Case 23-2005 — A 57-Year-Old Man with a Mass in the Liver
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《新英格兰医药杂志》
Presentation of Case
A 57-year-old man was admitted to the hospital because of a mass in the liver.
The patient had been well until approximately two years before admission, when a diagnosis of chronic active hepatitis associated with hepatitis B virus (HBV) infection was made at another hospital. Lamivudine was started one year before admission; the results of liver-function tests returned to normal after the treatment was initiated, and the viral load fell. A surveillance ultrasonograpic examination of the abdominal area performed five months before admission revealed a mass, 3 cm in diameter, in the right lobe of the liver. Four months before admission, computed tomographic (CT) scanning and magnetic resonance imaging (MRI) of the abdominal area documented a mass, 4 cm in diameter, in the dome of the right lobe of the liver. Multiple cysts were also present.
Two months before admission, a percutaneous fine-needle aspiration biopsy of the liver was performed at another hospital; pathological examination of a specimen revealed a poorly differentiated carcinoma, thought to be hepatocellular carcinoma, cholangiocarcinoma, or metastatic carcinoma. The patient was evaluated at another hospital for liver transplantation, and it was determined that he was eligible, but his Model for End-Stage Liver Disease (MELD) score1 was low and it was unlikely that he would receive a transplant within the next six months.
Six weeks before admission, the patient was referred to the gastrointestinal cancer center at this hospital. He had lost 1.4 kg in the preceding five months but felt well. His medications were loratadine and lamivudine. He had undergone a cholecystectomy nine years earlier. He had a history of 10 pack-years of smoking but had stopped two years earlier; he rarely drank alcohol and did not abuse intravenous drugs. He was a native of China and had immigrated to the United States fifteen years earlier. He was married with two children, who were well. His father was alive and well in his eighties, his mother had died in her seventies from congestive heart failure, and two of his five siblings were known to have hepatitis B infection.
On physical examination, the patient was a slender man who appeared to be well and without jaundice. His vital signs were normal. His performance status was 0, on a scale from 0 to 5 (with 0 indicating no adverse effects on his activity from the disease and 5 indicating death). The physical examination revealed no abnormalities. The results of a complete blood count and the serum levels of glucose, electrolytes, albumin, globulin, and bilirubin were all within the normal range, as were the results of renal-function and coagulation tests. The level of alanine aminotransferase was 135 U per liter and that of aspartate aminotransferase was 78 U per liter. The level of carcinoembryonic antigen was 1.6 ng per milliliter (1.6 μg per liter), and the alpha-fetoprotein level was 2.6 ng per milliliter (2.6 μg per liter).
Chest, abdominal, and pelvic CT scanning revealed an enhancing mass (Figure 1), 4.7 cm by 4.5 cm, within the right lobe of the liver and multiple hepatic cysts. There was no evidence of metastatic disease. MRI scanning of the liver showed simple cysts and an arterially enhancing, encapsulated lesion, 4.7 cm by 4.5 cm, straddling the right and left lobes of the liver.
Figure 1. Axial CT Images of the Liver.
An arterial-phase CT image (Panel A), obtained after the administration of contrast material, shows heterogeneous arterial enhancement and a hepatic mass, 4.7 cm by 4.5 cm (arrow). In the delayed-phase CT image (Panel B), the mass shows delayed enhancement of a peripheral capsule (arrow). The mass straddles the middle hepatic vein and is located in both segments IV and VIII of the liver. No gross venous invasion or evidence of cirrhosis is seen in the image.
The patient was admitted to the hospital and a diagnostic procedure was performed.
Discussion of Management
Dr. Michael A. Blake: Axial enhanced CT images were obtained during several phases after the administration of intravenous contrast material, including the arterial phase (Figure 1A), portal venous phase, and delayed phase (Figure 1B). These images, from an examination that had been performed approximately five weeks before admission, show a round mass, 4.7 cm by 4.5 cm, in the dome of the liver. They show heterogeneous arterial enhancement, heterogeneous enhancement on the portal venous phase, and delayed peripheral rim enhancement of a capsule. The mass straddles the middle hepatic vein, but there is no evidence of venous invasion, lymphadenopathy, or cirrhosis.
T1- and T2-weighted MRI scans show that the mass is hypointense relative to the liver (on the T1-weighted images) with a faint hypointense capsule, and slightly hyperintense relative to the liver on the T2-weighted images (Figure 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org). After the administration of gadolinium, T1-weighted images reveal heterogeneous central enhancement of the mass on arterial-phase images, heterogeneous enhancement on portal venous–phase images, and capsular enhancement (Figure 2 of the Supplementary Appendix). There is no evidence of venous invasion or cirrhosis.
The information provided by MRI with gadolinium is similar to that of triphasic CT scanning with regard to tumor enhancement and, in addition, provides greater intrinsic information about tissue characteristics; thus, gadolinium-enhanced MRI is the imaging method of choice for characterization of hepatic lesions.2 The overall appearance of this lesion is most consistent with a hepatocellular carcinoma in a patient with hepatitis. Other tumors that have a similar appearance on imaging, but less commonly, include an adenoma and, rarely, a hypervascular metastasis.
Hepatitis B Infection and Hepatocellular Carcinoma
Dr. Raymond T. Chung: This patient had chronic active HBV infection. He had emigrated from China, where HBV is endemic. He is likely to have contracted HBV perinatally, since two of his siblings were also infected. Epidemiologic studies have firmly identified chronic infection with HBV as a major risk factor for the development of hepatocellular carcinoma.3
HBV, a member of the family Hepadnaviridae, is a partially double-stranded DNA virus, the genome of which contains four partially open reading frames that overlap. These frames encode the pre-S1-S2-S, precore–core, polymerase, and X proteins. The pre-S1-S2-S gene product is processed to become hepatitis B surface antigen (HBsAg); the secretion of HBsAg from hepatocytes indicates chronic infection. In most cases, the gene products from the precore or core region yield secreted hepatitis B e antigen (HBeAg), a marker of active replication that can also be confirmed by molecular tests for circulating HBV DNA. Perinatal exposure to HBV is associated with high rates (90 percent) of chronic infection, which may alternate between replicative and nonreplicative phases.
