9 TUMORS OF THE PANCREAS, BILIARY TRACT, AND LIVER … of... · 9 Tumors of the Pancreas, Biliary...

© 2005 WebMD, Inc. All rights reserved.5 Gastrointestinal Tract and Abdomen

ACS Surgery: Principles and Practice9 Tumors of the Pancreas, Biliary Tract, and Liver — 1

Numerous types of tumors affect the pancreas, the biliary tree,and the liver. Each year, hundreds of papers are published on thetopics of pancreatic, biliary, and hepatic cancer. Accordingly, inthis chapter, we concentrate on essential principles rather thandetails. In particular, we focus on common malignant tumors,addressing benign tumors and uncommon tumors only insofar asthey are important in differential diagnosis.

When a patient presents with an apparent cancer of the pan-creas, the biliary tree, or the liver, the surgeon must attempt toanswer the following three important questions:

1. What is the diagnosis? 2. What is the surgical stage of the disease—that is, is the

tumor resectable?3. What is the operative rationale that will encompass the

disease and produce a margin-free resection (and, forpancreatobiliary cancers, an N1 resection)?

These questions form the underpinning for the process ofinvestigation and management. In what follows, we describe ourapproach to each of the cancers in these terms.

Pancreatic Cancer

DUCTAL ADENOCARCINOMA

Adenocarcinoma of Head of Pancreas

Adenocarcinoma of the pancreatic head is common (with 30,000new cases occurring annually in the United States) but remainsone of the hardest GI cancers to cure. In the past 25 years, the effi-cacy of surgical treatment has improved dramatically, but 5-yearactual survival rates in patients who have undergone resection arestill low (about 15%).1 Cancer of the head of the pancreas is theprototypical tumor that causes painless jaundice; however, othercancers that obstruct bile ducts also cause jaundice, includingextrahepatic bile duct cancers, gallbladder cancers, ampullarymalignancies, and some duodenal cancers. Some of the followingdiscussion is generalized with an eye to determining the diagnosisin patients presenting with obstructive jaundice [see 5:3 Jaundice].

Clinical evaluation History. The classic presentation ofcancer of the head of the pancreas is unremitting jaundice, usual-ly accompanied by dark urine, light stool, and pruritus. Darkeningof the urine or pruritus is often the first symptom, and scleralicterus frequently is first noted by family members or coworkers.The pruritus is often severe. The jaundice sometimes is painlessbut more frequently is associated with epigastric pain. This painusually is not severe; severe, acute pain is more often associatedwith other conditions that may cause jaundice (e.g., choledo-cholithiasis and pancreatitis). Back pain suggests that the tumorhas invaded tissues outside the pancreas and is unresectable.

Significant weight loss (≥ 10% of body weight) is common evenwhen the pancreatic cancer is resectable.

In some patients, steatorrhea or diarrhea from obstruction ofthe pancreatic duct, weight loss, pain, or a combination of these isthe presenting symptom, rather than jaundice. A presentationwith steatorrhea or diarrhea is usually the result of a tumor in theuncinate process that obstructs the pancreatic duct but not thebile duct. Often, these symptoms are overlooked until the tumorextends and causes jaundice. About 5% of patients have a historyof diabetes of recent onset. Migratory thrombophlebitis (theTrousseau sign) is uncommon and usually signifies metastatic dis-ease. Pancreatobiliary malignancies cause biliary obstruction, butsuch obstruction is not commonly associated with biliary tractinfection before instruments have been employed in the biliarytree. Therefore, in patients presenting with cholangitis who havenot undergone biliary tract instrumentation, other diagnosesshould be suspected. Patients with pancreatic cancer may alsopresent with acute pancreatitis as the first manifestation.Vomitingand GI bleeding are uncommon presenting symptoms and sug-gest the presence of advanced tumors that are obstructing or erod-ing the duodenum.

Physical examination. Examination reveals scleral icterus. Insome cases, the distended gallbladder may be palpable. Inadvanced cases, signs of metastatic disease (e.g., hepatomegalyand ascites) may be detected.

Investigative studies Laboratory tests. Liver function tests(LFTs) are of limited value in diagnosis.The serum bilirubin levelis elevated in jaundiced patients, with the direct fraction exceed-ing 50%. The serum alkaline phosphatase level is almost alwayselevated when the bile duct is obstructed, and levels three to fivetimes normal are common. Aminotransferase levels usually aremoderately elevated as well.Very high aminotransferase levels sug-gest a hepatocellular cause of jaundice, usually viral, thoughimpaction of a stone in the bile duct can cause transient rises inserum aspartate aminotransferase (AST) to levels higher than1,000 IU/ml. By themselves, LFTs cannot effectively distinguishamong jaundice arising from a hepatocellular cause (e.g., viralhepatitis or drug-induced cholestasis), jaundice resulting from adisease of microscopic bile ducts (e.g., primary biliary cirrhosis),and jaundice caused by any of the malignancies that obstruct themajor bile ducts.To make this distinction, radiologic imaging testsare required [see Imaging, below].

Serum concentrations of the tumor marker CA 19-9 are oftenelevated in patients with pancreatic or biliary adenocarcinomas.2The upper limit of the normal range is 37 U/ml. Concentrationshigher than 100 U/ml are highly suggestive of malignancy, but ele-vations between 37 and 100 U/ml are less specific. Serum levelsgenerally reflect the extent of the tumor: small tumors (< 1 cm indiameter) are rarely associated with levels higher than 100 U/ml,

9 TUMORS OF THE PANCREAS,BILIARY TRACT, AND LIVER

Steven M. Strasberg, M.D., F.A.C.S., and David C. Linehan, M.D., F.A.C.S.



whereas very high levels (> 1,000 U/ml) suggest metastatic dis-ease. High levels may also accompany cholangitis. Measurementof CA 19-9 concentrations may be employed to detect recurrencesin patients who have elevated CA 19-9 levels that return to nor-mal after tumor resection; a second rise in the CA 19-9 level in thefollow-up period is indicative of recurrence in most cases.

Imaging. Several different imaging tests may be used for diag-nostic purposes in jaundiced patients, including computed tomog-raphy, magnetic resonance imaging, endoscopic retrograde cholan-giopancreatography (ERCP), endoscopic ultrasonography (EUS),and transabdominal ultrasonography. The technical advances inimaging achieved over the past few years are remarkable. CT andMRI, which only a few years ago were limited to axial images, onone hand, and fuzzy MRI cholangiopancreatography (MRCP), onthe other, can now provide high-quality images of blood vesselsand ducts and their anatomic relation to tumors.These images caneven be projected in three dimensions if desired.

Selection of appropriate imaging tests in a jaundiced patient isinfluenced by patient characteristics and by the symptomsobserved. For instance, the type and order of investigations appro-priate for an older patient presenting with obstructive jaundice,who is likely to have a malignancy, differ from those appropriatefor a young woman with severe pain, who is more likely to havecholedocholithiasis. The best initial imaging test in a patient inwhom malignancy is suspected is either a fine-cut (3 mm betweenslices) three-phase (no-contrast phase, arterial phase, and venousphase) helical (spiral) CT scan or a high-quality MRI scan.AlthoughMRI has the advantage of being able to provide a cholangiogram(i.e., with MRCP), small and medium-sized radiologic facilitiescurrently tend to be more skilled at CT than at MRI; this differ-ence should be taken into account when the first test is ordered.High-quality MRI scanners and the very latest generation of CTscanners are capable of providing cholangiograms and angiograms,as well as axial images.

The typical pancreatic cancer appears as a lucent zone in thepancreatic head [see Figure 1], associated with upstream dilatationof the bile ducts and the gallbladder. Often, the pancreatic duct is

also obstructed. As a result, the pancreatic duct may be dilated inthe tail, body, and neck of the pancreas, with dilatation terminat-ing sharply at the edge of the tumor. Pancreatic duct dilatation isoften accompanied by atrophy of the body and the tail of the pan-creas [see Figure 2].

When a jaundiced patient is discovered to have a typical-appear-ing localized cancer of the pancreatic head on CT scanning, no fur-ther diagnostic tests are needed, and operative management shouldbe the next step.Tissue diagnosis is unnecessary. Negative biopsy re-sults rarely change the therapeutic approach, and in that they aresometimes falsely negative, they are potentially misleading. Further-more,omitting biopsy eliminates the small risk of tumor implantationin the needle tract. Selection of axial imaging as the first test oftenrenders diagnostic ERCP, which is a more invasive test, unnecessaryas well. Cholangiography also is not required for staging pancreatichead tumors [see Surgical Staging, below].The advantages of startingwith axial imaging in jaundiced patients with suspected cancer arediscussed in greater detail elsewhere [see Biliary Tract Cancer, Extra-hepatic Cholangiocarcinoma, Upper-Duct Cholangiocarcinoma,Investigative Studies, below].

Additional diagnostic imaging for atypical CT or MRI findings. Inmany patients with adenocarcinoma of the pancreatic head, thetypical CT findings are absent and additional diagnostic imagingis required. Such patients may be categorized into two groups:those with an atypical mass and those with no mass on axial imag-ing. In either case, before ordering additional tests, it is appropri-ate to determine whether the CT scan is of adequate quality. Forexample, the scan may have been performed without contrast, thearterial and venous phases may not have been captured appropri-ately, or the slice thickness may have been too great for precisevisualization of the head of the pancreas. Small adenocarcinomasmay be missed when the venous phase is timed poorly, especiallyif slice thickness is 5 mm or greater, and masses that appear atyp-ical initially may exhibit a typical appearance when the CT scan isoptimized. Neuroendocrine cancers commonly display arterial-phase enhancement, which will be missed if the scan is mistimed.In our experience, about 40% of referred patients who underwent

Figure 1 Shown is a typical hypoattenuating cancer of the pancreat-ic head.The tumor is invading the right side of the portosplenic con-fluence, as evidenced by the “beaking” of the vein at that point.

Figure 2 In the same patient as in Figure 1, pancreatic ductdilation is apparent in the body of the pancreas, with atrophy ofthe parenchyma.



CT scanning before arrival require a so-called pancreas protocolCT scan (i.e., a fine-cut three-phase helical scan) when they arefirst seen; in many of these cases, the second CT scan yieldsimportant diagnostic findings.

When no mass is present in a jaundiced patient with a peri-ampullary tumor or another focal obstructing process (e.g., pan-creatitis), the CT scan usually shows bile duct dilatation extend-ing down to the intrapancreatic portion of the duct.The dilatationmay terminate anywhere from the upper border of the pancreas tothe duodenum, depending on the site of the tumor and the natureof the process obstructing the bile duct. In these conditions,ERCP is a good choice as the second test.

