Tumors of the Liver and Biliary Tract

Home , Biliary tract, Cystadenoma, Hepatocellular adenoma, Liver tumor

gastrointestinal tract and abdomen TUMORS OF THE LIVER AND BILIARY TRACT

Gabriela M. Vargas, MD, Purvi Parikh, MD, FACS, and Kimberly M. Brown, MD, FACS*

Liver Tumors portion of the liver that is separate from the right and left hemilivers, is also referred to as segment 1. The left lateral anatomic considerations section comprises segments 2 and 3; the left medial section A necessary prerequisite to the discussion of liver tumors comprises segment 4 (which is sometimes further divided and their treatment is a clear understanding of internal liver into segments 4a and 4b); the right anterior section com- anatomy and a common point of reference for the terminol- prises segments 5 and 8; and the right posterior section ogy used in describing liver resections. In 2000, the Ameri- comprises segments 6 and 7. cas Hepato-Pancreato-Biliary Association (AHPBA) and the Following this terminology, one describes a hepatic re- International Hepato-Pancreato-Biliary Association (IHPBA) section or ablation by the anatomic portions of the liver presented the work of the AHPBA/IHPBA Ter minology involved [see Table 1]. Resection or ablation of a lesion that Committee at the annual meeting in Brisbane, Australia. The involves less than a segment would reference the segment results of this work to stand ardize terminology for descrip- in which the lesion is located. Resection of an anatomic tions of hepatic anatomy and resections have been widely segment would be described as a segmentectomy of the ap- accepted as standard nomenclature.1 p ropriate segment. Resection of segments 2 and 3, 4a and 4b, The basis for the Brisbane terminology is that the internal 5 and 8, or 6 and 7 would be termed a sectionectomy. Re- vascular and biliary anatomy determines the anatomic divi- section of segments 2 to 4 is a “left hepatectomy” or “left sions rather than surface markings [see Figure 1]. The he patic hemihepatectomy,” whereas resection of segments 5 to 8 artery and bile duct follow a similar pattern of branching, is a “right hepatectomy” or “right hemihepatectomy.” If the whereas the portal vein branching on the left side has a caudate lobe is resected with the hemihepatectomy, that variation due to the fetal umbilical vein traveling from the should be noted. Resections involving more than the ana- umbilical cord to the left portal vein. The postnatal remnant tomic hemiliver are referred to as “extended right hemi- of this structure (round ligament) carries blood away from hepatectomy” or “extended left hemihepatectomy,” with the liver. specifi cation of which additional segments were removed. The fi rst-order division of the proper hepatic artery and The terms right trisectionectomy and left trisectionectomy are the common hepatic duct into the right and left hepatic also appropriate. arteries and right and left hepatic ducts, respectively, results in division of the liver into two parts, referred to as the right primary liver cancers and left hemilivers (or the right and left livers) [see Figure 1 Hepatocellular Carcinoma and Table 1]. In this system of terminology, the term lobe is never used to denote a hemiliver, because it bears no rela- Hepatocellular carcinoma (HCC), also termed hepatoma, tion to the internal vascular anatomy. The plane between is the most common primary liver cancer worldwide. It is these two zones of vascular supply is called a watershed. seen more frequently in men than in women. HCC develops The border watershed of the fi rst-order division is a plane in the background of chronic liver disease, which has pro- that intersects the gallbladder fossa and the fossa for the gressed from acute liver injury to fi brosis to cirrhosis and, 2 inferior vena cava and is called the midplane of the liver. ultimately, carcinoma. In sub-Saharan Africa and Southeast The second-order division divides each of the hemilivers Asia, where HCC is more prevalent than in the Western into two parts, referred to as sections. The right hemiliver Hemisphere and Europe, hepatitis B virus (HBV) infection is comprises the right anterior section and the right posterior responsible for most cases. In the United States, HCC age- section. These sections are supplied by a right anterior adjusted incidence rates have doubled in the last decades.3 sectional artery and a right posterior sectional artery and are The rise in incidence has been linked to a concomitant rise drained by a right anterior sectional hepatic duct and a right in hepatitis C virus infection.4 Other important risk factors posterior sectional hepatic duct. The left hemiliver compris- in the development of cirrhosis and subsequently HCC es the left medial section and the left lateral section. These include alcoholism, afl atoxin B1 exposure, a1-antitrypsin sections are supplied by a left medial sectional hepatic artery defi ciency, obesity, hemochromatosis, primary biliary and a left lateral sectional hepatic artery and are drained cirrhosis, and nonalcoholic steatohepatitis (NASH). by a left medial sectional hepatic duct and a left lateral sectional hepatic duct. Clinical presentation HCC typically presents with non- The third-order division divides the liver into nine seg- specifi c symptoms such as abdominal pain, weight loss, ments, each of which has its own segmental artery and bile anorexia, jaundice, and malaise. Physical examination fi nd- duct [see Figure 1 and Table 1]. The caudate lobe, a unique ings may include hepatomegaly and ascites. In a patient with known liver disease, HCC often presents as an acute * The authors and editors gratefully acknowledge the contribu- deterioration of previously stable liver function, including tions of the previous authors, Steven M. Strasberg, MD, FACS, the appearance of ascites, encephalopathy, or jaundice. FRCSC, FRCS(Ed), and David C. Linehan, MD, FACS, to the Screening high-risk individuals for HCC can reduce development and writing of this chapter. mortality from HCC.5 Serum a-fetoprotein (AFP) testing and

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Right Hemiliver (Right Liver) Left Hemiliver (Left Liver)

Inferior Vena Cava Middle Hepatic Vein

Right Hepatic Vein Left Hepatic Vein

1 7

Falciform Ligament 5 Portal Vein 6 Common Hepatic Artery Common Bile Duct

Right Posterior Right Anterior Left Medial Left Lateral Section Section Section Section

Figure 1 Anatomic divisions of the liver according to the International Hepato-Pancreato-Biliary Association and the Americas Hepato- Pancreato-Biliary Association (IHPBA/AHPBA)-sanctioned terminology, including ﬁ rst-order divisions (hemilivers), second-order divisions (sections), and third-order divisions (segments). Each segment has a numeric designation. Segments 2, 3 and 4 comprise the left hemiliver, segments 5–8 comprise the right hemiliver, and segment 1 is also referred to as the caudate lobe. ultrasonography (US) are the two most widely employed 20 mm may be diagnosed by imaging with a speciﬁ city of screening strategies. Screening should be performed in a greater than 99%.6 To properly diagnose HCC radiographi- setting with standardized processes for follow-up of results cally and distinguish HCC from other tumors, such as chol- and quality control procedures, particularly given the angiocarcinoma, a four-phase study (CT or MRI) is required: operator dependence of US. Current guidelines recommend unenhanced, arterial, venous, and delayed phases. On US, US and AFP testing every 6 to 12 months for patients with most nodules will appear hypoechoic, but lesions may also cirrhosis of viral or nonviral etiology and HBV carriers with- appear as isoechoic, as hyperechoic, or of mixed echogenici- out cirrhosis. In addition, patients with HBV or hepatitis C ty. Contrast-enhanced US has fallen out of favor as a diag- virus (HCV)-associated cirrhosis should be referred to a nostic tool.7 Currently, positron emission tomography (PET) hepatologist for treatment of the viral hepatitis as treatment has no role in the diagnosis of HCC.8 Patients with lesions can improve HCC outcomes in these patients. exhibiting characteristic features for HCC, or with an elevated AFP, do not require a biopsy. An algorithm for the Diagnostic studies HCCs are hypervascular lesions management of suspicious liver nodules is summarized in whose blood supply is primarily from the hepatic artery; Figure 3 [see Figure 3]. therefore, on multidetector computed tomographic (CT) imaging, the lesion typically appears hyperintense during Staging Preoperative staging for HCC requires assess- the arterial phase and hypodense (referred to as “washout”) ment of tumor extent and the degree of underlying liver during the delayed phases [see Figure 2].6 Magnetic reso- dysfunction. A high-quality multiphase cross-sectional nance imaging (MRI) is more sensitive than CT for the imaging study of the abdomen is performed to assess the detection of HCC. On T2-weighted MRIs, the lesion usually size, location, and number of liver tumors, as well as any appears hyperintense; whereas its appearance is variable evidence of extrahepatic disease. CT of the chest is indicated on T1-weighted images. Up to 60 to 70% of HCCs of 10 to to exclude lung metastases. Bone scans are reserved for

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Table 1 Brisbane 2000 Terminology for Hepatic Anatomy and Resections from the IHPBA Level of Preferred Anatomic Corresponding Division Term Couinaud Segments Preferred Term for Surgical Resection* Comments First order Right hemiliver 5–8 (± caudate lobe) Right hepatectomy The border or watershed (hemiliver) or or separating the two Right liver Right hemihepatectomy (stipulate ± hemilivers is a plane that caudate lobe) intersects the gallbladder fossa and the IVC fossa; Left hemiliver 2–4 (± caudate lobe) Left hepatectomy this plane is referred to as or or the midplane of the liver Left liver Left hemihepatectomy (stipulate ± caudate lobe) Second order Right anterior section 5, 8 Right anterior sectionectomy The borders or watersheds (section) separating the sections Right posterior section 6, 7 Right posterior sectionectomy within the hemilivers are Left medial section 4 Left medial sectionectomy planes referred to as the right intersectional plane Left lateral section 2, 3 Left lateral sectionectomy (for which there is no — 4–8 (± caudate lobe) Right trisectionectomy (preferred) surface marking) and the or left intersectional plane Extended right hepatectomy (which passes through the or umbilical fissure and the Extended right hemihepatectomy attachment of the (stipulate ± caudate lobe) falciform ligament) — 2, 3, 4, 5, 8 Left trisectionectomy (preferred) (± caudate lobe) or Extended left hepatectomy or Extended left hemihepatectomy (stipulate ± caudate lobe) Third order Segments 1–8 Any segment Segmentectomy (stipulate segment— The borders or watersheds (segment) e.g., segmentectomy 7) of the segments are planes referred to as the Two contiguous Any two segments in Bisegmentectomy (stipulate intersegmental planes segments continuity segment—e.g., bisegmentectomy 7, 8)

IHPBA = International Hepato-Pancreato-Biliary Association; IVC = inferior vena cava. *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 segments 2 to 4 (or 1 to 4).

Figure 2 Computed tomographic imaging with intravenous contrast showing characteristic features for hepatocellular carcinoma: (a) hyperintense appearance on arterial imaging and (b) hypointense “washout” appearance in the venous phase.

