclerosing cholangitis, the incidence of cholangiocarcinoma ranges from 4% to 2OYo2; the cumulative risk for cholangiocarcinoma in these patients has been reported to be 11.2% at 10 years after diagn~sis. '~

Cystic Liver Diseases

Caroli's disease, choledochal cysts, hepatic cysts, Meyenburg's com- plexes, and congenital hepatic fibrosis, among others, have been implicated in the pathogenesis of cholangiocarcinoma.

Pathology

Peripheral cholangiocarcinomas represent 50% to 70% of the total, whereas hilar types account for the remainder.


Gross Pathology

Grossly, cholangiocarcinoma appears as a firm, gray-white infiltrative mass, ranging from 2 cm to 15 cm in diameter. Central necrosis and venous invasion (portal or hepatic) may be observed. Hemorrhage and tumor rupture are rare. Peripheral tumors tend to present as solitary masses, although multiple or diffusely nodular varieties may be encountered. Hilar cholangiocarcinomas (Klatskin tumors) may present as an infiltrative mass that extends from the hilum into the parenchyma, as a sclerotic mass encircling a large bile duct, or as a polypoid tumor invading the lumen of a large bile duct. Extrahepatic metastases occur more frequently through the lymphatic system than through the hematogenous route. Peripancreatic and hilar nodes are involved in approximately half of cases. Autopsy cases report an incidence of extrahepatic metastases of slightly less than 80Y0.~~

Microscopic Pa thology

Cholangiocarcinomas are classically well- to moderately differentiated adenocarcinomas that exhibit glandular or acinar structures; intracytoplasmic mucin is almost always observed. Cells tend to be cuboidal or low columnar and resemble biliary epithelium; bile production is not usually seen. A dense, fibrous stroma is characteristic and may dominate the histologic architecture. Cholangiocarcinomas tend to invade lym- phatics, blood vessels, perineural and periductal spaces, and portal tracts. Spread along the lumen of large bile ducts can be seen, especially with hilar tumors.

lmmunochemistry

Cholangiocarcinomas display immunoreactivity for several cytokeratins (Moll numbers 7, 8, 18, and 19) and multiple markers for adenocarcinomas, including CEA, epithelial membrane antigen, Leu-M1, tumor- associated glycoprotein 72 (B72.3), glycoprotein BCA-225 (CU-18), and carbohydrate 19-9 (CA 19-9). Other reactive agents include tissue poly- peptide antigen, a-amylase isoenzyme, and the Lewis blood group anti- gens Lex and Ley.

Clinical Features

Signs and symptoms are similar to those of hepatocellular carcinoma, except that biliary obstruction is more common. Affected individuals tend to present with jaundice, abdominal pain, fever, general malaise, abdominal distension, fullness, anorexia, pruritus, and weight loss.

54 MOLMENTI et a1

Diagnosis

Laboratory Findings Biochemistry. Biochemical tests are not specific. ALP is almost al-

ways elevated, and hypercalcemia may be encountered in some cases. Hepatic function in the absence of severe jaundice is well preserved.

Tumor Markers. Carcinoembryonic antigen and CA 19-9, although not specific, are of diagnostic value. Some have found CEA to be positive in more than 40% of cases.I7 CEA in combination with CA 19-9 is a factor used to differentiate cholangiocarcinoma from hepatocellular carcinoma. This combination, however, cannot help differentiate cholangiocarcinoma from metastatic tumors. AFP may be increased in some cases of cholangiocarcinoma, although the increase is less significant than for hepatocellular carcinoma.

Radioiogic Diagnosis Cholangiography. Cholangiography may prove diagnostic in hilar

tumors, but it is not as effective for peripheral lesions. Sonography. Cholangiocarcinoma may be either hypoechoic or hy-

perechoic. Computed Tomography. On plain scans, cholangiocarcinomas are

low-density lesions usually associated with dilated bile ducts. Because of their hypovascularity, they usually enhance only mildly on dynamic CT and are either faintly hypodense or isodense to liver parenchyma during the portal venous phase. If a major portal vein branch is compro- mised, the corresponding lobe atrophies. Hilar cholangiocarcinomas are hypodense or isodense and may not be readily detected. They may appear, however, on late-phase enhanced CT because of the presence of fibrous tissue within these tumors causing delayed persistent enhancement.