ERCP provides an endoscopic view of the duodenum that allowsidentification and biopsy of ampullary and duodenal tumors thatmay be blocking the bile duct and producing jaundice. It confirmsthe presence of a bile duct stricture and displays its form, which ishelpful in diagnosis. Focal strictures, especially those with shoulders,suggest malignancy. Long, tapering strictures limited to the intra-pancreatic portion of the bile duct suggest chronic pancreatitis. Con-comitant narrowing of the pancreatic duct in the head of the pan-creas (the double-duct sign) suggests the presence of a smallpancreatic cancer that is not visible on the CT scan. Longer or mul-tiple pancreatic strictures suggest chronic pancreatitis.A single focalbile duct stricture in the absence of pancreatic duct abnormalities isthe hallmark of cancer of the lower bile duct. Infiltrating cancers ofthe bile duct may cause more than one stricture along the bile duct,but when more than one stricture is present, other diagnoses (e.g.,primary sclerosing cholangitis) should be considered. Both pancre-atic and bile ducts may be assessed with brush cytology.This test hasa 45% to 50% sensitivity for cancer3; therefore, only a positive testresult is significant.

ERCP findings in a patient with no mass must be evaluated in thelight of findings from other investigations. Patients with the classicdouble-duct sign or single focal shouldered bile duct strictures arelikely to have small pancreatic or bile duct tumors. Further diagnos-tic support is usually not needed before laparotomy, though suchsupport may be reassuring when the CA 19-9 concentration is high-er than 100 U/ml.When doubt persists, EUS often helps resolve it.EUS may identify a small mass that was not seen on the CT scan,and biopsies may then be done. Occasionally, EUS reveals enlargedlymph nodes, which may also undergo biopsy. However, negativeEUS-guided biopsy results in patients who present with painlessjaundice do not exclude malignancy.When such patients have anidentifiable mass on EUS, pancreaticoduodenectomy is recom-mended, even if EUS-guided biopsy yields negative results. If a non-operative approach is taken, short-term follow-up at 4 to 6 weekswith repeat imaging and biopsy is mandatory. If the findings persist,laparotomy is advisable.

Occasionally, preoperative testing reveals no mass, but a mass issubsequently discovered by intraoperative palpation or intraoper-ative ultrasonography (IOUS). A mass palpated in the head of apancreas that is otherwise normal or near normal in texture ishighly suggestive of malignancy and constitutes sufficient justifi-cation for resection.The same is true of a mass detected by IOUSif the mass has characteristics of malignancy (i.e., is hypoechoic).If the IOUS findings are inconclusive, biopsy with frozen-sectionexamination is a reasonable approach. In many such cases, thewhole pancreas is diffusely firm or hard, and IOUS demonstratesa diffuse change in the normal texture of the gland.When the pan-creas is diffusely firm and no localized process is seen on IOUS,biopsies should be directed toward the stent in the bile duct at thepoint where the bile duct narrows (as seen on ultrasonography).

The ultimate diagnostic test is pancreaticoduodenectomy. Ifthere is a strong suspicion of cancer before laparotomy or the find-ings at laparotomy are strongly suggestive, this procedure shouldbe performed without preliminary biopsy. When this approach isfollowed, a small number of patients with suspected malignant dis-ease will ultimately turn out to have benign disease when operat-ed on; this possibility should be explained to patients who do notundergo confirmatory tissue diagnosis before operation. Becauseof the limited negative predictive value of currently available tests,pancreaticoduodenectomy is sometimes still required to make adefinitive diagnosis.

The finding of an atypical pancreatic head mass on a CT scanposes an additional challenge. Atypical masses may take differentforms. In some cases, they exhibit attenuation that differs onlyslightly from that of the surrounding pancreas; in others, they havea ground-glass appearance. They may extend into the body andtail of the pancreas, or they may be localized to the head. Withatypical masses, the most common problem is how to differentiatefocal pancreatitis from adenocarcinoma. This differentiation canbe very difficult to achieve. Pancreatitis may be present withoutantecedent acute attacks; without a history of alcoholism, gall-stones, or hyperlipidemia; without diabetes or steatorrhea; andwithout calcifications in the gland. Cancer appears to be morecommon in patients who have had chronic pancreatitis, and thediseases may coexist. Therefore, one cannot feel confident thatcancer is absent simply because chronic pancreatitis is present.Cancer should be suspected in patients with an established diag-nosis of chronic pancreatitis who undergo a rapid change in status(e.g., weight loss). Diabetes is common in patients with chronicpancreatitis, but it may also be the first sign of pancreatic cancerin patients without chronic pancreatitis. Chronic pancreatitis cancause painless jaundice. A rare immune form of chronic pancre-atitis, known as lymphoplasmacytic sclerosing pancreatitis, has beenrecognized that is particularly hard to differentiate from cancer.4

EUS is becoming increasingly important in the management ofpatients with atypical pancreatic head masses.5 When jaundice ispresent, ERCP followed by EUS is our usual approach; when it isabsent, EUS without ERCP is preferred. EUS-guided biopsy issuperior to CT-guided transabdominal biopsy, in that access to thehead of the pancreas is easier and the chance of needle tracking isreduced (because the biopsy is taken through the duodenal wall,which is resected if a Whipple procedure is done).

At the conclusion of all of the preceding investigations, it stillmay not be clear whether a malignancy is present. Clinical judg-ment must be exercised in deciding whether to operate or torepeat investigative studies after an interval of 2 to 3 months.Operation is favored in patients who are jaundiced, who haveless pain, who have elevated CA 19-9 levels, and whose mass issuspicious for cancer. Elevation of the CA 19-9 concentrationbeyond 100 U/ml should be regarded as a very important find-ing. When EUS is inconclusive, ultrasound-guided diagnosticlaparoscopy may be performed to obtain core tissue biopsiesfrom several areas of the mass. This technique is especially use-ful when chronic pancreatitis is strongly suspected,6 in that themultiple long core biopsies obtainable with this procedure pro-vide a greater degree of assurance against false-negative findingsfor cancer. Even this test, however, is not 100% accurate in thisregard.The penultimate diagnostic test is laparotomy with mobi-lization of the pancreatic head and IOUS-guided transduodenalcore biopsies of the mass.The ideal outcome with this approachis to perform pancreaticoduodenectomy in all patients who actu-ally have cancer while reducing to a reasonable minimum resec-



tion in patients with benign disease, who in most cases are bet-ter served by biliary bypass.

Surgical staging The term staging is currently used todenote the process by which the surgeon determines whether atumor is resectable.We prefer to use the term surgical staging forthis process so as to distinguish it from those staging classificationsthat define the life history and prognosis of tumors and provide thebasis for comparison of results—namely, the TNM classificationsdeveloped by the American Joint Committee on Cancer (AJCC).These latter systems are also of great importance to the surgeondealing with pancreatic tumors.

Surgical staging is started preoperatively and completed intra-operatively. Preoperative staging tests determine operability—thatis, whether the tumor appears resectable after preoperative testing.However, the final decision regarding resectability is made onlyduring the operation, on the basis of intraoperative staging. Atumor of the head of the pancreas is deemed unresectable when itis determined to have extended beyond the boundaries of a pan-creaticoduodenectomy. Common reasons for unresectability include(1) vascular invasion (i.e., invasion of the superior mesenteric vein,the portal vein, the superior mesenteric artery, or, less commonly,the hepatic artery); (2) lymph node metastases that fall outside thescope of a pancreaticoduodenectomy (e.g., metastases to para-aor-tic and celiac lymph nodes); (3) hepatic metastases; (4) peritonealmetastases; and (5) extra-abdominal metastases (usually pul-monary). Limited vascular invasion of the superior mesentericvein and the portal vein may be overcome by resection and recon-struction and thus is only a relative contraindication to resection.This is especially true when the tumor is small and has arisen inthe vicinity of the veins. In a series from our institution (WashingtonUniversity in St. Louis), about 20% of resections done for pan-creatic cancer involved resection of these veins.7

The tests used to establish the diagnosis and those used toaccomplish surgical staging go hand in hand. Abdominal CTscans, abdominal MRI, thoracic CT scans, and chest radiographsare obtained to detect hepatic metastases, vascular invasion, andpulmonary metastases.To assess vascular invasion, fine-cut three-phase helical CT scans or MRI scans are required.These tests maydetect enlarged lymph nodes, but it should be remembered thatnodes may be enlarged for reasons other than cancer. Sometimes,ascitic fluid collections or peritoneal or omental nodules are iden-

tified; ascitic fluid may be sent for cytologic analysis, and omentalnodules may undergo ultrasound-guided biopsy. Invasion of themesentery, the mesocolon, or retroperitoneal tissues may also bedetected by CT scanning. In the view of some surgeons, such inva-sion may render the tumor unresectable, but in our experience,this is rarely the case in the absence of concomitant vascular inva-sion: the resection may still be accomplished with clear margins byresecting the portion of the mesocolon or the mesentery that waslocally invaded.

EUS may be used to guide biopsy of suspicious lymph nodeswhen these lie outside the planned resection zone. It has also beenemployed to assess vascular invasion, but in our experience, it hasno advantage over CT scanning in this regard; what is more, it ishighly operator dependent. Staging laparoscopy is particularlyeffective at finding small hepatic and peritoneal nodules. About20% of patients thought to have resectable pancreatic adenocarci-noma of the head of the pancreas before staging laparoscopy arefound to have liver or peritoneal metastases upon laparoscopy.8Staging is completed intraoperatively by carefully inspecting theintra-abdominal contents, opening the lesser sac, mobilizing thehead of the pancreas, performing biopsies of suspicious nodules ornodes outside the planned resection zone, and attempting dissec-tion of the superior mesenteric vein or the portal vein. Formal clin-icopathologic staging according to the AJCC’s TNM system isuseful for establishing the prognosis and planning additional treat-ment [see Tables 1 and 2].

All authorities agree that axial imaging of the abdomen andchest (or roentgenography of the chest) is standard practice forstaging pancreatic cancer; however, not all agree on the value ofother staging tests. Many authorities advocate omission of staginglaparoscopy or EUS-guided biopsy of nodes, on the grounds thatpatients are better served by palliative surgery than by endoscopicstenting of the bile duct. There is no advantage in knowingwhether small liver metastases or celiac node metastases are pres-ent if laparotomy is to be undertaken anyway.The literature on thisissue is unclear regarding what constitutes best practice.The tworandomized trials published to date reported differing outcomes,with one favoring surgical bypass9 and the other endoscopic stent-ing. We continue to recommend staging laparoscopy in patientswith adenocarcinoma of the pancreas. In those considered likely tohave a short life expectancy because of peritoneal or hepaticmetastases discovered upon laparoscopy, the procedure is discon-tinued, and endoscopic stenting with metal stents is performed.We no longer advocate using staging laparoscopy with ultrasonog-raphy to determine if the tumor is unresectable solely because oflocal vascular invasion; these patients are likely to have a longer life

Table 1 American Joint Committee on Cancer TNMClinical Classification of Pancreatic Cancer

TX Primary tumor cannot be assessedT0 No evidence of primary tumorTis Carcinoma in situT1 Tumor limited to pancreas, ≤ 2 cm in greatest dimensionT2 Tumor limited to pancreas, > 2 cm in greatest dimensionT3 Tumor extends beyond pancreas but without involvement

of celiac axis or SMAT4 Tumor involves celiac axis or SMA

NX Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Regional lymph node metastasis

MX Distant metastasis cannot be assessedM0 No distant metastasisM1 Distant metastasis

Primarytumor (T)

Regionallymphnodes (N)

Distant metas-tasis (M)

SMA—superior mesenteric artery

Stage

Stage 0

Stage IA

Stage IB

Stage IIA

Stage IIB

Stage III

Stage IV

Table 2 American Joint Committee on CancerStaging System for Pancreatic Cancer

M

M0

M0

M0

M0

M0

M0

M1

T

Tis

T1

T2

T3

T1, T2, T3

T4

Any T

N

N0

B0

N0

N0

N1

Any N

Any N



expectancy and are treated with a double-bypass procedure. Finally,18F-fluorodeoxyglucose positron emission tomography (FDG-PET) may be useful in staging pancreatic cancer, but at present,its role is unclear. Given that inflammation is frequently confusedwith cancer, the major role of this modality will probably be in thedetection of distant metastases.