A diagnosis of hepatocellular carcinoma was made in this patient a few months before admission. HBV contributes to hepatocarcinogenesis through several mechanisms (Figure 2).4 HBV can be integrated into the DNA of the host chromosomes, where random insertion adjacent to proto-oncogenes or tumor-suppressor genes could activate proliferative pathways. In addition, the HBV X protein may itself be oncogenic.5 Finally, active viral replication in the liver causes a necrotizing inflammatory response, with necrosis and regeneration of hepatocytes, that results in an increase in the risk of the accumulation of mutations that contribute to malignant transformation.6 Fibrosis and cirrhosis ultimately develop; in general, hepatic cirrhosis from most causes is associated with an increased risk of hepatocellular carcinoma. The risk of hepatocellular carcinoma was increased 10 times among HBsAg-positive men in a recent study, as compared with those who were not HBsAg-positive, and 60 times among men who were both HBsAg-positive and HBeAg-positive, as compared with those who were not; this risk of cancer increased with age.7
Figure 2. Schematic Representation of the Development of Hepatocarcinogenesis in Association with HBV.
After acute infection with HBV, the paucity of a cytolytic immune response (as is seen in perinatally acquired infection) leads to the inactive carrier state. In contrast, a vigorous immune response (as is seen in infection acquired in adulthood) is associated with successful viral clearance. Between these two states, chronic hepatitis prevails, in which a nonclearing immune response produces ongoing inflammation, injury, and repair, resulting in an increase in cell turnover and oxidative stress. In this setting, cellular DNA damage, chromosomal abnormalities, and genetic mutations occur. In addition, direct viral effects, including insertional mutagenesis and possible direct effects of the hepatitis B X protein, ultimately result in loss of cell growth control and set the stage for malignant transformation in the form of hepatocellular carcinoma (HCC). The illustration is adapted from Chisari.4
Because replicative HBV infection is associated with an increased risk of chronic hepatitis, hepatic cirrhosis, liver failure, and hepatocellular carcinoma, antiviral therapy has become an important intervention in preventing or slowing the progression of HBV-associated liver disease. Lamivudine, which was given to the patient under discussion, is a nucleoside analogue that is one of four regimens approved by the Food and Drug Administration (along with interferon alfa, adefovir, and entecavir) for treating replicative HBV disease. This drug improves histopathological findings in the liver and the structure of liver tissue, increases the rate of HBeAg seroconversion, and may result in improved hepatic function and a decreased risk of hepatocellular carcinoma.8
Because of the increased risk of hepatocellular carcinoma associated with chronic HBV infection, patients such as the man in the case under discussion should undergo surveillance.9 Although recommendations vary as to frequency, regular screening by means of measurements of serum alpha-fetoprotein and ultrasonography appears to be cost-effective in persons from areas where the infection is endemic10; such screening is associated with the detection of tumors at a treatable stage in the majority of cases. This patient was at high risk for hepatocellular carcinoma, and his tumor was detected at a relatively early stage.
The patient in this case did not yet have cirrhosis, but for the many who do, the management of hepatocellular carcinoma poses a special challenge. Hepatocellular carcinoma in the cirrhotic liver may be multifocal, and recurrence rates after curative resections are high. Liver transplantation as a means of removing premalignant tissue is a curative procedure for carefully selected patients with hepatocellular carcinoma who have cirrhotic livers.
Pretreatment Staging of Hepatocellular Carcinoma
Dr. Lawrence S. Blaszkowsky: The stage of most solid tumors can be determined with the use of the American Joint Committee on Cancer Staging System, also known as the tumor–node–metastasis (TNM) system.11 It was recently modified for hepatocellular carcinoma in recognition of the prognostic importance of vascular invasion, and it distinguishes between major and minor vascular invasion; the latter may not be appreciated on preoperative evaluation. However, the majority of patients with hepatocellular carcinoma have advanced liver disease, and they often die of hepatic failure, rather than from extrahepatic tumor progression. The TNM staging system does not take into account the degree of hepatic dysfunction.
The Okuda Staging System was the first to include factors reflecting hepatic function in addition to tumor characteristics. It categorizes the disease in three stages on the basis of the size of the patient's tumor (greater than vs. less than or equal to 50 percent of the liver volume), levels of total bilirubin (greater than vs. less than or equal to 3 mg per deciliter) and albumin (greater than vs. less than or equal to 3 g per deciliter), and the presence or absence of ascites.12 Problems in determining the correct stage include the difficulty of accurately estimating the volume of tumor, the fact that the bilirubin level used as a criterion is so high that even those below the cutoff may have severe liver dysfunction, and the failure to integrate vascular invasion into the model. Furthermore, because of improvements in screening and radiographic techniques, many patients are now given a diagnosis with smaller tumors than was the case for the patients used in developing the model, so that more stages are needed to stratify these early tumors according to risk.
The Child–Turcotte–Pugh classification is commonly used by gastroenterologists to characterize the degree of hepatic dysfunction; it represents a composite score for the serum bilirubin level, prothrombin time, albumin level, stage of encephalopathy, and extent of ascites. There are three classes (A, B, C), with A the least sick and C the most sick. There are now several staging systems for hepatocellular carcinoma that take into account important factors from the Child–Turcotte–Pugh system, in addition to tumor-specific prognostic factors.13,14,15,16 Among these systems, the Cancer of the Liver Italian Program (CLIP) score has been validated by several groups and in populations of patients with HBV and hepatitis C virus infections. On the basis of this patient's preoperative evaluation, his CLIP score was 0 on a scale from 0 to 6 (with 0 representing the best prognosis and 6 the poorest). This score corresponds to a median survival of 31 to 69 months.
Primary Treatment of Hepatocellular Carcinoma
Dr. Kenneth K. Tanabe: Of the several treatment options available for this patient's hepatocellular carcinoma, liver transplantation has the benefits of simultaneous removal of the primary cancer and replacement of the underlying cirrhotic liver, from which subsequent cancers may arise. Disadvantages include the adverse effects of immune suppression on cancer control and the relative shortage of donor livers, which leads to prolonged waiting times for recipients. The results of liver transplantation are poor for tumors of an advanced stage, but relatively good for tumors that are small and incidentally identified in explanted livers.17,18
Because of the long wait for donor organs, more than 20 percent of patients need to consider other treatment options during the waiting period and do not actually undergo transplantation.19 In the case of this patient, because of his normal liver function, the wait for a transplant was estimated to be greater than six months. However, his tumor had grown rapidly, from 3 cm to 4.7 cm in diameter over a short interval, and we thought that continued tumor progression while awaiting liver transplantation would soon render him ineligible for transplantation because of the tumor size.