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Liver nodule

< 1 cm > 1 cm

4-phase MDCT/dynamic Repeat US at 3 months contrast-enhanced MRI

Arterial hypervascularity AND venous or delayed phase washout Growing/changing Stable character

Other contrast- Yes enhanced study (CT No or MRI)

Investigate according to Arterial hypervascularity HCC Biopsy size AND venous or delayed phase washout

Yes No

Figure 3 Algorithm summarizing the evaluation of a liver nodule in a patient with risk factors for hepatocellular carcinoma. Adapted with permission from Bruix J et al.6 CT = computed tomography; HCC = hepatocellular carcinoma; MDCT = multidetector computed tomography; MRI = magnetic resonance imaging; US = ultrasonography.

symptomatic patients. The Child-Pugh classifi cation and Table 2 American Joint Committee on Cancer the Model for End-Stage Liver Disease (MELD) scores are commonly used to report the severity of liver disease in TNM Clinical Classifi cation of Adult Primary cirrhotic patients. Surgical resection is typically performed Liver Cancer only in Child class A patients with no or minimal portal Primary tumor (T) TX Primary tumor cannot be assessed hypertension. T0 No evidence of primary tumor Staging systems for HCC include the American Joint T1 Solitary tumor without vascular Committee on Cancer (AJCC) Tumor-Node-Metastasis invasion (TNM) staging system [see Table 2 and Table 3], the Barcelona T2 Solitary tumor with vascular invasion; Clinic Liver Staging System (BCLC), the Okuda system, multiple tumors, none > 5 cm in greatest and the Cancer of the Liver Italian Program (CLIP) system. dimension T3 Multiple tumors > 5 cm in greatest The AJCC system is based on pathologic features of resected dimension or tumor involving major tumors and is therefore applicable only to a small subset branch of portal or hepatic vein of HCC patients. The BCLC is the staging system most T4 Tumor or tumors with direct invasion of commonly used in clinical practice to guide management. adjacent organs (other than gallbladder The BCLC has been used in several major clinical trials or visceral peritoneum and therefore is able to provide meaningful comparisons Regional lymph NX Regional lymph nodes cannot be between the outcomes reported in the study populations nodes (N) assessed and individual patients. In addition, no other classifi cation N0 No regional lymph node metastasis system has successfully linked staging stratifi cation with N1 Regional lymph node metastasis treatment options and estimates of life expectancy.7 Distant metastasis MX Distant metastasis cannot be assessed Management Patients with HCC are best managed with (M) M0 No distant metastasis a multidisciplinary approach. Treatment options for patients M1 Distant metastasis

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Table 3 American Joint Committee on Cancer have 5-year survival ranging from 50 to 75% with treatment. Patients with intermediate-stage disease have 3-year sur- Staging System for Adult Primary Liver Cancer vival of up to 50% without treatment. Advanced disease Stage T N M carries the worst prognosis, with only 50% of patients 7 IT1N0M0 surviving 1 year. II T2 N0 M0 Intrahepatic Cholangiocarcinoma IIIA T3 N0 M0 Intrahepatic cholangiocarcinoma (ICC) refers to the group IIIB T4 N0 M0 of tumors originating in the epithelium of the peripheral IIIC Any T N1 M0 biliary tree. Anatomically, these tumors are defi ned as arising from the secondary bile ducts or more peripherally IV Any T Any N M1 and do not involve the hepatic duct confl uence. Cholangio- carcinomas are divided into three macroscopic histologic subtypes that may also be seen in combination: mass form- with early-stage disease, which is defi ned by the Milan cri- ing, periductal infi ltrating, and intraductal growing [see teria (one nodule < 5 cm, or two or three nodules all < 3 cm, Figure 5]. Worldwide, ICC represents approximately 10 to no gross vascular invasion or extrahepatic spread) include 20% of all primary liver malignancies.14 Men are more com- resection, ablation, and transplantation. For patients without monly affected, and Asians are twice as likely as whites and cirrhosis and limited disease, resection is the preferred blacks to be affected.15 Risk factors for the development of treatment, although ablation may be an equally effective, ICC have not been well established, although there appears less invasive option.9 In patients with Child class A cirrhosis to be an association between chronic infl ammation, such as without evidence of portal hypertension and adequate liver chronic calculi, choledochal cysts, liver fl uke infections, and function, either liver resection or transplantation may be hepatitis B or C infection, and the development of ICC. In pursued. Due to HCCs’ growth along the portal veins, ana- addition, alcohol abuse, diabetes, and obesity have also been tomic resections are associated with lower recurrence rates implicated.13,16 and are preferred over nonanatomic resections when possible. Resection margins of at least 2 cm should be achieved Clinical presentation Early in their course, ICCs are when a nonanatomic resection is performed. The extent of often asymptomatic. Similar to HCCs, they are likely to resection is dependent on the location of the tumor and the present with nonspecifi c symptoms such as abdominal disease burden. In most patients without cirrhosis, 60 to 75% discomfort, fever, or weight loss. Jaundice as an initial of the liver may be excised without compromise to hepatic presentation is rare. function. When the function of the hepatic remnant is in question, portal vein embolization of the side to be resected Diagnostic studies Unlike HCC, there are no character- may be done preoperatively to induce hypertrophy of the istic radiographic fi ndings associated with ICC. ICC may future remnant. Inadequate size of the future remnant is a appear as an irregular or well-defi ned soft tissue mass along contraindication to resection. the intrahepatic ducts. US, contrast-enhanced CT, and MRI When surgical resection is not possible and the tumor are useful to establish the presence of a mass and to deter- burden meets the Milan criteria, transplantation is the mine resectability by establishing the relationship of the treatment of choice. The MELD scoring system currently mass to the nearby vessels and biliary tree. CT and MRI gives exception points to patients with HCC to decrease the are comparable in diagnostic accuracy.17 Enhancement on waiting time to transplantation. Radiofrequency ablation delayed-phase imaging is suggestive of cholangiocarcinoma. (RFA), transarterial chemoembolization (TACE) with cispla- PET has not been shown to be useful in diagnosing ICC but tin or doxorubicin drug-eluting beads, and embolization may be benefi cial in the detection of regional and distant with yttrium-90 radiolabeled beads are available treatment metastases or identifying an occult primary tumor.18,19 The options for transplantation-bridging therapy, unresectable initial workup of a patient suspected of ICC should include disease, or tumor burden in excess of the Milan criteria.10 laboratory studies: liver function tests, AFP (expected to be Sorafenib, a tyrosine kinase inhibitor, is the fi rst-line normal), carcinoembryonic antigen (CEA), cancer antigen treatment for patients with HCC who are not candidates (CA) 125, and CA 19-9. Since these tumor markers are not for other treatment modalities.7 Additionally, phase I trials specifi c serum markers for cholangiocarcinoma, extrahe patic studying the feasibility of stereotactic body radiotherapy malignancies must be excluded by cross-sectional imaging (SBRT) for primary HCC have demonstrated positive results of the chest, abdomen, and pelvis; endoscopy; and mam- for local control and improved survival.11,12 Currently, mography before a defi nite diagnosis of ICC can be SBRT is used for Child-Pugh class A patients with one to established. three tumors with a cumulative diameter of less than 6 cm without evidence of extrahepatic disease.13 An algorithm Staging ICC is staged using the AJCC TNM cancer stag- summarizing the management of HCC is shown in Figure 4 ing system. The seventh edition of the staging manual was [see Figure 4]. updated to provide a staging system for ICC independent of HCC and extrahepatic cholangiocarcinoma [see Table 4].20 Prognosis The prognosis depends on the degree of The tumor category is based on three major prognostic tumor involvement and extent of liver function impairment. factors: tumor number, vascular invasion, and direct extra- Patients with early disease and preserved liver function hepatic tumoral extension. The node category is based on

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HCC identified

Not liver Resection Liver transplant transplant candidate candidate candidate

1 lesion ≤ 5 cm 3 lesions ≤ 3 cm Yes No metastases Sorafenib RFA TACE/Yttrium90 Palliative care No vascular invasion

No cirrhosis Living donor Child class A UNOS list No metastases liver transplant donor

Orthotopic liver Neoadjuvant transplant therapy Figure 4 Algorithm for the management of hepatocellular carcinoma.82 HCC = hepatocellular carcinoma; RFA = radiofrequency ablation; TACE = transarterial chemoembolization; UNOS = United Network for Organ Sharing.

the presence or absence of regional lymph node metastases. cases. Despite the known prognostic inﬂ uence of lymph The metastasis category is based on the presence or absence node involvement, routine lymphadenectomy is not associ- of distant disease.13,21 ated with improved survival, which may explain why it has not been universally adopted. Management The management of ICC is best app- The role of adjuvant therapy in ICC is unclear. 5- roached with a multidisciplinary team. Prior to surgical Fluorouracil (5-FU) has largely been replaced by gemcitabine- intervention, distant metastatic disease must be ruled out containing regimens, based on data from pancreatic cancer and the adequacy of the future liver remnant must be estab- and unresectable biliary tract cancers. However, a retro- lished. Metastatic disease to the celiac or retroperitoneal spective review of patients undergoing chemotherapy in an lymph nodes is considered a contraindication to resection. adjuvant or neoadjuvant setting failed to show a difference Partial hepatectomy with negative margins is the only in survival with either approach. potentially curative option and is associated with improved Orthotopic liver transplantation (OLT) for ICC is limited survival compared with patients who do not undergo resec- by unacceptably high recurrence rates.17 However, some tion or who have residual disease. The extent of liver resec- institutions have reported acceptable survival rates with tion is determined by tumor size and location, with 80% of protocols using pretransplantation chemoradiation.22 Stud- patients requiring hemi- or extended hemihepatectomies ies comparing OLT and resection report similar survival,23 for complete tumor removal. Some groups, due to the poor but given the shortage of donor organs, ICC is considered a prognosis conferred by lymph node involvement, recom- contraindication for OLT. mend a lymphadenectomy. Left-sided tumors tend to spread toward the gastrohepatic ligament and along the lesser Prognosis Long-term survival is poor. A population- curve of the stomach, whereas right-sided tumors drain to based analysis of patients with ICC undergoing curative the hepatoduodenal ligament. However, left-sided tumors intent surgery between 1973 and 2010 found a median may also follow a “right-sided” drainage pattern in 50% of overall survival of 27.3 months. One-, 3-, and 5-year overall

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Tumor

Mass Forming

Periductal Infiltrating

Tumor

Intraductal Growth d

Mass Forming and Periductal Infiltrating

Figure 5 Macroscopic subtypes of intrahepatic cholangiocarcinoma. survival was 77.5%, 44.3%, and 30.7%, respectively.24 Factors liver being the isolated site of metastases in half of these associated with worse outcomes include increasing number patients.26,27 of lesions, N1 disease, large tumor size, and vascular invasion.25 Clinical presentation Most patients with colorectal liver metastases (CRLMs) are asymptomatic. Synchronous secondary cancers tumors are identiﬁ ed through preoperative staging or intra- operative examination of the liver. Fluorodeoxyglucose-PET Colorectal Metastases imaging is indicated in patients with potentially resectable In 2012, it was estimated that 143,000 Americans would metastatic disease seen on a contrast-enhanced CT scan. be diagnosed with colorectal cancer. Over 50% of those Metachronous tumors are identiﬁ ed through posttreatment patients will go on to develop metastatic disease, with the surveillance, either by cross-sectional imaging or routine