Management Preoperative preparation. All jaundiced pa-tients should receive vitamin K, a fat-soluble vitamin whoseabsorption is reduced by biliary or pancreatic duct obstruction.Routine preoperative bile duct decompression is unnecessary,except when jaundice has been prolonged or operative treatmentwill be delayed (e.g., for correction of cardiac or other comorbidconditions). Several studies have shown that surgical outcome isnot improved by routine preoperative decompression in jaundicedpatients. In fact, stent placement may increase the incidence ofpostoperative infection.10

Rationale for pancreaticoduodenectomy. The technical details ofpancreaticoduodenectomy are discussed more fully elsewhere [see5:24 Pancreatic Disease].Therapeutic decision-making necessar-ily includes consideration of the extent of the procedure.The oper-ative goal is to remove the tumor with clear margins, as well as theN1 regional lymph nodes. Numerous attempts have been made toimprove results by extending the operation, either through moreextensive lymph node dissections11 or through resection of thesuperior mesenteric artery.12 None of these attempts have beensuccessful in improving overall survival.The lesson is that invasionof additional lymph node regions or the superior mesenteric arterysignals an aggressive tumor biology that is unlikely to be overcomeby wider resections. Except for resection of the portal vein or thesuperior mesenteric vein to address invasion of these structures byotherwise favorable tumors, extended resections are no longer rec-ommended. Even these recommended venous resections are prob-ably best restricted to tumors that have arisen close to the veinsand involved them while still small; resections of large adenocarci-nomas that have grown over time to involve long stretches of theveins are best avoided.

There is also continuing controversy regarding the respective mer-its of the standard version of the operation and its pylorus-preservingvariant.There is no evidence that the two procedures differ with re-spect to overall survival. Pylorus preservation is associated with gas-tric-emptying problems in the postoperative period, but overall, itseems to be associated with less postoperative GI dysfunction.13 Weemploy pylorus preservation selectively in older, thinner patients,with the aim of minimizing disruption of GI function.

Adenocarcinoma of Body and Tail of Pancreas

Adenocarcinoma of the body and tail of the pancreas is lesscommon than adenocarcinoma of the head. Because it does notproduce jaundice, it tends to be recognized relatively late. Accord-ingly, patients are often in an advanced stage of disease at presen-tation. Tumors of the midbody tend to invade posteriorly toinvolve the superior mesenteric artery or the celiac axis, even whenthese lesions are only 2 to 3 cm in diameter. As a result, tumors ofthe tail are more likely to be resectable than tumors of the mid-body when they are discovered. Many resectable tumors are dis-covered incidentally; by the time the tumors give rise to symp-toms, they are frequently unresectable.

Clinical evaluation Symptoms are nonspecific, consistingof abdominal and back pain (which is usually relieved by sitting upand leaning forward), weight loss, and diabetes of recent onset.

Investigative studies The CA 19-9 concentration may beelevated. CT usually shows a lucent mass [see Figure 3], often withextension outside the pancreas and dilatation of the distal pancre-atic duct, when the tumor is proximal to the tail of the gland. EUSis very useful for assessing indeterminate lesions.

Surgical staging Surgical staging of cancers of the body andthe tail is similar to that of cancers of the pancreatic head and isbased primarily on CT scanning of the abdomen and the thorax.Unresectability by reason of local invasion is usually attributable tothe involvement of the superior mesenteric artery or the celiac arteryand less commonly to the involvement of the portal vein, the superi-or mesenteric vein, or the aorta.Another indicator of unresectabilityis enlarged para-aortic nodes, which sometimes appear along theaorta below the pancreas. Invasion of the spleen, the stomach, theleft adrenal gland, the mesocolon, the colon, the retroperitoneum, oreven the left kidney is not a contraindication to resection, providedthat clear margins may be expected.14 Staging laparoscopy is of greatvalue in this context: between 20% and 50% of patients are found tohave unresectable tumors with this modality.15 Cancer of the bodyand the tail differs from cancer of the head in that there is no effec-tive palliation and therefore no rationale for laparotomy if the lesionis unresectable. Celiac nerve block, which is very helpful in reducingthe use of narcotics for pain control, may also be performed laparo-scopically or endoscopically.

Management Rationale for radical antegrade modular pancre-atosplenectomy. Logically, the goal of resection of tumors of thebody and tail should be the same as that of resection of tumors ofthe head—namely, excision of the tumor with clear margins, alongwith the N1 lymph nodes. In practice, this goal generally is notachieved by the traditional retrograde distal pancreatectomy, inwhich the spleen is taken first and which is not based on the lymphnode drainage of the pancreas. Lymph node counts have been lowwith the traditional procedure, and positive posterior margin rateshave been high. As an alternative, we have developed a techniquereferred to as radical antegrade modular pancreatosplenectomy

Figure 3 Shown is a typical hypoattenuating cancer of the tail ofthe pancreas with invasion of the hilum of the spleen and thesplenic flexure of the colon. Peritumoral stranding suggestsinflammation or invasion of peripancreatic fat.



(RAMPS), which accomplishes the desired goals by performingthe resection in an antegrade manner from right to left and whichis based on the established lymph node drainage of the gland [seeFigure 4].16 RAMPS also allows early control of the vasculature.

Mucinous Adenocarcinoma

Mucin-producing cancers are special variants of adenocarcino-ma of the pancreas that often arise in preexisting lesions.The twomain types are mucinous cystic neoplasm (MCN) and intraduc-tal papillary mucinous neoplasm (IPMN) (also referred to asintraductal papillary mucinous tumor [IPMT]).17 A complete dis-cussion of pancreatic cyst disease is beyond the scope of this chap-ter. Accordingly, we briefly address such disease as it relates tocancer of the pancreas, omitting discussion of less common cysticmalignancies of the pancreas.

MCN MCN occurs most often in middle-aged women, typical-ly in the body and tail of the pancreas. MCNs are unilocular or sep-tated cysts whose diameter ranges from subcentimeter size to 15 cmor larger. Occasionally, calcium is present in the wall. Excrescencesmay be present on the inner wall; if so, malignancy is likely. Mostsymptomatic MCNs are between 4 and 7 cm in diameter.

Clinical evaluation and investigative studies. Patients with MCNstypically present with left-side pain, often in the flank and theback, though these lesions also are frequently discovered inciden-tally. Pancreatitis is rare and jaundice is uncommon, even whenthe lesions are situated in the head of the pancreas. MCNs mustbe differentiated from pseudocysts and from serous cystadenomas(SCAs), which are benign cysts. Differentiation between MCNsand pseudocysts is based on the history, imaging studies, and cystfluid analysis. The diagnosis of pseudocyst is supported by a his-tory of pancreatitits; a thick-walled, uncalcified cyst with associat-ed radiologic signs of pancreatitis; and cyst fluid with high levels ofamylase and lipase and a relatively low level of carcinoembryonicantigen (CEA) (< 500 ng/ml).

SCAs have the same clinical presentation as MCNs. SCAs aremore frequently polycystic than MCNs are, but this difference is nota certain means of discriminating between the two. In a minority(25%) of cases, SCAs have a pathognomonic central calcification

with radiating arms ringed by multiple grape-sized cysts.When thecysts are tiny (honeycomb pattern), SCAs may also appear to be sol-id tumors. Unlike pseudocysts and IPMNs, neither MCNs norSCAs communicate with the pancreatic duct, though they maycompress it. Measurement of the CEA level in cyst fluid is a goodmeans of distinguishing MCN from SCA. SCAs have very low levelsof CEA, with the cutoff being 5 ng/ml.18 In MCNs, the cyst fluid isoften mucinous, and cytologic assessment may show mucin-produc-ing cells; typically, the fluid is high in CEA.The CA 19-9 concentra-tion may also be used to distinguish MCNs from SCAs, but it is notas reliable as the CEA concentration for this purpose.18

Surgical staging. Surgical staging is required when MCNs aremalignant, and essentially the same methods are used as for anypancreatic adenocarcinoma (see above). Malignancy is suggestedby a solid intracystic or extramural component. Sometimes, a mu-cinous tumor is frankly malignant with a large or dominant solidcomponent. Such a tumor is better termed a mucinous adenocar-cinoma, and it should be evaluated and treated from the outset inthe same manner as any other adenocarcinoma of the pancreas.

Management. In symptomatic patients, preoperative differen-tiation between MCNs and SCAs is unnecessary, because resec-tion is the treatment for both. In asymptomatic patients, MCNsmore than 2 cm in diameter should be excised because of the pos-sibility of malignant degeneration. The standard procedure hasbeen open distal pancreatectomy with splenectomy, though lesserprocedures, such as spleen-sparing distal pancreatectomy,19

laparoscopic distal pancreatectomy,20 central pancreatectomy, andenucleation,21 have all been used as well.These procedures appearto be reasonable choices, provided that there is no suggestion ofinvasive malignancy on imaging (i.e., that there are no excres-cences on the inner lining and that the surrounding pancreasappears normal). Enucleation may be associated with a higherincidence of postoperative fistula. If invasive cancer is not detect-ed in the resected specimen, the chances that the malignancy willrecur are small; in fact, we have never seen such a recurrence.

The 2 cm cutoff for treatment of MCNs in asymptomatic pa-tients is arbitrary. It is still possible that malignant degenerationcould occur in a cyst smaller than 2 cm, but many cysts of this size

Celiac Nodes

InfrapancreaticNodes

GastroduodenalNodes

Gastrosplenic Nodes

Superior Mesenteric Nodes

SplenicNodes

Figure 4 Illustrated is the pattern of lymphaticdrainage of the pancreas. The darker nodes are N1nodes for the body and tail of the pancreas. Thelighter nodes on the aorta to the left side of theceliac artery and the superior mesenteric arteryare N1 for the central part of the pancreas and N2for other regions.



are found in the course of axial imaging performed for other rea-sons. Such cysts are difficult to diagnose because of the small vol-ume of cyst fluid present, and the benefit to be gained from per-forming a large number of pancreatectomies for these small cystsis questionable, even when they are diagnosable as MCNs. Someauthorities feel that large SCAs should also be excised because ofrare instances of malignant degeneration. Occasionally, MCNs orsymptomatic SCAs are located in the head of the pancreas andmust be treated with pancreaticoduodenectomy.