Several strategies have been developed to reduce the number of patients who drop out before liver transplantation because of tumor progression. The availability of a living donor essentially eliminates the issue of waiting times. However, the short-term and long-term risks to the donor are not yet well defined and raise important ethical issues concerning the appropriateness of this strategy.20 Transcatheter arterial chemoembolization, percutaneous ethanol injection, and radiofrequency ablation have been used in the hope that they may serve as "bridges" to transplantation. The absence of data from prospective, randomized, controlled trials of these bridging treatments precludes a clear understanding as to whether any of these strategies improves the outcome.
Percutaneous ethanol injection and radiofrequency ablation could also be considered primary treatment options for this patient. Percutaneous ethanol injection is associated with survival statistics that approach those for partial hepatectomy in patients with Child–Turcotte–Pugh class A or B cirrhosis and a single tumor.21 Radiofrequency ablation requires fewer treatments than percutaneous ethanol injection and leads to similar survival rates in studies with relatively short follow-up.22 Local recurrences after radiofrequency ablation of hepatocellular carcinomas are more common in tumors that are larger than 4 cm in size than in smaller tumors. This patient's tumor was approximately 4.7 cm in diameter, so his chances of recurrence after either of these procedures were high.
Because this patient's tumor straddled the right and left functional lobes of the liver, resection options included either an extended left hepatectomy or an extended right hepatectomy (Figure 3).23 The risk of postoperative liver failure after extensive resection is high when there is underlying liver disease, such as the hepatitis in this patient. We therefore opted to perform a central hepatectomy.24 This operation preserves more of the liver than an extended left or right hepatectomy and thereby reduces the risk of postoperative liver failure. The patient had transient mild hepatic insufficiency after the surgery, but he had recovered enough by the seventh postoperative day to be discharged home.
Figure 3. Anatomy of the Liver and the Implications for Partial Hepatectomy.
Panel A shows the functional anatomy of the liver. The left, middle, and right hepatic veins functionally divide the liver into four sectors, and these are further subdivided based on the portal inflow — into a total of eight segments. Panel B shows the morphologic anatomy, in which the right lobe and left lobe are divided by the falciform ligament and umbilical fissure (not shown). The tumor (tan circle) straddled segments IV and VIII. An extended right hepatectomy would remove segments IV through VIII and an extended left hepatectomy would remove segments II through V and VIII. A central hepatectomy, the surgical removal of individual segments (IV, V, and VIII), would allow for preservation of more liver tissue than either the extended left or extended right hepatectomy and would remove entirely those segments that were at greatest risk for intrahepatic micrometastases.
Pathological Discussion
Dr. Gregory Y. Lauwers: The resected liver specimen contained a well-circumscribed mass measuring 4.5 cm in greatest dimension, with the gross characteristics of a hepatocellular carcinoma. The TNM classification uses a cutoff of 5 cm to stratify hepatocellular carcinomas, and there is a statistically significant difference in overall survival, disease-free survival, and the frequency of intrahepatic and hematogenous metastases, as well as portal-vein thrombosis, in the case of tumors that are larger than 5 cm in diameter, as compared with those that are 5 cm or less.11,25,26
The pattern of growth in this tumor was classified as single nodular, or type 1 of the classification of the Liver Cancer Study Group of Japan.27 Different patterns of growth have been associated with varying risks of intrahepatic and extrahepatic spread.28 Type 1 nodular cancer is associated with the best prognosis, with only a 20 percent rate of recurrence at two years.29
The resection margin was negative, with a clearance of 0.5 cm. The importance of ensuring a wide surgical clearance in resections of hepatocellular carcinoma is controversial. Some reports have shown that a clearance of less than 1 cm is associated with higher rates of intrahepatic recurrence, but other reports have not.30,31,32 A critical argument against the usefulness of the 1-cm clearance is the frequent detection of synchronous tumors in the residual liver.
The surrounding parenchyma showed various degrees of fibrosis, but no established cirrhosis. In the short term, despite an initially increased operative risk, patients with cirrhosis who have a good hepatic reserve fare as well as patients who do not have cirrhosis.33 However, in patients who had survived at least five years after their initial surgery, moderate-to-severe fibrosis in the remnant liver was the most important predictor of higher mortality.34
The microscopical examination of the tumor revealed a complete fibrous capsule (Figure 4A). Encapsulation has not been shown to be a significant prognostic indicator of survival in a large multivariate analysis.32,34,35 The tumor was formed of compact, thickened plates of hepatocytes (Figure 4A, inset). The neoplastic hepatocytes had moderate atypia, and the tumor was classified as histologic grade 2. On the basis of a review of 425 curatively resected hepatocellular carcinomas, it was concluded that tumors of grade 1 (good prognosis) and grades 3 to 4 (poor prognosis) were significant predictors of survival in a multivariate analysis, but that tumors of intermediate grade (grade 2) could have either a good or poor prognosis, depending on the presence or absence of microscopic vascular invasion.32,36,37 Further evaluation of the specimen from this patient revealed microvascular invasion of a medium-sized vein (Figure 4B); this was not a surprising finding, since the prevalence of such microvascular invasion is about 50 percent in tumors that measure more than 4 cm.38
Figure 4. Pathology of the Liver Tumor.
The resected tumor was completely encapsulated (Panel A, hematoxylin and eosin). Microscopical examination revealed a fibrous capsule that was several millimeters thick at the interface. The tumor has a compact macrotrabecular architectural pattern (Panel A, inset). The cytologic features indicate a moderately differentiated hepatocellular carcinoma. Microvascular invasion was identified (Panel B, trichrome stain) in the form of a malignant thrombus that was away from the tumor, in the surrounding hepatic parenchyma.
