Hepatocellular carcinoma: Current surgical management

Hepatocellular carcinoma (HCC) is the fifth most common malignancy in the world, responsible for 500,000 deaths globally every year. Although HCC is a slow-growing tumor, it is often rapidly fatal because it is usually not discovered until the disease is advanced. HCC occurs primarily in individuals with cirrhosis, a condition that increases the risk of performing potentially curative surgical therapy. Over the last 2 decades, however, the safety of surgical resections has greatly improved because of advances in radiologic assessment, patient selection, and perioperative care. As such, the operative mortality rate for hepatectomy has decreased from the 10%–20% level seen in the 1980s to less than 5% today. The ultimate goal of treatment of HCC is to prolong the quality of life by eradicating the malignancy while preserving hepatic function. For treatment with a curative intent, the gold standard remains surgical resection, by either partial hepatectomy or total hepatectomy followed by liver transplantation. Resectability and choice of procedure depend on many factors, including baseline liver function, absence of extrahepatic metastases, size of residual liver, availability of resources including liver graft, and expertise of the surgical team. Patients without cirrhosis can tolerate extensive resections, and partial hepatectomy should be considered first. For Child class B and C patients with a small HCC, liver transplantation offers the best results, whereas partial liver resection is indicated in patients with well-compensated cirrhosis. Living donor liver transplantation should be considered using the same criteria as that used for cadaveric transplantation. Hepatocellular carcinoma (HCC) is the fifth most common malignancy in the world, responsible for 500,000 deaths globally every year. Although HCC is a slow-growing tumor, it is often rapidly fatal because it is usually not discovered until the disease is advanced. HCC occurs primarily in individuals with cirrhosis, a condition that increases the risk of performing potentially curative surgical therapy. Over the last 2 decades, however, the safety of surgical resections has greatly improved because of advances in radiologic assessment, patient selection, and perioperative care. As such, the operative mortality rate for hepatectomy has decreased from the 10%–20% level seen in the 1980s to less than 5% today. The ultimate goal of treatment of HCC is to prolong the quality of life by eradicating the malignancy while preserving hepatic function. For treatment with a curative intent, the gold standard remains surgical resection, by either partial hepatectomy or total hepatectomy followed by liver transplantation. Resectability and choice of procedure depend on many factors, including baseline liver function, absence of extrahepatic metastases, size of residual liver, availability of resources including liver graft, and expertise of the surgical team. Patients without cirrhosis can tolerate extensive resections, and partial hepatectomy should be considered first. For Child class B and C patients with a small HCC, liver transplantation offers the best results, whereas partial liver resection is indicated in patients with well-compensated cirrhosis. Living donor liver transplantation should be considered using the same criteria as that used for cadaveric transplantation. Hepatocellular carcinoma (HCC) is the fifth most common malignancy in the world, responsible for 500,000 deaths globally every year.1Parkin D.M. Bray F. Ferlay J. Pisani P. Estimating the world cancer burden Globocan 2000.Int J Cancer. 2001; 94: 153-156Crossref PubMed Scopus (3323) Google Scholar Although it is a slow-growing tumor,2Okuda K. Natural history of hepatocellular carcinoma including fibrolamellar and hepato-cholangiocarcinoma variants.J Gastroenterol Hepatol. 