IPMN IPMN begins as the cells lining the pancreatic ductsundergo a metaplastic alteration from a low cuboidal serous typeof cell to a mucin-producing type. These cells are prone to dys-plasia and eventual malignant transformation. Overall, IPMNsappear to undergo malignant transformation much more regular-ly than MCNs do. There are two recognized types of IPMN,which may occur either separately or together.The more commontype affects the main pancreatic duct [see Figure 5], which becomesdilated and filled with mucin. As the disease progresses towardmalignancy, papillary processes may project into the lumen. Theless common type, so-called side-branch IPMN, affects the small-er ducts and presents as multiple (usually small) pancreatic cysts.In either type of IPMN, the disease may be either diffuse or focal;when it is focal, the head of the pancreas is the site of disease inthe majority (60%) of cases. About 20% of IPMN patients have amalignancy at the time of diagnosis, though the cancer may not beevident until the specimen is examined pathologically.

Clinical evaluation and investigative studies. IPMN occurs pre-dominantly in males and usually affects patients in their 60s. Pain(usually attributable to pancreatitis arising from mucous obstruc-tion of the pancreatic duct) is a common presenting symptom.Another common presentation is pancreatic insufficiency with di-abetes or steatorrhea.Accordingly, it is not surprising that former-ly, many IPMN patients were diagnosed as having chronic pan-creatitis. IPMN may also be discovered incidentally or maypresent as a cancer with signs and symptoms similar to those ofother pancreatic cancers, depending on the part of the gland inwhich they arise. On rare occasions, cholangitis from obstructionof the common channel by mucus is the presenting problem.

The diagnosis is made on the basis of the presentation and thefindings from axial imaging and ERCP. ERCP sometimes showsmucus bulging from the mouth of the pancreatic duct when theduodenum is inspected. In main duct disease, the pancreatic duct isdilated, but sometimes, the mucus prevents complete filling. In thissituation, CT scans or MRI with MRCP may be quite useful for de-tecting ductal dilatation and atrophy of the pancreas. MRCP is bestat detecting excrescences emanating from the surface of the duct,which signal progression of the disease toward neoplasia. In side-branch IPMN, ERCP typically demonstrates communication be-tween the cysts and the main duct, which is often normal in size; thisfinding is not present in MCN or SCA and is very useful for distin-guishing side-branch IPMN from these other types of cysts.

Management. IPMN is treated by resecting the involved por-tion of the gland. In about 50% of patients, the resection marginis involved with atypia or cancer, and the planned resection mayhave to be extended.22 In some cases (about 20%), total pancrea-tectomy is required; in others, partial pancreatectomy and closefollow-up of the pancreatic remnant with MRCP and serum CA19-9 measurement are indicated. Most patients who require totalpancreatectomy tolerate the procedure well when they are enrolledin a program keyed to this operation.The mucinous cancers asso-ciated with IPMN have a better prognosis than ductal adenocar-cinomas do.23 Frank mucinous cancers may appear in patientswith IPMN as well; they should be managed in much the samefashion as other adenocarcinomas, with the additional require-ment that the resection should encompass the entire IPMN-bear-ing portion of the pancreas.

NEUROENDOCRINE CANCERS

In most large centers, neuroendocrine cancers account for fewerthan 5% of surgically treated pancreatic malignancies. Some of thesecancers are functional tumors, which produce hormones leading toparaneoplastic syndromes. Examples include gastrinoma, insulino-ma, glucagonoma and vasoactive intestinal polypeptide–secreting tu-mor (VIPoma), all of which are associated with characteristic clinicalsyndromes.These syndromes are often produced while the tumorsare still small.A detailed discussion of functional neuroendocrine tu-mors is beyond the scope of this chapter.

a b

Figure 5 (a) CT scan of a patient with main duct IPMN involv-ing the entire length of the pancreatic duct reveals substantialdistention of the duct. (b) Shown is a cross-section through theresected specimen.



Other neuroendocrine tumors are nonfunctional and, as a re-sult, reach a larger size before giving rise to symptoms. These le-sions present with symptoms caused by the mass effect and mustbe differentiated from ductal adenocarcinomas. Nonfunctionalneuroendocrine cancers are slow-growing tumors that tend topush rather than invade structures but are capable of metastasiz-ing to lymph nodes, as well as to the liver and other organs. Painis the most common presenting symptom. Jaundice, pancreatitis,and systemic symptoms (e.g., weight loss) are less common withthese tumors than with adenocarcinoma of the pancreas. Becauseof the propensity of neuroendocrine tumors to deflect rather thaninvade the bile duct, jaundice may be absent even when tumorsare located in the head of the gland.

Diagnosis, surgical staging, and treatment rationale are essen-tially the same for neuroendocrine cancers as for ductal adenocar-cinomas. On CT scans, these lesions characteristically show en-hancement in the arterial phase and are seen to push on bile ductsand vascular structures rather than encase them. Complete resec-tion by means of pancreatoduodenectomy or distal pancreatecto-my [see 5:24 Pancreatic Disease] is indicated. Given the slowgrowth rate of neuroendocrine cancers and their relatively favor-able prognosis (50% to 60% 5-year survival rate), removal of theprimary lesion and any hepatic secondary lesions is justified if alltumor tissue can be removed with clear margins.

Biliary Tract Cancer

EXTRAHEPATIC CHOLANGIOCARCINOMA

Extrahepatic cholangiocarcinoma (CCA) may be subdividedinto lower-duct CCA and upper-duct CCA, with the former aris-ing in the intrapancreatic or retroduodenal portion of the bile ductand the latter arising above it. In practice, most upper-duct CCAs(also referred to as hilar CCAs or Klatskin tumors) arise justbelow the union of the right and left hepatic ducts, at the union ofthe ducts, or in the main right or left hepatic ducts. Cancer of themidportion of the bile duct at the cystic duct’s usual insertionpoint is more likely to be an extension of a gallbladder cancer thana primary CCA. AJCC staging criteria for these tumors are useful

for establishing the prognosis and planning further treatment [seeTables 3 and 4].

Lower-Duct Cholangiocarcinoma

Clinical evaluation and investigative studies Much of whatthe surgeon needs to know about lower-duct CCA has already beenaddressed elsewhere [see Pancreatic Cancer, Adenocarcinoma ofHead of Pancreas, above]. By far the most common presentation ispainless jaundice with its constellation of associated symptoms (es-pecially pruritus).Laboratory tests reveal the characteristic pattern ofobstructive jaundice. A serum CA 19-9 concentration higher than100 U/ml facilitates the diagnosis. Axial imaging reveals dilation ofthe intrahepatic bile ducts, the gallbladder (in most cases), and theextrahepatic bile ducts down to the level of the pancreatic head,where the dilatation terminates abruptly. Usually, no mass is visible.ERCP or MRCP shows a focal stricture, and ERCP brushings arepositive in about 50% of cases.EUS may be helpful, in that it is moresensitive for small tumors than CT scanning is. Needle biopsy is di-rected toward the mass or, if no mass is visible, toward the narrowestsegment of the bile duct.A negative biopsy result does not rule out asmall bile duct cancer.

The differential diagnosis includes other potential causes of focalstrictures of the bile duct.24 The most common cause of a benignstricture of the intrapancreatic bile duct is pancreatitis, which maybe diffuse or focal. Other causes of benign stricture include iatro-genic injury, choledocholithiasis, sclerosing cholangitis, and benigninflammatory pseudotumors [see Upper-Duct Cholangiocarcinoma,Investigative Studies, Imaging, below]. Iatrogenic injuries rarelyinvolve the intrapancreatic portion of the bile duct, though suchinjuries can occur in this area as a consequence of forceful instru-mentation. Sclerosing cholangitis may affect this section of the bileduct but usually affects other areas of the biliary tree as well.Thediagnostic steps for differentiating benign neoplasms from malig-nant tumors are essentially the same for lower-duct CCA as forpancreatic cancer.As noted, resection may be required to make thediagnosis. In any patient presenting with jaundice and a focal stric-ture of the bile duct, lower-duct CCA should be strongly suspected.

Surgical staging Surgical staging of lower-duct CCAs isusually straightforward. These tumors are usually remote frommajor vascular structures and thus are not subject to the samelocal staging considerations as adenocarcinomas of the pancreatichead are.The exception is a tumor that extends to the top of theretroduodenal portion of the bile duct. At this point, the bile ductis apposed to the portal vein and the hepatic artery, and thesestructures may be invaded by bile duct tumors in this location.

Table 3 American Joint Committee on Cancer TNM Clinical Classification of Extrahepatic Bile

Duct Cancer

TX Primary tumor cannot be assessedT0 No evidence of primary tumorTis Carcinoma in situT1 Tumor confined to bile duct histologicallyT2 Tumor invades beyond wall of bile ductT3 Tumor invades liver, gallbladder, pancreas, or

unilateral branches of portal vein or hepatic arteryT4 Tumor invades any of the following: main portal vein

or branches bilaterally, coronary artery, or other adjacent structures (e.g., colon, stomach, duodenum, or abdominal wall)



Primary tumor (T)

Regional lymphnodes (N)


Stage

Stage 0

Stage IA

Stage IB

Stage IIA

Stage IIB

Stage III

Stage IV

Table 4 American Joint Committee on CancerStaging System for Extrahepatic Bile Duct Cancer

M

M0

M0

M0

M0

M0

M0

M1

T

Tis

T1

T2

T3

T1, T2, T3

T4

Any T

N

N0

N0

N0

N0

N1

Any N

Any N



Management The treatment for resectable lesions is pan-creaticoduodenectomy.

Upper-Duct Cholangiocarcinoma

Upper-duct (or hilar) CCA is a sporadically occurring tumorthat may also be seen in patients with primary sclerosing cholan-gitis, ulcerative colitis, or parasitic infestation. It is characteristi-cally slow growing and locally invasive, and it metastasizes morereadily to lymph nodes than systemically, though intrahepaticand peritoneal metastases are not uncommon. Most hilar CCAsare cicatrizing diffusely infiltrating cancers, but some are nodular,and others present as papillary ingrowths. These tumors aredivided into four types according to the Bismuth classification,which is based on the upper extent of the tumor [see Figure 6].25

When the CCA originates in one of the hepatic ducts, thatduct may be obstructed for a considerable period before thetumor causes jaundice by growing into the other hepatic duct orthe common bile duct. Such prolonged unilateral obstructionbefore the onset of the presenting symptom of jaundice mayresult in atrophy of the obstructed side of the liver, which mayaffect subsequent management. For example, because the diseaseis more advanced on the obstructed side, it is the atrophied halfof the liver that will be removed in almost all cases where resec-tion is indicated. In addition, when one side of the liver under-goes atrophy, the other side undergoes hypertrophy. Thesechanges lead to rotation of the liver, which in turn may cause thestructures in the hepatoduodenal ligament to be rotated out oftheir normal anatomic location. For instance, if hypertrophy of

the left hemiliver develops, the hepatic artery may come to liedirectly in front of the bile duct.

Clinical evaluation The usual presentation of hilar CCAconsists of painless jaundice with its accompanying symptoms(especially pruritus), though some pain may be present. Cholan-gitis before instrumentation of the bile duct is uncommon. In pa-tients who present in the late stages of the disease, general manifes-tations of cancer (e.g.,malaise,weight loss, or ascites) may be noted.

