- Email: [email protected]
Screening for hepatocellular carcinoma in patients with advanced cirrhosis
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 1999 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
Vol. 94, No. 10, 1999 ISSN 0002-9270/99/$20.00 PII S0002-9270(99)00504-3
Screening for Hepatocellular Carcinoma in Patients With Advanced Cirrhosis Naga Chalasani, M.D. John C. Horlander, Sr., M.D., Areen Said, M.D., Helena Hoen, M.S., Kenyon K. Kopecky, M.D., Stephan M. Stockberger, Jr., M.D., Rajesh Manam, M.D., Paul Y. Kwo, M.D., and Lawrence Lumeng, M.D. Divisions of Gastroenterology & Hepatology and Biostatistics, Department of Medicine, and Department of Radiology, Indiana University School of Medicine, Indianapolis, Indiana
OBJECTIVE: Most available data on screening for hepatocellular carcinoma (HCC) in patients with cirrhosis originate from Asia and Europe. These data may not be applicable to patients from the United States because of geographic variation in the underlying etiology and other factors. Our aim was to assess the risk of HCC in U.S. patients with cirrhosis undergoing standardized screening. METHODS: All cirrhotic patients evaluated for liver transplantation at our institution from January 1, 1994 –December 31, 1997 were included in this study. The screening strategy included initial screening, which was offered to all patients and consisted of alpha-fetoprotein (AFP), abdominal ultrasound, and computed tomography (CT) scan, and extended screening, which was performed only on transplant-eligible patients and consisted of semiannual AFP and ultrasound. RESULTS: During the study period, 285 patients with cirrhosis were evaluated for transplantation and underwent initial screening. Of these, 166 were eligible for transplantation and underwent extended screening during a median follow-up of 15 months (range 6 – 42 months). Twentyseven HCC were found, 22 during initial screening and five during extended screening. The cancer-free proportions of the cohort who underwent extended screening at 1, 2, and 3.5 yr were 98.6% ⫾ 1.4%, 96.4 ⫾ 1.8%, and 77.1% ⫾ 1.7%, respectively (mean ⫾ SE). Hepatitis C, either alone or in part, was the etiology in 63% of patients with HCC. The sensitivity of CT scan (88%) was significantly higher than AFP ⬎20 ng/ml (62%) and ultrasound (59%) for detecting HCC (p ⬍ 0.001). CONCLUSIONS: In patients with established cirrhosis, the risk of detecting HCC is maximal at the baseline screening (7%). Hepatitis C was the most common etiology for cirrhosis in study. In U.S. patients with established cirrhosis, CT scan exhibited higher sensitivity for detecting HCC than ultrasound or AFP. (Am J Gastroenterol 1999;94: 2988 –2993. © 1999 by Am. Coll. of Gastroenterology)
INTRODUCTION It has been estimated that 400,000 people have chronic liver disease or cirrhosis in the United States (1). Cirrhosis is a relatively frequent cause of death in the United States (annual death rate of 8.8 per 100,000) (2). The American Cancer Society estimates that there will be 13,900 new cases of hepatocellular carcinoma (HCC) in 1998 in the United States (1). Most patients diagnosed with HCC have underlying cirrhosis (3–5). HCC is a dreaded complication of cirrhosis, developing in European and Asian patients at an annual rate ranging between 1% and 6% (6 – 8). The survival of patients is very poor when HCC is diagnosed in a symptomatic stage (mean survival ⬍4 months) (4, 8, 9). However, prolonged survival has been reported for individuals with small, asymptomatic HCC (⬍5 cm in size) who undergo resection or liver transplantation (10, 11). Screening patients with cirrhosis for asymptomatic HCC appears to be a common practice in the countries where it is endemic (such as China and Japan), as well as the United States (12–14). Most published data on the risk of HCC in cirrhosis, as well as screening for HCC in cirrhotics, originate from Asia and Europe. Little is known about the risk of HCC in North American patients with cirrhosis. The aims of the present study were twofold: to assess the risk, etiology, and outcome of HCC in the United States patients with cirrhosis undergoing standardized screening protocol; and to analyze the sensitivity, specificity, and positive predictive value (PPV) of alpha-fetoprotein (AFP), abdominal ultrasound, and abdominal computed tomography (CT) for detecting HCC.
MATERIALS AND METHODS This was a retrospective analysis of all patients with cirrhosis who were evaluated for liver transplantation at Indiana University Medical Center (a tertiary referral center located in Indianapolis, Indiana) from January l, 1994 –December 31, 1997. The standardized screening strategy at our center consisted of initial screening and extended screening. All patients evaluated for liver transplantation underwent initial
AJG – October, 1999
screening consisting of AFP, liver ultrasound, and abdominal CT. The extended screening consisted of semiannual AFP and liver ultrasound and it was offered to only those patients who were considered eligible for liver transplantation. Any focal lesions detected on ultrasound or abnormal AFP values (⬎20 ng/ml) during the extended screening were followed up with an abdominal CT scan. All abdominal CT scans were performed on a spiral CT scanning machine (CT-Twin; Elscint, Inc; Rockleigh, NJ). The scanning was dual-phased in nature and performed after intravenous injection of 150 ml of nonionic contrast at 4 ml/s. The scanning was performed with a collimated slice width of 5 mm and a reconstruction increment of 4 mm. A suspicious lesion on CT was defined as a solid mass that showed enhancement on arterial phase and was hypo-, iso-, or hypervascular on venous-phase images. In general, ultrasonography technicians performed all the ultrasound examinations. Any lesions suspicious for HCC on ultrasound or abdominal CT were biopsied under ultrasound guidance. Only one lesion with the easiest accessibility was biopsied in those who had multiple lesions. The treatment for HCC was not standardized. It was provided according to the primary hepatologist’s discretion and the treatment modalities included transarterial chemoembolization (TACE) and/or percutaneous ethanol injection (PEI) or partial resection. Data Collection A list of patients with cirrhosis who were evaluated for transplantation was retrieved from transplant clinic records. This list was crosschecked with the pathology database as well as radiology records for the adequacy of data retrieval. The medical records were reviewed to obtain the necessary demographic, clinical, laboratory, and radiological data. Only those clinical and laboratory data that were recorded within the 6 wk before initial screening were collected. The continuous variables included age, bilirubin, albumin, creatinine, blood urea nitrogen, hemoglobin, white blood cell count, platelet count, international normalized ratio, prothrombin time, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, serum sodium concentration, and alpha-fetoprotein. Categorical variables included gender, etiology of cirrhosis, presence or past history of ascites, edema, jaundice, hepatic encephalopathy, splenomegaly, spider angiomata, and tobacco use. The patients were followed until liver transplantation, death, or December 31, 1997. Statistical Analysis Statistical analysis was performed using SAS software (15). For testing associations between HCC detection at initial screening and categorical explanatory variables, 2 or Fisher’s Exact test was used. Logistic regression analysis was used for the continuous predictors. Wald 2 was used to test whether odds ratios were statistically different than one. The effect of categorical variables on the time to HCC was
Screening for HCC in Cirrhosis
2989
Table 1. Demographics and Characteristics of Study Patients
Males (%) Age (mean ⫾ SD; range) Child’s class A/B/C (%) Active smokers (%) Etiology (%): Alcohol HCV Alcohol ⫹ HCV PSC or PBC Others* Ascites (%) Icterus (%) Encephalopathy (%) Splenomegaly (3%)
Initial Screening (n ⫽ 285)
Extended Screening (n ⫽166)
56 49 ⫾ 10 (22–73) 19/58/23 28
51 48 ⫾ 9 (22–64) 21/59/20 28
21 21 14 18 26 57 29 22 47
20 22 14 17 27 53 25 14 50
* Others included hepatitis B, cryptogenic, autoimmune liver disease, non-alcoholic steatohepatitis, and other miscellaneous etiologies.
assessed with the log-rank test. The Kaplan-Meier method was used to estimate the cancer-free rates reported for each level of categorical variables as well as survival rates of cancer patients. For the effect of continuous explanatory variables on time to liver cancer, the Wald 2 statistic from Cox’s proportional hazards regression was used to test relative risk different than one. The sensitivity, specificity, and PPV of screening tests were calculated from the initial screening, at which time all patients had AFP, abdominal ultrasound, and abdominal CT concurrently.