2002; 17: 401-405Crossref PubMed Scopus (88) Google Scholar it is usually rapidly fatal after clinical appearance. This is partly because of the asymptomatic nature of small HCC, in that cases of HCC are usually not discovered until the disease is far advanced. The disease also occurs mainly in individuals with cirrhosis, a condition that increases the risks when performing potentially curative surgical therapy. Over the last 2 decades, however, the safety of surgical resections has greatly improved because of advances in radiologic assessment, patient selection, and perioperative conduct. The operative mortality rate for hepatectomy has decreased from the 10%–20% level seen in the 1980s to less than 5% today.3Fong Y. Sun R.L. Jarnagin W. Blumgart L.H. An analysis of 412 cases of hepatocellular carcinoma at a Western center.Ann Surg. 1999; 229: 790-799Crossref PubMed Scopus (746) Google Scholar, 4Fan S.T. Ng I.O. Poon R.T. Lo C.M. Liu C.L. Wong J. Hepatectomy for hepatocellular carcinoma the surgeon’s role in long-term survival.Arch Surg. 1999; 134: 1124-1130Crossref PubMed Scopus (181) Google Scholar, 5Poon R.T. Fan S.T. Lo C.M. Ng I.O. Liu C.L. Lam C.M. Wong J. Improving survival results after resection of hepatocellular carcinoma a prospective study of 377 patients over 10 years.Ann Surg. 2001; 234: 63-70Crossref PubMed Scopus (535) Google Scholar This review will summarize the major changes that have resulted in these improvements, as well as the current standard of care. In addition, the current selection criteria for partial hepatectomy and the current preoperative assessment of a patient with HCC will be described, as will the relative merits of partial hepatectomy, ablative therapy, and liver transplantation. Finally, a workable algorithm will be proposed for using combinations of these modalities to best extend the life of the patient with HCC. Most patients with HCC present late in the course of the disease. Patients with HCC that is discovered during work-up for symptoms usually present with malaise, weight loss, abdominal pain, abdominal distension, hepatomegaly, ascites, fever, and jaundice.6Lai C.L. Lam K.C. Wong K.P. Wu P.C. Todd D. Clinical features of hepatocellular carcinoma review of 211 patients in Hong Kong.Cancer. 1981; 47: 2746-2755Crossref PubMed Scopus (137) Google Scholar, 7Pawarode A. Voravud N. Sriuranpong V. Kullavanijaya P. Patt Y.Z. Natural history of untreated primary hepatocellular carcinoma a retrospective study of 157 patients.Am J Clin Oncol. 1998; 21: 386-391Crossref PubMed Scopus (155) Google Scholar, 8Trevisani F. D’Intino P.E. Grazi G.L. Caraceni P. Gasbarrini A. Colantoni A. Stefanini G.F. Mazziotti A. Gozzetti G. Gasbarrini G. Bernardi M. Clinical and pathologic features of hepatocellular carcinoma in young and older Italian patients.Cancer. 1996; 77: 2223-2232Crossref PubMed Scopus (51) Google Scholar These symptoms usually occur at an advanced stage, and result from liver failure caused by tumor bulk, portal vein thrombosis, or deterioration of underlying liver failure.9Kassianides C. Kew M.C. The clinical manifestations and natural history of hepatocellular carcinoma.Gastroenterol Clin North Am. 1987; 16: 553-562PubMed Google Scholar When the associated liver insufficiency is severe, the risks of surgical therapy are prohibitive. Most of these patients are best relegated to ablative therapy or supportive care. Patients with HCC can also present with an acute abdomen caused by tumor rupture and hemoperitoneum.10Liu C.L. Fan S.T. Lo C.M. Tso W.K. Poon R.T. Lam C.M. Wong J. Management of spontaneous rupture of hepatocellular carcinoma single-center experience.J Clin Oncol. 