Magnetic Resonance Imaging. Well-differentiated cholangiocarcinoma has a high signal intensity on T2-weighted spin-echo imaging. Scirrhous cholangiocarcinoma, on the other hand, demonstrates a signal only slightly more intense than the liver parenchyma. Biliary dilatation and metastases to lymph nodes may be detected with this technique.

Angiography. Cholangiocarcinoma is usually hypovascular or avas- cular; however, the presence of thin, neoplastic vessels may give an appearance of hypervascularity. Venous obstruction, vascular encasement, and arterial collaterals may be encountered.

Treatment and Prognosis

Early diagnosis is seldom achieved.

Surgical Treatment Surgical Resection and Liver Transplantation for Cholangiocarci-

noma-University of Pittsburgh Experience. Although numerous cases

HEFATOBILIARY MALIGNANCIES 55

of surgical treatment of hilar cholangiocarcinoma have been reported, with few exceptions, long-term survival has been poor.zs, For hilar and peripheral cholangiocarcinoma, bile duct resection with or without par- tial hepatectomy is the procedure of choice for patients with anatomi- cally resectable tumors without advanced cirrhosis or sclerosing cholangitis. Total hepatectomy with liver replacement is the procedure of choice when tumor extension, underlying cirrhosis, or sclerosing cholangitis prevents resection. As will be shown later, subsets of patients with favorable tumor characteristics that justify transplantation in these patients can be defined.

Hilar Cholangiocarcinoma (Klatskin Tumor). Between 1981 and 1996, 34 patients underwent Hx, and 38 underwent transplantation (total 72), all with curative intent.'" Of the 38 patients who underwent transplantation, 27 had OLTx alone, and 11 had upper abdominal exenteration and organ cluster transplantation. Despite the curative intent, 41% of patients in the Hx group, 22% in the OLTx group, and 9% in the organ cluster transplant group had positive margins. Perioperative mortality occurred in 14.7% of the patients in the Hx group, 22.2% in the OLTx group, and 18.2% in the organ cluster transplant group. The 1-, 3-, and 5-year survival rates for the Hx group were 73.5%, 33.9%, and 9.1%, respectively, and for the OLTx group were 59.3%, 36.2%, and 36.2%, respectively; the organ cluster transplant group had corresponding survival rates of 54.6%, 9.1%, and 9.1%. (These differences were not significant.) Of the 10 patients who have survived more than 5 years postsurgery, 80% were treated with transplantation. For those 28 patients (transplant and resection combined) with both negative surgical margins and lymph nodes, the 1-, 3-, and 5-year survival rates were 68%, 50%, and 50%, respectively. As would be expected, the rate of negative margins increased with the extent of the surgical extirpation.

Peripheral Cholangiocarcinoma. Between 1981 and 1994, 34 patients underwent Hx and 20 underwent transplantation (total 54).4 Of the 38 patients who underwent transplantation, 11 had OLTx alone, and 9 had upper abdominal exenteration and organ cluster transplantation. Of the patients in the Hx group, 29.4% had positive margins compared with 20% in the OLTx group. Perioperative mortality was 7.4% for the entire group. The overall patient survival rates at 1, 3, and 5 years were 6470, 34%, and 26%, respectively. The patient survival rates for those undergoing Rx were 6O%, 37%, and 31% at 1, 3, and 5 years and were similar for those undergoing OLTx (YO%, 29%, and l8%, respectively). For the 21 patients (OLTx and Rx combined) with negative margins, negative nodes, and single tumors, the 1-, 3-, and 5-year survival rates were 74%, 64%, and 64%, respectively.

Nonsurgical Treatment

tion therapy have been used but with disappointing results.21 Chemotherapy and Radiation Therapy. Chemotherapy and radia-

Biliary Drainage. Inoperable cases benefit from biliary drainage.

56 MOLMENTI et a1

Percutaneous or endoscopic procedures should be undertaken in cases in which surgical treatments are not indicated or are impossible.

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Address repriri t requests to Ernesto P. Molmenti, MD

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Dallas, TX 75204

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HEPATOBILIARY MALIGNANCIES