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Table 4 AJCC Seventh Edition TNM Staging selected patients and experienced teams, synchronous resection of the primary tumor and liver metastases can be System for Intrahepatic Cholangiocarcinoma performed. T: Primary tumors (T) The introduction of oxaliplatin, irinotecan, and mono- TX Primary tumor cannot be assessed clonal antibodies such as bevacizumab has allowed down- T1 Solitary tumor, no vascular invasion T2 sizing and subsequent resection of hepatic metastases T2a Solitary tumor, vascular invasion previously considered unresectable. After treatment with T2b Multiple tumors, possible vascular invasion chemotherapy, patients should be restaged and resectability T3 Tumor perforates the serosa (visceral peritoneum) or reassessed. If complete radiologic response is seen on CT directly invades local extrahepatic structures or PET scans, surgical resection should still be undertaken T4 Tumor plus periductal invasion as a complete pathologic response is infrequent. The N: Regional lymph nodes (N) response to chemotherapy is considered a marker for the NX Regional lymph nodes cannot be assessed biologic behavior of the tumor, and resection of disease that N0 No regional lymph node metastasis N1 Regional lymph node metastasis progresses on modern chemotherapy should be undertaken with caution. M: Distant metastasis (M) In patients with extensive bilobar disease who are appro- MX Distant metastasis cannot be assessed M0 No distant metastasis priate surgical candidates, a two-stage approach can be an M1 Distant metastasis effective strategy to achieve complete resection. The use of thermal ablation with radiofrequency or microwave energy Staging Stage 0 Tis N0 M0 as an adjunct to resection has also expanded the number of Stage I T1 N0 M0 patients eligible for curative intent surgery. Ablation should Stage II T2 N0 M0 be reserved for small (≤ 3 cm and ideally ≤ 1 cm) lesions that Stage III T3 N0 M0 are not near major vessels or bile ducts. Patients who have Stage IVA T4 N0 M0, Any T N1 M0 Stage IVB Any T Any N M1 unresectable disease or who are poor surgical candidates may be treated with ablation or chemoembolization, with or without systemic therapy. Ablation in this setting may be performed by open, laparoscopic, or percutaneous methods. CEA levels. Symptomatic advanced disease may present Reevaluation for resection should be performed after 2 with abdominal pain, distention, weight loss, or hepatic months of systemic chemotherapy and every 2 months insuffi ciency. thereafter.28–31 Recurrences following hepatectomy may be managed by repeat liver resection, local ablative or chemo- Diagnostic studies CLRMs can be identifi ed by US, CT, embolization techniques, systemic chemotherapy, or a 32 PET/CT, or MRI. US has been largely replaced by cross- multimodality approach. sectional imaging studies as the latter are more sensitive for the detection of CRLMs and not user dependent. On Prognosis Patients with untreated CRLMs have a me- 32 CT, CLRMs are visualized more prominently in the portal dian survival of less than 1 year. In contrast, patients with venous phase as hypodense lesions. For small, subcenti- treated CRLMs can experience 5-year overall survival of 33–36 meter indeterminate lesions, MRI may be helpful in further up to 50 to 60%. Recurrence after resection remains a characterization. PET/CT is not recommended for routine common problem, with more than 70% of patients developing a second hepatic recurrence.37 Five-year overall survival surveillance in patients who have undergone resection of following a second hepatectomy ranges from 31 to 73%.32 a colorectal cancer. Patients with T3 or T4 tumors and/or node-positive disease are followed with yearly CT scans of Neuroendocrine Metastases the chest/abdomen/pelvis for 5 years. PET/CT is obtained Neoplasms originating from neural or endocrine struc- when there is a high clinical suspicion for metastatic disease tures form the family of tumors known as neuroendocrine but equivocal cross-sectional imaging or to evaluate for tumors (NETs). NETs may arise from nerve plexuses, extra- extrahepatic disease in a patient with potentially resectable adrenal paraganglia, thyroid, parathyroid, adrenal glands, liver metastases. and specialized elements of the endocrine system (islet cell tumors, carcinoids, large cell and small cell carcinomas).38 Management Surgical resection offers the only potential The presence of liver metastases is dependent on the pri- for cure in patients with isolated CRLM. The principles of mary tumor site, T stage, tumor differentiation, and tumor determining resectability include the following: (1) complete grade. NETs of the intestine and pancreas are frequently anatomic resection must be possible while maintaining metastatic at the time of diagnosis.39 adequate hepatic function, (2) the primary tumor must be amenable to R0 resection, and (3) there should be no unre- Clinical presentation The clinical presentation of meta- sectable extrahepatic disease. The considerations regarding static NET is dependent on the functionality of the primary the extent of resection and the use of portal vein emboliza- tumor. Functional tumors secrete hormones and/or tion are similar to those for HCC. In contrast to HCC, non- monoamines from the tumor cells. Carcinoid tumors secrete anatomic resections are as effective as anatomic resections serotonin, which produces a constellation of symptoms as long as negative margins are obtained. One-centimeter known as carcinoid syndrome. Patients with carcinoid margins should be the goal when feasible. In appropriately syndrome may present with fl ushing, diarrhea, wheezing,

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01/14 gastro tumors of the liver and biliary tract — 9 abdominal cramping, and heart palpitations. Gastrinomas Table 5 Neuroendocrine Tumors and Their may present with peptic ulcers secondary to excessive gas- 83 trin secretion (Zollinger-Ellison syndrome). Insulinomas Corresponding Biochemical Markers typically present with hypoglycemia. Glucagonomas may Tumor Markers present with rash, hyperglycemia, and diarrhea. VIPomas Carcinoid 5-HIAA (24 hr urine) and produce excess vasoactive intestinal peptide (VIP), which chromogranin A presents with severe watery diarrhea, hypokalemia, and PanNET Chromogranin A achlorhydria. Patients with nonfunctional tumors typically present with nonspecifi c symptoms, and often the diagnosis Gastrinoma Gastrin of stage IV disease is an incidental fi nding. Insulinoma Proinsulin, insulin/glucose ratio, and C-peptide Diagnostic studies Patients presenting with metastatic VIPoma VIP NETs require pathologic examination of the metastases, Glucagonoma Glucagon, blood glucose, and CBC assessment of disease burden by multiphasic CT or MRI, Pheochromocytoma/ Metanephrines (plasma and urine), biochemical analysis to assess for functionality, and serum paraganglioma catecholamines (urine), and tumor markers to rule out hereditary syndromes when sus- dopamine (urine) pected. The minimal biochemical workup should include Pituitary Growth hormone/IGF-1, prolactin, circulating chromogranin A and specifi c tumor markers in LH/FSH, TSH, alpha subunits, and suspected clinical syndromes [see Table 5].39 Somatostatin ACTH receptor imaging and harmonic imaging (abdominal US Ectopic hormones ACTH, GRH, and GHRH with contrast agents) coupled with Doppler imaging are helpful diagnostic studies if available. Other pancreas Somatostatin, pancreatic polypeptide, calcitonin, PTH-related peptide

Management The treatment approach to the patient ACTH = adrenocorticotropic hormone; CBC = complete blood count; FSH = follicle- with neuroendocrine metastases is illustrated in Figure 6 [see stimulating hormone; GHRH = growth hormone–releasing hormone; GRH = gonadotropin-releasing hormone; 5-HIAA = 5-hydroxyindoleacetic acid; IGF-1 = Figure 6]. Surgical resection with curative intent remains insulinlike growth factor–1; LH = luteinizing hormone; panNET = pancreatic the gold standard in the treatment of liver metastases. The neuroendocrine tumor; PTH = parathyroid hormone; TSH = thyroid-stimulating following minimal requirements must be met for curative hormone; VIP = vasoactive intestinal peptide. intent surgery: (1) resectable liver disease, (2) absence of right heart insufﬁ ciency in patients at risk for development of carcinoid heart disease, (3) absence of unresectable lymph node or extra-abdominal metastases, and (4) absence of treatment option in highly selected patients presenting with diffuse or unresectable peritoneal carcinomatosis.39 The ben- life-threatening hormonal disturbances related to a function- eﬁ t of debulking resections requires further analysis and al NET or in patients with diffuse unresectable liver metas- is currently not recommended. Liver transplantation is a tases refractory to standard medical or surgical therapies.

Confirmation of Diffuse neuroendocrine neoplasm. Bilobar disease Resection of primary tumor disease and no evidence of extrahepatic disease

Unilobar Surgical Nonsurgical Select disease candidate candidate cases

Somatos- Liver Surgical Nonsurgical One-step Two-step TACE or Chemo- Molecular tatin transplan- candidate candidate operation operation TAE therapy targeted analogues therapy tation

Ablation or Resection TACE

Figure 6 Treatment approach to neuroendocrine neoplasm liver metastases.39 TACE = transarterial chemoembolization; TAE = transcatheter arterial embolization.

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Locoregional techniques, including thermal ablation with lesions are increasingly identifi ed. Solid lesions may arise radiofrequency or microwave energy, or selective hepatic from epithelial elements, such as hepatic adenoma or focal transcatheter arterial embolization (TAE) or chemoemboli- nodular hyperplasia (FNH), or mesenchymal elements, of zation (TACE), may be used in conjunction with surgical which hemangioma is the most common. Cystic lesions resection or medical therapy. The response to locoregional identifi ed within the liver include benign simple hepatic therapies is largely dependent on tumor size. RFA is not cysts, bile duct cysts, and biliary cystadenoma or cystadeno- recommended for lesions greater than 5 cm in size. Laser- carcinoma. The precise identifi cation of these lesions is often induced thermotherapy is more precise than RFA and is possible with high-quality imaging, and biopsy is rarely suitable for larger tumors (up to 7 cm). TAE and TACE are indicated. Treatment options depend on the potential for typically reserved for patients whose tumors are not amena- complications, including malignant transformation or ble to surgical therapy. Contraindications to TAE and TACE hemorrhage, and the presence of symptoms. include portal vein thrombosis, poor liver function, the presence of a hepatopulmonary shunt, or severe comorbidities. Hemangioma In addition, TAE and TACE should be used with caution in Hepatic hemangioma is the most common liver tumor, potential liver transplantation candidates as arterial throm- with an incidence of 3 to 20%, equal distribution between bosis is likely to complicate arterial reconstruction during left and right hepatic lobes, and an approximately 5:1 transplantation. male-to-female ratio.44 The term giant hemangioma describes Control of hormonal hypersecretion symptoms and pro- phylaxis against carcinoid crisis should be performed prior lesions greater than 4 or 10 cm, depending on the source. to surgical resection or locoregional therapies. The gold Giant hemangiomas may have a more aggressive pattern of standard for long-term medical therapy is treatment with growth than smaller lesions, which tend to remain stable somatostatin analogues. These compounds have a low side- over time. effect profi le and are very effective at controlling symptoms These tumors are congenital vascular malformations, and retarding tumor growth.38 Everolimus is an inhibitor of with cavernous vascular spaces, a fl at endothelial lining, and mammalian target of rapamycin (mTOR) and may be effec- fi brous septations. They are usually asymptomatic, inciden- tive when given in conjuction with somatostatin analogues tal fi ndings, but pain and local compressive symptoms to prolong survival in advanced carcinoid tumors or as may result from the size and particular location of a tumor. 40 single-agent treatment in pancreatic NETs. Everolimus Other rare presentations include hemorrhage, infl ammatory and sunitinib, a tyrosine kinase inhibitor, are associated with changes, and coagulopathy. In the absence of these rare prolonged disease-free survival in metastatic pancreatic acute complications, liver function and coagulation labora- NET.41 tory profi les are normal. Imaging offers a reliable diagnosis in many cases. US Controversies Patient selection and timing of liver trans- reveals a hyperechoic, well-demarcated mass, with an plantation are subjects of controversy. Most of the available published data on liver transplantation for NET are single- absence of vascularity on color Doppler imaging. CT criteria institution retrospective studies with small sample sizes. diagnostic for hemangioma include a hypodense lesion The benefi t of liver transplantation in this setting has not in the precontrast phase; nodular, peripheral enhancement been well established.42 Radiolabeled somatostatin ana- followed by central enhancement in the arterial phase; and logues have also been used to treat advanced carcinoid persistent contrast enhancement on delayed series. On MRI, tumors, with encouraging results in nonrandomized hemangioma classically appears as a hypointense lesion 43 studies. on T1-weighted imaging and a hyperintense lesion on

T2-weighted sequences, and following contrast administra- Prognosis The prognosis for metastatic NET is better tion, the enhancement pattern is similar to that on CT: early than that for metastatic adenocarcinoma. Histologic differ- peripheral irregular enhancement pattern followed by entiation and tumor grade are the strongest predictors of progressive central ﬁ lling and homogeneous enhancement survival. Five-year survival of 60 to 80% has been achieved on delayed imaging [see Figure 7]. Atypical enhancement with complete surgical resection. In contrast, the 5-year patterns, including rapid and slow ﬁ lling, are not uncom- survival rate in unresectable disease is approximately mon and present a dilemma in a patient known to have or 30%.39 suspected of having a malignancy. noncolorectal, nonneuroendocrine metastases Treatment of asymptomatic hemangioma, irrespective of Liver metastases from other primary sites in the absence size, is observation, with no need for surveillance imaging. of extrahepatic disease can be managed according to the Indications for operation include severe pain, compressive same approach employed for CRLMs, although the outcome symptoms, hemorrhage, or uncertain diagnosis with a sus- is less satisfactory. Tumors that have been treated in this picion of malignancy. Surgical resection by means of a formal way with acceptable results include breast cancers, renal cell anatomic resection or an enucleation is the treatment of cancers, gastric cancers, acinar cell cancers of the pancreas, choice. Traditional open and laparoscopic approaches can and ovarian cancers. be employed, based on the lesion anatomy and surgical team experience.45 Arterial embolization, hepatic arterial benign or premalignant hepatic lesions ligation, and radiation have been described but are ineffec- With the extensive use of US and cross-sectional imaging, tive. Liver transplantation has been described for patients benign asymptomatic or questionably symptomatic liver with complications from unresectable giant hemangiomas.46

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Figure 7 Magnetic resonance images of a giant hemangioma showing typical appearance (a) on a T1-weighted image, (b) on a T2-weighted image, (c) in the early postcontrast phase, and (d) on delayed imaging.