RESULTS During the study period, 285 patients were evaluated for transplantation (90% were white, 10% were Asian, black, and Hispanic) . All patients were subjected to initial screening. Of these, 166 patients were considered eligible for transplantation. These patients were subjected to extended screening during a median follow-up of 15 months (range 6 – 42 months). Demographics and clinical features of these two groups of patients are shown in Table 1. All patients had biopsy-proven cirrhosis. During the study period, 27 patients were found to have HCC. The diagnosis of HCC was based on histology in 26 patients. In one patient, the diagnosis of HCC was based on characteristic CT and hepatic angiographic findings. Of these, 22 were found during the initial screening (7.7% of 285 patients). Viral etiology of cirrhosis (59% in cancer patents vs 35% in patients without cancer, p ⫽ 0.04) and older age (odds ratio of 1.42 for each 5-yr increment in age, p ⫽ 0.006) were associated with detecting HCC during the initial screening. The other five cancers were diagnosed during the extended screening. The 1-, 2-, and 3.5-yr cancer-free rates for patients who underwent extended screening were (mean ⫾ SE) 98.6% ⫾ 1.4%, 96.4 ⫾ 1.8%, and 77.1% ⫾ 1.7%, respectively (Fig. 1). The presence of jaundice (p ⫽ 0.02) and splenomegaly (p ⫽ 0.02) at initial evaluation were associated with finding HCC
2990
Chalasani et al.
AJG – Vol. 94, No. 10, 1999
Figure 2. Outcome of patients diagnosed with hepatocellular carcinoma (HCC) (n ⫽ 27). OLT ⫽ orthotopic liver transplantation.
Figure 1. Kaplan-Meier curve showing HCC-free proportion of patients who underwent extended screening (n ⫽ 166).
during the extended screening. The baseline AFP levels were not associated with finding HCC during the extended screening (p ⫽ 0.8). The etiology of cirrhosis in patients with HCC is shown in Table 2. Hepatitis C alone or in part was the etiology for cirrhosis in 63% of patients with HCC. The HCC presented as a single nodule ranging from 1 to 5 cm in 17 patients (14 at initial screening and three during extended screening), as ⱖ2 nodules in seven patients (five at initial screening and two during extended screening), and as diffuse involvement in three patients (all detected at the initial screening). There was no statistically significant difference in the size or number of nodules or the frequency of diffuse HCC between the tumors found at initial and extended screening. The treatment for HCC included TACE in 12, PEI in three, TACE and PEI in two, and partial resection in two patients. The remaining eight patients received no treatment for HCC (two with diffuse HCC, two with portal vein invasion, four with advanced liver disease). The outcomes of patients with HCC are shown in Figures 2 and 3. The patients diagnosed with HCC were followed for a median duration of 7.7 months (range 1.4 –21.7 months). The overall median survival of 27 patients diagnosed with HCC was 12.5 months. The survival rates were (mean ⫾ SE) 80% ⫾ 8%, 53% ⫾ 11%, and 18% ⫾ 15% at 6, 12, and 22 months, respectively (Fig. 3). The 22 patients with HCC detected at initial screening had significantly longer median survival than the pa-
tients with HCC detected during the extended screening (14.1 months vs 5.4 months, respectively, p ⫽ 0.008) (Fig. 3). The detection of HCC adversely impacted the candidacy for transplantation in nine patients (three with diffuse HCC, three with portal invasion, two with large multifocal HCC, and one with a large tumor on the liver surface) (Fig. 2). The sensitivity, specificity, and PPV of AFP, ultrasound, and abdominal CT scan are shown in Table 3. Abdominal CT scan had significantly higher sensitivity than AFP or ultrasound for detecting HCC (p ⬍ 0.001). Although an AFP level ⬎200 ng/ml had a PPV and specificity of 100%, its sensitivity ranged only between 29% and 62% (Table 3). The sensitivity, specificity, and PPV of ultrasound were 59%, 92%, and 45%, respectively. In three patients with diffuse HCC, ultrasound was abnormal in only one patient. In seven patients with multifocal HCC, ultrasound detected all nodules in only three patients. In the remainder patients with multifocal HCC, ultrasound detected no abnormality in two patients and partial abnormality in two patients. Ultrasound detected no abnormality in two patients with HCC ⬍2 cm in size.
Table 2. Etiology of Cirrhosis in Patients With Hepatocellular Carcinoma (n ⫽ 27) Hepatitis C Alcohol Hepatitis C ⫹ Alcohol Cryptogenic Others*
9 4 6 3 5
* Others ⫽ Hep B ⫹ C:1, Hep B ⫹ C ⫹ D:1, non-alcoholic steatohepatitis; 1, autoimmune hepatitis:1, primary sclerosing cholangitis:1.
Figure 3. Kaplan-Meier curve showing the survival of cirrhotic patients diagnosed with hepatocellular carcinoma (HCC).
AJG – October, 1999
Screening for HCC in Cirrhosis
Table 3. Sensitivity, Specificity, and PPV of Different Diagnostic Tests in the Detection of HCC AFP (ng/ml) ⬎20 ⬎100 ⬎200 Ultrasound CT scan*
Sensitivity
Specificity
PPV
63 41 27 59 91
87 97 100 93 96
30 60 100 44 66
* Sensitivity and PPV of CT scan were significantly higher than AFP ⬎20 or ultrasound (p ⬍ 0.001). PPV ⫽ positive predictive value; HCC ⫽ hepatocellular carcinoma; AFP ⫽ alpha-fetoprotein; CT ⫽ computed tomography.
During the study period, no incidental HCC were seen in any of 136 patients who had undergone liver transplantation. In two patients with HCC prior transplantation, cancer was seen in both patients in the explanted specimen. One patient died from tumor recurrence at 15 months and the other is alive at 48 months after liver transplantation.
