8 Hepatocellular Carcinoma Arising in the Non-viral, Non-alcoholic Liver 105 approximately 5 of 1000 patients of northern European descent having homozygos- ity for the C282Y mutation [31]. The end-stage results of HH-induced iron overload are diabetes, cirrhosis, and HCC, which are responsible for a reduced life expectancy from HH [32]. Patients with HH have a 20- to 200-fold increased risk of developing HCC [33–35]; in fact, primary liver carcinomas can account for up to 45% of deaths in HH patients [36]. Histologically, the overwhelming majority of these tumors are HCC and most occur in patients in their sixties. In a prospective longitudinal cohort study from Italy published in 2001, all cases of HCC in patients developed in those with cirrhotic livers [37]. However, there are approximately 10 case reports in the litera- ture of HCC in patients (all male, all between 50 and 70 years of age) with HH and non-cirrhotic livers [38–40]. Vigilance in this group is warranted, as increased iron deposition alone may be a risk factor for development of HCC in the non-cirrhotic setting. Aflatoxin Aflatoxin B1 (AFB1) is a toxin produced by a fungus of the genus Aspergillus. It is found in Asia and sub-Saharan Africa where climate and food storage tech- niques allow the fungus to be a common contaminant of foods, especially grains, and release its toxin which is then ingested. As discussed previously, these endemic areas have high incidences of not only HCC but also viral hepatitis, specifically hep- atitis B [41]. Therefore, aflatoxin may be more likely a potentiator of HCC rather than a director cause. Non-alcoholic Fatty Liver Disease Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disease ranging from benign fatty infiltration of the liver to fulminate hepatic failure secondary to cirrhosis from non-alcoholic steatohepatitis (NASH). NASH, first described in 1980 [42], is defined by the histologic presence of findings associated with alcoholic liver disease in the absence of a history of alcohol consumption. The prevalence of NASH has been reported to be as high as 2% of the general population [43], making this one of the most common causes of non-viral liver disease. It is associated with obesity and diabetes mellitus and likely represents the hepatic manifestations of the metabolic syndrome. Despite the prevalence of underlying liver disease, NASH-associated HCC has been rarely reported in the literature [44–46] beyond case reports. The connection can be difficult to establish because of regression of steatosis, inflammation, bal- looning degeneration, and Mallory bodies is common once cirrhosis appears, and some HCCs in NASH patients occur in non-cirrhotic livers. There is no gender predominance in the literature; most cases occur in patients in their seventh decade. 106 C.E. Woodall et al. Prospective studies linking NASH and HCC have been undertaken. They are limited by small numbers, highly selected subjects, and short-term follow-up [47]. The prodrome from the progression of fatty liver to NASH-associated cirrhosis can be quite pronounced, with estimates ranging from 10 to 16 years. As undiagnosed HCC may be somewhat indolent initially, it may be years after the onset of cirrho- sis that a malignancy is diagnosed. Therefore, two decades of follow-up may be required to fully establish the relationship and true incidence. References 1. Botha JF, Langnas AN (2006) Liver transplantation for hepatocellular carcinoma: an update. J Natl Compr Canc Netw 4:762–767. 2. El Serag HB, Davila JA, Petersen NJ et al (2003) The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med 139:817–823 3. 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Abdalla Keywords Liver resection · Orthotopic liver transplantation · HCC surgical resec- tion · Multinodular HCC · Child–Pugh (CP) classification · Metabolic assess- ment · Future liver remnant · HCC preoperative therapy · Fibrolamellar carcinoma (FLHCC) Preoperative Assessment The natural history of untreated HCC varies depending on the stage at presentation and the degree of underlying liver disease. However, even in patients with early stages, the prognosis is poor if the disease is left untreated [1, 2]. As primary medical therapy has failed to significantly improve survival, surgical resection and orthotopic liver transplantation (OLT) represent the only treatment options offering a prospect for cure with 5-year survival rates of up to 50% [3–5] and 70% [6, 7], respectively. Unfortunately, only approximately 20–40% [8, 9] of patients are candidates for resection due to the burden of hepatic tumor, the presence of extrahepatic spread, or the extent of underlying liver disease. Despite