On the basis of the histologic findings (size, vascular invasion, and limited fibrosis), this tumor was classified as stage 1 T2F0, according to the newly modified American Joint Committee on Cancer classification. Despite the relatively small size of the tumor, the presence of microvascular invasion and the moderate nuclear grade place the patient in a category of patients with a poor prognosis. According to a hepatocellular prognostic index designed in 2002 and based solely on histologic characteristics, the median survival after surgical resection alone of patients with tumors such as this, with microvascular invasion and a moderate nuclear grade, was calculated to be about 2.7 years.26,35
Adjuvant Treatment
Dr. Tanabe: Since the risk of relapse after primary treatment of hepatocellular carcinoma is high, several adjuvant therapies have been examined in clinical trials. Treatment with transarterial chemoembolization, interferon alfa, interferon beta, and adoptive immunotherapy has been associated with a reduction in the rate of recurrence of tumor in the liver, but not with improved survival, as compared with observation alone. Treatment with both intraarterial iodine-131–labeled ethiodized oil (Lipiodol)39 and polyprenoic acid, an analogue of vitamin A that inhibits hepatocarcinogenesis in rodents, has produced a reduction in tumor recurrence and an improvement in overall survival, as compared with observation, in randomized clinical trials.40,41 These agents are not yet available in the United States.
Dr. Blaszkowsky: The patient was not treated with adjuvant therapy after surgery, because of the lack of available effective agents. Eight months after his surgery, a follow-up MRI suggested that there had been a recurrence.
Dr. Blake: Gadolinium-enhanced T1-weighted images from the follow-up evaluation showed no evidence of local recurrence in the region of the resection site. However, there were new arterially enhancing masses scattered through the liver, which on delayed imaging showed peripheral rim enhancement (Figure 5, and Figure 3 of the Supplementary Appendix). These findings are consistent with metastatic disease or multifocal hepatocellular carcinoma.
Figure 5. A Follow-up, T1-Weighted Axial MRI, Obtained after the Administration of Gadolinium.
Eight months after the patient had undergone a partial hepatectomy, an MRI through the liver dome in delayed phase showed several small masses scattered throughout the liver. The masses show delayed peripheral enhancement (arrows) that was consistent with metastases or multifocal hepatocellular carcinoma.
Dr. Blaszkowsky: Since this patient now had at least eight or nine lesions in his liver, he was not a candidate for transplantation. There are several nonsurgical techniques that were options for this patient: percutaneous ethanol injection, percutaneous thermal ablation, systemic chemotherapy, hormonal therapy, interferon, novel agents, transhepatic arterial chemoembolization, and radiation therapy.
Systemic chemotherapy has had little impact on the course of hepatocellular carcinoma, and rates of response to most agents rarely exceed 10 percent.42 Hepatocellular carcinomas often express hormone receptors such as estrogen or somatostatin receptors. Seven randomized clinical trials were unable to demonstrate an antitumor effect of treatment with tamoxifen in hepatocellular carcinoma.43 Although there was no reduction in tumor volume, two of three relatively small, randomized clinical trials evaluating somatostatin analogues showed a statistically significant improvement in survival. There has recently been interest in thalidomide as a therapeutic drug. When it is used as a single agent, response rates are 5 to 7 percent, but in one report of 15 patients treated with thalidomide and capecitabine, the response rate was 18 percent, with 45 percent of the patients having stable disease.44 Treatment with interferon is minimally active, with considerable toxicity. None of these agents offered the patient under discussion much hope of prolonged survival.
Transhepatic arterial chemoembolization in hepatocellular carcinoma is associated with a response rate of approximately 35 percent. After several randomized clinical trials did not show a statistically significant improvement in survival, two randomized clinical trials did show an improvement in survival of up to two years in patients who received this treatment as compared with those who did not: in one trial, the two-year survival rate was 63 percent, as compared with 27 percent; in the other trial, the two-year survival rate was 31 percent, as compared with 11 percent.45,46 Use of chemoembolization rather than bland embolization was also associated with a reduction in the development of portal-vein thrombosis. In carefully selected patients, transhepatic arterial chemoembolization may be the most effective treatment currently available. Transhepatic arterial chemoembolization was a reasonable option for this patient; however, he declined the offer of this therapy.
The use of radiation therapy has been limited in hepatocellular carcinoma because of the sensitivity of the liver to radiation. The normal liver can typically tolerate 30 Gy. In selective internal-radiation therapy, yttrium-90–labeled resin-based or glass microspheres are infused into the hepatic artery, resulting in a target dose of 100 Gy to the tumor. One study using this method showed a response rate of 27 percent in 71 patients with unresectable tumors, and 4 of those patients ultimately underwent resection.47 This therapy is currently not widely available.
Since outcomes with currently available chemotherapeutic agents are disappointing, we offer all patients the option of participation in a clinical trial when available. This patient volunteered to participate in a clinical trial of gemcitabine, oxaliplatin, and the vascular endothelial growth factor–receptor inhibitor bevacizumab, but he had to drop out because of severe nosebleeds that required packing and transfusions. He was then observed for several months, during which he remained asymptomatic. He is now participating in a phase 1–2 clinical trial of a polyamine analogue, N1,N11-diethylnorspermine. After two months of therapy, CT scans show stable disease in the liver without extrahepatic spread. He remains asymptomatic two years after the partial hepatectomy.
Anatomical Diagnosis
Hepatocellular carcinoma.
Dr. Tanabe reports having received consulting fees from Ethicon Endosurgery. Dr. Blaszkowsky reports holding stock in Pfizer and having received lecture fees from Genentech.
Source Information
From the Departments of Surgical Oncology (K.K.T.), Hematology–Oncology (L.S.B.), Medicine, Gastrointestinal Unit (R.T.C.), Radiology (M.A.B.), and Pathology (G.Y.L.), Massachusetts General Hospital; and the Departments of Surgery, (K.K.T.), Medicine (L.S.B., R.T.C.), Radiology (M.A.B.), and Pathology (G.Y.L.), Harvard Medical School.
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Lau WY, Ho S, Leung TW, et al. Selective internal radiation therapy for nonresectable hepatocellular carcinoma with intraarterial infusion of 90yttrium microspheres. Int J Radiat Oncol Biol Phys 1998;40:583-592.(Kenneth K. Tanabe, M.D., )
A 57-year-old man was admitted to the hospital because of a mass in the liver.