Investigative studies Laboratory tests. Laboratory testingfollows the pattern previously described for obstructive jaundice[see Pancreatic Cancer, above]. Again, the most helpful diagnosticlaboratory test is the serum CA 19-9 concentration: levels higherthan 100 U/ml are strongly suggestive of cancer. In patients withprimary sclerosing cholangitis, the presence of CCA is often sug-gested by a rapid deterioration in condition. It is not unusual forpatients with hilar CCA to have undergone a cholecystectomy inthe recent past; the symptoms of pain and jaundice may be mis-taken for symptoms of gallbladder disease in patients who happenalso to have gallstones.

Imaging. Earlier [see Pancreatic Cancer, Ductal Adenocarcino-ma, Adenocarcinoma of Head of Pancreas, above], the point wasmade that it is preferable to employ axial imaging rather than ERCPas the first imaging test in the jaundiced patient because doing sowill often render ERCP, an invasive test, unnecessary.This point car-ries even more force in the setting of hilar CCA. Injection of dye

Type I Type II Type IIIa

Type IIIb Type IV

a b c

d e

Figure 6 Depicted is theBismuth classification of hilarCCA (a through e).



above the malignant stricture is an integral part of ERCP. Once thedye has been injected, stents must be placed to prevent post-ERCPcholangitis.This process may involve insertion of bilateral stents, in-cluding a stent in the atrophic hemiliver. Bilateral stenting is disad-vantageous, because the aim is to encourage atrophy of the hemiliv-er to be resected and hypertrophy of the hemiliver to be retained,and insertion of a stent in the atrophic side contravenes that aim.Starting with CT or MRI rather than with ERCP allows detectionof any hilar CCA present simultaneously with detection of atrophy.At this point, the patient can be evaluated by a multidisciplinaryteam with expertise in this disease, and a decision can be made re-garding which side of the biliary tree to decompress (if either).Whether stents should be employed in treating hilar CCA is debat-able, but if a stent is inserted, only the side to be retained should beintubated. MRCP now provides resolution that is close to that ob-tained with direct cholangiography [see Figure 7].

ERCP does have one significant advantage, in that it allowsbrushings to be obtained; however, brushings at this high level inthe biliary tree are even less sensitive than those at lower levels.Bile cytology has been tried, without much success. EUS has beenemployed to obtain diagnostic tissue, with some degree of success;however, because the biopsy needle passes through the peritonealcavity, concerns have been expressed regarding possible tumorseeding. Such seeding has not been an issue with lower-duct can-cers, because the biopsy tract is entirely within the future resectionspecimen. In many cases, a tissue diagnosis cannot be obtainedpreoperatively, and the diagnosis is based on the presence of afocal hilar stricture that causes jaundice.

Focal strictures of the upper bile ducts are strongly suggestiveof cancer, but CCAs must also be differentiated from benigninflammatory tumors (also referred to as hepatic inflammatorypseudotumors and benign fibrosing disease).26These inflammato-ry masses mimic upper-duct CCAs but consist of chronic inflam-matory cells and fibrous material. Even today, they are very diffi-cult to distinguish from cancers before pathologic examination ofa resected specimen.27 Benign inflammatory tumors appear tooccur most frequently in extrahepatic upper ducts, but they alsooccur intrahepatically and, less commonly, in lower ducts.

Gallbladder cancer may invade the porta hepatis and appearas a CCA, especially on ERCP. Gallstones are usually present.

Axial imaging usually shows thickening of the gallbladder wallor the presence of a mass involving the infundibulum. Mirizzisyndrome is another cause of a focal stricture of the middle orupper bile duct.This syndrome results from compression of thebile duct by a large gallstone in the infundibulum and is usual-ly associated with severe inflammation of the gallbladder andthe characteristic signs and symptoms of acute cholecystitis.The duct is typically bowed to the left rather than focally nar-rowed, as in cancer. Iatrogenic causes should be considered ifthe patient has had a cholecystectomy. On occasion, a strictureappears years after the operation. In these cases, the probablecause of the stricture is ischemic injury to the bile duct. Thepresence of clips close to or indenting the duct is a clue thatsuch injury is a possibility. Choledocholithiasis may also causestrictures, especially if cholangitis has occurred. Strictures arealso frequent with recurrent pyogenic (oriental) cholangitis. Otherrare tumors of the bile duct (e.g., neuroendocrine tumors) maymimic cholangiocarcinoma.

Surgical staging Often, the first axial imaging test revealsonly the presence of intrahepatic bile duct dilatation, which stopsabruptly as the ducts merge in the hepatic hilum. This finding,however, leads to MRI or CT aimed at providing high-qualitycholangiograms and angiograms of the hepatic arteries and theportal veins. Surgical staging of hilar CCA, unlike that of lower-duct CCA, requires exact knowledge of the macroscopic upperextent of the tumor in the bile duct. Furthermore, invasion ofhepatic arteries and portal veins is common and frequently affectsresectability.Thus, surgical staging also requires accurate determi-nation of the extent of hepatic arterial or portal venous invasionand assessment of the degree of atrophy.

Bismuth type IV tumors are not resectable, except by liver trans-plantation.Type I through III tumors are resectable, provided thatthe main portal vein and the proper hepatic artery, as well as the por-tal vein and the hepatic artery to the side of the liver to be retained,are not invaded by tumor and that the side to be retained is not atrophic. Involvement of the main portal vein or the hepatic artery isa relative rather than an absolute contraindication; lesser degrees ofinvolvement can be handled by means of vascular resection and re-construction in specialized centers. Unusual combinations of eventsmay prelude resection (e.g., atrophy on one side of the liver and in-vasion of the hepatic artery supplying the other side, or invasion ofthe portal vein to one side and the bile duct on the other side to thelevel of the secondary biliary branches).

MRI (with MRCP and magnetic resonance angiography [MRA]) or CT with the latest generation of scanners can providecomplete information regarding the extent of bile duct involve-ment and the degree of vascular invasion. Doppler ultrasonogra-phy is also excellent for evaluating vascular invasion. ERCP maybe used for additional assessment of the extent of the tumor onthe side to be retained if a stent on that side is deemed necessary.The use of percutaneous cholangiography is controversial, themain concern being the risk of tumor seeding along the tube, intothe peritoneal cavity, and onto the surface of the liver or theabdominal wall. Nevertheless, this procedure is used extensively inJapan, where surgeons have considerable experience with selectivedecompression of parts of the liver as a preoperative strategy.28

Assessment of distant metastases is achieved by means of axialimaging of the chest and the abdomen. Staging laparoscopy iden-tifies 10% to 15% of cancers that are unresectable because of peri-toneal or liver metastases. FDG-PET identifies about 15% ofpatients with distant metastases. At present, neither of these testsis routinely employed in this setting.

Figure 7 Shown is Bismuth type II CCA. The right and lefthepatic ducts are dilated (upper arrows), whereas the commonhepatic duct is normal sized.



Management Preoperative preparation. Unlike cancers ofthe lower bile duct, cancers of the upper bile duct usually necessi-tate major liver resection [see 5:22 Procedures for Benign andMalignant Biliary Tract Disease]. Consequently, it has been arguedthat the risk of postoperative hepatic failure may be lowered bypreoperative decompression, especially decompression of the sideto be retained, which has the dual purpose of allowing that side torecover function and of actually encouraging hypertrophy. On theother hand, stents may introduce bacteria and cause cholangitis.As noted (see above), selective percutaneous decompression is anaccepted strategy in Japan; often, multiple stents are inserted.28

A reasonable strategy is to proceed to operation if (1) thepatient is relatively young (< 70 years), (2) there are no seriouscomorbid conditions, (3) the jaundice has been present for lessthan 4 weeks, (4) the serum bilirubin concentration is lower than10 mg/dl, (5) the future remnant liver will include more than 30%of the total liver mass, and (6) the patient has not undergone bil-iary instrumentation (which always contaminates the obstructedbiliary tract). In all other cases, we routinely decompress the sideof the liver to be retained and wait until the serum bilirubin con-centration falls to 3 mg/dl. When the future remnant liver willinclude less than 30% to 35% of the total liver mass, portal veinembolization (PVE) of the side to be resected may be performedto induce hypertrophy of the remnant. Because resection for hilarCCA is a major procedure in a somewhat compromised liver, it iscontraindicated in patients who are in poor general condition orwho have major organ dysfunction.

Rationale for surgery. Patients with upper-duct CCA are can-didates for resection if they have no distant metastases (includingintrahepatic metastases) and if the tumor can be removed in itsentirety by means of bile duct resection [see 5:22 Procedures forBenign and Malignant Biliary Tract Disease] combined with liverresection [see 5:23 Hepatic Resection]. The goal of resection ofupper-duct CCA is to achieve clear resection margins by remov-ing the tumor, the portal and celiac lymph nodes, the side of theliver in which the ductal involvement is greater (via hemihepatec-tomy or trisectionectomy), and the caudate lobe. (The caudate

lobe is resected because cholangiocarcinomas tend to invadealong the short caudate bile ducts, which enter the posterior sur-faces of the main right and left bile ducts at the bifurcation of thecommon hepatic duct.)

Liver transplantation has been used successfully to manageBismuth type IV tumors and is usually performed after neoadju-vant chemoradiation therapy and staging laparotomy in highlyselected patients.29

GALLBLADDER CANCER

The incidence of gallbladder cancer in the United States is about9,000 cases a year. This cancer almost always arises in patientswith preexisting gallstones and is most often seen in elderlypatients. Like ductal adenocarcinoma of the pancreas, it is highlymalignant, and it tends to spread at an early stage to lymph nodes,to peritoneal surfaces, and through the bloodstream. AJCC stag-ing criteria are helpful for planning management of this cancer [seeTables 5 and 6].

Clinical Evaluation

Gallbladder cancer is discovered incidentally either duringperformance of cholecystectomy for symptomatic cholelithiasisor when the tumor causes symptoms related to invasion of thebile duct or metastatic disease. In stage I and II disease, which isconfined to the wall of the gallbladder, the symptoms are usuallythose of the associated stones—that is, the patient has biliary col-ic, and the cancer is silent. In later stages of disease, jaundice,weight loss, a palpable right upper quadrant mass, hepatomegaly,or ascites may develop. Jaundice occurs in about 50% of patients.It is a poor prognostic sign because it signifies extension of thetumor beyond the gallbladder and obstruction of the extrahepat-ic bile ducts. Consequently, most gallbladder cancer patientswith jaundice have unresectable tumors. Because the signs andsymptoms of gallbladder cancer are nonspecific, delays in diag-nosis are common. As a result, most gallbladder cancers are notdiagnosed until they have reached stage III or IV; thus, most ofthese aggressive tumors are unresectable at presentation, evenwhen the patient is not jaundiced.

Investigative Studies

Laboratory tests In stages I and II, LFTs usually yield nor-mal results. In later stages, laboratory test abnormalities may benoted that are not diagnostic but are consistent with bile ductobstruction. Elevated alkaline phosphatase and bilirubin levels arecommon. An elevation in the serum CA 19-9 concentration is themost helpful diagnostic indicator.