DISCUSSION Most published reports on the risk of cancer in patients with liver disease originate from Asia and Europe. The existing data on the risk of HCC in North American patients with liver disease are limited. The two Canadian studies by Sherman et al. (Toronto) and Villeneuve et al. (Montreal) dealt exclusively with asymptomatic hepatitis B surface antigen-positive carriers (16, 17). Likewise, the reports from Alaska by McMahon and colleagues studied the risk of liver cancer only in patients with chronic hepatitis B infection (18 –20). Our study consisted of patients with advanced cirrhosis due to mixed etiologies who were screened for asymptomatic HCC. To our knowledge, this is the first study to examine the risk of HCC in North American patients with cirrhosis due to mixed etiologies. This study highlights the role of hepatitis C cirrhosis in the etiology of HCC in the United States. Earlier studies reported that 16 –50% of patients with HCC in the U.S. are seropositive for hepatitis C (25–29). In our study, hepatitis C, either alone or in combination with other disorders was the etiology of cirrhosis in 63% of patients with HCC. It has been suggested that ethnic differences exist in the risk factors for HCC in the U.S. Hwang et al. found that,
2991
whereas chronic hepatitis B virus was the major etiology for HCC in Asian-American patients, chronic hepatitis C and alcohol were major etiological factors for HCC in white patients (24). Another recent study suggested that HispanicAmericans are more likely to have hepatitis-C–associated HCC than Asian-Americans (25). In our predominantly white cohort (⬇90% of our cohort were white), hepatitis C was the most frequent cause of cirrhosis in patients with HCC. Although any type of cirrhosis carries a risk of developing HCC, certain etiologies (such as genetic hemochromatosis or hepatitis B or C) are at higher risk for developing HCC than others (such as autoimmune liver disease, ␣1-antitrypsin deficiency, cholestatic liver disease, or Wilson’s disease) (7, 13, 30 –32). In a recent survey of 1021 AASLD members, half of the respondents reported that they do not routinely screen patients with cirrhosis due to low-risk etiologies for HCC (14). In our study, a sizable proportion of HCC (22%) was detected in patients with cirrhosis due to low-risk etiologies (Table 2). Thus, a practice of limiting screening only to patients with cirrhosis due to high-risk etiologies has the potential of missing HCC in a sizable proportion of HCC. In our study, the majority of HCC (81%) were detected during the initial screening and this is consistent with an earlier study by Colombo and colleagues (7). These findings suggest that, in patients with established cirrhosis, the risk of detecting HCC is maximal at the baseline screening. The estimated cumulative risk of HCC at 1, 2, and 3.5 yr in our cohort during the follow-up was 1.4%, 3.6%, and 22.9%, respectively. The risk of HCC at 3 yr was higher in our study than other similar studies from Asia and Europe (Table 4), likely because of the advanced nature of liver disease in our cohort. Our study found that older age and viral etiology of cirrhosis were significantly associated with the risk of detecting HCC at baseline. These findings are consistent with data from Asia and Europe (7, 12, 21–23, 30, 31). The previous studies suggested that, in patients without HCC, baseline AFP ⬎20 ng/ml predicts the risk of HCC during follow-up (7, 21, 22, 30). However, our study failed to show any such association. The presence of splenomegaly and jaundice at the initial examination were univariately asso-
Table 4. Risk of HCC in Patients With Cirrhosis Due to Mixed Etiologies
First Author
Country
Number of Patients
Colombo (7) Villaneuve (17) Heyward (18) McMohon (19) Current study
Italy France Japan Italy U.S.
417 118 140 164 166
Cumulative Risk of HCC*
Screening Methods*
Viral Cirrhosis (%)
Median Follow-up (Months)
1 yr
2 yr
3 yr
AFP/US AFP/US/DCP AFP/US AFP/US AFP/US
61 21 39 70 44
33 36 36.2 NA 15
1 3 5.3 3 1.4
3 5 8.1 10 3.6
8 12 8.8 15 22.9†
* Sample estimate for percent of population (of patients with cirrhosis) diagnosed with cancer. † Risk estimated at 37 months. AFP ⫽ alpha fetoprotein; US ⫽ ultrasound; DCP ⫽ des gamma-carboxyprothrombin.
2992
Chalasani et al.
ciated with the risk of developing HCC during follow-up. The significance of these findings is not clear. In a study based on the Boston tumor registry by Stuart et al., the overall median survival of 314 patients with HCC was 10 months (27). The survival of these patients (whose cancer was detected not as part of a screening strategy) was similar to the median survival (12.5 months) observed in our patients whose cancer was detected as a part of standardized screening strategy. Interestingly, the survival of 22 patients with HCC found at baseline was significantly better than the survival of five patients whose HCC was found during the follow-up (Fig. 2). Although it is possible that tumors found during follow-up are more aggressive, one can not exclude the role of other variables such as lead-time bias, ChildPugh class, and etiology of cirrhosis to explain such a survival difference. In our study, ultrasound had poor sensitivity in detecting small (⬍2 cm) or multifocal or diffuse HCC. There appears to be a widespread belief among hepatologists in the U.S. that CT scan has higher sensitivity than ultrasound for detecting small HCC (14). Our study, which showed a higher sensitivity of CT scan for detecting HCC than ultrasound or AFP, lends support to such a belief. However, this is inconsistent with the findings from Japan that report high detection rates (85–95%) for ultrasound, as well as superior sensitivity of ultrasound over CT scan for detecting small HCC (22, 34, 35). This discrepancy between the United States experience with liver ultrasound and published data from Japan may result from less steatosis to change liver echogenecity in Asian patients with predominantly viral cirrhosis (rather than alcoholic cirrhosis with associated steatosis in the United States), leaner body habitus in the Japanese patients resulting in better visualization of the liver by the ultrasound, the fact that physicians rather than technologists perform ultrasound examination in Japan, and advances in CT technology with the advent of spiral CT (which has been developed since these previous evaluations). The lower sensitivity of ultrasound for detecting HCC noticed in this study could also be related to the fact that all patients were cirrhotic; the ability to detect HCC in patients with small, nodular liver is much more difficult than in patients without cirrhosis. Our study demonstrated another advantage of HCC screening, that is, it averts liver transplantation in patients with HCC who are at high risk for posttransplant recurrence. Several patients with unfavorable HCC (such as diffuse HCC, HCC with vascular invasion) were found during our screening and it adversely affected their candidacy for transplantation. To our knowledge, this is the first study to describe the impact of HCC screening on the transplant selection process and it emphasizes the need for screening this group. In addition to its retrospective design, there are several other limitations to this study. The cohort studied represents a selected group of patients with cirrhosis referred for liver transplant evaluation. It was comprised of patients with
AJG – Vol. 94, No. 10, 1999
advanced cirrhosis, as evidenced by the fact that 81% of our patients belonged to Child-Pugh class B or C cirrhosis. The findings of this study might not apply to another cohort with less severe cirrhosis. Another limitation is the uncertainty about the reliability of radiological findings in a retrospective study. The performance of radiological investigations in a prospective study with standardized interpretation might be different from the findings in this study. Another limitation is the failure to detect any incidental HCC in any of the explanted livers. In previous studies, the reported probability of finding incidental HCC ranged between 8% and 12% (36). This striking absence of incidental HCC in our series could in part be related to the technique of sectioning of the explanted specimen. To summarize, the likelihood of detecting HCC in patients with established cirrhosis was maximal at the baseline screening. The cumulative 1-, 2-, 3.5-yr incidences of HCC in U.S. patients with advanced cirrhosis due to mixed etiologies were 1.4%, 3.6%, and 22.9% respectively. Hepatitis C was the most common cause of cirrhosis in patients with HCC. In patients with established cirrhosis, CT scan had higher sensitivity and PPV for detecting asymptomatic HCC than AFP or ultrasound.
ACKNOWLEDGMENTS We thank Drs. Mel Wilcox and David Crabb for their critical review of the manuscript and Ms. Brenda Neal for her secretarial assistance. This study was supported in part by an IUPUI faculty development grant (N.C.). Reprint requests and correspondence: Naga Chalasani, M.D., Indiana University School of Medicine, WD OPW 2005, 1001 West 10th Street, Indianapolis, IN 46202. Received Nov. 2, 1998; accepted Apr. 26, 1999.