this, liver resections are increasingly being performed due to better perioperative care, improved imaging, and advances in surgical technique. OLT represents the only surgical option in patients with small HCC and impaired liver function. However, in view of the severe graft shortage and restricted indi- cations for OLT, liver resection is considered the mainstay of therapy in patients with preserved hepatic function. At M.D. Anderson Cancer Center the criteria for resection in chronic liver disease are illustrated in Table 9.1. J N. Vauthey (B) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 109 K.M. McMasters, J N. Vauthey (eds.), Hepatocellular Carcinoma, DOI 10.1007/978-1-60327-522-4_9, C Springer Science+Business Media, LLC 2011 110 D.Zorzietal. Table 9.1 University of Texas M.D. Anderson Cancer Center criteria for resection in chronic liver disease Resection Criteria Minor Child–Pugh A Bilirubin ≤ 2 mg/dL Absence of ascites Platelets > 100.000/mm3 Major Criteria for minor resection plus: Bilirubin ≤ 1 mg/dL Absence of portal hypertension Portal vein embolization for future liver remnant of < 40% Patient Selection Optimal outcomes after surgical resection for HCC – optimal postoperative morbid- ity and mortality as well as optimal long-term survival – are contingent upon proper identification of appropriate candidates for safe, complete resection. A systematic and careful assessment of the patient’s general medical fitness, the tumor extent, the tumor stage, the underlying liver function, and the volume of the anticipated future liver remnant (FLR) is critical in ensuring proper patient selection. Patient age should not be considered per se a contraindication for resection, since it has not been shown to be an independent predictor of increased operative risk. However, in elderly patients, comorbid illnesses are prevalent and hidden medi- cal diseases are not uncommon. Recently it has been reported that the presence of comorbidities was one of the two independent factors predictive of postoperative mortality after extended hepatectomy. In general, patients with American Society of Anesthesiology (ASA) scores greater than 1 represent a population at greater risk for postoperative complications and death. The surgical risk becomes unaccept- ably high in some patients with congestive heart failure, severe chronic obstructive pulmonary disease, and chronic renal failure [10, 11]. Evaluation of Tumor Extent The assessment of tumor extent is the essential step for determining resectability and the appropriate type of surgical resection. At M. D. Anderson Cancer Center each patient is first staged with a triple phase (early vascular or arterial phase, por- tal phase, and delayed phase) helical computed tomography (CT) of the thorax and the abdomen because of its superior resolution throughout the whole body and the excellent liver anatomy detail. The liver is studied using thin slices acquired dur- ing the unenhanced phase and during the arterial, portal, and late or equilibrium phase after contrast administration. Tumors, such as HCC, are hypervascular dur- ing the early arterial phase and hypovascular in late phase (“washout”). Magnetic 9 Liver Resection for Hepatocellular Carcinoma 111 resonance imaging (MRI) is the imaging modality of choice when contrast agents are contraindicated, better lesion characterization is needed, or the anatomic rela- tionship between tumor and major vascular or biliary structures requires further delineation. As mortality rates after partial hepatectomy have fallen, in recent years to almost zero, many centers worldwide have expanded eligibility criteria for resection. Now included are tumors once considered unresectable such as large HCCs, multinodular and bilobar HCCs, and HCCs with portal vein or hepatic vein involvement. Based on preoperative i maging, patients are considered for resection when all tumor nod- ules can be safely excised with negative margins and when the volume and function of the FLR is adequate. Formal contraindications for resection are the presence of extrahepatic disease, extensive tumor thrombus in the inferior vena cava, and involvement of the common hepatic artery and portal vein trunk. Extension to sur- rounding structures, such as the diaphragm, does not represent a contraindication if a margin negative resection can be attained. Large Tumor Size In western countries, because of the lack of effective HCC screening, up to 50% of cases of HCC are diagnosed at an advanced stage, and tumor diameters sometimes exceed 10 cm. Large HCCs are more aggressive tumors, as indicated by higher alpha-fetoprotein levels and higher incidences of tumor rupture, multiple tumors, and