2001; 19: 3725-3732PubMed Google Scholar, 11Castells L. Moreiras M. Quiroga S. Alvarez-Castells A. Segarra A. Esteban R. Guardia J. Hemoperitoneum as a first manifestation of hepatocellular carcinoma in western patients with liver cirrhosis effectiveness of emergency treatment with transcatheter arterial embolization.Dig Dis Sci. 2001; 46: 555-562Crossref PubMed Scopus (41) Google Scholar In years past, the treatment for ruptured HCC was emergent surgery. With the recent advancements in interventional radiology, however, emergent transarterial embolization has become the treatment of choice. This will usually stop the bleeding and allow the patient to be resuscitated and stabilized, and ultimately to have safer elective definitive therapy for the cancer. Most patients considered for surgical therapy are asymptomatic. Some asymptomatic patients present because of incidental abnormal findings on imaging or blood tests obtained in the course of investigation for an unrelated disease. Increasingly, asymptomatic patients considered to be at high risk for development of HCC because of cirrhosis and/or chronic hepatitis B or C status are diagnosed by screening programs12Henrion J. Libon E. De Maeght S. Schapira M. Ghilain J.M. Maisin J.M. Heller F.R. Surveillance for hepatocellular carcinoma compliance and results according to the aetiology of cirrhosis in a cohort of 141 patients.Acta Gastroenterol Belg. 2000; 63: 5-9PubMed Google Scholar, 13Bolondi L. Sofia S. Siringo S. Gaiani S. Casali A. Zironi G. Piscaglia F. Gramantieri L. Zanetti M. Sherman M. Surveillance programme of cirrhotic patients for early diagnosis and treatment of hepatocellular carcinoma a cost effectiveness analysis.Gut. 2001; 48: 251-259Crossref PubMed Scopus (561) Google Scholar, 14Caturelli E. Bartolucci F. Biasini E. Vigliotti M.L. Andriulli A. Siena D.A. Attino V. Bisceglia M. Diagnosis of liver nodules observed in chronic liver disease patients during ultrasound screening for early detection of hepatocellular carcinoma.Am J Gastroenterol. 2002; 97: 397-405Crossref PubMed Google Scholar, 15Velazquez R.F. Rodriguez M. Navascues C.A. Linares A. Perez R. Sotorrios N.G. Martinez I. Rodrigo L. Prospective analysis of risk factors for hepatocellular carcinoma in patients with liver cirrhosis.Hepatology. 2003; 37: 520-527Crossref PubMed Scopus (381) Google Scholar (Table 1). These represent the best candidates for surgical therapy. Suitability of these patients for surgical resection should then be determined by liver function assessment and by radiologic tumor staging.Table 1Comparison of Results of Prospective Studies on Surveillance Programs (Using Both USG and AFP) for HCC in Cirrhotic PatientsAuthorYearCountryNo. patients/No. HCCMain cause of cirrhosisChild class A patients (%)Screening periodicity (mo)HCC annual incidence (%)Solitary nodule discovered < 5 cm (%)Patients eligible for curative treatment (%)Henrion et al.12Henrion J. Libon E. De Maeght S. Schapira M. Ghilain J.M. Maisin J.M. Heller F.R. Surveillance for hepatocellular carcinoma compliance and results according to the aetiology of cirrhosis in a cohort of 141 patients.Acta Gastroenterol Belg. 2000; 63: 5-9PubMed Google Scholar2000Belgium141/6Ethanol6962.46 (100)6 (100)Bolondi et al.13Bolondi L. Sofia S. Siringo S. Gaiani S. Casali A. Zironi G. Piscaglia F. Gramantieri L. Zanetti M. Sherman M. Surveillance programme of cirrhotic patients for early diagnosis and treatment of hepatocellular carcinoma a cost effectiveness analysis.Gut. 2001; 48: 251-259Crossref PubMed Scopus (561) Google Scholar2001Italy311/61Virus6364.149 (80)39 (69)Caturelli et al.14Caturelli E. Bartolucci F. Biasini E. Vigliotti M.L. Andriulli A. Siena D.A. Attino V. Bisceglia M. Diagnosis of liver nodules observed in chronic liver disease patients during ultrasound screening for early detection of hepatocellular carcinoma.Am J Gastroenterol. 2002; 97: 397-405Crossref PubMed Google Scholar2002Italy1,599/269Virus—4—252 (94)—Velazquez et al.15Velazquez R.F. Rodriguez M. Navascues C.A. Linares A. Perez R. Sotorrios N.G. Martinez I. Rodrigo L. Prospective analysis of risk factors for hepatocellular carcinoma in patients with liver cirrhosis.Hepatology. 