Focal Nodular Hyperplasia nodules with fi brous septations. This architecture is thought FNH is most commonly diagnosed in female patients to arise from a vascular malformation inducing a reactive in the third to fi fth decades of life. It is a completely benign hyperplasia. The fi brous septations appear grossly as a cen- process and the second most common benign liver tumor tral scar, identifi able on both pathologic and radiologic after hemangioma. Unlike hepatocellular adenoma, there is examination. FNH is usually a solitary lesion, but 20 to 30% no relationship between oral contraceptive use and the of patients will have more than one. growth of FNH and thus no reason to avoid the use of FNH typically appears as a hypoechoic lesion on US oral contraceptives in a patient with FHN. The histology of or may be isoechoic with a hyperechoic central scar. Large FNH is that of benign hepatocellular hyperplasia, forming ectatic peripheral feeding vessels may be identifi ed using

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a Adenoma Hepatocellular adenoma is a rare tumor, associated with oral contraceptive and androgen steroid use. The incidence is estimated at 0.1 per 100,000 in non–oral contraceptive users and three to four per 100,000 in long-term oral contraceptive users. The estrogen content and duration of exposure inﬂ uence the risk of hepatocellular adenoma. These lesions may present with pain, abdominal fullness, abnormal liver function tests, or complications such as bleeding. The risk of symptoms increases with increasing size, particularly greater than 5 cm, with as high as a 20 to 40% risk of spontaneous bleeding. Malignant transformation occurs in approximately 10% of cases.47 Most patients have a solitary lesion, but multiple lesions may be seen in up to 30% of patients. Adenomatosis is a b condition where 10 or more adenomas are present through- out the hepatic parenchyma. Histologically, adenomas consist of benign hepatocytes with an absence of normal liver architecture. Cellular atypia may make distinction from HCC difﬁ cult. On US, hepatocellular adenoma is a well-demarcated, hyperechoic mass with internal heterogeneity. Unenhanced CT images demonstrate a hypodense mass, which enhances heterogeneously in the arterial phase and washes out to an isodense or hypodense appearance in the portal venous phase. In addition to the absence of central scar, features distinguishing adenoma from FNH may include a smooth surface, tumor capsule, and internal hemorrhage in the adenoma.48 Unenhanced MRI reveals a hyperintense or iso-

intense lesion on T1-weighted images and a mildly hyperin-

tense lesion on T2-weighted images. Adenomas are usually hyperintense, with a heterogeneous pattern in the arterial Figure 8 Focal nodular hyperplasia as imaged by computed tomog- phase. raphy in the (a) arterial phase and (b) venous phase. The arrow points ≤ to a feeding vessel. Small adenomas ( 3 cm) may be observed, and oral contraceptive use stopped, with some reports of regression and resolution.49 Molecular profi ling may further guide decision color Doppler imaging. Contrast-enhanced CT [see Figure 8] making based on the prognosis.50 Complete surgical resec- reveals a hypodense lesion in the precontrast phase, rapid tion with negative margins is the standard of care for hepa- arterial enhancement, often with a less dense central scar, tocellular adenomas greater than 4 cm in diameter. There and an isodense or hyperdense lesion in the portal venous is no need for extended margins, and open or laparoscopic phase. FNH is a well-demarcated lesion, and feeding vessels approaches are acceptable depending on the tumor location may be seen on CT as well. FNH appears hypointense or and surgical team expertise. isointense, with a hypointense central scar on unenhanced In cases of ruptured adenoma, initial hemorrhage control T -weighted MRIs, and on T -weighted images, these lesions 1 2 is often possible with selective hepatic arterial embolization, are isointense or slightly hyperintense, with a strongly avoiding an emergent operation with attendant mortality hyperintense-appearing central scar. In postcontrast images, of 8%. After recovery from hemorrhage and resolution of there is arterial enhancement followed by an isointense peritumoral hematoma, the tumor can be more precisely appearance in the portal venous phase. Longer delay will show hyperintensity in the central scar. In lesions without a localized by imaging, and a less extensive, elective resection central scar, the diagnosis may be diffi cult. In cases of diag- can be performed. nostic uncertainty, a core-needle biopsy, either percutane- Patients with multiple adenomas have risks for bleeding ous or operative, will demonstrate histologic fi ndings con- and malignancy similar to those of patients with solitary sistent with FNH—hepatocytes in a trabecular pattern with adenomas of similar size. If anatomically feasible, patients fi brous septations. should undergo resection of all lesions greater than 4 cm, FNH should be managed nonoperatively. There is no either in a single or staged operation. When tumor volume malignant potential and no risk of rupture, bleeding, or or location precludes resection, patients should be closely other complications. In cases of diagnostic uncertainty or followed with examination, serial AFP levels, and surveil- a clear demonstration of symptoms, open or laparoscopic lance imaging to detect malignant transformation. Resection resection of the lesion with a surrounding margin of normal of a single malignant lesion is appropriate. Resection and hepatic parenchyma allows for controlled division of any liver transplantation have been described for patients with feeding vessels. multiple malignancies arising in adenomatosis, but the

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01/14 gastro tumors of the liver and biliary tract — 13 prognosis is extremely poor. Liver transplantation for hepa- with a biliary-enteric anastomosis. In patients with type IV tocellular adenomatosis in the absence of malignancy is an disease, the extent of intrahepatic involvement and degree extremely uncommon indication for liver transplantation.51 of cirrhosis and/or portal hypertension all infl uence treatment planning. Complete extrahepatic cyst excision with biliary-enteric anastomosis can be combined with hepatic Cystic Disease of the Liver and Biliary Tree lobectomy for unilateral intrahepatic disease. With bilobar Cystic lesions may be found within the liver or involving involvement, there is a risk of recurrent obstruction, hepato- the extrahepatic biliary tree. Nonparasitic cysts within the lithiasis, and stricture of the biliary-enteric anastomosis; liver are a common fi nding on cross-sectional or ultrasound some authors recommend fi xing the Roux limb to the imaging or may be discovered incidentally at laparotomy anterior abdominal wall to facilitate future percutaneous or laparoscopy. Although the majority of cysts are benign interventions. and asymptomatic, a thoughtful, organized approach will In type V disease, limited involvement may allow for ensure intervention only in those cases in which patients are resection as an initial and perhaps defi nitive treatment. likely to benefi t. Liver abscess (infectious cyst) and hydatid Liver transplantation is indicated in patients with un- cyst are not discussed here. successful treatment by resection and with diffuse type V disease that has progressed to cirrhosis and/or portal bile duct cysts hypertension. Bile duct cysts are most frequently identifi ed and treated in the young child; however, 20% of patients will present with symptomatic or asymptomatic bile duct cysts as adults. Nonparasitic Cystic Tumors of the Liver and Biliary Tree Cystic malformation can occur anywhere along the intrahe- simple hepatic cyst patic and extrahepatic biliary tree, which makes the term choledochal cyst a misnomer. The precise etiology is unknown, Simple hepatic cysts are the most common of the cystic but the most commonly accepted hypothesis is that an lesions in the liver, occurring in up to 18% of the popula- 52 anomalous pancreaticobiliary duct junction promotes refl ux tion. These congenital cysts do not communicate with the of pancreatic juice into the common bile duct. The resulting biliary tree, and the exact etiology is not known. Simple infl ammation causes ectasia and, eventually, dilation. cysts are lined by epithelium that secretes water and electro- Bile duct cysts are classifi ed based on anatomic location, lytes in concentrations similar to serum. Patients may have extent of involvement, and gross morphology [see Figure 9]. a single cyst or multiple cysts and are usually asymptomatic The majority of bile duct cysts are type I. In adults, bile duct at presentation. If present, symptoms may include pain, full- cysts may present as incidental fi ndings on cross-sectional ness, early satiety, or jaundice. Hemorrhage into a cyst can imaging or with symptoms including pain, jaundice, precipitate symptoms and can alter the radiologic appear- nausea/vomiting, cholangitis, or pancreatitis. Patients may ance of the cyst to that resembling a biliary cystadenoma. have undergone cholecystectomy, due to the overlap of US demonstrates a smooth, contoured anechoic lesion symptoms, or may have evidence of biliary cirrhosis from with a well-defi ned interface between tissue and fl uid. In the chronic obstruction at presentation. absence of hemorrhage, the lesion is homogeneous. Internal Bile duct cysts may be fi rst identifi ed on US or CT for septations or echoic debris in the cyst suggests hemorrhage. sym ptoms mimicking cholecystitis. However, for precise On CT images, simple cysts appear as homogeneous round anatomic information to guide treatment planning, cholan- or oval lesions with density similar to water. giography via percutaneous transhepatic cholangiography The differential diagnosis of an intrahepatic cystic lesion (PTC), endoscopic retrograde cholangiopancreatography includes an abscess, hydatid cysts, hematoma, hemangioma, (ERCP), and magnetic resonance cholangiopancreatogra- and necrotic tumor. Needle aspiration and serologic testing phy (MRCP) are the studies of choice. Initial treatment can be helpful in cases of diagnostic uncertainty. An asymp- should address acute issues such as biliary obstruction or tomatic simple hepatic cyst requires no treatment. Symp- cholangitis. toms are unlikely unless the cyst is large (> 8 to 10 cm) and The ultimate goal of treatment for extrahepatic bile duct stretching the liver capsule. A diagnostic aspiration can help cysts is complete excision of the abnormal duct, usually identify whether symptoms resolve with decompression of

Figure 9 Todani classiﬁ cation of bile duct cysts.