The patient had been well until approximately two years before admission, when a diagnosis of chronic active hepatitis associated with hepatitis B virus (HBV) infection was made at another hospital. Lamivudine was started one year before admission; the results of liver-function tests returned to normal after the treatment was initiated, and the viral load fell. A surveillance ultrasonograpic examination of the abdominal area performed five months before admission revealed a mass, 3 cm in diameter, in the right lobe of the liver. Four months before admission, computed tomographic (CT) scanning and magnetic resonance imaging (MRI) of the abdominal area documented a mass, 4 cm in diameter, in the dome of the right lobe of the liver. Multiple cysts were also present.
Two months before admission, a percutaneous fine-needle aspiration biopsy of the liver was performed at another hospital; pathological examination of a specimen revealed a poorly differentiated carcinoma, thought to be hepatocellular carcinoma, cholangiocarcinoma, or metastatic carcinoma. The patient was evaluated at another hospital for liver transplantation, and it was determined that he was eligible, but his Model for End-Stage Liver Disease (MELD) score1 was low and it was unlikely that he would receive a transplant within the next six months.
Six weeks before admission, the patient was referred to the gastrointestinal cancer center at this hospital. He had lost 1.4 kg in the preceding five months but felt well. His medications were loratadine and lamivudine. He had undergone a cholecystectomy nine years earlier. He had a history of 10 pack-years of smoking but had stopped two years earlier; he rarely drank alcohol and did not abuse intravenous drugs. He was a native of China and had immigrated to the United States fifteen years earlier. He was married with two children, who were well. His father was alive and well in his eighties, his mother had died in her seventies from congestive heart failure, and two of his five siblings were known to have hepatitis B infection.
On physical examination, the patient was a slender man who appeared to be well and without jaundice. His vital signs were normal. His performance status was 0, on a scale from 0 to 5 (with 0 indicating no adverse effects on his activity from the disease and 5 indicating death). The physical examination revealed no abnormalities. The results of a complete blood count and the serum levels of glucose, electrolytes, albumin, globulin, and bilirubin were all within the normal range, as were the results of renal-function and coagulation tests. The level of alanine aminotransferase was 135 U per liter and that of aspartate aminotransferase was 78 U per liter. The level of carcinoembryonic antigen was 1.6 ng per milliliter (1.6 μg per liter), and the alpha-fetoprotein level was 2.6 ng per milliliter (2.6 μg per liter).
Chest, abdominal, and pelvic CT scanning revealed an enhancing mass (Figure 1), 4.7 cm by 4.5 cm, within the right lobe of the liver and multiple hepatic cysts. There was no evidence of metastatic disease. MRI scanning of the liver showed simple cysts and an arterially enhancing, encapsulated lesion, 4.7 cm by 4.5 cm, straddling the right and left lobes of the liver.
Figure 1. Axial CT Images of the Liver.
An arterial-phase CT image (Panel A), obtained after the administration of contrast material, shows heterogeneous arterial enhancement and a hepatic mass, 4.7 cm by 4.5 cm (arrow). In the delayed-phase CT image (Panel B), the mass shows delayed enhancement of a peripheral capsule (arrow). The mass straddles the middle hepatic vein and is located in both segments IV and VIII of the liver. No gross venous invasion or evidence of cirrhosis is seen in the image.
The patient was admitted to the hospital and a diagnostic procedure was performed.
Discussion of Management
Dr. Michael A. Blake: Axial enhanced CT images were obtained during several phases after the administration of intravenous contrast material, including the arterial phase (Figure 1A), portal venous phase, and delayed phase (Figure 1B). These images, from an examination that had been performed approximately five weeks before admission, show a round mass, 4.7 cm by 4.5 cm, in the dome of the liver. They show heterogeneous arterial enhancement, heterogeneous enhancement on the portal venous phase, and delayed peripheral rim enhancement of a capsule. The mass straddles the middle hepatic vein, but there is no evidence of venous invasion, lymphadenopathy, or cirrhosis.
T1- and T2-weighted MRI scans show that the mass is hypointense relative to the liver (on the T1-weighted images) with a faint hypointense capsule, and slightly hyperintense relative to the liver on the T2-weighted images (Figure 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org). After the administration of gadolinium, T1-weighted images reveal heterogeneous central enhancement of the mass on arterial-phase images, heterogeneous enhancement on portal venous–phase images, and capsular enhancement (Figure 2 of the Supplementary Appendix). There is no evidence of venous invasion or cirrhosis.
The information provided by MRI with gadolinium is similar to that of triphasic CT scanning with regard to tumor enhancement and, in addition, provides greater intrinsic information about tissue characteristics; thus, gadolinium-enhanced MRI is the imaging method of choice for characterization of hepatic lesions.2 The overall appearance of this lesion is most consistent with a hepatocellular carcinoma in a patient with hepatitis. Other tumors that have a similar appearance on imaging, but less commonly, include an adenoma and, rarely, a hypervascular metastasis.
Hepatitis B Infection and Hepatocellular Carcinoma
Dr. Raymond T. Chung: This patient had chronic active HBV infection. He had emigrated from China, where HBV is endemic. He is likely to have contracted HBV perinatally, since two of his siblings were also infected. Epidemiologic studies have firmly identified chronic infection with HBV as a major risk factor for the development of hepatocellular carcinoma.3
HBV, a member of the family Hepadnaviridae, is a partially double-stranded DNA virus, the genome of which contains four partially open reading frames that overlap. These frames encode the pre-S1-S2-S, precore–core, polymerase, and X proteins. The pre-S1-S2-S gene product is processed to become hepatitis B surface antigen (HBsAg); the secretion of HBsAg from hepatocytes indicates chronic infection. In most cases, the gene products from the precore or core region yield secreted hepatitis B e antigen (HBeAg), a marker of active replication that can also be confirmed by molecular tests for circulating HBV DNA. Perinatal exposure to HBV is associated with high rates (90 percent) of chronic infection, which may alternate between replicative and nonreplicative phases.