2003; 37: 520-527Crossref PubMed Scopus (381) Google Scholar2003Spain463/38Ethanol723–63.015 (39)20 (53) Open table in a new tab The most important parameter to be considered in choosing patients for partial hepatectomy is the baseline hepatic function, because of the relationship between the degree of hepatic injury and the loss in hepatic regenerative capacity. Patients without cirrhosis or with well-compensated cirrhosis can regenerate the resected parenchyma within weeks. Patients with decompensated cirrhosis, however, not only may not regenerate functional liver but also will have difficulties maintaining hepatic function immediately after hepatectomy. Many techniques have been proposed for the assessment of liver function. The most useful evaluation tool for patients being considered for partial hepatectomy remains the Child-Pugh grading system16Child C.G. Turcotte J.G. Surgery and portal hypertension.in: Child C.G. The liver and portal hypertension. Saunders, Philadelphia, PA1964: 50-62Google Scholar, 17Pugh R.N. Murray-Lyon I.M. Dawson J.L. Pietroni M.C. Williams R. Transection of the oesophagus for bleeding oesophageal varices.Br J Surg. 1973; 60: 646-649Crossref PubMed Scopus (6867) Google Scholar (Table 2). It is simple and easy to compute, is the most widely used clinical grading for assessing the functional status of the liver, and is highly predictive of the prognosis in cirrhotic patients. In patients simultaneously being considered for liver transplantation, evaluation using the Model for End-stage Liver Disease (MELD) scoring system is also useful18Freeman Jr, R.B. Wiesner R.H. Harper A. McDiarmid S.V. Lake J. Edwards E. Merion R. Wolfe R. Turcotte J. Teperman L. The new liver allocation system moving toward evidence-based transplantation policy.Liver Transpl. 2002; 8: 851-858Crossref PubMed Scopus (621) Google Scholar (see companion articles on liver transplantation in this issue). In general, noncirrhotic patients or patients with Child-Pugh class A or good Child-Pugh class B liver function are good candidates for partial hepatectomy. In contrast, patients who have Child-Pugh class B or C liver function and high MELD scores should be considered candidates for liver transplantation.Table 2Child-Pugh Classification System16Child C.G. Turcotte J.G. Surgery and portal hypertension.in: Child C.G. The liver and portal hypertension. Saunders, Philadelphia, PA1964: 50-62Google Scholar, 17Pugh R.N. Murray-Lyon I.M. Dawson J.L. Pietroni M.C. Williams R. Transection of the oesophagus for bleeding oesophageal varices.Br J Surg. 1973; 60: 646-649Crossref PubMed Scopus (6867) Google ScholarParameterPoints123Bilirubin (mg/dL)<22–3>3Albumin (g/dL)>3.52.8–3.5<2.8International normalized ratio<1.71.7–2.3>2.3AscitesNoneSlightModerateEncephalopathy (grade)NoneI-IIIII-IVChild-Pugh grade: sum of individual points for the above 5 variables.A: 5–6; B: 7–9; C: 10–15 Open table in a new tab Child-Pugh grade: sum of individual points for the above 5 variables. A: 5–6; B: 7–9; C: 10–15 A high level of α-fetoprotein (AFP) >400 ng/mL19Bruix J. Sherman M. Llovet J.M. Beaugrand M. Lencioni R. Burroughs A.K. Christensen E. Pagliaro L. Colombo M. Rodes J. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver.J Hepatol. 2001; 35: 421-430Abstract Full Text Full Text PDF PubMed Scopus (3799) Google Scholar or even 200 ng/mL20Nguyen M.H. Garcia R.T. Simpson P.W. Wright T.L. Keeffe E.B. Racial differences in effectiveness of alpha-fetoprotein for diagnosis of hepatocellular carcinoma in hepatitis C virus cirrhosis.Hepatology. 2002; 36: 410-417Crossref PubMed Scopus (138) Google Scholar) and a positive imaging investigation result is considered diagnostic of HCC. In these patients, a needle biopsy is not necessary. One Japanese study has shown that HCC can be diagnosed using a noninvasive approach with 99.6% accuracy, 100% sensitivity, and 98.9% specificity.21Torzilli G. Minagawa M. Takayama T. Inoue K. Hui A.M. Kubota K. Ohtomo K. Makuuchi M. Accurate preoperative evaluation of liver mass lesions without fine-needle biopsy.Hepatology. 