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01/14 gastro tumors of the liver and biliary tract — 14 the cyst and thus defi nitive treatment would be expected to Imaging is usually diagnostic for cystadenoma, although confer benefi t to the patient. Simple aspiration of fl uid has a a simple cyst with internal hemorrhage may have a similar 100% rate of cyst recurrence. appearance; serologic tests for hydatid disease can help in Aspiration combined with injection of a sclerosing agent cases where parasitic disease is in the differential. CA 19-9 such as ethanol or minocycline has been used to try to is suggestive of cystadenoma over a simple hepatic cyst reduce the recurrence rate. Patients experience pain and side when elevated. Cyst aspiration is not necessary but if per- effects from diffusion of alcohol, and recurrence is still com- formed yields mucin-containing fl uid, usually with elevated mon. The infl ammation induced by sclerotherapy changes CA 19-9 levels. Treatment for cystadenoma in the medically the composition of the cyst fl uid, making it viscous and fi t patient is complete excision with a rim of normal paren- opaque. chyma. In a patient with a large, exophytic, symptomatic simple Biliary cystadenocarcinoma is an extremely rare tumor hepatic cyst, cyst fenestration involves excising the free thought to arise from a cystadenoma [see Figure 10]. A pre- wall of a cyst that protrudes from the surface of the liver, operative diagnosis is best obtained through a US-guided establishing a wide area of connection between the cyst needle aspiration biopsy of a soft tissue component. Tumor and the peritoneal cavity. The cyst fl uid freely moves into projects into the cyst and extends into the liver. There is the peritoneum, where it is absorbed. This can be done via a potential for extrahepatic metastases.53 Treatment is a laparoscopic or an open approach. The cyst wall should complete surgical excision and is associated with a 3-year be sampled and sent to Pathology to exclude cystadenoma survival of 55%.54 at the time of fenestration. Follow-up in the absence of symptoms is not indicated. Biliary Tract Cancer biliary cystadenoma and cystadenocarcinoma With an annual incidence of 7,500 new cases of cancer Biliary cystadenoma is a rare cystic tumor within the liver, of the biliary system in the United States, approximately with the potential to degenerate into a malignant cystadeno- two thirds are bile duct cancers (cholangiocarcinoma); the carcinoma. Cystadenoma is usually a multiloculated, mucin- remainder are cancers of the gallbladder. Over the last containing lesion of unknown etiology. Patients may present 30 years, the worldwide ratio of the extrahepatic and intra- with pain, fullness, nausea, early satiety, or jaundice or may hepatic cholangiocarcinoma has increased from 1:2 to 1:1, be asymptomatic. There are usually no laboratory abnor- compromising 3% of all malignancies.55 Most patients are malities in the absence of jaundice. diagnosed in the fi fth through the seventh decade of life, Imaging fi ndings may overlap with those of a simple cyst. with a higher predominance in males. Typically, a cystadenoma appears as an irregular fl uid- The etiology of cholangiocarcinoma is unknown. Most containing lesion with internal septations and mural nod- cases are sporadic, but several conditions have an increased ules. On US, the cyst is anechoic, with irregular margins risk of developing cholangiocarcinoma. Risk factors include and internal echoes from septations and nodules. On CT, primary sclerosing cholangitis (PSC), an autoimmune dis- cystadenoma appears as a hypodense structure, and the ease characterized by infl ammation of the periductal tissues, internal features may be less well visualized, particularly ultimately resulting in multifocal strictures of the intrahe- on noncontrast images. MRI demonstrates a hypointense patic and extrahepatic bile ducts. Patients with PSC have a 56 lesion on T1-weighted images and a hyperintense lesion on lifetime risk of 8 to 20% of developing cholangiocarcinoma.

T2-weighted images, with heterogeneous internal features The development of cholangiocarcinoma in patients with [see Figure 10]. choledochal cysts or Caroli disease has a 3 to 28% lifetime risk.57 Hepatolithiasis, also known as recurrent pyogenic cholangiohepatitis or Oriental cholangiohepatitis, is prevalent in Asia and shows an increased risk of cholangiocarcinoma. Finally, several radionuclides and chemical carcinogens, including thorium, radon, nitrosamines, dioxin, and asbestos, may be associated with an increased risk of cholangiocarcinoma. ICC is described in detail under the “Primary Liver Cancers” section of this chapter. Macroscopically, extrahepatic bile duct cancer may be sclerosing, nodular, or papillary. Microscopically, cholangiocarcinoma is most commonly a tubular adenocarcinoma, but papillary adenocarcinoma, signet cell carcinoma, mucoepidermoid carcinoma, and other histologic variants of cholangiocarcinoma may be observed. The type of growth pattern and location of the bile duct cancer affect clinical presentation, treatment, and prognosis. extrahepatic cholangiocarcinoma

Figure 10 T2-weighted magnetic resonance image of biliary cystad- Extrahepatic cholangiocarcinomas may be further sub- enoma, demonstrating internal septations. divided into distal and hilar cholangiocarcinomas, with the

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01/14 gastro tumors of the liver and biliary tract — 15 former arising in the intrapancreatic or retroduodenal por- Bismuth-Corlette system for establishing the prognosis and tion of the bile duct and the latter arising above it, up to and planning further treatment [see Figure 11].56 including involvement of the bifurcation of the common Distal Cholangiocarcinoma hepatic duct. In presentation, most hilar cholangiocarcinomas (also known as upper duct cholangiocarcinomas or Clinical presentation The most common presentation Klatskin tumors) arise just below the union of the right and of distal cholangiocarcinomas is painless jaundice. Other left hepatic ducts, at the union of the ducts, or in the main manifestations of biliary obstruction, such as acholic stools, right or left hepatic duct. Cancer of the midportion of the dark urine, and pruritis, are also prevalent. Abdominal bile duct at the usual insertion point of the cystic duct is pain, fatigue, malaise, and weight loss can also occur with more likely to be an extension of a gallbladder cancer than advanced disease. Signs of advanced bile duct cancer of a primary cholangiocarcinoma. Perihilar tumors may be fur- the lower duct include right upper quadrant abdominal ther classiﬁ ed according to the AJCC staging criteria and the tenderness, hepatomegaly, and a palpable gallbladder.

Type I

Type II

Type IIIa

Type IIIb

Type IV

Figure 11 Bismuth-Corlette classiﬁ cation system of perihilar cholangiocarcinoma.

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Cholangitis is unusual in the absence of previous biliary patients with cholangiocarcinoma continues to be studied tract manipulation. but is not well established. The differential diagnosis for patients with these pre- A particularly challenging situation can arise in patients sentations includes primary and metastatic hepatobiliary with PSC, 20 to 50% of whom will develop a benign domi- and pancreatic neoplasms and benign biliary strictures due nant biliary stricture.56 The diagnostic steps for differentiat- to conditions such as pancreatitis, PSC, choledocholithiasis, ing benign neoplasms from malignant tumors are essentially Mirizzi syndrome, benign infl ammatory pseudotumors, the same for distal cholangiocarcinoma as for pancreatic and postoperative strictures. The most common cause of the cancer. As noted, resection may be required to make the benign stricture of the intrapancreatic bile duct is pancreati- diagnosis. In any patient presenting with jaundice and a tis, which may be diffuse or focal. Iatrogenic injuries rarely focal stricture of the bile duct, distal cholangiocarcinoma involve the intrapancreatic portion of the bile duct, although should be strongly suspected. Mass-forming bile duct such injuries can occur in this area as a consequence of force- cancers may also arise in the intrapancreatic duct but, for ful instrumentation. Sclerosing cholangitis may affect this obvious reasons, are diffi cult to differentiate from pancre- section of this bile duct but usually affects other areas of the atic adenocarcinomas. biliary tree as well. Staging Surgical staging of the distal cholangiocarcino- Diagnosis In patients with extrahepatic cholangiocarci- mas is usually straightforward. These tumors are usually noma, laboratory tests are usually consistent with the pres- remote from major vascular structures and thus are not ence of obstructive jaundice with elevation of total bilirubin subject to the same local staging considerations as adenocar- and mildly elevated alkaline phosphatase. Tumor markers cinomas of the pancreatic head. The exception is a tumor (CEA, CA 19-9, and CEA in combination with CA 19-9) may that extends to the top of the retroduodenal portion of the be useful in differentiating patients from PSC; however, bile duct. At this point, the bile duct is apposed to the portal their sensitivities and specifi cities are too low for use in vein and the hepatic artery, and these structures may be screening or diagnosis in the general population. invaded by bile duct tumors in this location. Chest CT Axial imaging reveals dilation of the intrahepatic bile should be performed prior to treatment. ducts, the gallbladder, and the extrahepatic bile ducts down to the level of the pancreatic head, where the dilatation Surgical management Distal cholangiocarcinoma is terminates abruptly. Usually, no mass is visible. Transab- resected with a pancreaticoduodenectomy. The main criteria dominal US that reveals dilation of the biliary tree in the for resectability include the absence of metastatic disease absence of cholelithiasis suggests a possible biliary or pan- and lack of involvement of the portal and superior mesen- creatic malignancy and should prompt contrast-enhanced teric veins, the hepatic artery, and superior mesenteric spiral CT scanning. CT scan fi ndings of distal cholangiocar- artery. This operation is well described in the chapter on cinomas include dilation of the intra- and extrahepatic bile periampullary and pancreatic adenocarcinoma. ducts and the gallbladder, with or without a mass in the head of the pancreas. In addition to offering information on Hilar Cholangiocarcinoma the site of the lesion, the CT scan can inform staging and Hilar cholangiocarcinoma is a sporadically occurring planning of therapies, including the presence or absence of tumor that is associated with patients who have PSC, ulcer- local vascular invasion, regional lymphadenopathy, distant ative colitis, or parasitic infestation. It is slow growing and metastasis, and liver atrophy. If CT imaging fails to demon- locally invasive and metastasizes to the lymph nodes ahead strate the tumor itself, further studies may be required. of systemic spread, even though liver and peritoneal metas- For distal cholangiocarcinomas, patients are assessed by tases may occur. Most hilar cholangiocarcinomas are charac- ERCP, which shows a focal stricture, and ERCP brushings terized as diffusely infi ltrating cancers, mass forming, and are diagnostic in about 50% of cases. Recently, MRCP is papillary ingrowths. The tumors are further divided by the being used more commonly in this setting. Unlike con- location in the upper biliary tree. ventional cholangiography, MRCP is noninvasive, does not require contrast material to be injected in the biliary ductal Clinical presentation The early symptoms of hilar chol- system, and allows for visualization of the bile duct both angiocarcinoma are nonspecifi c. Abdominal pain or dis- proximal and distal to the stricture. Endoscopic ultrasono- comfort, jaundice, anorexia, weight loss, and pruritus are graphy (EUS) may be helpful in that it is more sensitive for the most common but are seen in only about one third of small tumors than CT. Needle biopsy is directed toward the patients. Fever or cholangitis is uncommon at the initial mass through the narrowest part of the bile duct. A negative presentation. It is not uncommon for patients with hilar biopsy result does not rule out a small bile duct cancer. The cholangiocarcinoma to have undergone a recent cholecystec- most accurate modality for diagnosing cholangiocarcinoma tomy; pain and jaundice can be mistaken for symptoms of in patients with PSC who present with a dominant biliary cholelithiasis. In some patients, pruritis precedes jaundice stricture is EUS–fi ne-needle aspiration, with sensitivity and by some weeks and should be investigated promptly, espe- specifi city reaching 80 and 100%, respectively.58 “Spyglass” cially if associated with abnormal liver function tests. These cholangioscopy, in which a small endoscope is directed into patients may have elevated bilirubin, alkaline phosphatase, the biliary tree along a catheter placed by duodenoscopy, or c-glutamyltransferase. facilitates direct biopsy of the bile duct wall and lesions that The physical fi ndings are nonspecifi c as well. Jaundice project into the lumen. Additional studies are not routinely and long-standing pruritis may cause patients to have mul- indicated. The role of PET scanning in the evaluation of tiple excoriations of the skin. The liver may feel enlarged as

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01/14 gastro tumors of the liver and biliary tract — 17 a result of biliary obstruction, and the gallbladder is decom- pressed and nonpalpable. Bacterial contamination of bile is relatively common in patients with hilar cholangiocarcinoma. Endoscopic or percutaneous instrumentation and previous operation signiﬁ - cantly increase the incidence of bacterial contamination and the risk of infection. The presence of infection at the time of surgery increases postoperative morbidity and mortality. Escherichia coli, Klebsiella species, and Enterococcus species are often the most common pathogens. When cholangiocarcinoma originates in one of the hepatic ducts, the duct may become obstructed for a considerable period before jaundice becomes apparent. The gradual and prolonged unilateral biliary obstruction or portal venous occlusion may cause atrophy of the obstructed portion of the liver. Long-standing biliary obstruction may cause moderate atrophy, whereas compromise of the portal inﬂ ow will cause rapid and severe atrophy of involved segments. Contralat- eral hypertrophy is the expected consequence.