Table 5 American Joint Committee on Cancer TNMClinical Classification of Gallbladder Cancer

TX Primary tumor cannot be assessedT0 No evidence of primary tumorTis Carcinoma in situT1 Tumor invades lamina propria or muscle layer

T1a: Tumor invades lamina propriaT1b: Tumor invades muscle layer

T2 Tumor invades perimuscular connective tissueT3 Tumor perforates serosa (visceral peritoneum) or di-

rectly invades one adjacent organ (≤ 2 cm into liver)T4 Tumor extends > 2 cm into liver or invades two or

more adjacent organs (e.g., duodenum, colon, pancreas, omentum, or extrahepatic bile ducts)

NX Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Metastasis in cystic duct, pericholedochal, or hilar

lymph nodes (i.e., in hepatoduodenal ligament)N2 Metastasis in peripancreatic (head only), periduo-

denal, periportal, celiac, or mesenteric lymph nodes


Primary tumor (T)



Stage

Stage 0

Stage I

Stage II

Stage III

Stage IVA

Stage IVB

Table 6 American Joint Committee on CancerStaging System for Gallbladder Cancer

M

M0

M0

M0

M0M0

M0

M0M1

T

Tis

T1

T2

T1, T2T3

T4

Any TAny T

N

N0

N0

N0

N1N0, N1

N0, N1

N2Any N



Imaging Because gallbladder cancer is most curable in itsearly stages and because the symptoms in those stages are those ofcholelithiasis, it is helpful to be aware of subtle signs of gallbladdercancer that are occasionally present on sonograms. These signsinclude thickening of the gallbladder wall, a mass projecting intothe lumen, multiple masses or a fixed mass in the gallbladder, cal-cification of the gallbladder wall (so-called porcelain gallbladder),and an extracholecystic mass. Displacement of a stone to one sideof the gallbladder should also be viewed with suspicion.

In later stages of disease, CT scans usually show a gallbladdermass with or without invasion of the liver or other adjacent organs.Obstruction of the bile duct produces the usual features associatedwith obstructive jaundice. Percutaneous CT-guided biopsy is a use-ful technique for confirming the diagnosis in patients with unre-sectable tumors. Porcelain gallbladder is a premalignant condition,though there is some evidence that the incidence of cancer dependson the pattern of calcification: selective mucosal calcification appar-ently carries a significant risk of cancer, whereas diffuse intramuralcalcification does not.30 It seems reasonable to resect only tumorswith the former pattern, but whenever there is a question about thepattern of calcification, one should err on the side of resection.

Surgical Staging

Staging of gallbladder cancer requires knowledge of the extentof direct invasion into the liver and other adjacent organs and tis-sues (especially the bile duct, the portal veins, and the hepaticarteries). As in hilar CCA, this information may be obtained bymeans of MRCP and MRA or CT with the latest-generation scan-ners. Staging laparoscopy is very helpful in managing gallbladdercancer. As many as 50% of patients with this disease are found tohave peritoneal or liver metastases upon staging laparoscopy,8 andas with carcinoma of the body of the pancreas, there are no usefulpalliative measures that can be undertaken at laparotomy.

Management

Rationale for surgery When early-stage gallbladder cancer issuspected on the basis of diagnostic imaging, open cholecystectomy,rather than laparoscopic cholecystectomy, is probably the procedureof choice [see 5:21 Cholecystectomy and Common Bile Duct Explorationand 5:22 Procedures for Benign and Malignant Biliary Tract Disease]. In-traoperatively, if there is no evidence of spread outside the gallblad-der, we recommend performing an extraserosal cholecystectomy, inwhich the fibrous liver plate is excised along with the gallbladder sothat bare liver is exposed. It is possible to perform an extraserosal re-section laparoscopically; however, in our opinion, this should not beattempted,because gallbladder perforation and bile spillage are morecommon with the laparoscopic version of the procedure.The nega-tive consequences of tumor implantation or incomplete excision faroutweigh any benefit that a minimally invasive approach might confer.

The excised specimen should be inked and a frozen sectionobtained. If there is gallbladder cancer in the specimen but theresection margins are clear and the tumor is a T1 lesion (i.e., hasnot penetrated the muscularis), the procedure is considered com-plete, in that lymph node metastases are uncommon with T1tumors (incidence < 10%). However, lymph node metastases arepresent in 50% of patients with T2 lesions (i.e., tumors that haveinvaded the muscularis). Therefore, if margins are positive or thetumor is a T2 lesion, resection of segments 4b and 5 of the liverand dissection of portal and celiac lymph nodes, along with resec-tion of the extrahepatic bile duct and hepaticojejunostomy, arerecommended. If it is already clear at the commencement of theoperation that the tumor is T2, one should proceed directly toliver, lymph node, and bile duct resection.

In more advanced stages of disease (T3 and T4), the aim is stillexcision with clear margins and resection of portal and celiaclymph nodes.To obtain clear local margins with these tumors, inaddition to what is required for T2 tumors, more extensive hepat-ic resections—up to a trisectionectomy (resection of segments 4through 8) [see Liver Cancer, Anatomic Considerations, below]31—may be necessary, as well as resection of adjacent organs.

Incidentally discovered gallbladder cancer Gallbladdercancer may be an incidental finding at laparoscopic cholecystecto-my, as it has been at open cholecystectomy.The incidence of thisfinding ranges from 0.3% to 1.0%. A concern that has arisen inthe current era, in which the laparoscopic approach to cholecys-tectomy is dominant, is the risk of port-site implantation of tumor.Port-site implantation may simply be the result of contact betweenthe malignancy and the tissues surrounding the port site at thetime of gallbladder extraction; however, positive pressure pneu-moperitoneum may also play a causative role. When evidence ofgallbladder wall thickening is noted intraoperatively, the gallblad-der should be extracted in a sac. The gallbladder should be in-spected at the time of extraction, and any questionable areasshould undergo biopsy.

If a gallbladder cancer is discovered at the time of operation, itshould be treated without delay according to the principles statedearlier (i.e., depending on whether the margins on the excised gall-bladder are clear and on the T stage of the tumor). From an onco-logic viewpoint, it would seem ideal to resect the tissue around alltrocar port sites. From a technical viewpoint, however, it would bevery difficult and impractical to excise the full thickness of theabdominal wall circumferentially around four port sites, especial-ly because the tract of the port site often is not at a 90° angle tothe abdominal wall. If the gallbladder was extracted through a portsite without having been placed into a bag, it is reasonable toattempt excision of that one port site.

Sometimes, cancer is suspected, but frozen-section examinationis inconclusive and the definitive diagnosis of cancer is not madeuntil the early postoperative period. More often, cancer is not sus-pected intraoperatively, and the diagnosis is made only when per-manent sections of the gallbladder are examined. In these situa-tions, patients with completely excised T1 lesions require no fur-ther therapy, and patients with higher-stage lesions should under-go reoperation in accordance with the principles outlined earlier(see above). Other appropriate reasons for not performing theadditional surgery at the time of the cholecystectomy are (1) thedesire to discuss the management scheme with the patient and (2)lack of experience with the procedure for T2 tumors. Not infre-quently, patients are referred to hepatic-pancreatic-biliary (HPB)centers 10 to 14 days after surgery, which is an inopportune timefor reoperation, especially if the first procedure was difficult.Surgery may then be delayed for 3 to 4 weeks.We restage patientswith abdominal CT scans when they are referred with this diag-nosis, and it is not unusual to find hepatic metastases when this isdone.The survival rate is much higher after radical resection thanafter cholecystectomy, even when cholecystectomy was the firstprocedure.32

Gallbladder polyps Gallbladder polyps are discovered inci-dentally on ultrasonograms or CT scans or are diagnosed whenthey cause biliary colic. They may be malignant but are rarely sowhen less than 1 cm in diameter, especially when they are multi-ple. Most gallbladder polyps are less than 0.5 cm in diameter;these are almost always benign cholesterol polyps and may be fol-lowed if they are not giving rise to symptoms. Single polyps



between 0.5 and 1 cm in diameter should probably be removed bymeans of cholecystectomy; multiple polyps in this size rangeshould be followed. About one quarter of all single gallbladderpolyps more than 1 cm in diameter are malignant, and such polypsshould be treated as malignant as a matter of policy. Almost allpolyps more than 1.8 cm in diameter are malignant.33

Liver Cancer

ANATOMIC CONSIDERATIONS

A long-standing problem in discussing any surgical liver disease,especially liver cancer, has been the confusing terminology appliedto liver anatomy and the various hepatic resections. Fortunately, alucid and cogent terminology has emerged that is sanctioned byboth the International Hepato-Pancreato-Biliary Association(IHPBA) and the American Hepato-Pancreato-Biliary Association(AHPBA).31 This terminology has been widely adopted around theworld and translated into many languages. It may be briefly sum-marized as follows.

The fundamental principle is that the anatomic divisions of theliver are based on vascular and biliary anatomy rather than on sur-face markings [see Figure 8]. This is an important point becausesurgical resection is a process of isolating specific liver volumes ser-viced by specific vascular and biliary structures. The anatomic

ramifications of the hepatic artery and the bile duct are regular andvirtually identical. Liver anatomy is best understood by first fol-lowing these structures through a series of orderly divisions. Thebranching of the portal vein on the right side is similar to that ofthe bile duct and the hepatic artery, but its branching on the leftside, because of the fetus’s need to use the umbilical portion of theportal vein as a conduit, is unusual.

The first-order division of the proper hepatic artery and thecommon hepatic duct into the right and left hepatic arteries andthe right and left hepatic ducts, respectively, results in division ofthe liver into two parts (or volumes), referred to as the right andleft hemilivers (or the right and left livers) [see Figure 8 and Table7]. In this system of terminology, the term lobe is never used todenote a hemiliver, because it bears no relation to the internalvascular anatomy. The right hepatic artery supplies the righthemiliver, and the left hepatic artery supplies the left hemiliver.The right and left hepatic ducts drain the correspondinghemilivers. The plane between these two zones of vascular sup-ply is called a watershed. The border or watershed of the first-order division is a plane that intersects the gallbladder fossa andthe fossa for the inferior vena cava and is called the midplane ofthe liver.

The second-order division divides each of the hemilivers intotwo parts [see Figure 8 and Table 7], referred to as sections. Theright hemiliver comprises the right anterior section and the right

Inferior Vena Cava

Right Hemiliver (Right Liver)

Right PosteriorSection

Right AnteriorSection

Left MedialSection

Left LateralSection

Left Hemiliver (Left Liver)

Right Hepatic Vein

7

8

2

1, 9

3

4

5

6

FalciformLigament

Portal Vein

Common Bile Duct

Common Hepatic Artery

Left Hepatic Vein

Middle Hepatic Vein

Figure 8 Illustrated are the anatomic divisions of the liver according to IHPBA/AHPBA-sanctioned terminology, including first-order divisions (hemilivers), second-order divisions(sections) and third-order divisions (segments).



posterior section. These sections are supplied by a right anteriorsectional hepatic artery and a right posterior sectional hepaticartery and are drained by a right anterior sectional hepatic ductand a right posterior sectional hepatic duct. The left hemilivercomprises the left medial section and the left lateral section.Thesesections are supplied by a left medial sectional hepatic artery anda left lateral sectional hepatic artery and are drained by a left medi-al sectional hepatic duct and a left lateral sectional hepatic duct.