invasion of portal or hepatic veins. Despite the technical problems encountered with large tumors – such as problems with liver mobilization, access and control of the hepatic veins – liver resection for large HCCs has been shown to be safe. A recent study reported a 30-day mortality rate of 5% in 300 patients who underwent partial hepatectomy for HCCs larger than 10 cm [12]. The 5-year survival rate in patients with tumors larger than 10 cm is about 27% and can reach up to 73% [13]. Thus, since in these patients cadaveric OLT and radiofrequency ablation (RFA) are not indicated, surgical resection remains the only treatment of choice that may cure large HCCs (Fig. 9.1). Multinodular Disease Multinodular HCC may represent independent tumors derived from multiple loci of hepatocarcinogenesis or may be a manifestation of advanced disease with intrahep- atic metastasis, an event associated with a poor prognosis. Multinodular HCC (>3 nodules or >1 nodule exceeding 3 cm in diameter) have been considered unsuitable for resection. Surgical resection for these patients often requires major resection because of substantial tumor volume. Ng et al. [14] reported the outcome after resection in a cohort of 380 patients with intermediate-stage HCC: the mortality rate was 2.4% with a 5-year survival rate of 39%. Some authors investigated the role of liver resection for bilobar HCC. In a series of 78 patients with bilobar HCC, Liu et al. [15] compared 15 patients treated with hepatectomy plus treat- ment of tumor nodules in the contralateral lobe (wedge resection in five patients, 112 D.Zorzietal. Fig. 9.1 A 59-year-old male patient had a 16 cm hepatocellular carcinoma in the right liver without evidence of extrahepatic disease. (a) Computed tomography revealed that the standardized FLR (sFLR) was 12%. (b) Right PVE was performed. (c) Four weeks after PVE, the sFLR was 21%. (d) The patient had no evidence of disease 5 years postresection (From [35], with permission) alcohol injection in five, cryotherapy in two, and transarterial oily chemoemboliza- tion in two) with 63 patients who underwent nonsurgical therapy and showed that partial hepatectomy resulted in better survival outcomes. Hence, when liver function permits and clearance of all tumor nodules is possible, en bloc extended hepa- tectomy, multiple bilobar resections, or hepatectomy plus effective local ablative therapy for treatment of contralateral nodules should be considered for patients with bilobar HCC. Major Portal or Hepatic Vein Involvement HCCs with major portal or hepatic vein involvement represent a technical and onco- logic challenge. These tumors are aggressive and often multifocal, and surgery to remove them may be difficult. However, hepatic resection for such tumors seems justified because resection results in better survival rates than are achieved with nonsurgical treatment. A recent series focusing on 102 patients with major portal vein branches or hepatic vein involvement reported a 5-year survival rate of 23% in patients without cirrhosis, which still exceeded the historical survival rate in similar 9 Liver Resection for Hepatocellular Carcinoma 113 patients treated nonsurgically [16]. In a series of 23 patients with portal vein involve- ment who were treated with partial hepatectomy, Minagawa et al. [17] r eported a median survival of 3.4 years and 1-, 3-, and 5-year survival rates of 82, 42, and 42%, respectively. Recurrent HCC Tumor recurrence represents the major drawback after curative liver resection and the most common cause of treatment failure. The cumulative 5-year recurrence rate is reported to be 70 to 100%. Recurrence in the liver remnant occurs in about 80–90% of cases as a result of vascular invasion leading to microsatellite tumors within the liver (“early recurrence”) or second primaries in the remnant liver associated with field effect from hepatitis and cirrhosis (“late recurrence”). In the largest series, reresection rates have been reported between 10 and 31% and depend on the underlying liver status, pattern of recurrence, and extent of first resec- tion with lower rates in series with high proportion of major resection during the first hepatectomy. Repeat hepatectomy has been proven to be a safe and worth- while procedure with mortality and 5-year survival rates of 0–8% and 50–69%, respectively. Evaluation of Hepatic Function In western countries, the Child–Pugh (CP) classification (Table 9.2), which was originally designed to estimate the risk of cirrhotic patients undergoing portocaval shunt surgery for portal hypertension [18], has traditionally been used to evaluate the hepatic function. Usually only patients with Child–Pugh class A disease