REFERENCES 1. Digestive Disease Statistics from National Institute of Diabetes and Digestive and Kidney Diseases. NIH publication no: 95-3873; Feb 1995. 2. Landis SH, Murray T, Bolden S, et al. Cancer statistics, 1998. CA Cancer J Clin 1998;48:6 –29. 3. Kew MC, Popper H. The relationship between hepatocellular carcinoma and cirrhosis. Semin Liver Dis 1984;4:136 – 46. 4. Stuart KE, Anand AJ, Jenkins RL. Hepatocellular carcinoma in the United States. Prognostic features, treatment outcomes, and survival. Cancer 1996;77:2217–22. 5. Zaman SN, Johnson PJ, Williams R. Silent cirrhosis in patients with hepatocellular carcinoma. Cancer 1990;65:1607–1610. 6. Zaman SN, Melia WM, Johnson RD, et al. Risk factors for the development of hepatocellular carcinoma in cirrhosis: A prospective study of 613 patients. Lancet 1985; 2:1357– 60. 7. Colombo M, De Franchis R, Del Ninno E, et al. Hepatocellular carcinoma in Italian patients with cirrhosis. N Engl J Med 1991;325:675– 80. 8. Calvert X, Briux J, Gines P, et al. Hepatocellular carcinoma in the west: A multivariate analysis in 206 patients. Hepatology 1990;12:753– 60.
AJG – October, 1999
9. Beasley RP, Hwang LY, Lin CC, et al. Hepatocellular carcinoma and hepatitis B virus: A prospective study of 22,700 men in Taiwan. Lancet 1981;2:1129 –33. 10. Anonymous. Primary liver cancer in Japan. Clinicopathologic features and results of surgical treatment. Liver Cancer Study Group of Japan. Ann Surg 1990;211:277– 87. 11. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinoma in patients with cirrhosis. N Engl J Med 1996;334:693–9. 12. Collier J, Sherman M. Screening for hepatocellular carcinoma. Hepatology 1998;27:273– 8. 13. Okuda K, Kojiro M, Okuda H. Neoplasms of the liver. In: Schiff L, Schiff ER, eds. Diseases of the liver, 7th ed. Philadelphia: JB Lippincott, 1993:1236 –96. 14. Chalasani N, Said A, Ness R, et al. Screening for hepatocellular carcinoma in patients with cirrhosis: Results of a national survey. Am J Gastroenterol 1999;94:2224 –9. 15. SAS Institute, Inc. SAS/STAT User’s guide. Version 6. Volume 1 and 2. 4th edition. Cary, NC: SAS Institute, Inc., 1990. 16. Sherman M, Peltekian KM, Lee C. Screening for hepatocellular carcinoma in chronic carriers of hepatitis B virus: Incidence and prevalence of hepatocellular carcinoma in a North American urban population. Hepatology 1995;22:432– 8. 17. Villeneuve J-P, Desrochers M, Infante-Rivard C, et al. A long-term follow-up study of asymptomatic hepatitis B surface antigen-positive carriers in Montreal. Gastroenterology 1994; 104:1000 –5. 18. Heyward WL, Lanier AP, McMahon BJ, et al. Early detection of primary hepatocellular carcinoma. Screening for primary hepatocellular carcinoma among persons infected with hepatitis B virus. JAMA 1985;254:3052– 4. 19. McMohan BJ, Alberts SR, Wainwright RB, et al. Hepatitis B-related sequelae. Prospective study of 1400 hepatitis B surface antigen-positive Alaska native carriers. Arch Intern Med 1990;150:1051– 4. 20. McMahon BJ, Bulkow L, Harpster A, et al. Early detection of hepatocellular carcinoma (HCC) in HBsAg positive carriers: A 15 year prospective population based study in Alaska. Hepatology 1998;28:388A (abstract). 21. Pateron D, Ganne N, Trinchet JC, et al. Prospective study of screening for hepatocellular carcinoma in Caucasian patients with cirrhosis. J Hepatol 1994;20:65–71. 22. Oka H, Kurioka N, Kim K, et al. Prospective study of early detection of hepatocellular carcinoma in patients with cirrhosis. Hepatology 1990;12:680 –7. 23. Zoli M, Magalotti D, Bianchi G, et al. Efficacy of surveillance program for early detection of hepatocellular carcinoma. Cancer 1996;78:977– 85.
Screening for HCC in Cirrhosis
2993
24. Hwang SJ, Tong MJ, Lai PP, et al. Evaluation of hepatitis B and C viral markers: Clinical significance in Asian and Caucasian patients with hepatocellular carcinoma in the United States of America. J Gastroenterol Hepatol 1996; 11:949 –54. 25. Reddy KR, Jeffers LJ, Tong M, et al. Comparison of etiologic characteristics of Asian and Hispanic populations with hepatocellular carcinoma from Los Angeles and Miami. AASLD clinical research single topic conference- Hepatocellular carcinoma, March 27–29, 1998, Abstract 26. 26. Di Bisceglie AM, Order SE, Klein JL, et al. The role of chronic viral hepatitis in hepatocellular carcinoma in the United States. Am J Gastroenterol 1991;86:335– 8. 27. Stuart KE, Anand AJ, Jenkins RL. Hepatocellular carcinoma in the United States. Prognostic features, treatment outcome, and survival. Cancer 1996;77:2217–22. 28. Hasan F, Jeffers LJ, De Medina M, et al. Hepatitis C-associated hepatocellular carcinoma. Hepatology 1990;12:589 –91. 29. Di Bisceglie AM, Simpson LH, Lotze MT, et al. Development of hepatocellular carcinoma among patients with chronic liver disease due to hepatitis C viral infection. J Clin Gastroenterol 1994;19:222– 6. 30. Tsukuma H, Hiyama T, Tanaka S, et al. Risk factors for hepatocellular carcinoma in patients with chronic liver disease. N Engl J Med 1993;328:1797–1801. 31. Benvegnu L, Fattovich G, Noventa F, et al. Concurrent hepatitis B and C virus infection and risk of hepatocellular carcinoma in cirrhosis. Cancer 1994;74:2442– 8. 32. Bradbear RA, Bain C, Siskind V, et al. Cohort study of internal malignancy in genetic hemochromatosis and other nonalcoholic liver disease. J Natl Cancer Inst 1985;75:81– 4. 33. Cottone M, Turri M, Caltagirone M, et al. Screening for hepatocellular carcinoma in patients with Child’s A cirrhosis: An 8-year prospective study by ultrasound and alpha-fetoprotein. J Hepatol 1994;21:1029 –34. 34. Shinagawa T, Ohto M, Kimura K, et al. Diagnosis and clinical features of small hepatocellular carcinoma with emphasis on the utility of real-time ultrasonography. Gastroenterology 1984;86:495–502. 35. Tanaka S, Kitamura T, Nakanishi K, et al. Effectiveness of periodic checkup by ultrasonography for the early detection of hepatocellular carcinoma. Cancer 1990; 66:2210 – 4. 36. Klintbalm GBG. Liver transplantation in patients with tumors. In: Maddrey WC, Sorrell MF, eds. Transplantation of the liver, second edition. Norwalk, Connecticut: Appleton & Lange, 1995:503–28.