1999; 30: 889-893Crossref PubMed Scopus (287) Google Scholar For patients with AFP < 200 ng/mL and lesions classic for HCC on imaging, biopsy is usually not necessary if the patient is otherwise a good surgical candidate. The clinical situations in which a preoperative percutaneous biopsy is useful are if (1) sufficient diagnostic uncertainty remains after radiologic imaging, (2) the patient is being considered for ablation or transplantation, or (3) the patient demands a definitive diagnosis before accepting hepatectomy as therapy. It is not necessary to definitively distinguish hepatic adenomas from HCC before resection. Hepatic adenomas are precancerous lesions that can also rupture and bleed, and should also be resected if technically feasible. Various pretreatment imaging techniques used for detection and characterization of liver lesions are also used in staging of HCC. The most useful and common techniques are percutaneous ultrasonography (US), multiphasic contrast-enhanced helical computed tomography (CT), CT arterial portography (CTAP), CT hepatic arteriography (CTHA) with lipiodol uptake CT, and magnetic resonance imaging (MRI). US is the most commonly used technique for assessment and screening of patients because of its noninvasive nature and low cost. It is, however, highly operator-dependent. US is a sensitive and specific tool for detecting large HCC nodules, and can detect 85%–95% of lesions 3–5 cm in diameter.22Ryder S.D. Guidelines for the diagnosis and treatment of hepatocellular carcinoma (HCC) in adults.Gut. 2003; 52: iii1-iii8PubMed Google Scholar It is a sensitive technique, often identifying small HCC lesions undetectable by CT, CTAP, angiogram, and lipiodol CT and MRI.23Teefey S.A. Hildeboldt C.C. Dehdashti F. Siegel B.A. Peters M.G. Heiken J.P. Brown J.J. McFarland E.G. Middleton W.D. Balfe D.M. Ritter J.H. Detection of primary hepatic malignancy in liver transplant candidates prospective comparison of CT, MR imaging, US, and PET.Radiology. 2003; 226: 533-542Crossref PubMed Scopus (185) Google Scholar, 24Tanaka Y. Sasaki Y. Katayama K. Hiramatsu N. Ito A. Murata H. Enomoto N. Oshita M. 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The typical US appearance of HCC is a heterogeneous nodule with peripheral sonolucency, lateral shadowing caused by a fibrotic pseudocapsule, and posterior acoustic enhancement.27Kamel I.R. Bluemke D.A. Imaging evaluation of hepatocellular carcinoma.J Vasc Interv Radiol. 2002; 13: S173-S184Abstract Full Text Full Text PDF PubMed Google Scholar The sonographic appearance for HCC may be either hypoechoic (caused by the presence of necrosis or sinusoidal dilatation) or hyperechoic (in the presence of hemorrhage, fatty change, or fibrosis).27Kamel I.R. Bluemke D.A. Imaging evaluation of hepatocellular carcinoma.J Vasc Interv Radiol. 2002; 13: S173-S184Abstract Full Text Full Text PDF PubMed Google Scholar, 28Szklaruk J. Silverman P.M. Charnsangavej C. Imaging in the diagnosis, staging, treatment, and surveillance of hepatocellular carcinoma.AJR Am J Roentgenol. 2003; 180: 441-454Crossref PubMed Scopus (57) Google Scholar Sonography is also very sensitive for the detection of vascular abnormalities that are commonly seen with HCC, including portal vein thrombosis, hepatic and portal vein invasion, or intrabiliary extension of tumor. In addition, the direction of portal blood flow can be assessed by Doppler ultrasound for evaluation of the degree of portal hypertension. In expert hands, US can determine the number, size, and distribution of lesions, as well as the relationship with the biliary tree, portal vein, hepatic vein, and inferior vena cava. At most centers, however, US is generally used as a screening tool or as an initial assessment tool. For further characterization and staging of hepatic tumors found with US, CT and its variations and MRI are commonly used. On an unenhanced CT, HCC appears hypodense, although in diffusely fatty liver it may appear hyperdense. It may appear as a solitary mass, as a dominant mass with satellite lesions, as multifocal masses, or as a diffusely infiltrating neoplasm. Three stages of contrast enhancement are suggested to optimize the detection of HCC.28Szklaruk J. Silverman P.M. Charnsangavej C. Imaging in the diagnosis, staging, treatment, and surveillance of hepatocellular carcinoma.AJR Am J Roentgenol. 