are considered good candidates for hepatectomy. However, Child–Pugh class is a crude measure and is prone to underestimate the surgical risk. Table 9.2 Child–Pugh classification Points Clinical and biochemical parameters 1 2 3 Albumin (g/dL) >3.5 2.8–3.5 <2.8 Bilirubin (mg/dL) <2 2–3 >3 Prothrombin time Seconds prolonged <4 4–6 >6 % >60 40–60 <60 INR <1.7 1.7–2.3 >2.3 Encephalopathy Absent Moderate (Stage I–II) Severe (Stage III–IV) Ascites Absent Moderate Refractory Total points: 5–6 points, Child–Pugh A; 7–9 points, Child–Pugh B; 10–15 points, Child–Pugh C 114 D.Zorzietal. While no individual test accurately predicts liver function, the CP classification, combining different parameters, provides a rough estimation of the gross synthetic and detoxification capacity of the liver. In general, the risk of death after surgery increases with each CP class. Operative mortality rates for CP class A, B, and C patients undergoing abdominal operations are approximately 10, 30, and 82%, respectively [19], therefore liver resection is only considered in CP class A patients. Nevertheless, recent series of hepatectomy in CP class A patients have reported a wide range of perioperative mortality rates, from 0 to 16% [20–22]. Portal hypertension is present if the portal venous pressure is greater than 10 mmHg (the normal value ranges from 5 to 8 mmHg). Undiagnosed and latent portal hypertension in a cirrhotic patient undergoing liver resection puts the patient at risk of major complications, such as variceal bleeding, endotoxemia, and hep- atic decompensation, in the postoperative period. In a prospective study in CP class A cirrhotic patients, Bruix et al. [23] showed that the hepatic venous pressure gra- dient (HVPG), a surrogate measurement of portal venous pressure, was the only predictor of hepatic decompensation following hepatic resection. Specifically, unre- solved hepatic decompensation developed in 11 of 15 patients with an HVPG > 10 mmHg versus none of the patients with an HVPG < 10 (P < 0.002) suggest- ing that the CP classification may be somewhat inaccurate in assessing risk. Thus, in most patients with clinical or radiologic signs of portal hypertension, including splenomegaly, abdominal collaterals, thrombocytopenia (platelets <100,000/mm 3 ), or esophagogastric varices, resection is contraindicated. Additionally, postoperative mortality has been shown to be almost sixfold higher in a cohort of 285 patients who underwent hepatectomy for HCC when there was histologic evidence of cirrhosis and active hepatitis versus cirrhosis alone [24]. Although the presence of hepatitis does not always correlate with serum transami- nase levels [25, 26], increased complication and death rates have been reported in those patients with elevated liver function tests. Patients with aspartate aminotrans- ferase level greater than 100 IU/L [27] or alanine aminotransferase level at least twice normal [28] are considered to be poor candidates for major hepatic resection. Bilirubin levels greater than 2 mg/dL contraindicate hepatic resection while patients with bilirubin levels between 1.1 and 2.0 mg/dL should be carefully selected and considered for only limited resection. In eastern countries several hepatobiliary units have employed more sophisti- cated quantitative liver function tests, such as indocyanine green (ICG) clearance, galactose elimination capacity, and aminopyrine clearance, to evaluate the hepatic metabolic function and to predict the risk of postoperative liver failure. The most widely used and validated metabolic assessment is the ICG clearance test. Makuuchi et al. have incorporated the ICGR15 and two clinical features, i.e., bilirubin and ascites, into a treatment-selection algorithm (Fig. 9.2)[22]. In patients without ascites and bilirubin levels less than 1.0 mg/dL, ICGR15 is used to predict the number of liver segments that can be safely resected (ICGR15 <10%, extended hepatectomy and right hemihepatectomy are safe; ICGR15 10–19%, left hemihep- atectomy and bisegmentectomy are safe; ICGR15 20–29%, only segmentectomies . adolescents and young adults with distinctive clinico-pathologic features. Cancer 46:372–379 15. Ichikawa T, Federle MP, Grazioli L et al (1999) Fibrolamellar hepatocellular carcinoma: imaging and pathologic. in genetic haemochromatosis. Scand J Gastroenterol 35:889–893 41. Gomaa AI, Khan SA, Toledano MB et al (2008) Hepatocellular carcinoma: epidemiology, risk factors and pathogenesis. World J Gastroenterol. permission) alcohol injection in five, cryotherapy in two, and transarterial oily chemoemboliza- tion in two) with 63 patients who underwent nonsurgical therapy and showed that partial hepatectomy resulted