A diagnosis of hepatocellular carcinoma was made in this patient a few months before admission. HBV contributes to hepatocarcinogenesis through several mechanisms (Figure 2).4 HBV can be integrated into the DNA of the host chromosomes, where random insertion adjacent to proto-oncogenes or tumor-suppressor genes could activate proliferative pathways. In addition, the HBV X protein may itself be oncogenic.5 Finally, active viral replication in the liver causes a necrotizing inflammatory response, with necrosis and regeneration of hepatocytes, that results in an increase in the risk of the accumulation of mutations that contribute to malignant transformation.6 Fibrosis and cirrhosis ultimately develop; in general, hepatic cirrhosis from most causes is associated with an increased risk of hepatocellular carcinoma. The risk of hepatocellular carcinoma was increased 10 times among HBsAg-positive men in a recent study, as compared with those who were not HBsAg-positive, and 60 times among men who were both HBsAg-positive and HBeAg-positive, as compared with those who were not; this risk of cancer increased with age.7
Figure 2. Schematic Representation of the Development of Hepatocarcinogenesis in Association with HBV.
After acute infection with HBV, the paucity of a cytolytic immune response (as is seen in perinatally acquired infection) leads to the inactive carrier state. In contrast, a vigorous immune response (as is seen in infection acquired in adulthood) is associated with successful viral clearance. Between these two states, chronic hepatitis prevails, in which a nonclearing immune response produces ongoing inflammation, injury, and repair, resulting in an increase in cell turnover and oxidative stress. In this setting, cellular DNA damage, chromosomal abnormalities, and genetic mutations occur. In addition, direct viral effects, including insertional mutagenesis and possible direct effects of the hepatitis B X protein, ultimately result in loss of cell growth control and set the stage for malignant transformation in the form of hepatocellular carcinoma (HCC). The illustration is adapted from Chisari.4
Because replicative HBV infection is associated with an increased risk of chronic hepatitis, hepatic cirrhosis, liver failure, and hepatocellular carcinoma, antiviral therapy has become an important intervention in preventing or slowing the progression of HBV-associated liver disease. Lamivudine, which was given to the patient under discussion, is a nucleoside analogue that is one of four regimens approved by the Food and Drug Administration (along with interferon alfa, adefovir, and entecavir) for treating replicative HBV disease. This drug improves histopathological findings in the liver and the structure of liver tissue, increases the rate of HBeAg seroconversion, and may result in improved hepatic function and a decreased risk of hepatocellular carcinoma.8
Because of the increased risk of hepatocellular carcinoma associated with chronic HBV infection, patients such as the man in the case under discussion should undergo surveillance.9 Although recommendations vary as to frequency, regular screening by means of measurements of serum alpha-fetoprotein and ultrasonography appears to be cost-effective in persons from areas where the infection is endemic10; such screening is associated with the detection of tumors at a treatable stage in the majority of cases. This patient was at high risk for hepatocellular carcinoma, and his tumor was detected at a relatively early stage.
The patient in this case did not yet have cirrhosis, but for the many who do, the management of hepatocellular carcinoma poses a special challenge. Hepatocellular carcinoma in the cirrhotic liver may be multifocal, and recurrence rates after curative resections are high. Liver transplantation as a means of removing premalignant tissue is a curative procedure for carefully selected patients with hepatocellular carcinoma who have cirrhotic livers.
Pretreatment Staging of Hepatocellular Carcinoma
Dr. Lawrence S. Blaszkowsky: The stage of most solid tumors can be determined with the use of the American Joint Committee on Cancer Staging System, also known as the tumor–node–metastasis (TNM) system.11 It was recently modified for hepatocellular carcinoma in recognition of the prognostic importance of vascular invasion, and it distinguishes between major and minor vascular invasion; the latter may not be appreciated on preoperative evaluation. However, the majority of patients with hepatocellular carcinoma have advanced liver disease, and they often die of hepatic failure, rather than from extrahepatic tumor progression. The TNM staging system does not take into account the degree of hepatic dysfunction.
The Okuda Staging System was the first to include factors reflecting hepatic function in addition to tumor characteristics. It categorizes the disease in three stages on the basis of the size of the patient's tumor (greater than vs. less than or equal to 50 percent of the liver volume), levels of total bilirubin (greater than vs. less than or equal to 3 mg per deciliter) and albumin (greater than vs. less than or equal to 3 g per deciliter), and the presence or absence of ascites.12 Problems in determining the correct stage include the difficulty of accurately estimating the volume of tumor, the fact that the bilirubin level used as a criterion is so high that even those below the cutoff may have severe liver dysfunction, and the failure to integrate vascular invasion into the model. Furthermore, because of improvements in screening and radiographic techniques, many patients are now given a diagnosis with smaller tumors than was the case for the patients used in developing the model, so that more stages are needed to stratify these early tumors according to risk.
The Child–Turcotte–Pugh classification is commonly used by gastroenterologists to characterize the degree of hepatic dysfunction; it represents a composite score for the serum bilirubin level, prothrombin time, albumin level, stage of encephalopathy, and extent of ascites. There are three classes (A, B, C), with A the least sick and C the most sick. There are now several staging systems for hepatocellular carcinoma that take into account important factors from the Child–Turcotte–Pugh system, in addition to tumor-specific prognostic factors.13,14,15,16 Among these systems, the Cancer of the Liver Italian Program (CLIP) score has been validated by several groups and in populations of patients with HBV and hepatitis C virus infections. On the basis of this patient's preoperative evaluation, his CLIP score was 0 on a scale from 0 to 6 (with 0 representing the best prognosis and 6 the poorest). This score corresponds to a median survival of 31 to 69 months.
Primary Treatment of Hepatocellular Carcinoma
Dr. Kenneth K. Tanabe: Of the several treatment options available for this patient's hepatocellular carcinoma, liver transplantation has the benefits of simultaneous removal of the primary cancer and replacement of the underlying cirrhotic liver, from which subsequent cancers may arise. Disadvantages include the adverse effects of immune suppression on cancer control and the relative shortage of donor livers, which leads to prolonged waiting times for recipients. The results of liver transplantation are poor for tumors of an advanced stage, but relatively good for tumors that are small and incidentally identified in explanted livers.17,18
Because of the long wait for donor organs, more than 20 percent of patients need to consider other treatment options during the waiting period and do not actually undergo transplantation.19 In the case of this patient, because of his normal liver function, the wait for a transplant was estimated to be greater than six months. However, his tumor had grown rapidly, from 3 cm to 4.7 cm in diameter over a short interval, and we thought that continued tumor progression while awaiting liver transplantation would soon render him ineligible for transplantation because of the tumor size.