Vol. 94, No. 10, 1999 ISSN 0002-9270/99/$20.00 PII S0002-9270(99)00504-3
Screening for Hepatocellular Carcinoma in Patients With Advanced Cirrhosis Naga Chalasani, M.D. John C. Horlander, Sr., M.D., Areen Said, M.D., Helena Hoen, M.S., Kenyon K. Kopecky, M.D., Stephan M. Stockberger, Jr., M.D., Rajesh Manam, M.D., Paul Y. Kwo, M.D., and Lawrence Lumeng, M.D. Divisions of Gastroenterology & Hepatology and Biostatistics, Department of Medicine, and Department of Radiology, Indiana University School of Medicine, Indianapolis, Indiana
OBJECTIVE: Most available data on screening for hepatocellular carcinoma (HCC) in patients with cirrhosis originate from Asia and Europe. These data may not be applicable to patients from the United States because of geographic variation in the underlying etiology and other factors. Our aim was to assess the risk of HCC in U.S. patients with cirrhosis undergoing standardized screening. METHODS: All cirrhotic patients evaluated for liver transplantation at our institution from January 1, 1994 –December 31, 1997 were included in this study. The screening strategy included initial screening, which was offered to all patients and consisted of alpha-fetoprotein (AFP), abdominal ultrasound, and computed tomography (CT) scan, and extended screening, which was performed only on transplant-eligible patients and consisted of semiannual AFP and ultrasound. RESULTS: During the study period, 285 patients with cirrhosis were evaluated for transplantation and underwent initial screening. Of these, 166 were eligible for transplantation and underwent extended screening during a median follow-up of 15 months (range 6 – 42 months). Twentyseven HCC were found, 22 during initial screening and five during extended screening. The cancer-free proportions of the cohort who underwent extended screening at 1, 2, and 3.5 yr were 98.6% ⫾ 1.4%, 96.4 ⫾ 1.8%, and 77.1% ⫾ 1.7%, respectively (mean ⫾ SE). Hepatitis C, either alone or in part, was the etiology in 63% of patients with HCC. The sensitivity of CT scan (88%) was significantly higher than AFP ⬎20 ng/ml (62%) and ultrasound (59%) for detecting HCC (p ⬍ 0.001). CONCLUSIONS: In patients with established cirrhosis, the risk of detecting HCC is maximal at the baseline screening (7%). Hepatitis C was the most common etiology for cirrhosis in study. In U.S. patients with established cirrhosis, CT scan exhibited higher sensitivity for detecting HCC than ultrasound or AFP. (Am J Gastroenterol 1999;94: 2988 –2993. © 1999 by Am. Coll. of Gastroenterology)
INTRODUCTION It has been estimated that 400,000 people have chronic liver disease or cirrhosis in the United States (1). Cirrhosis is a relatively frequent cause of death in the United States (annual death rate of 8.8 per 100,000) (2). The American Cancer Society estimates that there will be 13,900 new cases of hepatocellular carcinoma (HCC) in 1998 in the United States (1). Most patients diagnosed with HCC have underlying cirrhosis (3–5). HCC is a dreaded complication of cirrhosis, developing in European and Asian patients at an annual rate ranging between 1% and 6% (6 – 8). The survival of patients is very poor when HCC is diagnosed in a symptomatic stage (mean survival ⬍4 months) (4, 8, 9). However, prolonged survival has been reported for individuals with small, asymptomatic HCC (⬍5 cm in size) who undergo resection or liver transplantation (10, 11). Screening patients with cirrhosis for asymptomatic HCC appears to be a common practice in the countries where it is endemic (such as China and Japan), as well as the United States (12–14). Most published data on the risk of HCC in cirrhosis, as well as screening for HCC in cirrhotics, originate from Asia and Europe. Little is known about the risk of HCC in North American patients with cirrhosis. The aims of the present study were twofold: to assess the risk, etiology, and outcome of HCC in the United States patients with cirrhosis undergoing standardized screening protocol; and to analyze the sensitivity, specificity, and positive predictive value (PPV) of alpha-fetoprotein (AFP), abdominal ultrasound, and abdominal computed tomography (CT) for detecting HCC.
MATERIALS AND METHODS This was a retrospective analysis of all patients with cirrhosis who were evaluated for liver transplantation at Indiana University Medical Center (a tertiary referral center located in Indianapolis, Indiana) from January l, 1994 –December 31, 1997. The standardized screening strategy at our center consisted of initial screening and extended screening. All patients evaluated for liver transplantation underwent initial
AJG – October, 1999
screening consisting of AFP, liver ultrasound, and abdominal CT. The extended screening consisted of semiannual AFP and liver ultrasound and it was offered to only those patients who were considered eligible for liver transplantation. Any focal lesions detected on ultrasound or abnormal AFP values (⬎20 ng/ml) during the extended screening were followed up with an abdominal CT scan. All abdominal CT scans were performed on a spiral CT scanning machine (CT-Twin; Elscint, Inc; Rockleigh, NJ). The scanning was dual-phased in nature and performed after intravenous injection of 150 ml of nonionic contrast at 4 ml/s. The scanning was performed with a collimated slice width of 5 mm and a reconstruction increment of 4 mm. A suspicious lesion on CT was defined as a solid mass that showed enhancement on arterial phase and was hypo-, iso-, or hypervascular on venous-phase images. In general, ultrasonography technicians performed all the ultrasound examinations. Any lesions suspicious for HCC on ultrasound or abdominal CT were biopsied under ultrasound guidance. Only one lesion with the easiest accessibility was biopsied in those who had multiple lesions. The treatment for HCC was not standardized. It was provided according to the primary hepatologist’s discretion and the treatment modalities included transarterial chemoembolization (TACE) and/or percutaneous ethanol injection (PEI) or partial resection. Data Collection A list of patients with cirrhosis who were evaluated for transplantation was retrieved from transplant clinic records. This list was crosschecked with the pathology database as well as radiology records for the adequacy of data retrieval. The medical records were reviewed to obtain the necessary demographic, clinical, laboratory, and radiological data. Only those clinical and laboratory data that were recorded within the 6 wk before initial screening were collected. The continuous variables included age, bilirubin, albumin, creatinine, blood urea nitrogen, hemoglobin, white blood cell count, platelet count, international normalized ratio, prothrombin time, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, serum sodium concentration, and alpha-fetoprotein. Categorical variables included gender, etiology of cirrhosis, presence or past history of ascites, edema, jaundice, hepatic encephalopathy, splenomegaly, spider angiomata, and tobacco use. The patients were followed until liver transplantation, death, or December 31, 1997. Statistical Analysis Statistical analysis was performed using SAS software (15). For testing associations between HCC detection at initial screening and categorical explanatory variables, 2 or Fisher’s Exact test was used. Logistic regression analysis was used for the continuous predictors. Wald 2 was used to test whether odds ratios were statistically different than one. The effect of categorical variables on the time to HCC was
Screening for HCC in Cirrhosis
2989
Table 1. Demographics and Characteristics of Study Patients
Males (%) Age (mean ⫾ SD; range) Child’s class A/B/C (%) Active smokers (%) Etiology (%): Alcohol HCV Alcohol ⫹ HCV PSC or PBC Others* Ascites (%) Icterus (%) Encephalopathy (%) Splenomegaly (3%)
Initial Screening (n ⫽ 285)
Extended Screening (n ⫽166)
56 49 ⫾ 10 (22–73) 19/58/23 28
51 48 ⫾ 9 (22–64) 21/59/20 28
21 21 14 18 26 57 29 22 47
20 22 14 17 27 53 25 14 50
* Others included hepatitis B, cryptogenic, autoimmune liver disease, non-alcoholic steatohepatitis, and other miscellaneous etiologies.
assessed with the log-rank test. The Kaplan-Meier method was used to estimate the cancer-free rates reported for each level of categorical variables as well as survival rates of cancer patients. For the effect of continuous explanatory variables on time to liver cancer, the Wald 2 statistic from Cox’s proportional hazards regression was used to test relative risk different than one. The sensitivity, specificity, and PPV of screening tests were calculated from the initial screening, at which time all patients had AFP, abdominal ultrasound, and abdominal CT concurrently.