The third-order division divides the liver into nine segments,each of which has its own segmental artery and bile duct [seeFigure 8 and Table 7]. The caudate lobe, a unique portion of theliver that is separate from the right and left hemilivers, comprisessegments 1 and 9. The left lateral section comprises segments 2and 3; the left medial section comprises segment 4 (which is some-times further divided into segments 4a and 4b); the right anteriorsection comprises segments 5 and 8; and the right posterior sec-tion comprises segments 6 and 7.

PRIMARY CANCERS

Hepatocellular Cancer

Hepatocellular cancer (HCC), or hepatoma, is the fifth most

common cancer in the world. About 90% of cases arise inpatients with chronic liver disease, especially when the diseasehas progressed to cirrhosis. Although any condition that pro-duces cirrhosis may lead to HCC, the most common cause isviral hepatitis. In the United States, some 3 million people areinfected with hepatitis C virus (HCV), and more than 1 millionpeople have liver disease associated with hepatitis B virus(HBV). HCV infection is much more likely to lead to HCC thanHBV infection is. AJCC staging criteria are useful for planningthe management of liver cancer [see Tables 8 and 9].

Clinical evaluation The usual presentation of sporadicHCC consists of pain, mass, and systemic symptoms of cancer,though the disease may also be discovered incidentally. HCCoccurring as a complication of liver disease may present similar-ly, but it is often manifested first as a deterioration of liver func-tion with the onset of jaundice, ascites, or encephalopathy.

Investigative studies Screening programs are employed inhigh-risk populations. These programs, which use α-fetoprotein(AFP) levels and ultrasonographic examination of the liver todetect early HCC, may detect asymptomatic tumors.

Preferred AnatomicTerm

Right hemiliveror

Right liver

Left hemiliveror

Left liver

Right anterior section

Right posterior section

Left medial section

Left lateral section

—

—

Segments 1–9

Two contiguous segments

CorrespondingCouinaud

Segments (Sg)

Sg 5–8 (± caudatelobe†)

Sg 2–4 (± caudatelobe)

Sg 5, 8

Sg 6, 7

Sg 4

Sg 2, 3

Sg 4–8 (± caudatelobe)

Sg 2, 3, 4, 5, 8 (± caudate lobe)

Any Sg

Any two Sg in continuity

Table 7 Brisbane 2000 Terminology for Hepatic Anatomy and Resections from IHPBA

Level of Division

First order (hemiliver)

Second order (section)

Third order (segment)

Comments

The border or watershed separating the two hemilivers is aplane that intersects the gallbladder fossa and the inferiorvena cava fossa; this plane is referred to as the midplaneof the liver

The borders or watersheds separating the sections within thehemilivers are planes referred to as the right intersectionalplane (for which there is no surface marking) and the leftintersectional plane (which passes through the umbilicalfissure and the attachment of the falciform ligament)

The borders or watersheds of the segments are planesreferred to as the intersegmental planes

Preferred Term for SurgicalResection*

Right hepatectomyor

Right hemihepatectomy(stipulate ± caudate lobe)

Left hepatectomyor

Left hemihepatectomy(stipulate ± caudate lobe)

Right anterior sectionectomy

Right posterior sectionectomy

Left medial sectionectomy

Left lateral sectionectomy

Right trisectionectomy (preferred)or

Extended right hepatectomyor

Extended right hemihepatectomy(stipulate ± caudate lobe)

Left trisectionectomy (preferred)or

Extended left hepatectomyor

Extended left hemihepatectomy(stipulate ± caudate lobe)

Segmentectomy (stipulate Sg—e.g., segmentectomy 7)

Bisegmentectomy (stipulate Sg—e.g., bisegmentectomy 7, 8)

*It is also permissible to refer to any resection in terms of its third-order components. Thus, a left hemihepatectomy may be referred to as a resection Sg 2–4 (or 1–4).†The caudate lobe comprises segments 1 and 9. IHPBA—International Hepato-Pancreato-Biliary Association



The diagnosis of sporadic HCC is based on elevation of AFP lev-els (an indicator with 50% to 60% sensitivity) and the presence of ahepatic mass on axial images. HCCs typically demonstrate hyper-vascularity, which is best seen on arterial-phase images [see Figure 9].A pseudocapsule is often visualized, which is best seen on portal ve-nous–phase images. Multifocality is also common in HCC, and thisfinding often serves to differentiate it from other hepatic neoplasms.Routine biopsy is not indicated in patients with a characteristic mass,those who have a mass and an elevated AFP level, or those who aresymptomatic and require treatment for pain. HCC may be very welldifferentiated and difficult to distinguish from hepatic adenoma andfocal nodular hyperplasia on biopsy. It may also be hard to distin-guish from cirrhotic nodules. Biopsy is associated with a small risk ofbleeding or tumor seeding.

Surgical staging Staging of sporadic HCC requires axialimaging of the abdomen and imaging of the chest. FDG-PETscanning is only marginally useful: HCCs are typically well differ-entiated, and as a result, only 50% of the tumors are visualized.Staging laparoscopy is helpful: additional tumors are found inabout 15% of patients.34

Staging also requires evaluation of the extent of liver disease.TheChild-Pugh classification is used to determine operability.With fewexceptions, resection is limited to Child class A patients with near-normal bilirubin levels (< 1.5 mg/dl), a normal or marginally raisedprothrombin time (PT), and no or minimal portal hypertension.The extent of resection must be tailored to the severity of the liver

disease. For instance, resection of more than two segments is limitedto patients with normal liver function.Too-extensive resection putsthe patients at risk for liver failure in the postoperative period. InJapan and China, indocyanine green (ICG) clearance is used inChild class A patients to determine the possible extent of resection.

Management Rationale for surgery. The rationale for sur-gery is clear in patients without liver disease or in Child class B orC patients with chronic liver disease.The rationale for surgery inChild class A patients, however, remains controversial.

Partial liver resection [see 5:23 Hepatic Resection] is the proce-dure of choice for sporadic HCC in patients with normal livers. InChild class B or C patients with chronic liver disease, liver resec-tion can be hazardous, and orthotopic liver transplantation (OLT)is the procedure of choice.To justify the use of donor organs, how-ever, it is necessary to select patients with HCC so that the long-term outcome of OLT for HCC is similar to that of OLT forbenign conditions. To achieve this goal, OLT is restricted topatients with a single tumor less than 5 cm in diameter or to pa-tients with as many as three tumors, none of which are more than3 cm in diameter (the Milan criteria). These criteria have beenshown to be associated with OLT outcomes comparable to thosefor benign conditions.35

In Child class A patients with liver disease, hepatic resectionand OLT are options if the Milan criteria are met. The optimaltherapeutic approach in this situation has been the subject of con-siderable debate, with proponents arguing for one of two strate-gies—namely, (1) primary OLT or (2) resection followed by OLTif HCC recurs, provided that the patients still meet criteria forOLT (so-called salvage OLT). A complete discussion of this con-troversy is beyond the scope of this chapter. Currently, it wouldseem that the best strategy in patients who meet the criteria forOLT is to perform primary OLT for HCV-associated disease36

and to perform resection and salvage OLT for HBV-associateddisease37 and other HCCs of non-HCV origin. In patients who donot meet the OLT criteria, resection would be performed even ifthe tumor is of HCV origin.At present, there is a trend toward lib-eralizing the OLT criteria to include single tumors 6 or 7 cm indiameter, especially if the source of the organ is a living donor.

When OLT is to be performed, it is important that the waitingtime be short; these tumors progress over a timescale of a fewmonths, and when viewed on an intention-to-treat basis, theresults of OLT deteriorate significantly if the waiting time islong.38 In the United States, this concern has been dealt with by

Table 8 American Joint Committee on Cancer TNMClinical Classification of Adult Primary Liver Cancer

TX Primary tumor cannot be assessedT0 No evidence of primary tumorT1 Solitary tumor without vascular invasionT2 Solitary tumor with vascular invasion; multiple

tumors, none > 5 cm in greatest dimensionT3 Multiple tumors > 5 cm in greatest dimension or

tumor involving major branch of portal or hepatic veinT4 Tumor or tumors with direct invasion of adjacent

organs (other than gallbladder) or visceral peritoneum



Primary tumor (T)


Distant metastasis (M)

Stage

Stage I

Stage II

Stage IIIA

Stage IIIB

Stage IIIC

Stage IV

Table 9 American Joint Committee on CancerStaging System for Adult Primary Liver Cancer

M

M0

M0

M0

M0

M0

M0

T

T1

T2

T3

T4

Any T

Any T

N

N0

N0

N0

N0

N1

Any NFigure 9 CT scan shows a hypervascular HCC of theleft liver.



the introduction of the Model for End-stage Liver Disease(MELD) scoring system, which gives priority to recipients withHCC. It is common in the United States—and usual in countrieswith longer waiting times—to inhibit the growth of the HCC withvarious bridging-to-transplantation strategies during the waitingperiod for OLT. Such strategies include systemic chemotherapy,local treatments (e.g., radiofrequency [RF] ablation and alcoholinjection), transarterial chemoembolization (TACE), and evenresection of the HCC (so-called bridge resection).

In patients with nondiseased livers, the extent of the resectiondepends on the size and position of the tumor. As much as 70%of the liver may be safely excised when normal liver function ispresent.The size of the future hepatic remnant may be determinedby means of imaging. PVE of the side of the liver to be resectedmay be performed preoperatively to increase the size of the futureremnant. It may also be used for this purpose in patients with liverdisease. In these patients, PVE functions as a test of the liver’s abil-ity to regenerate. Failure to respond to PVE is itself a contraindi-cation to surgery in patients with chronic liver disease.

As a rule, liver resections for HCC should be anatomic [see 5:23Hepatic Resection]. Recurrence rates are higher with nonanatomicresections because HCCs grow along portal veins and metastasizelocally within segments, sections, or hemilivers, depending on howfar they reach back along the portal veins.When HCC reaches themain portal vein, resection is generally contraindicated; the resultsare very poor in this situation.

Intrahepatic Cholangiocarcinoma

Clinical evaluation Intrahepatic CCAs arise from intrahe-patic bile ducts.There are three types: a mass-forming type (MF),a periductal infiltrating type (PI), and a type that grows as an intra-ductal papillary tumor (IG).The MF type is by far the most com-mon. Intrahepatic CCA tumor usually occurs in normal livers.The presentation is similar to that of sporadic HCC.