Several strategies have been developed to reduce the number of patients who drop out before liver transplantation because of tumor progression. The availability of a living donor essentially eliminates the issue of waiting times. However, the short-term and long-term risks to the donor are not yet well defined and raise important ethical issues concerning the appropriateness of this strategy.20 Transcatheter arterial chemoembolization, percutaneous ethanol injection, and radiofrequency ablation have been used in the hope that they may serve as "bridges" to transplantation. The absence of data from prospective, randomized, controlled trials of these bridging treatments precludes a clear understanding as to whether any of these strategies improves the outcome.
Percutaneous ethanol injection and radiofrequency ablation could also be considered primary treatment options for this patient. Percutaneous ethanol injection is associated with survival statistics that approach those for partial hepatectomy in patients with Child–Turcotte–Pugh class A or B cirrhosis and a single tumor.21 Radiofrequency ablation requires fewer treatments than percutaneous ethanol injection and leads to similar survival rates in studies with relatively short follow-up.22 Local recurrences after radiofrequency ablation of hepatocellular carcinomas are more common in tumors that are larger than 4 cm in size than in smaller tumors. This patient's tumor was approximately 4.7 cm in diameter, so his chances of recurrence after either of these procedures were high.
Because this patient's tumor straddled the right and left functional lobes of the liver, resection options included either an extended left hepatectomy or an extended right hepatectomy (Figure 3).23 The risk of postoperative liver failure after extensive resection is high when there is underlying liver disease, such as the hepatitis in this patient. We therefore opted to perform a central hepatectomy.24 This operation preserves more of the liver than an extended left or right hepatectomy and thereby reduces the risk of postoperative liver failure. The patient had transient mild hepatic insufficiency after the surgery, but he had recovered enough by the seventh postoperative day to be discharged home.
Figure 3. Anatomy of the Liver and the Implications for Partial Hepatectomy.
Panel A shows the functional anatomy of the liver. The left, middle, and right hepatic veins functionally divide the liver into four sectors, and these are further subdivided based on the portal inflow — into a total of eight segments. Panel B shows the morphologic anatomy, in which the right lobe and left lobe are divided by the falciform ligament and umbilical fissure (not shown). The tumor (tan circle) straddled segments IV and VIII. An extended right hepatectomy would remove segments IV through VIII and an extended left hepatectomy would remove segments II through V and VIII. A central hepatectomy, the surgical removal of individual segments (IV, V, and VIII), would allow for preservation of more liver tissue than either the extended left or extended right hepatectomy and would remove entirely those segments that were at greatest risk for intrahepatic micrometastases.
Pathological Discussion
Dr. Gregory Y. Lauwers: The resected liver specimen contained a well-circumscribed mass measuring 4.5 cm in greatest dimension, with the gross characteristics of a hepatocellular carcinoma. The TNM classification uses a cutoff of 5 cm to stratify hepatocellular carcinomas, and there is a statistically significant difference in overall survival, disease-free survival, and the frequency of intrahepatic and hematogenous metastases, as well as portal-vein thrombosis, in the case of tumors that are larger than 5 cm in diameter, as compared with those that are 5 cm or less.11,25,26
The pattern of growth in this tumor was classified as single nodular, or type 1 of the classification of the Liver Cancer Study Group of Japan.27 Different patterns of growth have been associated with varying risks of intrahepatic and extrahepatic spread.28 Type 1 nodular cancer is associated with the best prognosis, with only a 20 percent rate of recurrence at two years.29
The resection margin was negative, with a clearance of 0.5 cm. The importance of ensuring a wide surgical clearance in resections of hepatocellular carcinoma is controversial. Some reports have shown that a clearance of less than 1 cm is associated with higher rates of intrahepatic recurrence, but other reports have not.30,31,32 A critical argument against the usefulness of the 1-cm clearance is the frequent detection of synchronous tumors in the residual liver.
The surrounding parenchyma showed various degrees of fibrosis, but no established cirrhosis. In the short term, despite an initially increased operative risk, patients with cirrhosis who have a good hepatic reserve fare as well as patients who do not have cirrhosis.33 However, in patients who had survived at least five years after their initial surgery, moderate-to-severe fibrosis in the remnant liver was the most important predictor of higher mortality.34
The microscopical examination of the tumor revealed a complete fibrous capsule (Figure 4A). Encapsulation has not been shown to be a significant prognostic indicator of survival in a large multivariate analysis.32,34,35 The tumor was formed of compact, thickened plates of hepatocytes (Figure 4A, inset). The neoplastic hepatocytes had moderate atypia, and the tumor was classified as histologic grade 2. On the basis of a review of 425 curatively resected hepatocellular carcinomas, it was concluded that tumors of grade 1 (good prognosis) and grades 3 to 4 (poor prognosis) were significant predictors of survival in a multivariate analysis, but that tumors of intermediate grade (grade 2) could have either a good or poor prognosis, depending on the presence or absence of microscopic vascular invasion.32,36,37 Further evaluation of the specimen from this patient revealed microvascular invasion of a medium-sized vein (Figure 4B); this was not a surprising finding, since the prevalence of such microvascular invasion is about 50 percent in tumors that measure more than 4 cm.38
Figure 4. Pathology of the Liver Tumor.
The resected tumor was completely encapsulated (Panel A, hematoxylin and eosin). Microscopical examination revealed a fibrous capsule that was several millimeters thick at the interface. The tumor has a compact macrotrabecular architectural pattern (Panel A, inset). The cytologic features indicate a moderately differentiated hepatocellular carcinoma. Microvascular invasion was identified (Panel B, trichrome stain) in the form of a malignant thrombus that was away from the tumor, in the surrounding hepatic parenchyma.