Diagnosis Diagnostic investigations are directed to elu- Figure 12 Magnetic resonance cholangiopancreatographic image cidate the cause of biliary tract obstruction. Axial imaging depicting a hilar cholangiocarcinoma. The mass is present at the bifur- is preferable to ERCP in the jaundice patient. US is nonin- cation (arrow), and the proximal intrahepatic ducts are all dilated. vasive and may show the level of biliary obstruction and There is no visualization of the distal duct leading to the duodenum. tumor extension into the bile duct and/or the periductal tissues. Doppler US is highly accurate in predicting vascular involvement, particularly portal venous invasion and resect- sensitive than those at lower levels, but spyglass technology ability. CT is also an important study to determine the has opened this area of the biliary tree to direct biopsy on a level of biliary obstruction, vascular involvement, and liver routine basis. EUS has been employed to obtain diagnostic atrophy. tissue, with some degrees of success; however, because More recently, MRCP has emerged as a powerful investi- the biopsy needle passes through the peritoneal cavity, there gative tool and has almost replaced ERCP or PTC for the are concerns for tumor seeding. Such tumor seeding has not preoperative assessment of hilar cholangiocarcinoma.59 been a problem for distal cholangiocarcinomas because the MRCP may reveal obstruction in isolated ducts not seen on biopsy tract is entirely within the future resection specimens. ERCP or PTC and provides information about the patency In many cases, a tissue diagnosis cannot be obtained pre- of hilar vascular structures, the presence of nodal or distant operatively, and the diagnosis is based on the presence of metastases, and the presence of lobar atrophy. Using data focal hilar stricture that causes jaundice. from cross-sectional imaging and MRCP, a multidisciplinary team with expertise in this disease can recommend treat- Alternative diagnosis Focal strictures of the upper bile ment options, including the role of selective biliary decom- ducts are strongly suggestive of cancer, but cholangiocarci- pression [see Figure 12]. nomas must also be differentiated from other diagnoses. ERCP has fallen out of favor in diagnosing hilar cholan- Alternative diagnoses can be expected in 10 to 15% patients. giocarcinoma because it is invasive, requires injection of dye The most common of these are gallbladder carcinoma, above the malignant stricture, and often is unable to delin- Mirizzi syndrome, and idiopathic infl ammatory benign eate the proximal extent of disease, which is required to tumors. Gallbladder carcinoma usually has a thickened, determine the feasibility of reconstruction. Once the dye has irregular gallbladder wall with infi ltration into segments IV been injected, stents must be placed to prevent post-ERCP and V of the liver, selective involvement of the right portal cholangitis. This process may involve insertion of bilateral pedicle, and obstruction of the common hepatic duct with stents, including a stent in the atrophic hemiliver. Bilateral occlusion of the cystic duct on endoscopic cholangiography. stenting is disadvantageous because the aim is to encourage Mirrizzi syndrome is a benign condition resulting from a atrophy of the hemiliver to be resected and hypertrophy of large gallstone impacted in the neck of the gallbladder with the hemiliver to be retained, and insertion of a stent in the pericholecystic and periductal infl ammation and fi brosis atrophic side negates that aim. Whether stents should be that can obstruct the proximal bile duct, which is often dif- employed in treating hilar cholangiocarcinoma is debatable, fi cult to distinguish from a malignant cause. Hepatic infl am- but if a stent is inserted, only the side to be retained should matory pseudotumors and benign fi brosing disease can be intubated. Although ERCP may provide some useful mimic hilar cholangiocarcinomas but do not involve blood information, PTC displays the intrahepatic bile ducts more vessels. reliably and has been the preferred study. The fi nding of a smooth, tapered stricture on cholangio- ERCP does have one signifi cant advantage in that it graphy suggests a benign stricture. Diagnostic assessments allows brushing to be obtained. Standard brushing tech- based on the cholangiographic appearance of the stricture niques at this high level in the biliary tree are even less are unreliable, so hilar cholangiocarcinoma must remain the

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01/14 gastro tumors of the liver and biliary tract — 18 leading diagnosis. In most cases, hilar cholangiocarcinoma The AJCC staging system for cholangiocarcinoma does cannot be ruled out without exploration. The alternative not adequately account for resectability. Recently, Jarnagin conditions that are encountered in the operating room can and colleagues proposed the Blumgart staging system, which be addressed at the time. Relying on the results of percuta- incorporates local tumor extent.60 In this system, tumors neous needle biopsy or biliary brush cytology is dangerous are classifi ed according to three factors: bile duct involve- and misleading. In the absence of clear contraindications, ment according to the Bismuth-Corlette system, portal vein exploration is indicated in all patients in whom there is invasion, and hepatic lobar atrophy [see Table 6]. suspicion of hilar lesions. Iatrogenic causes should be considered if the patient has Surgical management Because complete surgical re- had a cholecystectomy. Strictures often present years after section is the only potentially curative therapy for patients the operation secondary to ischemic injury to the bile duct. with cholangiocarcinoma, all patients should be considered The presence of clips close to or indenting the duct is a clue for surgical exploration. However, there is potential for that such injury is a possibility. Choledocholithiasis may signifi cant morbidity and mortality associated with cholan- also cause strictures, especially if a history of recurrent pyo- giocarcinoma resection, and all patients considered for re- genic cholangitis is present. section should receive preoperative treatment for correctable medical comorbidities, such as malnutrition, coagulopathy, Staging Surgical staging of hilar cholangiocarcinoma, and treatable cardiac, pulmonary, and renal disease. unlike that of distal cholangiocarcinoma, requires exact The use of preoperative stenting is no longer routine and knowledge of the macroscopic upper extent of the tumor in may increase the rate of infectious complications. However, the bile duct. Furthermore, invasion of hepatic arteries and selective application of stenting in patients may be bene- portal veins is common and affects resectability. Thus, surgi- fi cial. Advantages to stenting include decompressing an ob- cal staging also requires accurate determination of the extent structed biliary tree (in patients with a bilirubin > 10 mg/dL, of hepatic arterial or portal venous invasion and assessment to allow hepatic function to improve) and providing patients of the degree of atrophy. suffering from malnutrition, biliary sepsis, or other medical

Table 6 Staging of Cholangiocarcinoma20,60 Staging System Stage Tumor Node Metastasis AJCC TNM 0 Tis N0 M0 Distal IA T1 N0 M0 IB T2 N0 M0 IIA T3 N0 M0 IIB T1 to T3 N1 M0 III T4 Any N M0 IV Any T Any N M1 Tis, carcinoma in situ; T1, confined to bile duct; T2, beyond bile duct; T3, invades gallbladder, pancreas, duodenum without involving celiac axis or SMA; T4, celiac axis or SMA; N1, regional LN metastasis; M1, distant metastasis Perihilar 0 Tis N0 M0 IT1 N0 M0 II T2a–b N0 M0 IIIA T3 N0 M0 IIIB T1–3 N1 M0 IVA T4 N0–1 M0 IVB Any T N2 M0 Any T Any N M1 Tis, carcinoma in situ; T1, confined to bile duct; T2a, beyond bile duct; T2b, tumor invades adjacent hepatic parenchyma; T3, invades unilateral branches of the PV or HA; T4, invades main PV or HA; N1, regional LN metastasis; N2, metastasis to periaortic, pericaval, SMA, celiac nodes; M1, distant metastasis Blumgart T stage: T1 Tumor involving biliary confluence ± unilateral extension to second-order biliary criteria perihilar radicals T2 Tumor involving biliary confluence ± unilateral extension to second-order biliary radicals and ipsilateral PV involvement ± ipsilateral hepatic lobar atrophy T3 Tumor involving biliary confluence plus bilateral extension to second-order biliary radicals; or unilateral extension to second-order biliary radicals with contralateral PV involvement; or unilateral extension to second-order radicals with contralateral hepatic lobar atrophy; or main or bilateral PV involvement

AJCC = American Joint Committee on Cancer; HA = hepatic artery; LN = lymph node; PV = portal vein; SMA = superior mesenteric artery; TNM staging system: T = primary tumor, N = regional lymph nodes, M = distant metastasis.

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01/14 gastro tumors of the liver and biliary tract — 19 problems time to recover before an elective operation. If biliary decompression. Current indications for biliary decom- biliary stenting is applied, we recommend decompressing pression for unresectable patients are to provide symptom- the side of the liver to be retained and waiting until the atic relief for intractable pruritis, treat cholangitis, gain serum bilirubin falls to 3 mg/dL. access for intraluminal radiotherapy, and allow hepatic A reasonable strategy is to proceed to operation if (1) the function recovery in patients receiving chemotherapy. patient is relatively young (< 70 years), (2) there are no seri- Endoscopic placement of biliary stents has low complica- ous comorbid conditions, (3) the jaundice had been present tion rates and high rates of symptomatic relief for patients for less than 4 weeks, (4) the serum bilirubin concentration with biliary obstruction caused by unresectable tumors, is lower than 10 mg/dL, and (5) the future remnant liver especially distal cholangiocarcinoma. The effectiveness of will include more than 35% of the total liver mass. Patient- biliary stents is limited because of frequent obstruction and related contraindications include severe medical comorbi- the need for replacement. Self-expanding metallic biliary dities, especially major cardiopulmonary disease, cirrhosis, stents have improved patency rates but are more diffi cult and metastatic disease. Blumgart and colleagues proposed to change when they become obstructed. Hilar tumors are local tumor-related criteria for resectability.60 Tumor-related more diffi cult to traverse with the endoscopic technique. contraindications include encasement or occlusion of the The failure rates and incidence of subsequent cholangitis are main portal vein or hepatic artery either bilaterally or prox- high. Most patients with unresectable hilar tumors are not imal to the bifurcation, involvement of the bilateral second- candidates for endoscopic biliary drainage. ary ducts or unilateral ducts with contralateral vascular Percutaneous transhepatic biliary drainage and sub- compromise, and hepatic lobe atrophy with contralateral sequent placement of a self-expanding metallic stent can be secondary duct or portal vein involvement. performed in most patients with unresectable hilar cholan- There are two objectives in the therapy of hilar cholangiocarcinoma. Satisfactory drainage of only 25 to 30% of giocarcinoma: (1) complete tumor excision with negative functional hepatic parenchyma is required for resolution of margins and (2) restoration of biliary-enteric continuity. jaundice. Often hilar cholangiocarcinoma obstructs more The surgery for hilar cholangiocarcinoma includes removal than one region of the duct and two or more stents must be of the extrahepatic biliary tree and bile duct bifurcation, the placed for adequate drainage. Revision of these percutane- side of the liver with greater ductal involvement, extensive ous drains is relatively straightforward, and they can be hilar lymphadenectomy, and then reconstruction of biliary- kept internalized for physiologic excretion into the small enteric continuity. Many centers advocate caudate resection intestine. because the caudate has short bile ducts that enter the pos- For patients who are found to have carcinomatosis at terior surfaces of the main right and left bile ducts at the the time of exploratory laparoscopy, laparoscopic cholecys- bifurcation of the common hepatic duct. When the future tectomy was traditionally recommended, to prevent sub- remnant liver will include less than 30 to 35% of the total sequent development of acute cholecystitis related to biliary liver mass, portal vein embolization of the side to be re sected stent–induced cystic duct obstruction. The value of doing may be performed to induce hypertrophy of the remnant. a prophylactic cholecystectomy is unproven and should be Some centers have advocated resection of the portal venous performed only if it can be done safely. Endoscopic or per- bifurcation and anastomosis of the main and remnant cutaneous stenting should be performed postoperatively. portal vein to avoid dissection in the hilum with the poten- For patients who are found to have unresectable disease tial for tumor dissemination. Liver transplantation has at the time of open exploration, surgical biliary enteric been used successfully to manage Bismuth-Corlette type IV bypass offers more durable palliation than percutaneous tumors (extending to the bilateral secondary bile ducts) [see or endoscopic stenting. Patients with unresectable distal Figure 12] and is usually performed after neoadjuvant cholangiocarcinoma should undergo choledocho- or hepa- chemoradiation therapy and staging laparotomy in highly ticojejunostomy. The palliative options for patients with selected patients. unresectable hilar cholangiocarcinoma include tumor debulking with Roux-en-Y hepaticojejunostomy and intra- Adjuvant therapy Adjuvant chemotherapy, radiothera- operative placement of Silastic transhepatic catheters. The py, or chemoradiotherapy is commonly offered to patients. Roux-en-Y hepaticojejunostomy is most commonly done to Several small trials of adjuvant chemotherapy have been segment III hepatic ducts. The segment III hepatic duct can reported, but these demonstrated only low partial-response be approached by following the falciform ligament into the rates and no major survival benefi t. Two separate trials recess of the left lobe in the umbilical fi ssure. showed no benefi t of adjuvant external beam and intralumi- External-beam radiation and transcatheter brachytherapy nal radiation therapy.61,62 At present, there are no data to may help with pain relief and biliary decompression; support the routine use of adjuvant or neoadjuvant che- however, the effects of radiation on survival are confl icting. motherapy or radiation therapy except in the context of a Recently published data from a clinical trial indicate that the clinical trial. combination of gemcitabine plus cisplatin should be offered to patients with advanced bile duct cancer. Of nearly 60% Palliation Palliative treatment for cholangiocarcinoma patients who were enrolled in the phase III clinical trial that is important because many patients with hilar cholangiocar- had locally advanced cholangiocarcinoma, the gemcitabine- cinoma are not suitable for resection. In this setting, manage- cisplatin combination was associated with prolongation ment options include some form of biliary decompression of overall and progression-free survival compared with ad- or supportive care. Jaundice alone is not an indication for ministration of gemcitabine alone.61 Finally, photodynamic