RESULTS During the study period, 285 patients were evaluated for transplantation (90% were white, 10% were Asian, black, and Hispanic) . All patients were subjected to initial screening. Of these, 166 patients were considered eligible for transplantation. These patients were subjected to extended screening during a median follow-up of 15 months (range 6 – 42 months). Demographics and clinical features of these two groups of patients are shown in Table 1. All patients had biopsy-proven cirrhosis. During the study period, 27 patients were found to have HCC. The diagnosis of HCC was based on histology in 26 patients. In one patient, the diagnosis of HCC was based on characteristic CT and hepatic angiographic findings. Of these, 22 were found during the initial screening (7.7% of 285 patients). Viral etiology of cirrhosis (59% in cancer patents vs 35% in patients without cancer, p ⫽ 0.04) and older age (odds ratio of 1.42 for each 5-yr increment in age, p ⫽ 0.006) were associated with detecting HCC during the initial screening. The other five cancers were diagnosed during the extended screening. The 1-, 2-, and 3.5-yr cancer-free rates for patients who underwent extended screening were (mean ⫾ SE) 98.6% ⫾ 1.4%, 96.4 ⫾ 1.8%, and 77.1% ⫾ 1.7%, respectively (Fig. 1). The presence of jaundice (p ⫽ 0.02) and splenomegaly (p ⫽ 0.02) at initial evaluation were associated with finding HCC
2990
Chalasani et al.
AJG – Vol. 94, No. 10, 1999
Figure 2. Outcome of patients diagnosed with hepatocellular carcinoma (HCC) (n ⫽ 27). OLT ⫽ orthotopic liver transplantation.
Figure 1. Kaplan-Meier curve showing HCC-free proportion of patients who underwent extended screening (n ⫽ 166).
during the extended screening. The baseline AFP levels were not associated with finding HCC during the extended screening (p ⫽ 0.8). The etiology of cirrhosis in patients with HCC is shown in Table 2. Hepatitis C alone or in part was the etiology for cirrhosis in 63% of patients with HCC. The HCC presented as a single nodule ranging from 1 to 5 cm in 17 patients (14 at initial screening and three during extended screening), as ⱖ2 nodules in seven patients (five at initial screening and two during extended screening), and as diffuse involvement in three patients (all detected at the initial screening). There was no statistically significant difference in the size or number of nodules or the frequency of diffuse HCC between the tumors found at initial and extended screening. The treatment for HCC included TACE in 12, PEI in three, TACE and PEI in two, and partial resection in two patients. The remaining eight patients received no treatment for HCC (two with diffuse HCC, two with portal vein invasion, four with advanced liver disease). The outcomes of patients with HCC are shown in Figures 2 and 3. The patients diagnosed with HCC were followed for a median duration of 7.7 months (range 1.4 –21.7 months). The overall median survival of 27 patients diagnosed with HCC was 12.5 months. The survival rates were (mean ⫾ SE) 80% ⫾ 8%, 53% ⫾ 11%, and 18% ⫾ 15% at 6, 12, and 22 months, respectively (Fig. 3). The 22 patients with HCC detected at initial screening had significantly longer median survival than the pa-
tients with HCC detected during the extended screening (14.1 months vs 5.4 months, respectively, p ⫽ 0.008) (Fig. 3). The detection of HCC adversely impacted the candidacy for transplantation in nine patients (three with diffuse HCC, three with portal invasion, two with large multifocal HCC, and one with a large tumor on the liver surface) (Fig. 2). The sensitivity, specificity, and PPV of AFP, ultrasound, and abdominal CT scan are shown in Table 3. Abdominal CT scan had significantly higher sensitivity than AFP or ultrasound for detecting HCC (p ⬍ 0.001). Although an AFP level ⬎200 ng/ml had a PPV and specificity of 100%, its sensitivity ranged only between 29% and 62% (Table 3). The sensitivity, specificity, and PPV of ultrasound were 59%, 92%, and 45%, respectively. In three patients with diffuse HCC, ultrasound was abnormal in only one patient. In seven patients with multifocal HCC, ultrasound detected all nodules in only three patients. In the remainder patients with multifocal HCC, ultrasound detected no abnormality in two patients and partial abnormality in two patients. Ultrasound detected no abnormality in two patients with HCC ⬍2 cm in size.
Table 2. Etiology of Cirrhosis in Patients With Hepatocellular Carcinoma (n ⫽ 27) Hepatitis C Alcohol Hepatitis C ⫹ Alcohol Cryptogenic Others*
9 4 6 3 5
* Others ⫽ Hep B ⫹ C:1, Hep B ⫹ C ⫹ D:1, non-alcoholic steatohepatitis; 1, autoimmune hepatitis:1, primary sclerosing cholangitis:1.
Figure 3. Kaplan-Meier curve showing the survival of cirrhotic patients diagnosed with hepatocellular carcinoma (HCC).
AJG – October, 1999
Screening for HCC in Cirrhosis
Table 3. Sensitivity, Specificity, and PPV of Different Diagnostic Tests in the Detection of HCC AFP (ng/ml) ⬎20 ⬎100 ⬎200 Ultrasound CT scan*
Sensitivity
Specificity
PPV
63 41 27 59 91
87 97 100 93 96
30 60 100 44 66
* Sensitivity and PPV of CT scan were significantly higher than AFP ⬎20 or ultrasound (p ⬍ 0.001). PPV ⫽ positive predictive value; HCC ⫽ hepatocellular carcinoma; AFP ⫽ alpha-fetoprotein; CT ⫽ computed tomography.
During the study period, no incidental HCC were seen in any of 136 patients who had undergone liver transplantation. In two patients with HCC prior transplantation, cancer was seen in both patients in the explanted specimen. One patient died from tumor recurrence at 15 months and the other is alive at 48 months after liver transplantation.