On the basis of the histologic findings (size, vascular invasion, and limited fibrosis), this tumor was classified as stage 1 T2F0, according to the newly modified American Joint Committee on Cancer classification. Despite the relatively small size of the tumor, the presence of microvascular invasion and the moderate nuclear grade place the patient in a category of patients with a poor prognosis. According to a hepatocellular prognostic index designed in 2002 and based solely on histologic characteristics, the median survival after surgical resection alone of patients with tumors such as this, with microvascular invasion and a moderate nuclear grade, was calculated to be about 2.7 years.26,35
Adjuvant Treatment
Dr. Tanabe: Since the risk of relapse after primary treatment of hepatocellular carcinoma is high, several adjuvant therapies have been examined in clinical trials. Treatment with transarterial chemoembolization, interferon alfa, interferon beta, and adoptive immunotherapy has been associated with a reduction in the rate of recurrence of tumor in the liver, but not with improved survival, as compared with observation alone. Treatment with both intraarterial iodine-131–labeled ethiodized oil (Lipiodol)39 and polyprenoic acid, an analogue of vitamin A that inhibits hepatocarcinogenesis in rodents, has produced a reduction in tumor recurrence and an improvement in overall survival, as compared with observation, in randomized clinical trials.40,41 These agents are not yet available in the United States.
Dr. Blaszkowsky: The patient was not treated with adjuvant therapy after surgery, because of the lack of available effective agents. Eight months after his surgery, a follow-up MRI suggested that there had been a recurrence.
Dr. Blake: Gadolinium-enhanced T1-weighted images from the follow-up evaluation showed no evidence of local recurrence in the region of the resection site. However, there were new arterially enhancing masses scattered through the liver, which on delayed imaging showed peripheral rim enhancement (Figure 5, and Figure 3 of the Supplementary Appendix). These findings are consistent with metastatic disease or multifocal hepatocellular carcinoma.
Figure 5. A Follow-up, T1-Weighted Axial MRI, Obtained after the Administration of Gadolinium.
Eight months after the patient had undergone a partial hepatectomy, an MRI through the liver dome in delayed phase showed several small masses scattered throughout the liver. The masses show delayed peripheral enhancement (arrows) that was consistent with metastases or multifocal hepatocellular carcinoma.
Dr. Blaszkowsky: Since this patient now had at least eight or nine lesions in his liver, he was not a candidate for transplantation. There are several nonsurgical techniques that were options for this patient: percutaneous ethanol injection, percutaneous thermal ablation, systemic chemotherapy, hormonal therapy, interferon, novel agents, transhepatic arterial chemoembolization, and radiation therapy.
Systemic chemotherapy has had little impact on the course of hepatocellular carcinoma, and rates of response to most agents rarely exceed 10 percent.42 Hepatocellular carcinomas often express hormone receptors such as estrogen or somatostatin receptors. Seven randomized clinical trials were unable to demonstrate an antitumor effect of treatment with tamoxifen in hepatocellular carcinoma.43 Although there was no reduction in tumor volume, two of three relatively small, randomized clinical trials evaluating somatostatin analogues showed a statistically significant improvement in survival. There has recently been interest in thalidomide as a therapeutic drug. When it is used as a single agent, response rates are 5 to 7 percent, but in one report of 15 patients treated with thalidomide and capecitabine, the response rate was 18 percent, with 45 percent of the patients having stable disease.44 Treatment with interferon is minimally active, with considerable toxicity. None of these agents offered the patient under discussion much hope of prolonged survival.
Transhepatic arterial chemoembolization in hepatocellular carcinoma is associated with a response rate of approximately 35 percent. After several randomized clinical trials did not show a statistically significant improvement in survival, two randomized clinical trials did show an improvement in survival of up to two years in patients who received this treatment as compared with those who did not: in one trial, the two-year survival rate was 63 percent, as compared with 27 percent; in the other trial, the two-year survival rate was 31 percent, as compared with 11 percent.45,46 Use of chemoembolization rather than bland embolization was also associated with a reduction in the development of portal-vein thrombosis. In carefully selected patients, transhepatic arterial chemoembolization may be the most effective treatment currently available. Transhepatic arterial chemoembolization was a reasonable option for this patient; however, he declined the offer of this therapy.
The use of radiation therapy has been limited in hepatocellular carcinoma because of the sensitivity of the liver to radiation. The normal liver can typically tolerate 30 Gy. In selective internal-radiation therapy, yttrium-90–labeled resin-based or glass microspheres are infused into the hepatic artery, resulting in a target dose of 100 Gy to the tumor. One study using this method showed a response rate of 27 percent in 71 patients with unresectable tumors, and 4 of those patients ultimately underwent resection.47 This therapy is currently not widely available.
Since outcomes with currently available chemotherapeutic agents are disappointing, we offer all patients the option of participation in a clinical trial when available. This patient volunteered to participate in a clinical trial of gemcitabine, oxaliplatin, and the vascular endothelial growth factor–receptor inhibitor bevacizumab, but he had to drop out because of severe nosebleeds that required packing and transfusions. He was then observed for several months, during which he remained asymptomatic. He is now participating in a phase 1–2 clinical trial of a polyamine analogue, N1,N11-diethylnorspermine. After two months of therapy, CT scans show stable disease in the liver without extrahepatic spread. He remains asymptomatic two years after the partial hepatectomy.
Anatomical Diagnosis
Hepatocellular carcinoma.
Dr. Tanabe reports having received consulting fees from Ethicon Endosurgery. Dr. Blaszkowsky reports holding stock in Pfizer and having received lecture fees from Genentech.
Source Information
From the Departments of Surgical Oncology (K.K.T.), Hematology–Oncology (L.S.B.), Medicine, Gastrointestinal Unit (R.T.C.), Radiology (M.A.B.), and Pathology (G.Y.L.), Massachusetts General Hospital; and the Departments of Surgery, (K.K.T.), Medicine (L.S.B., R.T.C.), Radiology (M.A.B.), and Pathology (G.Y.L.), Harvard Medical School.
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Lau WY, Ho S, Leung TW, et al. Selective internal radiation therapy for nonresectable hepatocellular carcinoma with intraarterial infusion of 90yttrium microspheres. Int J Radiat Oncol Biol Phys 1998;40:583-592.(Kenneth K. Tanabe, M.D., )