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01/14 gastro tumors of the liver and biliary tract — 20 therapy, which involves a photosensitizer to be injected and with gallbladder cancer.67 However, 70 to 90% of patients direct illumination via cholangiography to allow for tumor diagnosed with gallbladder cancer have gallstones present cell death, has shown some promising results. A random- at the time of diagnosis. Gallstone size directly increases ized study in patients with unresectable cholangiocarcinoma the relative risk of developing gallbladder cancer; patients suggested improved survival with bilary stenting combined with stones less than 3 cm have a relative risk of developing with photodynamic therapy compared with biliary stenting cancer of 2.5 compared with patients with stones greater alone.63 However, because of the limitations and fl aws in the than 3 cm, which has a relative risk of 10. However, there study, the improved survival observed with photodynamic is no recommendation for prophylactic cholecystectomy in therapy is attributed to better biliary decompression rather asymptomatic patients with large stones. than the reduction of tumor burden. Additional study of this Other risk factors implicated for the development of gall- modality is necessary. bladder cancer include porcelain gallbladder, adenomatous polyps of the gallbladder, chronic infection with Salmonella Outcomes Extrahepatic cholangiocarcinoma resectabi- typhi, carcinogen exposure (e.g., miners exposed to radon), lity rates are reported to range from 30 to 50%.64 The pro- and abnormal pancreaticobiliary duct junction (APBDJ). portion of patients undergoing resection was far greater The incidence of gallbladder cancer was previously reported for distal lesions than for hilar lesions. Complication rates to range from 12.5 to 60% in patients with porcelain gall- after operation of cholangiocarcinoma range from 10 to 60% bladder; however, modern series have shown a much lower depending on the location of the tumor. Perihilar resections incidence that is closer to 5 to 10%.68 The type of calcifi cation have the highest rates of complication. Overall mortality seems to be associated with the degree of risk; stippled rates range from 0 to 15%. Long-term survival rates for chol- classifi cation of the mucosa is higher risk than diffuse intra- angiocarcinoma depend on tumor location and are highest mural calcifi cation. Patients with APBDJ have a long com- for intrahepatic tumors and lowest for perihilar tumors. In mon channel formed by an abnormally proximal junction of the Johns Hopkins series, the 5-year survival for R0-resected the pancreatic and common bile duct and elevated sphincter intrahepatic, perihilar, and distal tumors was 63%, 30%, and of Oddi pressures that create a predisposition to refl ux of 27%, respectively.62 Survival following resection of cholan- pancreatic exocrine secretions into the bile ducts. APBDJ giocarcinoma depends on several factors, especially margin appears to increase the risk of biliary cancers, especially status, lymph node status, tumor size, and differentiation. gallbladder cancers.69 When R0 patients are analyzed, lymph node status remains a signifi cant predictor of survival. Palliated patients have a Pathogenesis median survival of less than 12 months.65 The median over- Chronic infl ammation of the gallbladder mucosa related all survival among patients treated with the combination of to gallstones is hypothesized to be the major factor leading gemcitabine and cisplatin was 11.7 months compared with to malignant transformation in most cases of gallbladder 8.1 months in patients treated with gemcitabine alone.61 cancer. The progression from dysplasia to carcinoma in situ to invasive carcinoma over a 15-year period has been de- gallbladder carcinoma scribed for gallbladder cancer. Chronic infl ammation from Gallbladder cancer is rare in most Western countries and stones or other processes is postulated to be the inciting is associated with a poor prognosis due to late presentation event in the dysplasia to carcinoma pathway. The molecular and a lack of effective therapy. However, there have been an changes associated with this progression are under investi- increasing number of early-stage cases found incidentally gation: K-ras mutations appear to be relatively uncommon, with some hope of cure. It is the most common malignancy whereas TP53 mutations are prevalent and tend to arise of the biliary tract and fi fth most common malignancy of the early during this progression.66 gastrointestinal tract. In the United States, there are an esti- Eighty percent of primary gallbladder carcinomas are mated 6,500 new cases, with 3,200 deaths from gallbladder adenocarcinomas. Other histologic types include small cell cancer annually. cancer, squamous cell carcinoma, lymphoma, and sarcoma. Worldwide, the highest incidence rates occur among Gallbladder carcinomas are also classifi ed according to mor- populations in the Western part of South America (e.g., phology as infi ltrative, nodular, or papillary. Infi ltrative or Chile and Peru), North American Indians, Mexican Ameri- nodular cancers have a more diffuse pattern of growth that cans, and northern India. The highest worldwide incidence is diffi cult to recognize on imaging studies. These lesions are is in Delhi, India, at 21.5 per 100,000; by comparison, in the more likely to invade the liver and have usually metasta- United States, the overall incidence is 2.5 per 100,000.66 sized to lymph nodes by the time of diagnosis. Papillary The incidence of gallbladder cancer parallels that of choleli- cancers are associated with a better prognosis because thiasis, increasing with age and two to six times higher in they tend to grow within the gallbladder lumen and are less women than in men. likely to invade the liver or metastasize to lymph nodes. The best characterized risk factor for the development of gallbladder carcinoma is chronic infl ammation associated Clinical Presentation with gallstones, which raises the question of whether gall- Patients with gallbladder cancer are asymptomatic or stones predispose to gallbladder carcinoma. The prevalence have symptoms such as abdominal pain, anorexia, nausea, of cholelithiasis is greater than 25 million individuals, but and vomiting that may be impossible to differentiate from only 0.5 to 3% of patients who undergo a laparoscopic cho- symptomatic cholelithiasis or cholecystitis. In early stages of lecystectomy for symptomatic cholelithiasis are diagnosed the disease in which the tumor is confi ned to the wall of the

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01/14 gastro tumors of the liver and biliary tract — 21 gallbladder, the symptoms are usually those of biliary colic adjacent liver involvement is particularly important in plan- from associated stones, and the cancer is silent. Gallbladder ning the extent of liver resection. The fi nding of para-aortic cancer is discovered incidentally during performance of or peripancreatic nodal disease beyond the head of the cholecystectomy or on specimen processing. With advanced pancreas on imaging precludes surgical resection. Imaging disease, patients can present with weight loss, obstructive should also include the chest because this is a common site jaundice (from tumor invasion into the biliary tree), and of distant disease. Recently, PET has proved to be the most duodenal obstruction. On physical examination, patients sensitive modality to determine distant metastasis and can with advanced disease may have a palpable abdominal reduce unnecessary explorations. mass, hepatomegaly, or ascites. Jaundice occurs in about MRI and MRCP can offer additional information on local 50% of patients and is a poor prognostic sign because it invasion, particularly in the porta hepatitis. They may not be signifi es extension of the tumor beyond the gallbladder necessary if CT fi ndings are adequate. Similarly, endoscopic and ob struction of the extrahepatic ducts. Most gallbladder or percutaneous cholangiography is not routinely indicated; cancer patients with jaundice have unresectable tumors. however, it may be used for palliation or preoperative man- Diagnosis agement of jaundice. EUS offers greater accuracy in assess- ing gallbladder wall penetration by masses and regional Laboratory studies are generally nonspecifi c in gallblad- lymph node involvement. Selective application of EUS in der cancer. Serum alkaline phosphatase, alanine amino- patients with a gallbladder mass can help in the determina- transferase, and aspartate aminotransferase levels may be tion of whether the mass is nonneoplastic. In addition, EUS- elevated, especially in the presence of advanced hepatic guided biopsy is an effective technique in cases in which a invasion or metastasis. CEA and CA 19-9 levels have been tissue diagnosis is required. Percutaneous US- or CT-guided shown to be elevated in gallbladder cancer in 18 to 30% of biopsy is a useful technique for confi rming the diagnosis in patients, respectively; however, they lack suffi cient sensitiv- patients with unresectable tumors but is not recommended ity or specifi city to be useful in clinical decision making for for surgical candidates because of potential tumor seeding. individual patients. The initial imaging study performed for a patient with Staging gallbladder symptoms includes US. Findings suggestive of Gallbladder cancer can spread locally through direct gallbladder cancer on US are mural thickening or calcifi ca- invasion of the liver or adjacent organs such as the colon tion, a gallbladder mass greater than 1 cm in diameter, and or duodenum. High-risk hepatic areas for local extension loss of the normal gallbladder wall–liver interface. The diag- are segments IVb and V. Dissemination also occurs via lym- nostic accuracy of this examination is greater than 80% for phatics, which run just beneath the muscle layer of the gall- gallstones but only 50% for gallbladder cancer.70 bladder wall, which accounts for the 80% of lymph node CT scanning should be performed on patients suspected involvement in T2–T4 disease. The third route of dissemina- of having gallbladder cancer. Findings for gallbladder tion is hematogenous, and the sites most involved are the cancer include a mass protruding into the gallbladder lumen lung and brain. Finally, gallbladder carcinoma can spread or completely replacing the gallbladder and focal or diffuse directly via the peritoneum. Gallbladder cancer has the thickening of the gallbladder wall. CT scanning also shows ability to seed the peritoneum, surgical wounds, and laparo- information on the presence or absence of distant metasta- scopic port sites. Therefore, advanced disease should be ap- ses, regional lymph node involvement, and local invasion proached with a diagnostic laparoscopy before a laparotomy into the liver and porta hepatis [see Figure 13]. The extent of is attempted. The newest edition of the AJCC, published in 2010, con- tains important modifi cations to the staging of gallbladder cancer contained in the older editions. N stage now includes N1 (metastasis to cystic duct, common bile duct, hepatic artery, and/or portal vein lymph nodes) and N2 (metastasis to periaortic, pericaval, superior mesenteric artery, and/or celiac artery lymph nodes) designations. Stage classi fi cations have also been revised to better refl ect patient outcomes [see Table 7]. Surgical Treatment Surgical resection is the only known potentially curative treatment for gallbladder cancer. Unfortunately, most patients present with advanced disease, and curative resection is feasible in only 10 to 30% of patients. The overall 5-year survival for patients with gallbladder cancer is less than 5%, with a median survival of 5 to 8 months.71 An aggressive surgical approach to advanced regional disease has shown the potential for long-term survival. Figure 13 Computed tomographic scan depicting a gallbladder Treatment for gallbladder cancer is primarily based on the carcinoma. T stage of the tumor. Factors such as age, nutritional status,