DISCUSSION Most published reports on the risk of cancer in patients with liver disease originate from Asia and Europe. The existing data on the risk of HCC in North American patients with liver disease are limited. The two Canadian studies by Sherman et al. (Toronto) and Villeneuve et al. (Montreal) dealt exclusively with asymptomatic hepatitis B surface antigen-positive carriers (16, 17). Likewise, the reports from Alaska by McMahon and colleagues studied the risk of liver cancer only in patients with chronic hepatitis B infection (18 –20). Our study consisted of patients with advanced cirrhosis due to mixed etiologies who were screened for asymptomatic HCC. To our knowledge, this is the first study to examine the risk of HCC in North American patients with cirrhosis due to mixed etiologies. This study highlights the role of hepatitis C cirrhosis in the etiology of HCC in the United States. Earlier studies reported that 16 –50% of patients with HCC in the U.S. are seropositive for hepatitis C (25–29). In our study, hepatitis C, either alone or in combination with other disorders was the etiology of cirrhosis in 63% of patients with HCC. It has been suggested that ethnic differences exist in the risk factors for HCC in the U.S. Hwang et al. found that,
2991
whereas chronic hepatitis B virus was the major etiology for HCC in Asian-American patients, chronic hepatitis C and alcohol were major etiological factors for HCC in white patients (24). Another recent study suggested that HispanicAmericans are more likely to have hepatitis-C–associated HCC than Asian-Americans (25). In our predominantly white cohort (⬇90% of our cohort were white), hepatitis C was the most frequent cause of cirrhosis in patients with HCC. Although any type of cirrhosis carries a risk of developing HCC, certain etiologies (such as genetic hemochromatosis or hepatitis B or C) are at higher risk for developing HCC than others (such as autoimmune liver disease, ␣1-antitrypsin deficiency, cholestatic liver disease, or Wilson’s disease) (7, 13, 30 –32). In a recent survey of 1021 AASLD members, half of the respondents reported that they do not routinely screen patients with cirrhosis due to low-risk etiologies for HCC (14). In our study, a sizable proportion of HCC (22%) was detected in patients with cirrhosis due to low-risk etiologies (Table 2). Thus, a practice of limiting screening only to patients with cirrhosis due to high-risk etiologies has the potential of missing HCC in a sizable proportion of HCC. In our study, the majority of HCC (81%) were detected during the initial screening and this is consistent with an earlier study by Colombo and colleagues (7). These findings suggest that, in patients with established cirrhosis, the risk of detecting HCC is maximal at the baseline screening. The estimated cumulative risk of HCC at 1, 2, and 3.5 yr in our cohort during the follow-up was 1.4%, 3.6%, and 22.9%, respectively. The risk of HCC at 3 yr was higher in our study than other similar studies from Asia and Europe (Table 4), likely because of the advanced nature of liver disease in our cohort. Our study found that older age and viral etiology of cirrhosis were significantly associated with the risk of detecting HCC at baseline. These findings are consistent with data from Asia and Europe (7, 12, 21–23, 30, 31). The previous studies suggested that, in patients without HCC, baseline AFP ⬎20 ng/ml predicts the risk of HCC during follow-up (7, 21, 22, 30). However, our study failed to show any such association. The presence of splenomegaly and jaundice at the initial examination were univariately asso-
Table 4. Risk of HCC in Patients With Cirrhosis Due to Mixed Etiologies
First Author
Country
Number of Patients
Colombo (7) Villaneuve (17) Heyward (18) McMohon (19) Current study
Italy France Japan Italy U.S.
417 118 140 164 166
Cumulative Risk of HCC*
Screening Methods*
Viral Cirrhosis (%)
Median Follow-up (Months)
1 yr
2 yr
3 yr
AFP/US AFP/US/DCP AFP/US AFP/US AFP/US
61 21 39 70 44
33 36 36.2 NA 15
1 3 5.3 3 1.4
3 5 8.1 10 3.6
8 12 8.8 15 22.9†
* Sample estimate for percent of population (of patients with cirrhosis) diagnosed with cancer. † Risk estimated at 37 months. AFP ⫽ alpha fetoprotein; US ⫽ ultrasound; DCP ⫽ des gamma-carboxyprothrombin.
2992
Chalasani et al.
ciated with the risk of developing HCC during follow-up. The significance of these findings is not clear. In a study based on the Boston tumor registry by Stuart et al., the overall median survival of 314 patients with HCC was 10 months (27). The survival of these patients (whose cancer was detected not as part of a screening strategy) was similar to the median survival (12.5 months) observed in our patients whose cancer was detected as a part of standardized screening strategy. Interestingly, the survival of 22 patients with HCC found at baseline was significantly better than the survival of five patients whose HCC was found during the follow-up (Fig. 2). Although it is possible that tumors found during follow-up are more aggressive, one can not exclude the role of other variables such as lead-time bias, ChildPugh class, and etiology of cirrhosis to explain such a survival difference. In our study, ultrasound had poor sensitivity in detecting small (⬍2 cm) or multifocal or diffuse HCC. There appears to be a widespread belief among hepatologists in the U.S. that CT scan has higher sensitivity than ultrasound for detecting small HCC (14). Our study, which showed a higher sensitivity of CT scan for detecting HCC than ultrasound or AFP, lends support to such a belief. However, this is inconsistent with the findings from Japan that report high detection rates (85–95%) for ultrasound, as well as superior sensitivity of ultrasound over CT scan for detecting small HCC (22, 34, 35). This discrepancy between the United States experience with liver ultrasound and published data from Japan may result from less steatosis to change liver echogenecity in Asian patients with predominantly viral cirrhosis (rather than alcoholic cirrhosis with associated steatosis in the United States), leaner body habitus in the Japanese patients resulting in better visualization of the liver by the ultrasound, the fact that physicians rather than technologists perform ultrasound examination in Japan, and advances in CT technology with the advent of spiral CT (which has been developed since these previous evaluations). The lower sensitivity of ultrasound for detecting HCC noticed in this study could also be related to the fact that all patients were cirrhotic; the ability to detect HCC in patients with small, nodular liver is much more difficult than in patients without cirrhosis. Our study demonstrated another advantage of HCC screening, that is, it averts liver transplantation in patients with HCC who are at high risk for posttransplant recurrence. Several patients with unfavorable HCC (such as diffuse HCC, HCC with vascular invasion) were found during our screening and it adversely affected their candidacy for transplantation. To our knowledge, this is the first study to describe the impact of HCC screening on the transplant selection process and it emphasizes the need for screening this group. In addition to its retrospective design, there are several other limitations to this study. The cohort studied represents a selected group of patients with cirrhosis referred for liver transplant evaluation. It was comprised of patients with
AJG – Vol. 94, No. 10, 1999
advanced cirrhosis, as evidenced by the fact that 81% of our patients belonged to Child-Pugh class B or C cirrhosis. The findings of this study might not apply to another cohort with less severe cirrhosis. Another limitation is the uncertainty about the reliability of radiological findings in a retrospective study. The performance of radiological investigations in a prospective study with standardized interpretation might be different from the findings in this study. Another limitation is the failure to detect any incidental HCC in any of the explanted livers. In previous studies, the reported probability of finding incidental HCC ranged between 8% and 12% (36). This striking absence of incidental HCC in our series could in part be related to the technique of sectioning of the explanted specimen. To summarize, the likelihood of detecting HCC in patients with established cirrhosis was maximal at the baseline screening. The cumulative 1-, 2-, 3.5-yr incidences of HCC in U.S. patients with advanced cirrhosis due to mixed etiologies were 1.4%, 3.6%, and 22.9% respectively. Hepatitis C was the most common cause of cirrhosis in patients with HCC. In patients with established cirrhosis, CT scan had higher sensitivity and PPV for detecting asymptomatic HCC than AFP or ultrasound.
ACKNOWLEDGMENTS We thank Drs. Mel Wilcox and David Crabb for their critical review of the manuscript and Ms. Brenda Neal for her secretarial assistance. This study was supported in part by an IUPUI faculty development grant (N.C.). Reprint requests and correspondence: Naga Chalasani, M.D., Indiana University School of Medicine, WD OPW 2005, 1001 West 10th Street, Indianapolis, IN 46202. Received Nov. 2, 1998; accepted Apr. 26, 1999.