2003; 180: 441-454Crossref PubMed Scopus (57) Google Scholar, 29Kim T. Murakami T. Takahashi S. Tsuda K. Tomoda K. Narumi Y. Oi H. Sakon M. Nakamura H. Optimal phases of dynamic CT for detecting hepatocellular carcinoma evaluation of unenhanced and triple-phase images.Abdom Imaging. 1999; 24: 473-480Crossref PubMed Scopus (77) Google Scholar, 30Kanematsu M. Oliver III, J.H. Carr B. Baron R.L. Hepatocellular carcinoma the role of helical biphasic contrast-enhanced CT versus CT during arterial portography.Radiology. 1997; 205: 75-80PubMed Google Scholar After infusion of contrast material at a rate of 4–8 mL/sec, the hepatic arterial phase is obtained at 20–30 sec (to detect hypervascular lesions); the early parenchymal phase is obtained at 40–55 sec, and the portal venous phase is obtained at 70–80 sec. A scan with the above 3 phases is a triple-phase scan, whereas a dual-phase scan has the early parenchymal phase omitted. HCC characteristically shows maximal enhancement during the hepatic arterial phase, and becomes hypoattenuating compared with the surrounding liver in the portal venous phase as a result of rapid washout of contrast. A heterogeneous attenuation may be seen (mosaic pattern). A capsule, if present, is usually hypodense on the hepatic arterial phase, is of mixed density on the portal venous phase, and shows enhancement on the delayed images.28Szklaruk J. Silverman P.M. Charnsangavej C. Imaging in the diagnosis, staging, treatment, and surveillance of hepatocellular carcinoma.AJR Am J Roentgenol. 2003; 180: 441-454Crossref PubMed Scopus (57) Google Scholar CTAP is an invasive variation of CT, requiring catheterization through the femoral artery and injection of contrast into the splenic and/or superior mesenteric arteries. Such contrast injection results in opacification of the hepatic parenchyma via the portal system while bypassing the hepatic arterial circulation. Most hepatic lesions supplied by the hepatic artery (including HCC and metastases) become hypoattenuated compared with the surrounding liver. CTAP is highly sensitive in the detection of small liver lesions, particularly small hepatic tumors such as HCC.31Kim H.C. Kim T.K. Sung K.B. Yoon H.K. Kim P.N. Ha H.K. Kim A.Y. Kim H.J. Lee M.G. 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Using multidetector CT for preoperative vascular evaluation of liver neoplasms technique and results.AJR Am J Roentgenol. 2002; 179: 53-59Crossref PubMed Scopus (117) Google Scholar HCC shows variable signal intensity on T1-weighted imaging: 35% have high signal intensity, 25% have isointensity, and 40% have low signal intensity compared with the surrounding liver parenchyma.27Kamel I.R. Bluemke D.A. Imaging evaluation of hepatocellular carcinoma.J Vasc Interv Radiol. 2002; 13: S173-S184Abstract Full Text Full Text PDF PubMed Google Scholar HCC classically shows high signal intensity on T2-weighted images and intense enhancement during the arterial phase of dynamic gadolinium-enhanced imaging.42Hussain S.M. Zondervan P.E. IJzermans J.N. Schalm S.W. de Man R.A. Krestin G.P. Benign versus malignant hepatic nodules MR imaging findings with pathologic correlation.Radiographics. 2002; 22: 1023-1036Crossref PubMed Scopus (153) Google Scholar A large HCC lesion may present with additional characteristic MRI features,42Hussain S.M. Zondervan P.E. IJzermans J.N. Schalm S.W. de Man R.A. Krestin G.P. Benign versus malignant hepatic nodules MR imaging findings with pathologic correlation.Radiographics. 2002; 22: 1023-1036Crossref PubMed Scopus (153) Google Scholar, 43Kadoya M. Matsui O. Takashima T. Nonomura A. Hepatoc