Investigative studies On diagnostic imaging, the appear-ance of intrahepatic CCA is suggestive of a secondary tumor [seeFigure 10]. Unlike diagnosis of HCC, diagnosis of intrahepaticCCA usually requires a biopsy, which reveals an adenocarcinoma

that is indistinguishable from a hepatic metastasis arising from aprimary adenocarcinoma in one of several intra-abdominal orextra-abdominal sites. Special stains may be helpful in differenti-ating this tumor from a true secondary malignancy, but the differ-entiation is rarely certain. An elevated CA 19-9 concentration isstrongly suggestive of this diagnosis if it is higher than 100 U/ml.To make the diagnosis of intrahepatic CCA, primary tumors inother sites must be excluded by means of axial imaging of thechest, the abdomen, and the pelvis; upper and lower GI endos-copy; and mammography. FDG-PET scanning is another meansby which an extrahepatic primary may be identified, but it has notbeen fully evaluated in this setting.

Surgical staging FDG-PET scanning appears to be apromising staging tool for identifying portal lymph node and dis-tant metastases when the primary is actually an intrahepatic CCA.Portal lymph node metastases are a contraindication to resectionin patients with MF tumors; the results of resection in this situa-tion are very poor. Left-side tumors may metastasize to lymphnodes at the cardia of the stomach and along the lesser curvature.

Management The considerations related to resection forintrahepatic CCA are similar to those for sporadic HCC (seeabove). Liver transplantation generally is not performed for thistumor, because of the typically poor results.

SECONDARY CANCERS

Colorectal Metastases

Clinical evaluation and investigative studies About 50%of the 150,000 patients who are diagnosed with colorectal cancerannually in the United States either have or will have liver metas-tases. About 10% of patients with these colorectal metastases(CRMs) are eligible for liver resection. CRMs may be diagnosedeither at the time of treatment of the primary colorectal cancer(synchronous tumors) or at a later stage (metachronous tumors).

Synchronous tumors are diagnosed by means of either preop-erative CT scanning [see Figure 11] or intraoperative palpation.LFTs may show elevations (especially of the serum alkaline phos-phatase level), but these results are not specific. CEA levels are nothelpful as long as the primary tumor is in place. Metachronoustumors are most often diagnosed in the course of a postcolectomysurveillance program, either by imaging the liver with CT scans orFDG-PET scans or by detecting a rise in the CEA level. Whensynchronous metastases are discovered preoperatively, a FDG-PET scan should be done to complete the staging.

Surgical staging In about 25% of patients, FDG-PET scan-ning changes management by detecting unsuspected extrahepaticor intrahepatic disease. Sometimes, it demonstrates that apparentmetastases are actually benign lesions. Second primaries are notuncommon in patients with metachronous lesions; accordingly,such patients should also be staged by means of colonoscopy, ifthis procedure was not done in the preceding 6 months, as well asFDG-PET scanning. Staging laparoscopy adds little to staging ifan FDG-PET scan has been done.

Intraoperative staging consists of careful palpation of intra-abdominal structures, including hepatic and portal venous lymphnodes. In patients with metachronous lesions, however, palpationof the entire abdomen may be limited by adhesions from previousoperations. IOUS of the liver may also detect unsuspected lesions,though this is less likely if the patient has already been staged bymeans of FDG-PET.Figure 10 CT scan shows a mass-forming intrahepatic CCA.



The main value of FDG-PET in this setting is its ability to discov-er unsuspected extrahepatic disease. In so doing, it helps eliminatefutile hepatic resections. If a patient with extrahepatic disease is treat-ed with hepatic resection, a “recurrence” is inevitable. Elimination ofpointless resections has a positive effect on survival: a 2004 studyfrom our institution found that the overall 5-year survival rate afterFDG-PET was about 60%, compared with 40% after conventionalimaging.39 Furthermore, the study showed that after FDG-PETscanning, the classic prognostic factors of the secondary tumor (e.g.,tumor number and tumor size) were no longer significant; rather, themost important prognostic factor was the grade of the primary tu-mor. FDG-PET–scanned patients with poorly differentiated prima-ry tumors did very poorly in terms of overall survival after hepatic re-section.39 Currently, standard PET scanners are rapidly beingreplaced with CT-PET scanners, which fuse the images and providesuperior diagnosis and staging. For planning surgical extirpation,however, the level of detail provided by high-quality contrast-en-hanced CT or MRI is also required.

Management Rationale for surgery. The criteria that deter-mine eligibility for resection are (1) that the primary tumor has beenor can be completely resected, (2) that (with uncommon exceptions)there is no extrahepatic tumor (other than the primary), and (3) thatit is possible to resect all tumors in the liver while leaving enough of ahepatic remnant to ensure that hepatic failure does not develop post-operatively.The considerations governing the extent of the resectionand the use of PVE are similar to those for sporadic HCC.

Treatment of multiple tumors is much more common withCRMs than with HCC. However, nonanatomic resections are aseffective as anatomic resections as long as the resection margin ismicroscopically clear.The traditional view has been that resectionmargins of 1 cm are mandatory.Whereas 1 cm margins may stillbe a reasonable goal, margins as narrow as 1 mm are satisfactoryand are probably as effective as traditional margins, provided thatthey are free of microscopic and gross cancer.When close marginsare expected, transection of the liver with a saline-linked RF abla-tion device may be useful, in that this device leaves a margin ofdevitalized tissue in the patient, as well as in the specimen.40Whenthe margin is very close, it may be extended by painting the cutsurface of the hepatic remnant with the RF device.

Synchronous resection of the primary tumor and the livermetastases has proved to be safe41 and is desired by many patients.The decision to proceed with hepatic resection should not bemade until resection of the primary tumor has been completedand it has been determined that the margins are clear and thepatient is stable. Some patients with a small number of lunglesions in addition to liver lesions have been cured by resection.

Ablation of colorectal metastases. In situ destruction of tumorswith cryotherapy or RF ablation may expand the surgeon’s abilityto eradicate CRMs localized to the liver.42 RF ablation has largelysupplanted cryotherapy in this context as a result of its lower inci-dence of complications and greater ease of use. Ablation may beused either as an adjunct to operative management or as the soletreatment when there are many metastases (but usually < 10).Theefficacy of RF ablation as an adjunct to surgery remains to bedetermined. It is doubtful, however, that using this modality aloneto eradicate multiple lesions will improve overall survival signifi-cantly, because the tumor biology in such cases is likely to be thatof an aggressive tumor. FDG-PET scans should be performed inall such patients; the likelihood of discovering extrahepatic tumorsincreases as the number of hepatic tumors increases.39

RF ablation is not recommended for treatment of resectablemetastases: it is not approved for this purpose, and using it in thisway would mean substituting an unproven therapy of unknownefficacy for a proven therapy of known value. If a consentingpatient with resectable metastases nevertheless insists on this lessinvasive therapy, the surgeon should document that the precedingconsiderations have been explained to him or her. RF ablationmay be applied by means of open, laparoscopic, or percutaneousmethods. There is good reason to believe that targeting ability isdegraded as one moves to less invasive methods. This considera-tion should also be explained to patients, though undoubtedlythere are some patients who, because of comorbid conditions, arecandidates only for percutaneous or laparoscopic approaches.

Neuroendocrine Metastases

Neuroendocrine metastases are characteristically slow growing.Some are functional, especially if they arise from the ileum; metastat-ic liver disease from this source may produce carcinoid syndrome.

Figure 11 (a) CT scan shows a single large CRM. (b) Shown is the specimen after resection.

a b



111In-pentetreotide imaging (OctreoScan; Mallinckrodt Inc., Hazel-wood, Missouri) provides staging information comparable to thatprovided by FDG-PET in patients with CRMs.

The aims of surgical treatment are (1) to eradicate the cancer and(2) to reduce hormonal symptoms.The considerations regarding tu-mor eradication for neuroendocrine metastases are similar to thosefor CRMs—that is, resection should be performed if all cancer canbe removed and no extrahepatic cancer is detectable. In highlysymptomatic patients in whom conservative therapy with octreotidehas failed, debulking the tumor by means of either chemoemboliza-tion or surgery may provide relief.The former is more suitable forpatients with multiple small, diffuse metastases, whereas the latter ispreferred for patients with large localized tumors. RF ablation mayalso be employed, either combined with surgical treatment or alone;this is an excellent use of this procedure, in that the aim is cytore-duction rather than eradication. Debulking tumors in asymptomaticpatients with the intention of extending survival is controversial.

Noncolorectal, Nonneuroendocrine Metastases

Occasionally, liver metastases from other primary sites behave likeCRMs, in that they are localized to part of the liver in the absence ofextrahepatic disease.Such patients can be managed according to thesame approach employed for CRMs, though the outcome is some-what less satisfactory.Tumors that have been treated in this way withacceptable results include breast cancers, renal cell cancers, gastriccancers, acinar cell cancers of the pancreas, and ovarian cancers.Liver resection for more aggressive malignancies (e.g., metastasesfrom gallbladder cancer and pancreatic ductal adenocarcinomas)can be expected to yield very poor results.

INCIDENTALLY DISCOVERED ASYMPTOMATIC HEPATIC MASS

Now that transaxial imaging of the abdomen is commonly per-formed for a variety of complaints, the problem of the incidental-ly discovered asymptomatic hepatic mass is being encounteredwith increased frequency. Generally, cysts are easily distinguishedfrom solid tumors; the main diagnostic issue is differentiation ofthe various solid lesions.

The differential diagnosis of the benign solid hepatic mass in-cludes hepatic adenoma, focal nodular hyperplasia (FNH), focalfatty infiltration, cavernous hemangioma, and other rare neo-plasms (e.g., mesenchymal hamartoma and teratoma)—all ofwhich must be distinguished not only from one another but alsofrom malignant tumors. In the past, several diagnostic tests (e.g.,ultrasonography, CT, sulfur colloid scanning, and angiography)were used to differentiate these neoplasms. Currently, our usualpractice is to perform MRI with gadolinium contrast enhance-ment, which generally allows accurate differentiation among be-nign tumors with a single test. Cavernous hemangiomas are usu-ally easy to distinguish because they have a characteristic appearanceon MRI (hypointense on T1-weighted images, very intense on T2-weighted images, and filling in from the periphery with gado-linium injection); if they are asymptomatic, they need not be re-sected. It is important to distinguish asymptomatic FNHs fromhepatic adenomas: whereas resection is recommended for adeno-mas, because of their potential for hemorrhage or malignant de-generation, asymptomatic FNHs can safely be observed. AnFNH is nearly isointense on T1- and T2- weighted images; it showsslightly more enhancement than normal liver parenchyma in theearly phase after contrast injection, then becomes isointense. Acentral scar is often, but not always, seen. Conversely, a hepaticadenoma exhibits strong early-phase enhancement with contrastadministration, and it tends to be hyperintense on T1-weightedimages.

Given that a symptomatic hepatic mass is usually treated withresection, preoperative biopsy for tissue diagnosis is rarely neces-sary or desirable. Modern noninvasive radiologic tests, in con-junction with a careful patient history, are often quite accurate inpredicting histologic diagnosis. Biopsy of hepatic lesions shouldnot be performed indiscriminately, because there is a small risk ofcomplications or tumor tracking and because biopsy results oftendo not change management. As a rule, biopsies should be per-formed when definitive surgical intervention is not planned andwhen pathologic confirmation is necessary for institution of non-surgical therapy.

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AcknowledgmentFigures 4, 6, and 8 Tom Moore.

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