REFERENCES 1. Digestive Disease Statistics from National Institute of Diabetes and Digestive and Kidney Diseases. NIH publication no: 95-3873; Feb 1995. 2. Landis SH, Murray T, Bolden S, et al. Cancer statistics, 1998. CA Cancer J Clin 1998;48:6 –29. 3. Kew MC, Popper H. The relationship between hepatocellular carcinoma and cirrhosis. Semin Liver Dis 1984;4:136 – 46. 4. Stuart KE, Anand AJ, Jenkins RL. Hepatocellular carcinoma in the United States. Prognostic features, treatment outcomes, and survival. Cancer 1996;77:2217–22. 5. Zaman SN, Johnson PJ, Williams R. Silent cirrhosis in patients with hepatocellular carcinoma. Cancer 1990;65:1607–1610. 6. Zaman SN, Melia WM, Johnson RD, et al. Risk factors for the development of hepatocellular carcinoma in cirrhosis: A prospective study of 613 patients. Lancet 1985; 2:1357– 60. 7. Colombo M, De Franchis R, Del Ninno E, et al. Hepatocellular carcinoma in Italian patients with cirrhosis. N Engl J Med 1991;325:675– 80. 8. Calvert X, Briux J, Gines P, et al. Hepatocellular carcinoma in the west: A multivariate analysis in 206 patients. Hepatology 1990;12:753– 60.
AJG – October, 1999
9. Beasley RP, Hwang LY, Lin CC, et al. Hepatocellular carcinoma and hepatitis B virus: A prospective study of 22,700 men in Taiwan. Lancet 1981;2:1129 –33. 10. Anonymous. Primary liver cancer in Japan. Clinicopathologic features and results of surgical treatment. Liver Cancer Study Group of Japan. Ann Surg 1990;211:277– 87. 11. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinoma in patients with cirrhosis. N Engl J Med 1996;334:693–9. 12. Collier J, Sherman M. Screening for hepatocellular carcinoma. Hepatology 1998;27:273– 8. 13. Okuda K, Kojiro M, Okuda H. Neoplasms of the liver. In: Schiff L, Schiff ER, eds. Diseases of the liver, 7th ed. Philadelphia: JB Lippincott, 1993:1236 –96. 14. Chalasani N, Said A, Ness R, et al. Screening for hepatocellular carcinoma in patients with cirrhosis: Results of a national survey. Am J Gastroenterol 1999;94:2224 –9. 15. SAS Institute, Inc. SAS/STAT User’s guide. Version 6. Volume 1 and 2. 4th edition. Cary, NC: SAS Institute, Inc., 1990. 16. Sherman M, Peltekian KM, Lee C. Screening for hepatocellular carcinoma in chronic carriers of hepatitis B virus: Incidence and prevalence of hepatocellular carcinoma in a North American urban population. Hepatology 1995;22:432– 8. 17. Villeneuve J-P, Desrochers M, Infante-Rivard C, et al. A long-term follow-up study of asymptomatic hepatitis B surface antigen-positive carriers in Montreal. Gastroenterology 1994; 104:1000 –5. 18. Heyward WL, Lanier AP, McMahon BJ, et al. Early detection of primary hepatocellular carcinoma. Screening for primary hepatocellular carcinoma among persons infected with hepatitis B virus. JAMA 1985;254:3052– 4. 19. McMohan BJ, Alberts SR, Wainwright RB, et al. Hepatitis B-related sequelae. Prospective study of 1400 hepatitis B surface antigen-positive Alaska native carriers. Arch Intern Med 1990;150:1051– 4. 20. McMahon BJ, Bulkow L, Harpster A, et al. Early detection of hepatocellular carcinoma (HCC) in HBsAg positive carriers: A 15 year prospective population based study in Alaska. Hepatology 1998;28:388A (abstract). 21. Pateron D, Ganne N, Trinchet JC, et al. Prospective study of screening for hepatocellular carcinoma in Caucasian patients with cirrhosis. J Hepatol 1994;20:65–71. 22. Oka H, Kurioka N, Kim K, et al. Prospective study of early detection of hepatocellular carcinoma in patients with cirrhosis. Hepatology 1990;12:680 –7. 23. Zoli M, Magalotti D, Bianchi G, et al. Efficacy of surveillance program for early detection of hepatocellular carcinoma. Cancer 1996;78:977– 85.
Screening for HCC in Cirrhosis
2993
24. Hwang SJ, Tong MJ, Lai PP, et al. Evaluation of hepatitis B and C viral markers: Clinical significance in Asian and Caucasian patients with hepatocellular carcinoma in the United States of America. J Gastroenterol Hepatol 1996; 11:949 –54. 25. Reddy KR, Jeffers LJ, Tong M, et al. Comparison of etiologic characteristics of Asian and Hispanic populations with hepatocellular carcinoma from Los Angeles and Miami. AASLD clinical research single topic conference- Hepatocellular carcinoma, March 27–29, 1998, Abstract 26. 26. Di Bisceglie AM, Order SE, Klein JL, et al. The role of chronic viral hepatitis in hepatocellular carcinoma in the United States. Am J Gastroenterol 1991;86:335– 8. 27. Stuart KE, Anand AJ, Jenkins RL. Hepatocellular carcinoma in the United States. Prognostic features, treatment outcome, and survival. Cancer 1996;77:2217–22. 28. Hasan F, Jeffers LJ, De Medina M, et al. Hepatitis C-associated hepatocellular carcinoma. Hepatology 1990;12:589 –91. 29. Di Bisceglie AM, Simpson LH, Lotze MT, et al. Development of hepatocellular carcinoma among patients with chronic liver disease due to hepatitis C viral infection. J Clin Gastroenterol 1994;19:222– 6. 30. Tsukuma H, Hiyama T, Tanaka S, et al. Risk factors for hepatocellular carcinoma in patients with chronic liver disease. N Engl J Med 1993;328:1797–1801. 31. Benvegnu L, Fattovich G, Noventa F, et al. Concurrent hepatitis B and C virus infection and risk of hepatocellular carcinoma in cirrhosis. Cancer 1994;74:2442– 8. 32. Bradbear RA, Bain C, Siskind V, et al. Cohort study of internal malignancy in genetic hemochromatosis and other nonalcoholic liver disease. J Natl Cancer Inst 1985;75:81– 4. 33. Cottone M, Turri M, Caltagirone M, et al. Screening for hepatocellular carcinoma in patients with Child’s A cirrhosis: An 8-year prospective study by ultrasound and alpha-fetoprotein. J Hepatol 1994;21:1029 –34. 34. Shinagawa T, Ohto M, Kimura K, et al. Diagnosis and clinical features of small hepatocellular carcinoma with emphasis on the utility of real-time ultrasonography. Gastroenterology 1984;86:495–502. 35. Tanaka S, Kitamura T, Nakanishi K, et al. Effectiveness of periodic checkup by ultrasonography for the early detection of hepatocellular carcinoma. Cancer 1990; 66:2210 – 4. 36. Klintbalm GBG. Liver transplantation in patients with tumors. In: Maddrey WC, Sorrell MF, eds. Transplantation of the liver, second edition. Norwalk, Connecticut: Appleton & Lange, 1995:503–28.