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01/14 gastro tumors of the liver and biliary tract — 22

Table 7 AJCC Staging of Gallbladder Carcinoma margin. Overall, the cure rates with simple cholecystectomy to negative margins are 85 to 100%.72 Laparoscopic and open (7th edition), 2010 cholecystectomies have shown equal survival rates and local T: Primary tumors (T) control rates. However, if a patient has suspected gallblad- Tx Primary tumor cannot be assessed der cancer or a high-risk polypoid lesion, the laparoscopic T0 No evidence of primary tumor Tis Carcinoma in situ approach should not be performed because of the increased T1 Tumor invades lamina propria or muscular layer risk of peritoneal spread and seeding if there is spillage of T1a Tumor invades lamina propria gallbladder contents, as well as the possibility of trocar site T1b Tumor invades muscular layer implantation. T2 Tumor invades perimuscular connective tissue; no extension beyond serosa or into liver T3 Tumor perforates the serosa (visceral peritoneum) T1b and T2 lesions The management of T1b lesions, and/or directly invades the liver and/or one other which invade the muscularis but do not extend into the adjacent organ or structure, such as the stomach, perimuscular connective tissue, has been controversial. T2 duodenum, colon, pancreas, omentum, or lesions invade the perimuscular connective tissue but do extrahepatic bile ducts T4 Tumor invades main portal vein or hepatic artery or not go beyond the serosa or into the liver. T1b lesions have invades two or more extrahepatic organs or structures a 15% rate of lymph node metastasis, and in T2 lesions, regional lymph node metastases are found in 40 to 80% of N: Regional lymph nodes (N) 73 NX Regional lymph nodes cannot be assessed cases. Invasion of the perimuscular connective tissue of N0 No regional lymph node metastasis the gallbladder increases the chance of extension into the N1 Metastases to nodes along the cystic duct, common bile adjacent hepatic parenchyma. A simple cholecystectomy is duct, hepatic artery, and/or portal vein not appropriate treatment for these tumors because the re- N2 Metastases to periaortic, pericaval, superior mesenteric section plane is subserosal and can leave cancer cells in the artery, and/or celiac artery lymph nodes serosa that can extend into the liver. In patients who have M: Distant metastasis (M) only received a simple cholecystectomy, reexploration MX Distant metastasis cannot be assessed reveals residual tumor in 40 to 76% of cases.74 M0 No distant metastasis M1 Distant metastasis For T1b or T2 lesions, as long as preoperative and intra- operative staging shows no obvious metastases or unresect- Staging able local disease, the gallbladder is resected en bloc with a Stage 0 Tis N0 M0 Stage I T1 N0 M0 minimum of a 2 cm hepatic parenchyma margin, and lym- Stage II T2 N0 M0 phadenectomy is performed. Lymphadenectomy consists Stage IIIA T3 N0 M0 of dissection of lymph node beds in the porta hepatis, Stage IIIB T1–T3 N1 M0 gastroduodenal ligament, and gastrohepatic ligament and a Stage IVA T4 N0–1 M0 Stage IVB Any T N2 M0 Kocher maneuver with removal of the lymph nodes along Any T Any N M1 the posterior duodenum and behind the pancreatic head [see Figure 14]. Some studies show that to perform an ade- AJCC = American Joint Committee on Cancer. quate porta hepatis dissection, it is necessary to resect the extrahepatic bile duct and undertake a biliary reconstruction. Extrahepatic resection should be performed in patients and cardiopulmonary and hepatic function must also be who present with obstructive jaundice resulting from inva- considered. Contraindications for surgical resection include sion of tumor and for tumors located in the neck of the liver metastases, malignant ascites, peritoneal metastases, gallbladder or in the cystic duct. However, it is unclear if distant disease, extensive involvement of the hepatoduode- extrahepatic resection is of any beneﬁ t to patients who are nal ligament, encasement or occlusion of major vessels, and not jaundiced. poor performance status. Studies also show that para-aortic There is convincing evidence that such radical surgery is lymph node involvement has a survival similar to distant associated with improved survival for patients with T1b and metastasis in gallbladder cancer and is considered a con- T2 gallbladder cancer. In published series, the 5-year sur- traindication for surgery.71 vival rate for patients with T1b gallbladder cancer having undergone radical resection averages 87.5%, whereas it Early lesions: Tis and T1a For patients with early Tis averages only 61.3% in patients who underwent simple and T1a stage cancers where invasion is limited to the cholecystectomy alone.75 In T2 lesions, extended resection lamina propria, a simple cholecystectomy is the treatment of or radical cholecystectomy (61%) is associated with a much choice. Typically, these tumors are diagnosed incidentally better overall survival than simple cholecystectomy alone in cholecystectomy specimens because they are usually not (19%).76 Extended cholecystectomy can be performed with obvious in imaging studies. Since these tumors do not minimal morbidity and a 1% mortality rate. invade the muscular layer, a simple cholecystectomy dis- sects the perimuscular layer and, theoretically, should be T3 lesions The most controversial aspect of the surgical curative. There is minimal chance of lymph node involve- treatment of gallbladder cancer involves patients with non- ment, but it is crucial to get negative margins along the gall- metastatic locally advanced tumors that perforate the gallbladder wall and the cut edge of the cystic duct. If the cystic bladder serosa or directly invade the liver and/or adjacent duct margin is positive, it is necessary to resect the common organ. Historically, these patients were documented to have bile duct with biliary reconstruction to obtain a negative extremely poor survival and surgical resection was thought

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Extent of Node Clearance

b c d

Figure 14 Lymph node designations used to describe the extent of dissection in a radical cholecystectomy for gallbladder carcinoma. (a–e) Lymph node ﬁ eld.

to be futile. However, numerous small studies have docu- minimal extension into the liver can usually be approached mented that with varying levels of extended resections, with simple wedge or segment IVb and V resection. As the long-term survival is possible in highly selected patients. lesion size increases or vascular structure are affected, more Diagnostic laparoscopy should be strongly considered extensive resections are required. It does not appear that before exploratory laparotomy in locally advanced T3 anatomically based resections have any survival beneﬁ t over tumors to identify patients with peritoneal seeding of the plain wedge resection, but to obtain R0 resection in T3 cancer prior to an open operation. If the tumor locally lesions, larger liver resections are necessary. invades the colon, duodenum, or liver, complete local resection is indicated and can improve survival if negative T4 lesions Patients with a T4 lesion that invades the margins can be obtained. main portal vein or hepatic artery or invades two or more A 25 to 44% 5-year survival rate can be achieved with extrahepatic organs or structures meet the criteria for unre- radical surgery.77 The extent of hepatic resection is deter- sectability. Anecdotal reports of superradical procedures mined by the local invasion of the liver. Lesions that have involving resection of the main portal vein and/or common

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01/14 gastro tumors of the liver and biliary tract — 24 hepatic artery exist, but these procedures are associated with 5-FU is associated with diminished rates of local recurrence. increased morbidity and mortality rates and are unlikely to The impact of these regimens on survival is unclear; no data confer any survival benefi t. There is no evidence to support derived from prospective randomized clinical trials on the debulking cholecystectomy to prevent subsequent episodes effi cacy of these regimens exist. of cholecystitis. Palliation incidental gallbladder cancer The most common problem with gallbladder cancer is Incidental fi nding of malignancy after laparoscopic chole- palliation because most patients are unresectable at presen- cystectomy occurs in 1 to 2% of laparoscopic cholecy- tation. The outcome for these patients is poor, and chemo- stectomies and represents a relatively new and challenging therapy offers minimal increase in survival. Patients who problem in the treatment of gallbladder cancer.78 A majority present with locally unresectable or metastatic disease of these patients will have T1a mucosal lesions. For Tis and have an overall dismal prognosis, often with survival of less T1a, no further resection is necessary if the cystic duct mar- than 1 year. The majority of patients require palliation for gins are negative for tumor, and the 5-year survival rate for pain, jaundice, and possibly intestinal obstruction. Minimal these patients is 85 to 100%.72 morbidity is important for any palliative procedures, con- Patients who are found to have T1b lesions on pathologic sidering that median survival in this group may be only 2 review of the gallbladder should be appropriately staged to 4 months. If unresectable disease is encountered during and, in the absence of distant disease and peritoneal spread, an exploratory laparotomy, jaundice and obstruction can be offered liver resection to improve long-term survival.76 treated with choledochojejunostomy and gastrojejunostomy Before resection, staging with imaging and possible laparos- depending on the location of the tumor. Biliary obstruction copy should be performed to rule out distant disease can also be treated with endoscopic or percutaneous drain- or peritoneal spread. Some authors also advocate resection age. In general, operative exploration should be avoided of port sites at the time of resection, but this remains con- because median survival is already poor; endoscopic stent troversial. placement for biliary or intestinal obstructions can offer During routine cholecystectomy, suspicion of cancer these patients symptom relief without the need for postsur- should be considered if the procedure is more diffi cult or gical recovery. Chemotherapy and radiotherapy have been unusual than expected. Conversion to an open operation to largely unsuccessful in treating this disease. Response rates prevent spillage and seeding should be considered. If a sus- are low, but occasionally disease stabilization can be achieved picious lesion is identifi ed, a frozen section can be performed for a few months. Patients can also be referred for enrolment to confi rm the diagnosis and to assess the depth of tumor in a clinical trial or offered 5-FU- or gemcitabine-based invasion. If the diagnosis of T2 or greater gallbladder cancer chemotherapy or best supportive care. is confi rmed, the surgeon can proceed to an open radical Outcomes cholecystectomy. Another choice is to perform simple chole- The National Cancer Data Base reports 5-year survival cystectomy, closure, and image-guided staging and then rates for patients with T1N0, T2N0, and T3N0 (or node- refer the patient to a local hepatobiliary expert. Long-term negative) disease at 39%, 15%, and 5%, respectively.80 How- survival is the same if the extended cholecystectomy is per- ever, more contemporary surgical series suggest that sub- formed at the initial operation or during a later operation.76 stantially improved outcomes can be achieved in resectable Unfortunately, some patients present with extensive gallbladder cancers. In these reports, 5-year survival rates peritoneal seeding or port-site disease even though their following resection of T1 lesions range from 85 to 100%. primary cancer was small or undetected after routine chole- With radical resection of T2, T3, and T4 lesions, 5-year sur- cystectomy. Port-site seeding after laparoscopic cholecy- vival is 80 to 90%, 15 to 63%, and 2 to 25%, respectively.81 stectomy with presentation as advanced disease had been 79 reported in 5 to 20% of cases. Recognition of this problem Financial Disclosures: Gabriela M. Vargas, MD, Purvi Parikh, MD, FACS, and has prompted surgeons to use extraction bags and to adopt Kimberly M. Brown, MD, FACS, have no fi nancial relationships to disclose. This a liberal policy of converting to an open procedure if there chapter was previously authored by Steven M. Strasberg, MD, FACS, FRCSC, is any question of a cancer because perforation and spillage FRCS(Ed), and David C. Linehan, MD, FACS, with disclosure made at the time of initial publication. This chapter has been reviewed, updated, and rereleased by the have been reported to lead to a high rate (40%) of port-site authors listed. recurrence.79

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